Clinical use of autologous cell-based therapies in an evolving regulatory landscape: A survey of patient experiences and perceptions

Clinical use of autologous cell-based therapies... | F1000Research "use strict";function _typeof(t){return(_typeof="function"==typeof Symbol&&"symbol"==typeof Symbol.iterator?function(t){return typeof t}:function(t){return t&&"function"==typeof Symbol&&t.constructor===Symbol&&t!==Symbol.prototype?"symbol":typeof t})(t)}!function(){var t=function(){var t,e,o=[],n=window,r=n;for(;r;){try{if(r.frames.__tcfapiLocator){t=r;break}}catch(t){}if(r===n.top)break;r=r.parent}t||(!function t(){var e=n.document,o=!!n.frames.__tcfapiLocator;if(!o)if(e.body){var r=e.createElement("iframe");r.style.cssText="display:none",r.name="__tcfapiLocator",e.body.appendChild(r)}else setTimeout(t,5);return!o}(),n.__tcfapi=function(){for(var t=arguments.length,n=new Array(t),r=0;r 3&&2===parseInt(n[1],10)&&"boolean"==typeof n[3]&&(e=n[3],"function"==typeof n[2]&&n[2]("set",!0)):"ping"===n[0]?"function"==typeof n[2]&&n[2]({gdprApplies:e,cmpLoaded:!1,cmpStatus:"stub"}):o.push(n)},n.addEventListener("message",(function(t){var e="string"==typeof t.data,o={};if(e)try{o=JSON.parse(t.data)}catch(t){}else o=t.data;var n="object"===_typeof(o)&&null!==o?o.__tcfapiCall:null;n&&window.__tcfapi(n.command,n.version,(function(o,r){var a={__tcfapiReturn:{returnValue:o,success:r,callId:n.callId}};t&&t.source&&t.source.postMessage&&t.source.postMessage(e?JSON.stringify(a):a,"*")}),n.parameter)}),!1))};"undefined"!=typeof module?module.exports=t:t()}(); dataLayer = dataLayer || []; // Standard GTM initialization - Google Consent Mode handles consent automatically (function(w,d,s,l,i){w[l]=w[l]||[];w[l].push({'gtm.start': new Date().getTime(),event:'gtm.js'});var f=d.getElementsByTagName(s)[0], j=d.createElement(s),dl=l!='dataLayer'?'&l='+l:'';j.async=true;j.src= 'https://www.googletagmanager.com/gtm.js?id='+i+dl+ '>m_auth=hzk0Vc3qFsQYhCrIoHz68A>m_preview=env-1>m_cookies_win=x';f.parentNode.insertBefore(j,f); })(window,document,'script','dataLayer','GTM-MWFK8L5J'); ;window.NREUM||(NREUM={});NREUM.init={distributed_tracing:{enabled:true},privacy:{cookies_enabled:true},ajax:{deny_list:["bam.nr-data.net"]}}; ;NREUM.loader_config={accountID:"438030",trustKey:"438030",agentID:"772317073",licenseKey:"97f8f67f26",applicationID:"772317073"} ;NREUM.info={beacon:"bam.nr-data.net",errorBeacon:"bam.nr-data.net",licenseKey:"97f8f67f26",applicationID:"772317073",sa:1} ;/*! For license information please see nr-loader-spa-1.236.0.min.js.LICENSE.txt */ (()=>{"use strict";var e,t,r={5763:(e,t,r)=>{r.d(t,{P_:()=>l,Mt:()=>g,C5:()=>s,DL:()=>v,OP:()=>T,lF:()=>D,Yu:()=>y,Dg:()=>h,CX:()=>c,GE:()=>b,sU:()=>_});var n=r(8632),i=r(9567);const o={beacon:n.ce.beacon,errorBeacon:n.ce.errorBeacon,licenseKey:void 0,applicationID:void 0,sa:void 0,queueTime:void 0,applicationTime:void 0,ttGuid:void 0,user:void 0,account:void 0,product:void 0,extra:void 0,jsAttributes:{},userAttributes:void 0,atts:void 0,transactionName:void 0,tNamePlain:void 0},a={};function s(e){if(!e)throw new Error("All info objects require an agent identifier!");if(!a[e])throw new Error("Info for ".concat(e," was never set"));return a[e]}function c(e,t){if(!e)throw new Error("All info objects require an agent identifier!");a[e]=(0,i.D)(t,o),(0,n.Qy)(e,a[e],"info")}var u=r(7056);const d=()=>{const e={blockSelector:"[data-nr-block]",maskInputOptions:{password:!0}};return{allow_bfcache:!0,privacy:{cookies_enabled:!0},ajax:{deny_list:void 0,enabled:!0,harvestTimeSeconds:10},distributed_tracing:{enabled:void 0,exclude_newrelic_header:void 0,cors_use_newrelic_header:void 0,cors_use_tracecontext_headers:void 0,allowed_origins:void 0},session:{domain:void 0,expiresMs:u.oD,inactiveMs:u.Hb},ssl:void 0,obfuscate:void 0,jserrors:{enabled:!0,harvestTimeSeconds:10},metrics:{enabled:!0},page_action:{enabled:!0,harvestTimeSeconds:30},page_view_event:{enabled:!0},page_view_timing:{enabled:!0,harvestTimeSeconds:30,long_task:!1},session_trace:{enabled:!0,harvestTimeSeconds:10},harvest:{tooManyRequestsDelay:60},session_replay:{enabled:!1,harvestTimeSeconds:60,sampleRate:.1,errorSampleRate:.1,maskTextSelector:"*",maskAllInputs:!0,get blockClass(){return"nr-block"},get ignoreClass(){return"nr-ignore"},get maskTextClass(){return"nr-mask"},get blockSelector(){return e.blockSelector},set blockSelector(t){e.blockSelector+=",".concat(t)},get maskInputOptions(){return e.maskInputOptions},set maskInputOptions(t){e.maskInputOptions={...t,password:!0}}},spa:{enabled:!0,harvestTimeSeconds:10}}},f={};function l(e){if(!e)throw new Error("All configuration objects require an agent identifier!");if(!f[e])throw new Error("Configuration for ".concat(e," was never set"));return f[e]}function h(e,t){if(!e)throw new Error("All configuration objects require an agent identifier!");f[e]=(0,i.D)(t,d()),(0,n.Qy)(e,f[e],"config")}function g(e,t){if(!e)throw new Error("All configuration objects require an agent identifier!");var r=l(e);if(r){for(var n=t.split("."),i=0;i {r.d(t,{D:()=>i});var n=r(50);function i(e,t){try{if(!e||"object"!=typeof e)return(0,n.Z)("Setting a Configurable requires an object as input");if(!t||"object"!=typeof t)return(0,n.Z)("Setting a Configurable requires a model to set its initial properties");const r=Object.create(Object.getPrototypeOf(t),Object.getOwnPropertyDescriptors(t)),o=0===Object.keys(r).length?e:r;for(let a in o)if(void 0!==e[a])try{"object"==typeof e[a]&&"object"==typeof t[a]?r[a]=i(e[a],t[a]):r[a]=e[a]}catch(e){(0,n.Z)("An error occurred while setting a property of a Configurable",e)}return r}catch(e){(0,n.Z)("An error occured while setting a Configurable",e)}}},6818:(e,t,r)=>{r.d(t,{Re:()=>i,gF:()=>o,q4:()=>n});const n="1.236.0",i="PROD",o="CDN"},385:(e,t,r)=>{r.d(t,{FN:()=>a,IF:()=>u,Nk:()=>f,Tt:()=>s,_A:()=>o,il:()=>n,pL:()=>c,v6:()=>i,w1:()=>d});const n="undefined"!=typeof window&&!!window.document,i="undefined"!=typeof WorkerGlobalScope&&("undefined"!=typeof self&&self instanceof WorkerGlobalScope&&self.navigator instanceof WorkerNavigator||"undefined"!=typeof globalThis&&globalThis instanceof WorkerGlobalScope&&globalThis.navigator instanceof WorkerNavigator),o=n?window:"undefined"!=typeof WorkerGlobalScope&&("undefined"!=typeof self&&self instanceof WorkerGlobalScope&&self||"undefined"!=typeof globalThis&&globalThis instanceof WorkerGlobalScope&&globalThis),a=""+o?.location,s=/iPad|iPhone|iPod/.test(navigator.userAgent),c=s&&"undefined"==typeof SharedWorker,u=(()=>{const e=navigator.userAgent.match(/Firefox[/\s](\d+\.\d+)/);return Array.isArray(e)&&e.length>=2?+e[1]:0})(),d=Boolean(n&&window.document.documentMode),f=!!navigator.sendBeacon},1117:(e,t,r)=>{r.d(t,{w:()=>o});var n=r(50);const i={agentIdentifier:"",ee:void 0};class o{constructor(e){try{if("object"!=typeof e)return(0,n.Z)("shared context requires an object as input");this.sharedContext={},Object.assign(this.sharedContext,i),Object.entries(e).forEach((e=>{let[t,r]=e;Object.keys(i).includes(t)&&(this.sharedContext[t]=r)}))}catch(e){(0,n.Z)("An error occured while setting SharedContext",e)}}}},8e3:(e,t,r)=>{r.d(t,{L:()=>d,R:()=>c});var n=r(2177),i=r(1284),o=r(4322),a=r(3325);const s={};function c(e,t){const r={staged:!1,priority:a.p[t]||0};u(e),s[e].get(t)||s[e].set(t,r)}function u(e){e&&(s[e]||(s[e]=new Map))}function d(){let e=arguments.length>0&&void 0!==arguments[0]?arguments[0]:"",t=arguments.length>1&&void 0!==arguments[1]?arguments[1]:"feature";if(u(e),!e||!s[e].get(t))return a(t);s[e].get(t).staged=!0;const r=[...s[e]];function a(t){const r=e?n.ee.get(e):n.ee,a=o.X.handlers;if(r.backlog&&a){var s=r.backlog[t],c=a[t];if(c){for(var u=0;s&&u {let[t,r]=e;return r.staged}))&&(r.sort(((e,t)=>e[1].priority-t[1].priority)),r.forEach((e=>{let[t]=e;a(t)})))}function f(e,t){var r=e[1];(0,i.D)(t[r],(function(t,r){var n=e[0];if(r[0]===n){var i=r[1],o=e[3],a=e[2];i.apply(o,a)}}))}},2177:(e,t,r)=>{r.d(t,{c:()=>f,ee:()=>u});var n=r(8632),i=r(2210),o=r(1284),a=r(5763),s="nr@context";let c=(0,n.fP)();var u;function d(){}function f(e){return(0,i.X)(e,s,l)}function l(){return new d}function h(){u.aborted=!0,u.backlog={}}c.ee?u=c.ee:(u=function e(t,r){var n={},c={},f={},g=!1;try{g=16===r.length&&(0,a.OP)(r).isolatedBacklog}catch(e){}var p={on:b,addEventListener:b,removeEventListener:y,emit:v,get:x,listeners:w,context:m,buffer:A,abort:h,aborted:!1,isBuffering:E,debugId:r,backlog:g?{}:t&&"object"==typeof t.backlog?t.backlog:{}};return p;function m(e){return e&&e instanceof d?e:e?(0,i.X)(e,s,l):l()}function v(e,r,n,i,o){if(!1!==o&&(o=!0),!u.aborted||i){t&&o&&t.emit(e,r,n);for(var a=m(n),s=w(e),d=s.length,f=0;fn,p:()=>i});var n=r(2177).ee.get("handle");function i(e,t,r,i,o){o?(o.buffer([e],i),o.emit(e,t,r)):(n.buffer([e],i),n.emit(e,t,r))}},4322:(e,t,r)=>{r.d(t,{X:()=>o});var n=r(5546);o.on=a;var i=o.handlers={};function o(e,t,r,o){a(o||n.E,i,e,t,r)}function a(e,t,r,i,o){o||(o="feature"),e||(e=n.E);var a=t[o]=t[o]||{};(a[r]=a[r]||[]).push([e,i])}},3239:(e,t,r)=>{r.d(t,{bP:()=>s,iz:()=>c,m$:()=>a});var n=r(385);let i=!1,o=!1;try{const e={get passive(){return i=!0,!1},get signal(){return o=!0,!1}};n._A.addEventListener("test",null,e),n._A.removeEventListener("test",null,e)}catch(e){}function a(e,t){return i||o?{capture:!!e,passive:i,signal:t}:!!e}function s(e,t){let r=arguments.length>2&&void 0!==arguments[2]&&arguments[2],n=arguments.length>3?arguments[3]:void 0;window.addEventListener(e,t,a(r,n))}function c(e,t){let r=arguments.length>2&&void 0!==arguments[2]&&arguments[2],n=arguments.length>3?arguments[3]:void 0;document.addEventListener(e,t,a(r,n))}},4402:(e,t,r)=>{r.d(t,{Ht:()=>u,M:()=>c,Rl:()=>a,ky:()=>s});var n=r(385);const i="xxxxxxxx-xxxx-4xxx-yxxx-xxxxxxxxxxxx";function o(e,t){return e?15&e[t]:16*Math.random()|0}function a(){const e=n._A?.crypto||n._A?.msCrypto;let t,r=0;return e&&e.getRandomValues&&(t=e.getRandomValues(new Uint8Array(31))),i.split("").map((e=>"x"===e?o(t,++r).toString(16):"y"===e?(3&o()|8).toString(16):e)).join("")}function s(e){const t=n._A?.crypto||n._A?.msCrypto;let r,i=0;t&&t.getRandomValues&&(r=t.getRandomValues(new Uint8Array(31)));const a=[];for(var s=0;s {r.d(t,{Bq:()=>n,Hb:()=>o,oD:()=>i});const n="NRBA",i=144e5,o=18e5},7894:(e,t,r)=>{function n(){return Math.round(performance.now())}r.d(t,{z:()=>n})},7243:(e,t,r)=>{r.d(t,{e:()=>o});var n=r(385),i={};function o(e){if(e in i)return i[e];if(0===(e||"").indexOf("data:"))return{protocol:"data"};let t;var r=n._A?.location,o={};if(n.il)t=document.createElement("a"),t.href=e;else try{t=new URL(e,r.href)}catch(e){return o}o.port=t.port;var a=t.href.split("://");!o.port&&a[1]&&(o.port=a[1].split("/")[0].split("@").pop().split(":")[1]),o.port&&"0"!==o.port||(o.port="https"===a[0]?"443":"80"),o.hostname=t.hostname||r.hostname,o.pathname=t.pathname,o.protocol=a[0],"/"!==o.pathname.charAt(0)&&(o.pathname="/"+o.pathname);var s=!t.protocol||":"===t.protocol||t.protocol===r.protocol,c=t.hostname===r.hostname&&t.port===r.port;return o.sameOrigin=s&&(!t.hostname||c),"/"===o.pathname&&(i[e]=o),o}},50:(e,t,r)=>{function n(e,t){"function"==typeof console.warn&&(console.warn("New Relic: ".concat(e)),t&&console.warn(t))}r.d(t,{Z:()=>n})},2587:(e,t,r)=>{r.d(t,{N:()=>c,T:()=>u});var n=r(2177),i=r(5546),o=r(8e3),a=r(3325);const s={stn:[a.D.sessionTrace],err:[a.D.jserrors,a.D.metrics],ins:[a.D.pageAction],spa:[a.D.spa],sr:[a.D.sessionReplay,a.D.sessionTrace]};function c(e,t){const r=n.ee.get(t);e&&"object"==typeof e&&(Object.entries(e).forEach((e=>{let[t,n]=e;void 0===u[t]&&(s[t]?s[t].forEach((e=>{n?(0,i.p)("feat-"+t,[],void 0,e,r):(0,i.p)("block-"+t,[],void 0,e,r),(0,i.p)("rumresp-"+t,[Boolean(n)],void 0,e,r)})):n&&(0,i.p)("feat-"+t,[],void 0,void 0,r),u[t]=Boolean(n))})),Object.keys(s).forEach((e=>{void 0===u[e]&&(s[e]?.forEach((t=>(0,i.p)("rumresp-"+e,[!1],void 0,t,r))),u[e]=!1)})),(0,o.L)(t,a.D.pageViewEvent))}const u={}},2210:(e,t,r)=>{r.d(t,{X:()=>i});var n=Object.prototype.hasOwnProperty;function i(e,t,r){if(n.call(e,t))return e[t];var i=r();if(Object.defineProperty&&Object.keys)try{return Object.defineProperty(e,t,{value:i,writable:!0,enumerable:!1}),i}catch(e){}return e[t]=i,i}},1284:(e,t,r)=>{r.d(t,{D:()=>n});const n=(e,t)=>Object.entries(e||{}).map((e=>{let[r,n]=e;return t(r,n)}))},4351:(e,t,r)=>{r.d(t,{P:()=>o});var n=r(2177);const i=()=>{const e=new WeakSet;return(t,r)=>{if("object"==typeof r&&null!==r){if(e.has(r))return;e.add(r)}return r}};function o(e){try{return JSON.stringify(e,i())}catch(e){try{n.ee.emit("internal-error",[e])}catch(e){}}}},3960:(e,t,r)=>{r.d(t,{K:()=>a,b:()=>o});var n=r(3239);function i(){return"undefined"==typeof document||"complete"===document.readyState}function o(e,t){if(i())return e();(0,n.bP)("load",e,t)}function a(e){if(i())return e();(0,n.iz)("DOMContentLoaded",e)}},8632:(e,t,r)=>{r.d(t,{EZ:()=>u,Qy:()=>c,ce:()=>o,fP:()=>a,gG:()=>d,mF:()=>s});var n=r(7894),i=r(385);const o={beacon:"bam.nr-data.net",errorBeacon:"bam.nr-data.net"};function a(){return i._A.NREUM||(i._A.NREUM={}),void 0===i._A.newrelic&&(i._A.newrelic=i._A.NREUM),i._A.NREUM}function s(){let e=a();return e.o||(e.o={ST:i._A.setTimeout,SI:i._A.setImmediate,CT:i._A.clearTimeout,XHR:i._A.XMLHttpRequest,REQ:i._A.Request,EV:i._A.Event,PR:i._A.Promise,MO:i._A.MutationObserver,FETCH:i._A.fetch}),e}function c(e,t,r){let i=a();const o=i.initializedAgents||{},s=o[e]||{};return Object.keys(s).length||(s.initializedAt={ms:(0,n.z)(),date:new Date}),i.initializedAgents={...o,[e]:{...s,[r]:t}},i}function u(e,t){a()[e]=t}function d(){return function(){let e=a();const t=e.info||{};e.info={beacon:o.beacon,errorBeacon:o.errorBeacon,...t}}(),function(){let e=a();const t=e.init||{};e.init={...t}}(),s(),function(){let e=a();const t=e.loader_config||{};e.loader_config={...t}}(),a()}},7956:(e,t,r)=>{r.d(t,{N:()=>i});var n=r(3239);function i(e){let t=arguments.length>1&&void 0!==arguments[1]&&arguments[1],r=arguments.length>2?arguments[2]:void 0,i=arguments.length>3?arguments[3]:void 0;return void(0,n.iz)("visibilitychange",(function(){if(t)return void("hidden"==document.visibilityState&&e());e(document.visibilityState)}),r,i)}},1214:(e,t,r)=>{r.d(t,{em:()=>v,u5:()=>N,QU:()=>S,_L:()=>I,Gm:()=>L,Lg:()=>M,gy:()=>U,BV:()=>Q,Kf:()=>ee});var n=r(2177);const i="nr@original";var o=Object.prototype.hasOwnProperty,a=!1;function s(e,t){return e||(e=n.ee),r.inPlace=function(e,t,n,i,o){n||(n="");var a,s,c,u="-"===n.charAt(0);for(c=0;c 2?n-2:0),o=2;o {r(A[T],e,w),r(E[T],e,w)})),r(l._A,"fetch",y),t.on(y+"end",(function(e,r){var n=this;if(r){var i=r.headers.get("content-length");null!==i&&(n.rxSize=i),t.emit(y+"done",[null,r],n)}else t.emit(y+"done",[e],n)})),t}const O={},j=["pushState","replaceState"];function S(e){const t=function(e){return(e||n.ee).get("history")}(e);return!l.il||O[t.debugId]++||(O[t.debugId]=1,s(t).inPlace(window.history,j,"-")),t}var P=r(3239);const C={},R=["appendChild","insertBefore","replaceChild"];function I(e){const t=function(e){return(e||n.ee).get("jsonp")}(e);if(!l.il||C[t.debugId])return t;C[t.debugId]=!0;var r=s(t),i=/[?&](?:callback|cb)=([^&#]+)/,o=/(.*)\.([^.]+)/,a=/^(\w+)(\.|$)(.*)$/;function c(e,t){var r=e.match(a),n=r[1],i=r[3];return i?c(i,t[n]):t[n]}return r.inPlace(Node.prototype,R,"dom-"),t.on("dom-start",(function(e){!function(e){if(!e||"string"!=typeof e.nodeName||"script"!==e.nodeName.toLowerCase())return;if("function"!=typeof e.addEventListener)return;var n=(a=e.src,s=a.match(i),s?s[1]:null);var a,s;if(!n)return;var u=function(e){var t=e.match(o);if(t&&t.length>=3)return{key:t[2],parent:c(t[1],window)};return{key:e,parent:window}}(n);if("function"!=typeof u.parent[u.key])return;var d={};function f(){t.emit("jsonp-end",[],d),e.removeEventListener("load",f,(0,P.m$)(!1)),e.removeEventListener("error",l,(0,P.m$)(!1))}function l(){t.emit("jsonp-error",[],d),t.emit("jsonp-end",[],d),e.removeEventListener("load",f,(0,P.m$)(!1)),e.removeEventListener("error",l,(0,P.m$)(!1))}r.inPlace(u.parent,[u.key],"cb-",d),e.addEventListener("load",f,(0,P.m$)(!1)),e.addEventListener("error",l,(0,P.m$)(!1)),t.emit("new-jsonp",[e.src],d)}(e[0])})),t}var k=r(5763);const H={};function L(e){const t=function(e){return(e||n.ee).get("mutation")}(e);if(!l.il||H[t.debugId])return t;H[t.debugId]=!0;var r=s(t),i=k.Yu.MO;return i&&(window.MutationObserver=function(e){return this instanceof i?new i(r(e,"fn-")):i.apply(this,arguments)},MutationObserver.prototype=i.prototype),t}const z={};function M(e){const t=function(e){return(e||n.ee).get("promise")}(e);if(z[t.debugId])return t;z[t.debugId]=!0;var r=n.c,o=s(t),a=k.Yu.PR;return a&&function(){function e(r){var n=t.context(),i=o(r,"executor-",n,null,!1);const s=Reflect.construct(a,[i],e);return t.context(s).getCtx=function(){return n},s}l._A.Promise=e,Object.defineProperty(e,"name",{value:"Promise"}),e.toString=function(){return a.toString()},Object.setPrototypeOf(e,a),["all","race"].forEach((function(r){const n=a[r];e[r]=function(e){let i=!1;[...e||[]].forEach((e=>{this.resolve(e).then(a("all"===r),a(!1))}));const o=n.apply(this,arguments);return o;function a(e){return function(){t.emit("propagate",[null,!i],o,!1,!1),i=i||!e}}}})),["resolve","reject"].forEach((function(r){const n=a[r];e[r]=function(e){const r=n.apply(this,arguments);return e!==r&&t.emit("propagate",[e,!0],r,!1,!1),r}})),e.prototype=a.prototype;const n=a.prototype.then;a.prototype.then=function(){var e=this,i=r(e);i.promise=e;for(var a=arguments.length,s=new Array(a),c=0;c e())),t};function m(e,t){i.inPlace(t,["onreadystatechange"],"fn-",E)}function b(){var e=this,t=r.context(e);e.readyState>3&&!t.resolved&&(t.resolved=!0,r.emit("xhr-resolved",[],e)),i.inPlace(e,f,"fn-",E)}if(function(e,t){for(var r in e)t[r]=e[r]}(o,p),p.prototype=o.prototype,i.inPlace(p.prototype,J,"-xhr-",E),r.on("send-xhr-start",(function(e,t){m(e,t),function(e){h.push(e),a&&(y?y.then(A):u?u(A):(w=-w,x.data=w))}(t)})),r.on("open-xhr-start",m),a){var y=c&&c.resolve();if(!u&&!c){var w=1,x=document.createTextNode(w);new a(A).observe(x,{characterData:!0})}}else t.on("fn-end",(function(e){e[0]&&e[0].type===d||A()}));function A(){for(var e=0;e {r.d(t,{t:()=>n});const n=r(3325).D.ajax},6660:(e,t,r)=>{r.d(t,{A:()=>i,t:()=>n});const n=r(3325).D.jserrors,i="nr@seenError"},3081:(e,t,r)=>{r.d(t,{gF:()=>o,mY:()=>i,t9:()=>n,vz:()=>s,xS:()=>a});const n=r(3325).D.metrics,i="sm",o="cm",a="storeSupportabilityMetrics",s="storeEventMetrics"},4649:(e,t,r)=>{r.d(t,{t:()=>n});const n=r(3325).D.pageAction},7633:(e,t,r)=>{r.d(t,{Dz:()=>i,OJ:()=>a,qw:()=>o,t9:()=>n});const n=r(3325).D.pageViewEvent,i="firstbyte",o="domcontent",a="windowload"},9251:(e,t,r)=>{r.d(t,{t:()=>n});const n=r(3325).D.pageViewTiming},3614:(e,t,r)=>{r.d(t,{BST_RESOURCE:()=>i,END:()=>s,FEATURE_NAME:()=>n,FN_END:()=>u,FN_START:()=>c,PUSH_STATE:()=>d,RESOURCE:()=>o,START:()=>a});const n=r(3325).D.sessionTrace,i="bstResource",o="resource",a="-start",s="-end",c="fn"+a,u="fn"+s,d="pushState"},7836:(e,t,r)=>{r.d(t,{BODY:()=>A,CB_END:()=>E,CB_START:()=>u,END:()=>x,FEATURE_NAME:()=>i,FETCH:()=>_,FETCH_BODY:()=>v,FETCH_DONE:()=>m,FETCH_START:()=>p,FN_END:()=>c,FN_START:()=>s,INTERACTION:()=>l,INTERACTION_API:()=>d,INTERACTION_EVENTS:()=>o,JSONP_END:()=>b,JSONP_NODE:()=>g,JS_TIME:()=>T,MAX_TIMER_BUDGET:()=>a,REMAINING:()=>f,SPA_NODE:()=>h,START:()=>w,originalSetTimeout:()=>y});var n=r(5763);const i=r(3325).D.spa,o=["click","submit","keypress","keydown","keyup","change"],a=999,s="fn-start",c="fn-end",u="cb-start",d="api-ixn-",f="remaining",l="interaction",h="spaNode",g="jsonpNode",p="fetch-start",m="fetch-done",v="fetch-body-",b="jsonp-end",y=n.Yu.ST,w="-start",x="-end",A="-body",E="cb"+x,T="jsTime",_="fetch"},5938:(e,t,r)=>{r.d(t,{W:()=>o});var n=r(5763),i=r(2177);class o{constructor(e,t,r){this.agentIdentifier=e,this.aggregator=t,this.ee=i.ee.get(e,(0,n.OP)(this.agentIdentifier).isolatedBacklog),this.featureName=r,this.blocked=!1}}},9144:(e,t,r)=>{r.d(t,{j:()=>m});var n=r(3325),i=r(5763),o=r(5546),a=r(2177),s=r(7894),c=r(8e3),u=r(3960),d=r(385),f=r(50),l=r(3081),h=r(8632);function g(){const e=(0,h.gG)();["setErrorHandler","finished","addToTrace","inlineHit","addRelease","addPageAction","setCurrentRouteName","setPageViewName","setCustomAttribute","interaction","noticeError","setUserId"].forEach((t=>{e[t]=function(){for(var r=arguments.length,n=new Array(r),i=0;i 1?r-1:0),i=1;i {e.exposed&&e.api[t]&&o.push(e.api[t](...n))})),o.length>1?o:o[0]}(t,...n)}}))}var p=r(2587);function m(e){let t=arguments.length>1&&void 0!==arguments[1]?arguments[1]:{},m=arguments.length>2?arguments[2]:void 0,v=arguments.length>3?arguments[3]:void 0,{init:b,info:y,loader_config:w,runtime:x={loaderType:m},exposed:A=!0}=t;const E=(0,h.gG)();y||(b=E.init,y=E.info,w=E.loader_config),(0,i.Dg)(e,b||{}),(0,i.GE)(e,w||{}),(0,i.sU)(e,x),y.jsAttributes??={},d.v6&&(y.jsAttributes.isWorker=!0),(0,i.CX)(e,y),g();const T=function(e,t){t||(0,c.R)(e,"api");const h={};var g=a.ee.get(e),p=g.get("tracer"),m="api-",v=m+"ixn-";function b(t,r,n,o){const a=(0,i.C5)(e);return null===r?delete a.jsAttributes[t]:(0,i.CX)(e,{...a,jsAttributes:{...a.jsAttributes,[t]:r}}),x(m,n,!0,o||null===r?"session":void 0)(t,r)}function y(){}["setErrorHandler","finished","addToTrace","inlineHit","addRelease"].forEach((e=>h[e]=x(m,e,!0,"api"))),h.addPageAction=x(m,"addPageAction",!0,n.D.pageAction),h.setCurrentRouteName=x(m,"routeName",!0,n.D.spa),h.setPageViewName=function(t,r){if("string"==typeof t)return"/"!==t.charAt(0)&&(t="/"+t),(0,i.OP)(e).customTransaction=(r||"http://custom.transaction")+t,x(m,"setPageViewName",!0)()},h.setCustomAttribute=function(e,t){let r=arguments.length>2&&void 0!==arguments[2]&&arguments[2];if("string"==typeof e){if(["string","number"].includes(typeof t)||null===t)return b(e,t,"setCustomAttribute",r);(0,f.Z)("Failed to execute setCustomAttribute.\nNon-null value must be a string or number type, but a type of was provided."))}else(0,f.Z)("Failed to execute setCustomAttribute.\nName must be a string type, but a type of was provided."))},h.setUserId=function(e){if("string"==typeof e||null===e)return b("enduser.id",e,"setUserId",!0);(0,f.Z)("Failed to execute setUserId.\nNon-null value must be a string type, but a type of was provided."))},h.interaction=function(){return(new y).get()};var w=y.prototype={createTracer:function(e,t){var r={},i=this,a="function"==typeof t;return(0,o.p)(v+"tracer",[(0,s.z)(),e,r],i,n.D.spa,g),function(){if(p.emit((a?"":"no-")+"fn-start",[(0,s.z)(),i,a],r),a)try{return t.apply(this,arguments)}catch(e){throw p.emit("fn-err",[arguments,this,"string"==typeof e?new Error(e):e],r),e}finally{p.emit("fn-end",[(0,s.z)()],r)}}}};function x(e,t,r,i){return function(){return(0,o.p)(l.xS,["API/"+t+"/called"],void 0,n.D.metrics,g),i&&(0,o.p)(e+t,[(0,s.z)(),...arguments],r?null:this,i,g),r?void 0:this}}function A(){r.e(439).then(r.bind(r,7438)).then((t=>{let{setAPI:r}=t;r(e),(0,c.L)(e,"api")})).catch((()=>(0,f.Z)("Downloading runtime APIs failed...")))}return["actionText","setName","setAttribute","save","ignore","onEnd","getContext","end","get"].forEach((e=>{w[e]=x(v,e,void 0,n.D.spa)})),h.noticeError=function(e,t){"string"==typeof e&&(e=new Error(e)),(0,o.p)(l.xS,["API/noticeError/called"],void 0,n.D.metrics,g),(0,o.p)("err",[e,(0,s.z)(),!1,t],void 0,n.D.jserrors,g)},d.il?(0,u.b)((()=>A()),!0):A(),h}(e,v);return(0,h.Qy)(e,T,"api"),(0,h.Qy)(e,A,"exposed"),(0,h.EZ)("activatedFeatures",p.T),T}},3325:(e,t,r)=>{r.d(t,{D:()=>n,p:()=>i});const n={ajax:"ajax",jserrors:"jserrors",metrics:"metrics",pageAction:"page_action",pageViewEvent:"page_view_event",pageViewTiming:"page_view_timing",sessionReplay:"session_replay",sessionTrace:"session_trace",spa:"spa"},i={[n.pageViewEvent]:1,[n.pageViewTiming]:2,[n.metrics]:3,[n.jserrors]:4,[n.ajax]:5,[n.sessionTrace]:6,[n.pageAction]:7,[n.spa]:8,[n.sessionReplay]:9}}},n={};function i(e){var t=n[e];if(void 0!==t)return t.exports;var o=n[e]={exports:{}};return r[e](o,o.exports,i),o.exports}i.m=r,i.d=(e,t)=>{for(var r in t)i.o(t,r)&&!i.o(e,r)&&Object.defineProperty(e,r,{enumerable:!0,get:t[r]})},i.f={},i.e=e=>Promise.all(Object.keys(i.f).reduce(((t,r)=>(i.f[r](e,t),t)),[])),i.u=e=>(({78:"page_action-aggregate",147:"metrics-aggregate",242:"session-manager",317:"jserrors-aggregate",348:"page_view_timing-aggregate",412:"lazy-feature-loader",439:"async-api",538:"recorder",590:"session_replay-aggregate",675:"compressor",733:"session_trace-aggregate",786:"page_view_event-aggregate",873:"spa-aggregate",898:"ajax-aggregate"}[e]||e)+"."+{78:"ac76d497",147:"3dc53903",148:"1a20d5fe",242:"2a64278a",317:"49e41428",348:"bd6de33a",412:"2f55ce66",439:"30bd804e",538:"1b18459f",590:"cf0efb30",675:"ae9f91a8",733:"83105561",786:"06482edd",860:"03a8b7a5",873:"e6b09d52",898:"998ef92b"}[e]+"-1.236.0.min.js"),i.o=(e,t)=>Object.prototype.hasOwnProperty.call(e,t),e={},t="NRBA:",i.l=(r,n,o,a)=>{if(e[r])e[r].push(n);else{var s,c;if(void 0!==o)for(var u=document.getElementsByTagName("script"),d=0;d {s.onerror=s.onload=null,clearTimeout(h);var i=e[r];if(delete e[r],s.parentNode&&s.parentNode.removeChild(s),i&&i.forEach((e=>e(n))),t)return t(n)},h=setTimeout(l.bind(null,void 0,{type:"timeout",target:s}),12e4);s.onerror=l.bind(null,s.onerror),s.onload=l.bind(null,s.onload),c&&document.head.appendChild(s)}},i.r=e=>{"undefined"!=typeof Symbol&&Symbol.toStringTag&&Object.defineProperty(e,Symbol.toStringTag,{value:"Module"}),Object.defineProperty(e,"__esModule",{value:!0})},i.j=364,i.p="https://js-agent.newrelic.com/",(()=>{var e={364:0,953:0};i.f.j=(t,r)=>{var n=i.o(e,t)?e[t]:void 0;if(0!==n)if(n)r.push(n[2]);else{var o=new Promise(((r,i)=>n=e[t]=[r,i]));r.push(n[2]=o);var a=i.p+i.u(t),s=new Error;i.l(a,(r=>{if(i.o(e,t)&&(0!==(n=e[t])&&(e[t]=void 0),n)){var o=r&&("load"===r.type?"missing":r.type),a=r&&r.target&&r.target.src;s.message="Loading chunk "+t+" failed.\n("+o+": "+a+")",s.name="ChunkLoadError",s.type=o,s.request=a,n[1](s)}}),"chunk-"+t,t)}};var t=(t,r)=>{var n,o,[a,s,c]=r,u=0;if(a.some((t=>0!==e[t]))){for(n in s)i.o(s,n)&&(i.m[n]=s[n]);if(c)c(i)}for(t&&t(r);u {i.r(o);var e=i(3325),t=i(5763);const r=Object.values(e.D);function n(e){const n={};return r.forEach((r=>{n[r]=function(e,r){return!1!==(0,t.Mt)(r,"".concat(e,".enabled"))}(r,e)})),n}var a=i(9144);var s=i(5546),c=i(385),u=i(8e3),d=i(5938),f=i(3960),l=i(50);class h extends d.W{constructor(e,t,r){let n=!(arguments.length>3&&void 0!==arguments[3])||arguments[3];super(e,t,r),this.auto=n,this.abortHandler,this.featAggregate,this.onAggregateImported,n&&(0,u.R)(e,r)}importAggregator(){let e=arguments.length>0&&void 0!==arguments[0]?arguments[0]:{};if(this.featAggregate||!this.auto)return;const r=c.il&&!0===(0,t.Mt)(this.agentIdentifier,"privacy.cookies_enabled");let n;this.onAggregateImported=new Promise((e=>{n=e}));const o=async()=>{let t;try{if(r){const{setupAgentSession:e}=await Promise.all([i.e(860),i.e(242)]).then(i.bind(i,3228));t=e(this.agentIdentifier)}}catch(e){(0,l.Z)("A problem occurred when starting up session manager. This page will not start or extend any session.",e)}try{if(!this.shouldImportAgg(this.featureName,t))return void(0,u.L)(this.agentIdentifier,this.featureName);const{lazyFeatureLoader:r}=await i.e(412).then(i.bind(i,8582)),{Aggregate:o}=await r(this.featureName,"aggregate");this.featAggregate=new o(this.agentIdentifier,this.aggregator,e),n(!0)}catch(e){(0,l.Z)("Downloading and initializing ".concat(this.featureName," failed..."),e),this.abortHandler?.(),n(!1)}};c.il?(0,f.b)((()=>o()),!0):o()}shouldImportAgg(r,n){return r!==e.D.sessionReplay||!1!==(0,t.Mt)(this.agentIdentifier,"session_trace.enabled")&&(!!n?.isNew||!!n?.state.sessionReplay)}}var g=i(7633),p=i(7894);class m extends h{static featureName=g.t9;constructor(r,n){let i=!(arguments.length>2&&void 0!==arguments[2])||arguments[2];if(super(r,n,g.t9,i),("undefined"==typeof PerformanceNavigationTiming||c.Tt)&&"undefined"!=typeof PerformanceTiming){const n=(0,t.OP)(r);n[g.Dz]=Math.max(Date.now()-n.offset,0),(0,f.K)((()=>n[g.qw]=Math.max((0,p.z)()-n[g.Dz],0))),(0,f.b)((()=>{const t=(0,p.z)();n[g.OJ]=Math.max(t-n[g.Dz],0),(0,s.p)("timing",["load",t],void 0,e.D.pageViewTiming,this.ee)}))}this.importAggregator()}}var v=i(1117),b=i(1284);class y extends v.w{constructor(e){super(e),this.aggregatedData={}}store(e,t,r,n,i){var o=this.getBucket(e,t,r,i);return o.metrics=function(e,t){t||(t={count:0});return t.count+=1,(0,b.D)(e,(function(e,r){t[e]=w(r,t[e])})),t}(n,o.metrics),o}merge(e,t,r,n,i){var o=this.getBucket(e,t,n,i);if(o.metrics){var a=o.metrics;a.count+=r.count,(0,b.D)(r,(function(e,t){if("count"!==e){var n=a[e],i=r[e];i&&!i.c?a[e]=w(i.t,n):a[e]=function(e,t){if(!t)return e;t.c||(t=x(t.t));return t.min=Math.min(e.min,t.min),t.max=Math.max(e.max,t.max),t.t+=e.t,t.sos+=e.sos,t.c+=e.c,t}(i,a[e])}}))}else o.metrics=r}storeMetric(e,t,r,n){var i=this.getBucket(e,t,r);return i.stats=w(n,i.stats),i}getBucket(e,t,r,n){this.aggregatedData[e]||(this.aggregatedData[e]={});var i=this.aggregatedData[e][t];return i||(i=this.aggregatedData[e][t]={params:r||{}},n&&(i.custom=n)),i}get(e,t){return t?this.aggregatedData[e]&&this.aggregatedData[e][t]:this.aggregatedData[e]}take(e){for(var t={},r="",n=!1,i=0;i t.max&&(t.max=e),e 2&&void 0!==arguments[2])||arguments[2];super(e,r,j.t,n),c.il&&((0,t.OP)(e).initHidden=Boolean("hidden"===document.visibilityState),(0,N.N)((()=>(0,s.p)("docHidden",[(0,p.z)()],void 0,j.t,this.ee)),!0),(0,O.bP)("pagehide",(()=>(0,s.p)("winPagehide",[(0,p.z)()],void 0,j.t,this.ee))),this.importAggregator())}}var P=i(3081);class C extends h{static featureName=P.t9;constructor(e,t){let r=!(arguments.length>2&&void 0!==arguments[2])||arguments[2];super(e,t,P.t9,r),this.importAggregator()}}var R,I=i(2210),k=i(1214),H=i(2177),L={};try{R=localStorage.getItem("__nr_flags").split(","),console&&"function"==typeof console.log&&(L.console=!0,-1!==R.indexOf("dev")&&(L.dev=!0),-1!==R.indexOf("nr_dev")&&(L.nrDev=!0))}catch(e){}function z(e){try{L.console&&z(e)}catch(e){}}L.nrDev&&H.ee.on("internal-error",(function(e){z(e.stack)})),L.dev&&H.ee.on("fn-err",(function(e,t,r){z(r.stack)})),L.dev&&(z("NR AGENT IN DEVELOPMENT MODE"),z("flags: "+(0,b.D)(L,(function(e,t){return e})).join(", ")));var M=i(6660);class B extends h{static featureName=M.t;constructor(r,n){let i=!(arguments.length>2&&void 0!==arguments[2])||arguments[2];super(r,n,M.t,i),this.skipNext=0;try{this.removeOnAbort=new AbortController}catch(e){}const o=this;o.ee.on("fn-start",(function(e,t,r){o.abortHandler&&(o.skipNext+=1)})),o.ee.on("fn-err",(function(t,r,n){o.abortHandler&&!n[M.A]&&((0,I.X)(n,M.A,(function(){return!0})),this.thrown=!0,(0,s.p)("err",[n,(0,p.z)()],void 0,e.D.jserrors,o.ee))})),o.ee.on("fn-end",(function(){o.abortHandler&&!this.thrown&&o.skipNext>0&&(o.skipNext-=1)})),o.ee.on("internal-error",(function(t){(0,s.p)("ierr",[t,(0,p.z)(),!0],void 0,e.D.jserrors,o.ee)})),this.origOnerror=c._A.onerror,c._A.onerror=this.onerrorHandler.bind(this),c._A.addEventListener("unhandledrejection",(t=>{const r=function(e){let t="Unhandled Promise Rejection: ";if(e instanceof Error)try{return e.message=t+e.message,e}catch(t){return e}if(void 0===e)return new Error(t);try{return new Error(t+(0,D.P)(e))}catch(e){return new Error(t)}}(t.reason);(0,s.p)("err",[r,(0,p.z)(),!1,{unhandledPromiseRejection:1}],void 0,e.D.jserrors,this.ee)}),(0,O.m$)(!1,this.removeOnAbort?.signal)),(0,k.gy)(this.ee),(0,k.BV)(this.ee),(0,k.em)(this.ee),(0,t.OP)(r).xhrWrappable&&(0,k.Kf)(this.ee),this.abortHandler=this.#e,this.importAggregator()}#e(){this.removeOnAbort?.abort(),this.abortHandler=void 0}onerrorHandler(t,r,n,i,o){"function"==typeof this.origOnerror&&this.origOnerror(...arguments);try{this.skipNext?this.skipNext-=1:(0,s.p)("err",[o||new F(t,r,n),(0,p.z)()],void 0,e.D.jserrors,this.ee)}catch(t){try{(0,s.p)("ierr",[t,(0,p.z)(),!0],void 0,e.D.jserrors,this.ee)}catch(e){}}return!1}}function F(e,t,r){this.message=e||"Uncaught error with no additional information",this.sourceURL=t,this.line=r}let U=1;const q="nr@id";function G(e){const t=typeof e;return!e||"object"!==t&&"function"!==t?-1:e===c._A?0:(0,I.X)(e,q,(function(){return U++}))}function V(e){if("string"==typeof e&&e.length)return e.length;if("object"==typeof e){if("undefined"!=typeof ArrayBuffer&&e instanceof ArrayBuffer&&e.byteLength)return e.byteLength;if("undefined"!=typeof Blob&&e instanceof Blob&&e.size)return e.size;if(!("undefined"!=typeof FormData&&e instanceof FormData))try{return(0,D.P)(e).length}catch(e){return}}}var X=i(7243);class W{constructor(e){this.agentIdentifier=e,this.generateTracePayload=this.generateTracePayload.bind(this),this.shouldGenerateTrace=this.shouldGenerateTrace.bind(this)}generateTracePayload(e){if(!this.shouldGenerateTrace(e))return null;var r=(0,t.DL)(this.agentIdentifier);if(!r)return null;var n=(r.accountID||"").toString()||null,i=(r.agentID||"").toString()||null,o=(r.trustKey||"").toString()||null;if(!n||!i)return null;var a=(0,_.M)(),s=(0,_.Ht)(),c=Date.now(),u={spanId:a,traceId:s,timestamp:c};return(e.sameOrigin||this.isAllowedOrigin(e)&&this.useTraceContextHeadersForCors())&&(u.traceContextParentHeader=this.generateTraceContextParentHeader(a,s),u.traceContextStateHeader=this.generateTraceContextStateHeader(a,c,n,i,o)),(e.sameOrigin&&!this.excludeNewrelicHeader()||!e.sameOrigin&&this.isAllowedOrigin(e)&&this.useNewrelicHeaderForCors())&&(u.newrelicHeader=this.generateTraceHeader(a,s,c,n,i,o)),u}generateTraceContextParentHeader(e,t){return"00-"+t+"-"+e+"-01"}generateTraceContextStateHeader(e,t,r,n,i){return i+"@nr=0-1-"+r+"-"+n+"-"+e+"----"+t}generateTraceHeader(e,t,r,n,i,o){if(!("function"==typeof c._A?.btoa))return null;var a={v:[0,1],d:{ty:"Browser",ac:n,ap:i,id:e,tr:t,ti:r}};return o&&n!==o&&(a.d.tk=o),btoa((0,D.P)(a))}shouldGenerateTrace(e){return this.isDtEnabled()&&this.isAllowedOrigin(e)}isAllowedOrigin(e){var r=!1,n={};if((0,t.Mt)(this.agentIdentifier,"distributed_tracing")&&(n=(0,t.P_)(this.agentIdentifier).distributed_tracing),e.sameOrigin)r=!0;else if(n.allowed_origins instanceof Array)for(var i=0;i 2&&void 0!==arguments[2])||arguments[2];super(r,n,Z.t,i),(0,t.OP)(r).xhrWrappable&&(this.dt=new W(r),this.handler=(e,t,r,n)=>(0,s.p)(e,t,r,n,this.ee),(0,k.u5)(this.ee),(0,k.Kf)(this.ee),function(r,n,i,o){function a(e){var t=this;t.totalCbs=0,t.called=0,t.cbTime=0,t.end=E,t.ended=!1,t.xhrGuids={},t.lastSize=null,t.loadCaptureCalled=!1,t.params=this.params||{},t.metrics=this.metrics||{},e.addEventListener("load",(function(r){_(t,e)}),(0,O.m$)(!1)),c.IF||e.addEventListener("progress",(function(e){t.lastSize=e.loaded}),(0,O.m$)(!1))}function s(e){this.params={method:e[0]},T(this,e[1]),this.metrics={}}function u(e,n){var i=(0,t.DL)(r);i.xpid&&this.sameOrigin&&n.setRequestHeader("X-NewRelic-ID",i.xpid);var a=o.generateTracePayload(this.parsedOrigin);if(a){var s=!1;a.newrelicHeader&&(n.setRequestHeader("newrelic",a.newrelicHeader),s=!0),a.traceContextParentHeader&&(n.setRequestHeader("traceparent",a.traceContextParentHeader),a.traceContextStateHeader&&n.setRequestHeader("tracestate",a.traceContextStateHeader),s=!0),s&&(this.dt=a)}}function d(e,t){var r=this.metrics,i=e[0],o=this;if(r&&i){var a=V(i);a&&(r.txSize=a)}this.startTime=(0,p.z)(),this.listener=function(e){try{"abort"!==e.type||o.loadCaptureCalled||(o.params.aborted=!0),("load"!==e.type||o.called===o.totalCbs&&(o.onloadCalled||"function"!=typeof t.onload)&&"function"==typeof o.end)&&o.end(t)}catch(e){try{n.emit("internal-error",[e])}catch(e){}}};for(var s=0;s 1?e[1]=i:e.push(i)}else e[0]&&e[0].headers&&s(e[0].headers,n)&&(this.dt=n);function s(e,t){var r=!1;return t.newrelicHeader&&(e.set("newrelic",t.newrelicHeader),r=!0),t.traceContextParentHeader&&(e.set("traceparent",t.traceContextParentHeader),t.traceContextStateHeader&&e.set("tracestate",t.traceContextStateHeader),r=!0),r}}function x(e,t){this.params={},this.metrics={},this.startTime=(0,p.z)(),this.dt=t,e.length>=1&&(this.target=e[0]),e.length>=2&&(this.opts=e[1]);var r,n=this.opts||{},i=this.target;"string"==typeof i?r=i:"object"==typeof i&&i instanceof Y?r=i.url:c._A?.URL&&"object"==typeof i&&i instanceof URL&&(r=i.href),T(this,r);var o=(""+(i&&i instanceof Y&&i.method||n.method||"GET")).toUpperCase();this.params.method=o,this.txSize=V(n.body)||0}function A(t,r){var n;this.endTime=(0,p.z)(),this.params||(this.params={}),this.params.status=r?r.status:0,"string"==typeof this.rxSize&&this.rxSize.length>0&&(n=+this.rxSize);var o={txSize:this.txSize,rxSize:n,duration:(0,p.z)()-this.startTime};i("xhr",[this.params,o,this.startTime,this.endTime,"fetch"],this,e.D.ajax)}function E(t){var r=this.params,n=this.metrics;if(!this.ended){this.ended=!0;for(var o=0;o 2&&void 0!==arguments[2])||arguments[2];super(e,t,we.t,r),this.importAggregator()}}new class{constructor(e){let t=arguments.length>1&&void 0!==arguments[1]?arguments[1]:(0,_.ky)(16);c._A?(this.agentIdentifier=t,this.sharedAggregator=new y({agentIdentifier:this.agentIdentifier}),this.features={},this.desiredFeatures=new Set(e.features||[]),this.desiredFeatures.add(m),Object.assign(this,(0,a.j)(this.agentIdentifier,e,e.loaderType||"agent")),this.start()):(0,l.Z)("Failed to initial the agent. Could not determine the runtime environment.")}get config(){return{info:(0,t.C5)(this.agentIdentifier),init:(0,t.P_)(this.agentIdentifier),loader_config:(0,t.DL)(this.agentIdentifier),runtime:(0,t.OP)(this.agentIdentifier)}}start(){const t="features";try{const r=n(this.agentIdentifier),i=[...this.desiredFeatures];i.sort(((t,r)=>e.p[t.featureName]-e.p[r.featureName])),i.forEach((t=>{if(r[t.featureName]||t.featureName===e.D.pageViewEvent){const n=function(t){switch(t){case e.D.ajax:return[e.D.jserrors];case e.D.sessionTrace:return[e.D.ajax,e.D.pageViewEvent];case e.D.sessionReplay:return[e.D.sessionTrace];case e.D.pageViewTiming:return[e.D.pageViewEvent];default:return[]}}(t.featureName);n.every((e=>r[e]))||(0,l.Z)("".concat(t.featureName," is enabled but one or more dependent features has been disabled (").concat((0,D.P)(n),"). This may cause unintended consequences or missing data...")),this.features[t.featureName]=new t(this.agentIdentifier,this.sharedAggregator)}})),(0,T.Qy)(this.agentIdentifier,this.features,t)}catch(e){(0,l.Z)("Failed to initialize all enabled instrument classes (agent aborted) -",e);for(const e in this.features)this.features[e].abortHandler?.();const r=(0,T.fP)();return delete r.initializedAgents[this.agentIdentifier]?.api,delete r.initializedAgents[this.agentIdentifier]?.[t],delete this.sharedAggregator,r.ee?.abort(),delete r.ee?.get(this.agentIdentifier),!1}}}({features:[J,m,S,class extends h{static featureName=oe;constructor(t,r){if(super(t,r,oe,!(arguments.length>2&&void 0!==arguments[2])||arguments[2]),!c.il)return;const n=this.ee;let i;(0,k.QU)(n),this.eventsEE=(0,k.em)(n),this.eventsEE.on(se,(function(e,t){this.bstStart=(0,p.z)()})),this.eventsEE.on(ae,(function(t,r){(0,s.p)("bst",[t[0],r,this.bstStart,(0,p.z)()],void 0,e.D.sessionTrace,n)})),n.on(ce+ne,(function(e){this.time=(0,p.z)(),this.startPath=location.pathname+location.hash})),n.on(ce+ie,(function(t){(0,s.p)("bstHist",[location.pathname+location.hash,this.startPath,this.time],void 0,e.D.sessionTrace,n)}));try{i=new PerformanceObserver((t=>{const r=t.getEntries();(0,s.p)(te,[r],void 0,e.D.sessionTrace,n)})),i.observe({type:re,buffered:!0})}catch(e){}this.importAggregator({resourceObserver:i})}},C,xe,B,class extends h{static featureName=de;constructor(e,r){if(super(e,r,de,!(arguments.length>2&&void 0!==arguments[2])||arguments[2]),!c.il)return;if(!(0,t.OP)(e).xhrWrappable)return;try{this.removeOnAbort=new AbortController}catch(e){}let n,i=0;const o=this.ee.get("tracer"),a=(0,k._L)(this.ee),s=(0,k.Lg)(this.ee),u=(0,k.BV)(this.ee),d=(0,k.Kf)(this.ee),f=this.ee.get("events"),l=(0,k.u5)(this.ee),h=(0,k.QU)(this.ee),g=(0,k.Gm)(this.ee);function m(e,t){h.emit("newURL",[""+window.location,t])}function v(){i++,n=window.location.hash,this[ve]=(0,p.z)()}function b(){i--,window.location.hash!==n&&m(0,!0);var e=(0,p.z)();this[pe]=~~this[pe]+e-this[ve],this[ye]=e}function y(e,t){e.on(t,(function(){this[t]=(0,p.z)()}))}this.ee.on(ve,v),s.on(be,v),a.on(be,v),this.ee.on(ye,b),s.on(ge,b),a.on(ge,b),this.ee.buffer([ve,ye,"xhr-resolved"],this.featureName),f.buffer([ve],this.featureName),u.buffer(["setTimeout"+le,"clearTimeout"+fe,ve],this.featureName),d.buffer([ve,"new-xhr","send-xhr"+fe],this.featureName),l.buffer([me+fe,me+"-done",me+he+fe,me+he+le],this.featureName),h.buffer(["newURL"],this.featureName),g.buffer([ve],this.featureName),s.buffer(["propagate",be,ge,"executor-err","resolve"+fe],this.featureName),o.buffer([ve,"no-"+ve],this.featureName),a.buffer(["new-jsonp","cb-start","jsonp-error","jsonp-end"],this.featureName),y(l,me+fe),y(l,me+"-done"),y(a,"new-jsonp"),y(a,"jsonp-end"),y(a,"cb-start"),h.on("pushState-end",m),h.on("replaceState-end",m),window.addEventListener("hashchange",m,(0,O.m$)(!0,this.removeOnAbort?.signal)),window.addEventListener("load",m,(0,O.m$)(!0,this.removeOnAbort?.signal)),window.addEventListener("popstate",(function(){m(0,i>1)}),(0,O.m$)(!0,this.removeOnAbort?.signal)),this.abortHandler=this.#e,this.importAggregator()}#e(){this.removeOnAbort?.abort(),this.abortHandler=void 0}}],loaderType:"spa"})})(),window.NRBA=o})(); window.jQuery || document.write(' ') CKEDITOR_BASEPATH='https://f1000research.com/js/vendor/ckeditor/' window.reactTheme = 'research'; window.MathJax = { CommonHTML: { linebreaks: { automatic: true } }, 'HTML-CSS': { linebreaks: { automatic: true } }, SVG: { linebreaks: { automatic: true } }, AuthorInit: function() { MathJax.Hub.Register.MessageHook('End Process', function () { let timeout = false; // holder for timeout id const delay = 250; // delay after event is "complete" to run callback const reflowMath = function() { const dispFormulas = document.querySelectorAll('.disp-formula.panel'); if (!dispFormulas) { return; } for (const dispFormula of dispFormulas) { const child = dispFormula.querySelector('.MathJax_Preview').nextSibling.firstChild; const isMultiline = MathJax.Hub.getAllJax(dispFormula)[0].root.isMultiline; if (dispFormula.offsetWidth < child.offsetWidth || isMultiline) { MathJax.Hub.Queue(['Rerender', MathJax.Hub, dispFormula]); } } }; window.addEventListener('resize', function() { clearTimeout(timeout); // clear the timeout timeout = setTimeout(reflowMath, delay); // start timing for event "completion" }); }); }, }; if (window.location.hash == '#_=_'){ window.location = window.location.href.split('#')[0] } !function(f,b,e,v,n,t,s){if(f.fbq)return;n=f.fbq=function() {n.callMethod? n.callMethod.apply(n,arguments):n.queue.push(arguments)} ;if(!f._fbq)f._fbq=n; n.push=n;n.loaded=!0;n.version='2.0';n.queue=[];t=b.createElement(e);t.async=!0; t.src=v;s=b.getElementsByTagName(e)[0];s.parentNode.insertBefore(t,s)}(window, document,'script','https://connect.facebook.net/en_US/fbevents.js'); fbq('init', '1641728616063202'); fbq('track', "PixelInitialized", {}); (function(h,o,t,j,a,r){ h.hj=h.hj||function(){(h.hj.q=h.hj.q||[]).push(arguments)}; h._hjSettings={hjid:2318163,hjsv:6}; a=o.getElementsByTagName('head')[0]; r=o.createElement('script');r.async=1; r.src=t+h._hjSettings.hjid+j+h._hjSettings.hjsv; a.appendChild(r); })(window,document,'https://static.hotjar.com/c/hotjar-','.js?sv='); search file_upload Submit your research search menu close search Browse Gateways & Collections How to Publish Submit your Research My Submissions Article Guidelines Article Guidelines (New Versions) Open Data, Software and Code Guidelines Open Data and Accessible Source Materials Guidelines (HSS) Open Data, Software and Code Guidelines (PSE) Prepublication Checks Production Process Posters and Slides Guidelines Document Guidelines Article Processing Charges Peer Review Finding Article Reviewers About How it Works For Reviewers Our Advisors Policies Glossary FAQs For Developers Newsroom Contact My Research Submissions Content and Tracking Alerts My Details Sign In file_upload Submit your research { "@context": "https://schema.org", "@type": "ScholarlyArticle", "mainEntityOfPage": { "@type": "WebPage", "@id": "https://f1000research.com/articles/12-1165" }, "headline": "Clinical use of autologous cell-based therapies in an evolving regulatory landscape: A survey of patient...", "datePublished": "2023-09-18T10:22:46", "dateModified": "2024-08-27T09:59:44", "author": [ { "@type": "Person", "name": "Ubaka Ogbogu" }, { "@type": "Person", "name": "Nevicia Case" } ], "publisher": { "@type": "Organization", "name": "F1000Research", "logo": { "@type": "ImageObject", "url": "https://f1000research.com/img/AMP/F1000Research_image.png", "height": 480, "width": 60 } }, "image": { "@type": "ImageObject", "url": "https://f1000research.com/img/AMP/F1000Research_image.png", "height": 1200, "width": 150 }, "description": " Background: Clinical treatments involving autologous cell-based therapies (ACBT) remain prevalent despite a lack of scientific backing and an evolving regulatory landscape aimed at assessing their safety and efficacy for clinical adoption. This study seeks to assess patients’ experiences and perceptions of clinical treatments involving ACBT and their knowledge and views of the regulatory context and associated governance issues. Methods: An anonymous online survey of 181 participants who have been treated or are in the process of being treated with ACBT was conducted. Recruitment was via social media platforms. Data was collected through Qualtrics and analyzed using SPSS 29 for the quantitative responses and NVivo 1.7.1 for the qualitative responses. Results: Several themes emerged from the data, including the prominent role of healthcare providers throughout the patient journey, informational practices during the clinical encounter, the high prevalence of pay-for-participation trials, patients’ gaps in regulatory knowledge, and patients’ priorities regarding clinical trials and regulation of ACBT. Conclusions: The study makes a novel contribution to the literature by providing the first analysis of patients’ experiences and perceptions of an emerging cell-based therapy within an evolving regulatory landscape. The findings serve as a valuable resource for developing policy, promoting scientific rigor, and ensuring ethical oversight of ACBT and other upcoming cell-based therapies." } { "@context": "http://schema.org", "@type": "BreadcrumbList", "itemListElement": [ { "@type": "ListItem", "position": "1", "item": { "@id": "https://f1000research.com/", "name": "Home" } }, { "@type": "ListItem", "position": "2", "item": { "@id": "https://f1000research.com/browse/articles", "name": "Browse" } }, { "@type": "ListItem", "position": "3", "item": { "@id": "https://f1000research.com/articles/12-1165", "name": "Clinical use of autologous cell-based therapies in an evolving regulatory..." } } ] } Home Browse Clinical use of autologous cell-based therapies in an evolving regulatory... ALL Metrics - Views Downloads Get PDF Get XML Cite How to cite this article Ogbogu U and Case N. Clinical use of autologous cell-based therapies in an evolving regulatory landscape: A survey of patient experiences and perceptions [version 2; peer review: 2 approved] . F1000Research 2024, 12 :1165 ( https://doi.org/10.12688/f1000research.141002.2 ) NOTE: If applicable, it is important to ensure the information in square brackets after the title is included in all citations of this article. Close Copy Citation Details Export Export Citation Sciwheel EndNote Ref. Manager Bibtex ProCite Sente EXPORT Select a format first Track Share ▬ ✚ Research Article Revised Clinical use of autologous cell-based therapies in an evolving regulatory landscape: A survey of patient experiences and perceptions [version 2; peer review: 2 approved] Ubaka Ogbogu https://orcid.org/0000-0001-7764-6799 1 , Nevicia Case https://orcid.org/0000-0002-5040-6346 1 Ubaka Ogbogu https://orcid.org/0000-0001-7764-6799 1 , Nevicia Case https://orcid.org/0000-0002-5040-6346 1 PUBLISHED 27 Aug 2024 Author details Author details 1 Faculty of Law, University of Alberta, Edmonton, Alberta, T6G2H5, Canada Ubaka Ogbogu Roles: Conceptualization, Data Curation, Formal Analysis, Funding Acquisition, Investigation, Methodology, Project Administration, Resources, Software, Supervision, Validation, Visualization, Writing – Original Draft Preparation, Writing – Review & Editing Nevicia Case Roles: Data Curation, Formal Analysis, Investigation, Methodology, Project Administration, Validation, Visualization, Writing – Original Draft Preparation, Writing – Review & Editing OPEN PEER REVIEW DETAILS REVIEWER STATUS This article is included in the Cell & Molecular Biology gateway. Abstract Background : Clinical treatments involving autologous cell-based therapies (ACBT) remain prevalent despite a lack of scientific backing and an evolving regulatory landscape aimed at assessing their safety and efficacy for clinical adoption. This study seeks to assess patients’ experiences and perceptions of clinical treatments involving ACBT and their knowledge and views of the regulatory context and associated governance issues. Methods : An anonymous online survey of 181 participants who have been treated or are in the process of being treated with ACBT was conducted. Recruitment was via social media platforms. Data was collected through Qualtrics and analyzed using SPSS 29 for the quantitative responses and NVivo 1.7.1 for the qualitative responses. Results : Several themes emerged from the data, including the prominent role of healthcare providers throughout the patient journey, informational practices during the clinical encounter, the high prevalence of pay-for-participation trials, patients’ gaps in regulatory knowledge, and patients’ priorities regarding clinical trials and regulation of ACBT. Conclusions : The study makes a novel contribution to the literature by providing the first analysis of patients’ experiences and perceptions of an emerging cell-based therapy within an evolving regulatory landscape. The findings serve as a valuable resource for developing policy, promoting scientific rigor, and ensuring ethical oversight of ACBT and other upcoming cell-based therapies. READ ALL READ LESS Keywords autologous cell-based therapy, cell therapy, stem cells, advanced therapies, regenerative medicines, health product regulation, patient experience, patient education, stem cell regulation, clinical trial ethics, pay-to-participate trials, healthcare providers Corresponding Author(s) Ubaka Ogbogu ( [email protected] ) Close Corresponding author: Ubaka Ogbogu Competing interests: No competing interests were disclosed. Grant information: This study received funding from the Stem Cell Network. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. Copyright: © 2024 Ogbogu U and Case N. This is an open access article distributed under the terms of the Creative Commons Attribution License , which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. How to cite: Ogbogu U and Case N. Clinical use of autologous cell-based therapies in an evolving regulatory landscape: A survey of patient experiences and perceptions [version 2; peer review: 2 approved] . F1000Research 2024, 12 :1165 ( https://doi.org/10.12688/f1000research.141002.2 ) First published: 18 Sep 2023, 12 :1165 ( https://doi.org/10.12688/f1000research.141002.1 ) Latest published: 27 Aug 2024, 12 :1165 ( https://doi.org/10.12688/f1000research.141002.2 ) Revised Amendments from Version 1 This version addresses the peer reviewers' comments as follows: 1. We included a statement noting that participants were entered into a lottery draw for an incentive approved by the Research Ethics Board. 2. We acknowledged an additional limitation of the study, stating that the quantitative data is not sufficiently representative of the population of patients seeking ACBT in the U.S. and Canada. 3. We added a statement in the Discussion section acknowledging the reviewer's comment that the nature of the ACBT industry necessitates caution when interpreting providers' informational practices. This version addresses the peer reviewers' comments as follows: 1. We included a statement noting that participants were entered into a lottery draw for an incentive approved by the Research Ethics Board. 2. We acknowledged an additional limitation of the study, stating that the quantitative data is not sufficiently representative of the population of patients seeking ACBT in the U.S. and Canada. 3. We added a statement in the Discussion section acknowledging the reviewer's comment that the nature of the ACBT industry necessitates caution when interpreting providers' informational practices. See the authors' detailed response to the review by Li Du See the authors' detailed response to the review by Yann Joly READ REVIEWER RESPONSES Introduction It has been widely reported in the literature and news media that individuals are seeking and obtaining putative cell-based therapies in advance of regulatory approvals and, in many instances, prior to the availability of any or high-quality evidence 1 , 2 supporting their safety, effectiveness and/or clinical adoption. 3 The first study of this phenomenon, published in 2005, described stem cell-based therapies with little or no evidentiary support offered mainly via online marketing to patients who were willing to travel internationally to receive them. 4 Since then, the phenomenon has evolved into a national and international industry in many jurisdictions, including in countries with highly developed health products regulatory systems, such as Canada, Australia, the European Union, and the United States (U.S.). 5 – 7 Studies have tracked the proliferation of treatment providers in countries around the world serving local and international clientele, 8 using a variety of strategies to reach potential clients, 9 and offering a variety of interventions that are often neither approved by regulators, nor backed by high quality evidence. 10 Studies have also reported on the adverse events associated with these interventions, 11 the experiences of patients who access the treatments, and their reasons for doing so, 11 , 12 provider perspectives, 13 and the evolution of and trends in the industry. 14 The phenomenon has attracted regulatory, legal, ethical and media scrutiny and responses, including sanction by regulators, 15 court challenges, 16 legislative and policy reform, 17 and policy recommendations addressing associated issues and challenges, such as the role of consumer protection and truthful advertising in addressing false therapeutic claims, 18 and healthcare professional involvement and ethics. 19 Some jurisdictions have established or are in the process of establishing legal and regulatory changes designed to clarify and strengthen the framework for regulatory review and marketing authorization of regenerative medicines, which include cell-based therapies. 15 , 19 , 20 These changes respond, in part, to legitimate questions about how to classify and assess these therapies, many of which are innovative and present differently from conventional pharmaceuticals. 21 Regulatory difficulties also arise from claims, usually made by treatment providers that certain cell-based therapies are not within regulatory scope because they are not health products per se, but, rather, are simply medical procedures that utilize cells or cell-based products. 22 – 24 The latter claim is most evident in the regulatory debate surrounding the use of human-derived autologous cells in medical procedures, which is often referred to as “autologous cell-based therapy” (ACBT). Generally, ACBT “involves the removal, some level of manipulation or processing, and re-introduction of a person’s own cells to treat or prevent a disease, disorder or medical condition.” 25 There is mounting evidence of providers applying ACBT for the clinical management of a variety of medical conditions, and especially for osteoarthritis, musculoskeletal disorders, and sports injuries. 26 Jurisdictions such as the U.S., the European Union, Canada and Australia have sought to clarify whether and what cells used in ACBT constitute regulated health products. 27 While the details as to what constitutes a regulated “ACBT product” (i.e., cell or cell-derived material used in ACBT) varies by jurisdiction, some commonalities exist. Generally, some ACBT products are exempt from health product regulation (under certain conditions), while others require full pre-marketing approval under an appropriate regulatory pathway. 17 , 28 , 29 The differences between both categories depends largely on risk classification and in some cases, on whether and to what extent the cells have been manipulated prior to clinical administration. 16 , 30 , 31 However, this increased clarity appears not to have prevented the use of regulated but unapproved and/or unauthorized ACBT products in medical procedures, and there is evidence that patients continue to access such products. 31 – 33 As part of efforts to achieve regulatory compliance, some regulators, such as Health Canada and the Australian Therapeutic Goods Administration, have required treatment providers to conduct clinical trials to obtain evidence to support clinical deployment of various ACBT products. 17 , 34 , 35 This requirement has led to a proliferation of “pay-to-participate” or “pay-to-play” clinical trials, whereby patients seeking ACBT are asked to pay to participate in the trials. 36 , 37 There is also speculation that patients who have paid for what they think is a medical procedure are unwittingly enrolled in what is actually a clinical trial. 38 Both practices, to the extent that they exist, raise serious ethical concerns regarding informed consent, therapeutic misconception (mistaking participation in research as receiving clinical therapy and benefit), and exploitation of vulnerable patients. 39 , 40 In this study, we sought to assess patients’ experiences with and attitudes towards ACBT, and their knowledge regarding associated legal and regulatory matters. The study seeks to provide evidence regarding how and why patients are accessing innovative regenerative medicines in a context that is fraught with scientific, legal, ethical and regulatory uncertainties, questions, and concerns. The study advances and makes two important contributions to the existing literature on questions surrounding the clinical use of cell-based therapy products in the absence of regulatory authorization or high-quality evidentiary support. First, it is the earliest known examination of patient perspectives regarding cell-based therapy products that are within regulatory scope, in the sense that regulators have defined parameters for their authorization and use for clinical research and/or clinical management of medical conditions. Second, the study offers insights on how patients are experiencing the impacts of emerging regulatory frameworks for ACBT products and cell-based therapy products more generally. Both contributions provide a basis for analyzing associated ethical, legal and regulatory concerns, including concerns regarding pay-to-participate trials, informed consent, therapeutic misconception, and regulatory compliance. The study also provides data that different policymaking bodies, including governments, scientific bodies, and health professions regulators, can rely on to develop policies aimed at addressing ethical and regulatory compliance issues, and at improving the clinical experience of patients accessing ACBT. Methods Ethics and consent Ethics approval for this study was granted by the University of Alberta’s Research Ethics Board (Pro00128173). Participants provided full and voluntary consent to participate in the study and to the publication of the anonymous study results via a consent form approved by the University of Alberta’s Research Ethics Board. Participants read the consent form prior to completing the survey, and per the terms of the approved consent form, their consent to participate in the study was implied from the completion of the survey. Participants The study participants included individuals who received or were in the process of receiving treatments involving ACBT. Recruitment was conducted through posts on social media platforms, including Facebook, Twitter, LinkedIn, and Reddit. Survey instrument, administration and response rate The survey instrument explored participants’ knowledge about, perspectives of, and experiences with clinical procedures involving ACBT. The survey included a mix of questions eliciting quantitative and qualitative responses and took approximately 10 minutes to complete. The survey instrument is reproduced in the extended data . 48 The survey was administered via Qualtrics. Data collection occurred for the duration of 11 days (06-17 March 2023). The survey was closed when the response rate reached what we considered optimal for analysis and no new responses had been received for two days. Following data collection, the initial dataset, consisting of 347 responses, was cleaned for analysis. Responses marked by Qualtrics as duplicates ( n = 22), as likely bots ( n = 101), and as both duplicates and likely bots ( n = 5) were deleted from the dataset. Through manual data cleaning, any responses which were completely blank ( n = 18) or had multiple nonsensical text entries were categorised as likely bots ( n = 2) and were deleted from the dataset. We added a screening variable to ensure that participants had received ACBT. Seventeen participants indicated that the treatment they received did not involve taking cells, blood, or tissue from their own body, and one participant did not respond to the variable. We excluded these 18 participants based on the non-response or because it is likely they did not receive ACBT. The final dataset used for our analysis consisted of 181 responses. Among the 181 responses, missing data accounted for 1.3% of the values. As the percentage of missing values was below the 5% threshold that would likely affect the integrity of the dataset, 41 they were ignored in the analysis. For items where participants were asked to “check all that apply”, the total number of responses is reported. The final dataset is available in underlying data . 48 Respondents were entered into a lottery draw for a chance to win a $50 CAD gift card. This incentive was approved by the University of Alberta Research Ethics Board. One respondent won and received the incentive. Data analysis The quantitative survey data were analysed using SPSS 29. Chi-square tests were used to identify patterns in the quantitative data. Qualitative survey responses were analysed by identifying themes emerging from the data using NVivo 1.7.1. The data analyses were not pre-registered. Results Part 1: Summary of participants’ experiences Participants were asked to report what type of ACBT they received, how they learned about it, where and in what facility they received it, which type of treatment provider administered it, why and for what condition they sought it, whether the ACBT was combined with another product, whether it was presented as a clinical trial or as a medical procedure, and whether there were any side effects. They were also asked about payment, including whether and how much they paid for the ACBT, and if and how they were reimbursed for the amount paid, and about whether their treatment provider discussed details with them concerning the purpose of cells being removed from their body and side effects from the ACBT. Of 181 participants, 53 (29.3%) reported that they received an autologous fat transplant, 48 (26.5%) received autologous human fibroblasts, 41 (22.7%) received an autologous serum therapy, 25 (13.8%) received autologous mesenchymal stem cells, and 14 (7.7%) received platelet-rich plasma. Of the 180 participants who responded to the variable regarding how they learned about the ACBT, 78 (43.3%) reported that they learned about the ACBT from the treatment provider, 47 (26.1%) were referred by a physician or clinic other than the treatment provider , 19 (10.6%) learned about it through social media, 16 (8.9%) received a referral from another healthcare provider (other than a physician or clinic), 12 (6.7%) learned about it through a clinic website, 4 (2.2%) through advertisements in a clinic, and 4 (2.2%) by word of mouth. Of 181 participants, public hospitals were the most common treatment facility (42.0%, n = 76), followed by specialists’ clinics (28.7%, n = 52), private hospitals (13.3%, n = 24), family doctors’ clinics (9.9%, n = 18), and walk-in clinics (6.1%, n = 11). Of 179 participants, most reported that their treatment provider was a doctor (89.9%, n = 161), while others reported that their treatment provider was a nurse practitioner (7.8%, n = 14), a nurse (1.7%, n = 3), or a physician assistant (0.6%, n = 1). Among 176 of the participants whose treatment provider was a doctor, their specialty was either in orthopaedics (46.0%, n = 81), sports medicine (31.8%, n = 56), plastic surgery (20.5%, n = 36), oncology (0.6%, n = 1), physiatry (0.6%, n = 1), or chiropractic medicine (0.5%, n = 1). Of 178 participants who responded, the majority received the ACBT in the U.S. (74.7%, n = 133), while the remainder received it in Canada (25.3%, n = 45). When asked to select all that apply, out of 260 selected responses, the reasons for seeking the ACBT varied with 106 (40.8%) participants reporting that their doctor or other healthcare provider recommended it, 82 (31.5%) indicated that they tried other treatments and they didn’t work, 39 (15.0%) indicated it was their only treatment option, 32 (12.3%) reported that a friend or family member recommended it, and 1 (0.4%) indicated that patients with their condition recommended it. Of 180 participants, the majority sought the ACBT for a sports injury (47.2%, n = 85) or osteoarthritis (36.7%, n = 66), while others sought it for cosmetic reasons (12.2%, n = 22) or other conditions (3.9%, n = 7). Three-quarters (76.2%, n = 138) of 181 participants reported that the ACBT was combined with another product, such as a medical device. The remainder of participants did not have an ACBT that was combined with another product (21.0%, n = 38) or were unsure (2.8%, n = 5). Of 181 participants, most reported that the ACBT was presented as a medical procedure (70.2%, n = 127), 45 (24.9%) participants reported that it was presented as a clinical trial, and 9 (5.0%) participants were unsure. Of 181 participants, 170 (93.9%) reported that the purpose of removing the cells, blood, or tissue from their body was explained to them, while 11 (6.1%) indicated that the purpose was not explained. Of 181 participants, while most did not report experiencing any side effects from the ACBT (60.2%, n = 109), 72 (39.8%) reported that they experienced side effects. Of 181 participants, the majority (86.7%, n = 157) indicated that the treatment provider informed them about any possible side effects. The remainder of participants either indicated that the treatment provider did not inform them (3.9%, n = 7) or that they didn’t remember (9.4%, n = 17). Of 181 participants, the vast majority reported paying for the ACBT (92.8%, n = 168), while 10 (5.5%) reported that they didn’t pay, and 3 (1.7%) didn’t remember. Among all of the participants who paid, most paid $100-$499 (39.9%, n = 67) or $500-$999 (32.7%, n = 55), while 37 (22.0%) paid $1000 or more. Only 9 (5.4%) paid $99 or less. All amounts were reported in Canadian Dollars. Among all of the participants who paid, 61 (36.3%) were reimbursed and 74 (44.0%) paid out-of-pocket. Thirty-three participants (19.6%) reported both being reimbursed and paying out-of-pocket. Out of 132 selected responses among those who received some degree of reimbursement, when asked to select all that apply, 61 (46.2%) participants indicated that they were reimbursed by government (public) health insurance, while 50 (37.9%) were reimbursed by private insurance through their employer, and 21 (15.9%) were reimbursed by private insurance not through their employer. Part 2: Knowledge of regulation of the treatment Participants indicated their knowledge of who the ACBT is regulated by and the evidence for the ACBT. They also reported whether their treatment provider discussed these details with them. Participants rated their confidence in knowing who to contact if they would like to make a complaint regarding the ACBT and shared their knowledge of who to contact. Of 176 participants, most indicated that the treatment provider discussed with them how the ACBT is regulated (88.6%, n = 156), while 8 (4.5%) participants indicated that it was not discussed, and 12 (6.8%) participants didn’t remember. When asked to select all that apply, out of 360 selected responses, 89 (24.7%) participants indicated that, to the best of their knowledge, the ACBT is regulated by a provincial medical regulatory authority, 88 (24.4%) indicated a provincial ministry of health, 77 (21.4%) indicated a federal regulatory authority, 41 (11.4%) indicated a federal medical regulatory authority, 31 (8.6%) indicated a research ethics board, 21 (5.8%) were unsure, and 13 (3.6%) indicated that there is no regulatory authority. In the event that they would like to make a complaint regarding the ACBT, 170 participants reported an average of 70.2% ( SD = 21.2) confidence in knowing who to contact. When asked to select all that apply, out of 361 selected responses, most participants indicated that they would contact the clinic where they received the treatment procedure (37.4%, n = 135), 100 (27.7%) indicated a government regulator, 75 (20.8%) a research ethics board, and 51 (14.1%) the professional regulator. Of 180 participants, while 165 (91.7%) indicated that the treatment provider explained to them the evidence for the ACBT, 7 (3.9%) indicated that they did not, and 8 (4.4%) didn’t remember whether or not this was explained. When asked to select all that apply, to the best of their knowledge, out of 438 selected responses, 121 (27.6%) participants indicated that the evidence for the ACBT was the treatment provider’s clinical experience, 111 (25.3%) indicated peer-reviewed scientific research, 97 (22.1%) indicated patient testimonials, 64 (14.6%) indicated randomised controlled trials, and 45 (10.3%) indicated regulatory approval. Part 3: Participants’ perceptions of the clinical encounter Participants reported whether they thought the ACBT should be provided without going through clinical trials or regulation and why or why not. They indicated whether they would recommend the ACBT and treatment procedure to someone else. Participants were asked whether and how their perception of the ACBT would change if they were to learn that it did not go through clinical trials and was not approved by a regulator. Of 179 participants, 74 (41.3%) indicated that they thought the ACBT should be provided without going through clinical trials or regulation and 105 (58.7%) disagreed. Participants provided 81 unique short answer text responses that expanded on their views. Sixteen of the participants who indicated that the ACBT should be provided without going through clinical trials or regulation provided reasons that were coded as relating to their beliefs (62.5%, n = 10), feelings (18.8% n = 3), subjective experiences (12.5% n = 2), or perspectives (6.3% n = 1). Among participants who shared their beliefs, 4 participants had beliefs regarding clinical trials, including the possibility of being assigned to a control group if they participate in a clinical trial and concerns about missing the best time for treatment given the lengthiness of clinical trials and regulatory approval. The remaining 6 participants were divided regarding whether they believed safety was a concern for ACBT. One participant expressed their feelings around the lack of safety, while two participants did not feel as though there is anything wrong with the ACBT. Two participants shared subjective experiences of the ACBT having helped them and one shared a perspective of wanting to give it a try regardless of undergoing clinical trials or regulatory approval. Of the participants who thought that the ACBT should not be provided without going through clinical trials or regulation, 57 shared reasons that were coded as relating to their beliefs (77.2%, n = 44), feelings (17.5%, n = 10), perspectives (3.5%, n = 2), or subjective experience (1.8%, n = 1). Safety was their primary concern. Participants mentioned safety both with regards to their beliefs about the role of clinical trials and regulation in determining safety ( n = 23) and with regards to their subjective feelings of security and reassurance ( n = 10). Participants also expressed that their responses stemmed from their beliefs regarding the professionalism of healthcare providers in upholding the rigour of medicine ( n = 13) and the importance of regulation for ensuring accountability and reliability ( n = 4). The remaining 4 participants shared beliefs regarding the role of clinical trials in ensuring efficacy, systemic responsibility for people’s health, and a belief that the technology is immature. Two participants shared their perspectives of not wanting to be tested on and one participant mentioned a subjective experience of pain. Of 180 participants, most indicated that they would recommend the ACBT to someone else (77.8%, n = 140), while 40 participants (22.2%) indicated that they would not recommend it. Of 180 participants, the majority indicated that if they were to learn that the ACBT they received did not go through clinical trials and was not approved by a regulator, it would change their perception of the ACBT (85.6%, n = 154), while the remainder (14.4%, n = 26) indicated that it would not change their perception of the ACBT. Of these participants, 85 followed up with unique short answer text responses to share how their perceptions would change or not change. Among 67 of the participants who indicated that their perception would change, their reasons were coded to be rooted in their beliefs (50.7%, n = 34), feelings (28.4%, n = 19), perspectives (14.9%, n = 10) or subjective experiences (6.0%, n = 4). Participants shared their beliefs regarding safety concerns ( n = 18) and the lack of other treatments for their condition ( n = 6). The remaining 10 participants shared beliefs of uncertainty about the efficacy of ACBT and high risk in the absence of regulation and in the absence of clinical trials. Participants expressed their feelings of uncertainty regarding ACBT safety ( n = 15) and concerns around efficacy ( n = 4). Ten participants shared their perspectives regarding hesitation to receive ACBT and four participants based their response on their subjective experiences, including having tried many other treatments or the ACBT being the only available treatment option. Among 13 of the participants who indicated that their perception would not change, their reasons were coded as relating to their beliefs (38.5%, n = 5), perspectives (23.1%, n = 3), awareness (15.4%, n = 2), subjective experiences (15.4%, n = 2), or feelings (7.7%, n = 1). Participants’ beliefs included the lack of other options and were divided regarding the safety of the ACBT. The remainder of participants expressed their perspectives regarding the risk of missing the best time for treatment, their subjective experiences of having tried other treatments that were unsuccessful, and the efficacy of the ACBT. Association between study variables depending on whether participants reported involvement in a clinical trial versus a medical procedure Chi-square analyses identified statistically significant associations between several variables and the variable regarding whether participants received the ACBT as part of a clinical trial or a medical procedure. The facility where participants received the treatment procedure varied depending on whether they indicated receiving it as part of a clinical trial, or as a medical procedure, or were unsure, X 2 (8, 181) = 39.73, p < .001. Among participants who reported receiving the ACBT as part of a clinical trial, 18 (40.0%) reported received it in a specialist’s clinic, 11 (24.4%) in a family doctor’s clinic, 6 (13.3%) in a public hospital, 5 (11.1%) in a private hospital, and 5 (11.1%) in a walk-in clinic. Participants who reported receiving the ACBT as a medical procedure were most likely to receive it in a public hospital (53.5%, n = 68), followed by 32 (25.2%) in a specialist’s clinic, 16 (12.3%) in a private hospital, 7 (5.5%) in a family doctor’s clinic, and 4 (3.1%) in a walk-in clinic. Participants who received the ACBT as part of a clinical trial or as a medical procedure varied in whether the treatment provider discussed with them how the ACBT is regulated, χ 2 (4, 176) = 10.80, p = .029. The majority of participants who indicated that they received the ACBT as part of a clinical trial reported having this information discussed with them (86.4%, n = 38), while 5 (11.4%) did not have this information discussed with them and 1 (2.3%) did not remember whether or not it was discussed. Participants who indicated that they received the ACBT as a medical procedure and reported having this information discussed with them were also in the majority (90.2%, n = 111), while 3 (2.4%) did not have this information discussed with them and 9 (7.3%) did not remember whether or not it was discussed. Based on whether they reported having received the ACBT within a clinical trial or as a medical procedure, participants differed in whether they thought the ACBT should be provided without going through clinical trials or regulation, χ 2 (2, 179) = 20.40, p < .001. Participants who indicated that they received the ACBT as part of a clinical trial were more likely to think that ACBT should be provided without going through clinical trials or regulation (70.5%, n = 31) than participants who indicated that they received the treatment procedure as a medical procedure (31.7%, n = 40; Figure 1A ). The same participants differed in whether they would recommend the ACBT to someone else, χ 2 (2, 180) = 8.11, p = .017. Participants who indicated that they received the ACBT within a clinical trial were less likely to indicate that they would recommend the ACBT (63.6%, n = 28) than participants who indicated that they received the ACBT as a medical procedure (83.5%, n = 106; Figure 1B ). Based on whether they reported having received the ACBT within a clinical trial or as a medical procedure, participants differed in whether their perception of the ACBT they received would change if they learned that the ACBT did not go through clinical trials and was not approved by a regulator, χ 2 (2, 180) = 21.76, p < .001. Participants who indicated that they received the ACBT as part of a clinical trial were less likely to indicate that their perception would change (84.1%, n = 37) than participants who indicated that they received the ACBT as a medical procedure (89.8%, n = 114; Figure 1C ). Figure 1. Perspectives on ACBT based on whether participants received it by clinical trial or by medical procedure. Non-significant statistical analyses were found between whether the ACBT was presented within a clinical trial or as a medical procedure and what type of ACBT participants received, how participants learned about the ACBT, who the treatment provider was, in what country they received the ACBT, whether or not the treatment provider informed them about any possible side effects of the ACBT, whether and how much they paid for the ACBT, whether the payment for the ACBT was reimbursed or paid out-of-pocket, and whether the evidence for the ACBT was explained. Association between study variables depending on whether participants reported having paid and or not paid for the ACBT Chi-square analyses also revealed that participants differed based on whether or not they paid for the ACBT. Participants’ reports of whether or not they paid for the ACBT varied with the condition for which they sought treatment, χ 2 (6, 180) = 13.04, p = .042. Among participants who reported that they paid for the ACBT, 81 (48.5%) participants indicated that they sought treatment for a sports injury, 60 (35.9%) participants indicated that they sought treatment for osteoarthritis, 20 (12.0%) sought a cosmetic treatment, and 6 (3.6%) sought other treatments. Among participants who reported that they did not pay for the ACBT, 6 (60.0%) indicated that they sought treatment for osteoarthritis, 3 (30.0%) sought treatment for a sports injury, and 1 (10.0%) sought another treatment. Participants who paid for the ACBT also differed from participants who did not pay with regards to whether their treatment provider discussed with them how the ACBT is regulated, χ 2 (4, 176) = 48.99, p < .001. Participants who indicated that they paid for the ACBT were more likely to indicate that the treatment provider discussed with them how the ACBT is regulated (92.0%, n = 150) than participants who indicated that they did not pay for the ACBT (30.0%, n = 3). Participants who paid for the ACBT differed from participants who did not pay with regards to whether or not they would recommend the ACBT to someone else, χ 2 (2, 180) = 12.59, p = .002. Among participants who reported paying for the ACBT, 135 (80.8%) indicated that they would recommend the ACBT, while 4 (40.0%) participants who did not pay for the ACBT agreed with these views. Statistically non-significant results were found for analyses between whether or not participants paid for the ACBT and the type of ACBT they received, the facility where they received the ACBT, who the treatment provider was, in what country they received the ACBT, whether they thought the ACBT should be provided without going through clinical trials or regulation, and whether their perceptions of the ACBT would change if they learned that the ACBT they received did not go through clinical trials and was not approved by a regulator. Discussion This study surveyed participants who have received ACBT regarding their experiences, knowledge of the regulation and governance of ACBT, and perspectives of the clinical encounter. It explored issues pertaining to pay-to-participate trials, informed consent, and regulatory compliance. Several themes emerged from the data, including the prominent role of healthcare providers throughout the patient journey, informational practices during the clinical encounter, the high prevalence of pay-to-participate trials, patients’ gaps in regulatory knowledge, and patients’ priorities regarding clinical trials and regulation of ACBT. The role of healthcare providers The most commonly reported source through which participants learned about the ACBT was healthcare providers, with other sources such as clinic advertisements and websites, and social media playing a comparatively minor role. Treatment providers were mainly physicians. Our findings highlight the critical role of healthcare providers in providing patients with access to and information about the ACBT. Together, these findings suggest that physicians and healthcare providers play a key role in the patient journey and are at the forefront of the ACBT industry. These findings are consistent with previous studies that report the involvement of physicians in the clinical use and marketing of stem cell therapies ahead of regulatory authorization and supporting evidence. 42 , 43 Informational practices during the clinical encounter Although it is not clear from the survey findings what specific side effects participants were informed about, the finding that the majority of participants were informed by their treatment providers about these side effects is encouraging as it indicates that treatment providers are cognizant of the need to discuss side effects that may be associated with an emerging therapy. The finding that the majority of the participants reported that their treatment providers discussed how ACBTs are regulated and the evidence for the treatment with them strengthens this conclusion. The latter indicates that providers recognize that the evidentiary and regulatory context for ACBT are an important point of emphasis for an emerging therapy that is receiving much social, scientific and regulatory attention and scrutiny. This is supported by our findings that patient perspectives are primarily driven by their beliefs about ACBT. A noteworthy caution is that the study did not assess the quality or accuracy of the information shared and discussed with participants. Medical regulatory authorities may be important for ensuring medical education for healthcare providers on providing and informing patients about ACBT. It is also important to note that questions regarding the legitimacy of clinical offerings and practices related to ACBT may make the findings concerning clinicians’ informational practices less reassuring. Additionally, the nature of the ACBT industry necessitates caution when interpreting the findings related to providers’ informational practices. 1 Medical procedures as the primary means of receiving ACBT The finding that the majority of participants reported that the treatment was presented as a medical procedure rather than a clinical trial is a signal to health product regulators regarding how the industry is operating. Given the push by regulators in some jurisdictions for clinical trials [ Health Canada Policy Position Paper – Autologous Cell Therapy Products ] and that the evidentiary and regulatory status of ACBTs remains unclear, it might also serve to alert health products and health professional regulators of the need to work together to ensure that treatment providers are complying with the requirement to conduct clinical trials for treatments that are not established scientifically. Reimbursement of payment for ACBT The finding that some participants received reimbursement for treatment expenses from public and private health insurers is noteworthy as it suggests that insurers view ACBT as beneficial. In maintaining and expanding insurance coverage, care should be taken to align coverage with health technology assessments that weigh the cost of ACBT with its health and economic impacts, even in light of scientific support and regulatory approval. 44 Pay-to-participate trials Although the majority of participants in the study received ACBT as a medical procedure, a significant number reported having received the ACBT in a clinical trial in which they paid to participate (91.1%, n = 41). Of these, all but one participant paid $100 or more (97.6%, n = 40) and 21 (51.2%) participants paid out-of-pocket without any reimbursement. Pay-to-participate clinical trials raise a number of ethical concerns, including the skewing of clinical trial funding towards conditions affecting the wealthy, the exploitation of participants’ desire for a treatment, and compromising the scientific integrity of clinical trials. 45 – 47 These concerns may be acute in the context of ACBT given that the majority of treatment providers are clinicians who may not ordinarily conduct clinical trials and are presumably only doing so mainly for purposes of regulatory compliance. Our findings suggest that regulators ought to be mindful of the ethical issues that may arise from regulatory enforcement initiatives, especially as they impact patient access to care and the conditions under which such care is received. Gaps in regulatory knowledge While participants who received the ACBT as a medical procedure were more likely to think that it should go through clinical trials or receive regulatory approval before being provided, they also indicated that their perception of the treatment would change if they learned it had not gone through clinical trials or received regulatory approval. These responses suggest an assumption among participants that ACBT provided as medical procedures are under the purview of a regulatory body. Participants expressed a wide variability in what type of regulatory body they thought was responsible for regulating ACBT, with only a minority of them (21.4%, n = 77) correctly indicating that a federal regulatory authority (Health Canada and/or the US FDA) was responsible. Designing the regulatory system to be consistent with patients’ expectations of regulatory oversight therefore represents an important step in maintaining the trust of patients in ACBT. Improving clinical trials and regulations Safety emerged as a major theme of concern among participants, suggesting a public expectation for regulatory initiatives to prioritize safety. Regulations that address safety concerns may therefore be more likely to receive public support. Limitations While the use of an anonymous online survey had several advantages, including quick data collection from a broad sample of patients and minimization of self-reporting bias, these methods also limited our certainty in the authenticity of responses. The use of lottery draws may incentivize invalid responses for monetary gain. To minimize these risks, we removed any likely bot or duplicate responses from our analyses. Lastly, the quantitative data reported in this study is not sufficiently representative of the population of patients seeking ACBT in the U.S. and Canada. Therefore, the data should not be interpreted as generalizable to this population. Conclusion and future directions The study makes a novel contribution to the literature by providing the first analysis of patients’ experiences and perceptions of an emerging cell-based therapy within an evolving regulatory landscape. The findings serve as a valuable resource for developing policy, promoting scientific rigor, and ensuring ethical oversight of ACBT and other upcoming cell-based therapies. The study also highlights participants’ prioritization of the safety of ACBT while identifying critical gaps in their regulatory knowledge. Their experiences, knowledge, and perspectives provide critical insights towards the advancement of regulations pertaining to ACBT in Canada and the U.S. The important role of healthcare providers in how participants are informed about and receive ACBT warrants the involvement of provincial and state medical regulatory authorities in the regulation and enforcement of standards around informed consent, particularly among ACBT that are being provided as medical procedures. Conducting research on healthcare providers to explore their informed consent processes and pricing structure more thoroughly for ACBT may support recommendations for their regulation. To this end, our team is currently conducting a complementary study based on interviews with clinicians and clinical researchers who have sponsored ACBT in clinical trials in Canada and Australia. Our amplification of the patient voice by assessing their experiences, knowledge, and perspectives contributes a patient-centred perspective to the advancement of regulations pertaining to ACBT. Data availability Underlying data Open Science Framework: Clinical Use of Autologous Cell-Based Therapies in an Evolving Regulatory Landscape: A Survey of Patient Experiences and Perceptions (Dataset and Survey Questionnaire), https://doi.org/10.17605/OSF.IO/7RSJX . 48 This project contains the following underlying data: - S2 Appendix - Dataset.xlsx Extended data Open Science Framework: Clinical Use of Autologous Cell-Based Therapies in an Evolving Regulatory Landscape: A Survey of Patient Experiences and Perceptions (Dataset and Survey Questionnaire), https://doi.org/10.17605/OSF.IO/7RSJX . 48 This project contains the following extended data: - S1 Appendix - Survey.pdf Data are available under the terms of the Creative Commons Attribution 4.0 International license (CC-BY 4.0). Acknowledgments The authors thank Amy Zarzeczny and Timothy Caulfield for their feedback on the design of the survey and for reviewing a draft manuscript. We are also grateful to the participants who shared their experiences, knowledge, and perspectives. References 1. Turner L: The US direct-to-consumer marketplace for autologous stem cell interventions: portrayal of therapies, risks, and benefits. Regen. Med. 2018; 13 (6): 725–736. 2. Bianco P: Don’t market stem-cell products ahead of proof. Nature. 2013; 499 : 255. Publisher Full Text 3. Knoepfler PS: From bench to FDA to bedside: US regulatory trends for new stem cell therapies. Adv. Drug Deliv. Rev. 2014; 82-83 : 192–196. Publisher Full Text 4. Lau D, Ogbogu U, Taylor B, et al. : Stem cell clinics online: the direct-to-consumer portrayal of stem cell medicine. Cell Stem Cell. 2008; 3 (6): 591–594. PubMed Abstract | Publisher Full Text 5. McLean AK, Stewart C, Kerridge I: Untested, unproven, and unethical: the promotion and provision of autologous stem cell therapies in Australia. Stem Cell Res Ther. 2015; 6 : 33. PubMed Abstract | Publisher Full Text | Free Full Text 6. Ghasroldasht MM, Seok J, Park HS, et al. : Stem cell therapy: From idea to clinical practice. Int. J. Mol. Sci. 2022; 23 (5): 2850. PubMed Abstract | Publisher Full Text | Free Full Text 7. Li MD, Atkins H, Bubela T: The global landscape of stem cell clinical trials. Regen. Med. 2014; 9 (1): 27–39. PubMed Abstract | Publisher Full Text 8. Sipp D, Caulfield T, Kaye J, et al. : Marketing of unproven stem cell–based interventions: A call to action. Sci. Transl. Med. 2019; 11 (498): 0426. 9. Connolly R, O’Brien T, Flaherty G: Stem cell tourism—a web-based analysis of clinical services available to international travellers. Travel Med. Infect. Dis. 2014; 12 (6): 695–701. PubMed Abstract | Publisher Full Text 10. Lysaght T, Lipworth W, Hendl T, et al. : The deadly business of an unregulated global stem cell industry. J. Med. Ethics. 2017; 43 (11): 744–746. Publisher Full Text 11. Berger I, Ahmad A, Bansal A, et al. : Global distribution of businesses marketing stem cell-based interventions. Cell Stem Cell. 2016; 19 (2): 158–162. Publisher Full Text 12. Master Z, Robertson K, Frederick D, et al. : Stem cell tourism and public education: the missing elements. Cell Stem Cell. 2014; 15 (3): 267–270. Publisher Full Text 13. McMahon DS, Singer PA, Daar AS, et al. : Regenerative medicine in Brazil: small but innovative. Regen. Med. 2014; 5 (5): 749–761. 14. Zarzeczny A, Rachul C, Nisbet M, et al. : Stem cell clinics in the news. Nat. Biotechnol. 2010; 28 (12): 1243–1246. Publisher Full Text 15. Sipp D: The unregulated commercialization of stem cell treatments: a global perspective. Front. Med. 2011; 5 : 348–355. Publisher Full Text 16. Cyranoski D: FDA challenges stem-cell clinic. Nature. 2010; 466 (7309): 909–910. PubMed Abstract | Publisher Full Text 17. Caulfield T, Murdoch B: Regulatory and policy tools to address unproven stem cell interventions in Canada: the need for action. BMC Med. Ethics. 2019; 20 : 1–7. 18. Turner L, Knoepfler P: Selling Stem Cells in the USA: Assessing the Direct-to-Consumer Industry. Cell Stem Cell. 2016; 19 (2): 154–157. PubMed Abstract | Publisher Full Text 19. Zarzeczny A, Clark M: Unproven stem cell-based interventions & physicians’ professional obligations; a qualitative study with medical regulatory authorities in Canada. BMC Med. Ethics. 2014; 15 : 1–10. 20. Levine AD: Policy uncertainty and the conduct of stem cell research. Cell Stem Cell. 2020; 6 (1): 20–24. 21. Cyranoski D: Korean deaths spark inquiry. Nature. 2019; 468 (7323): 485. Publisher Full Text 22. Sipp D, Turner L: U.S. regulation of stem cells as medical products. Science. 2012; 338 (6112): 1296–1297. Publisher Full Text 23. Cyranoski D: Stem cells cruise to clinic. Nature. 2013; 494 (7438): 413. Publisher Full Text 24. Cyranoski D: Stem cells boom in vet clinics. Nature. 2012; 488 (7411): 272–273. 25. Marks P, Gottlieb S: Balancing safety and innovation for cell-based regenerative medicine. N. Engl. J. Med. 2018; 378 (10): 954–959. Publisher Full Text 26. Shapiro SA, Kazmerchak SE, Heckman MG, et al. : A prospective, single-blind, placebo-controlled trial of bone marrow aspirate concentrate for knee osteoarthritis. Am. J. Sports Med. 2017; 45 (1): 82–90. PubMed Abstract | Publisher Full Text 27. Daley GQ, Hyun I, Apperley JF, et al. : Setting global standards for stem cell research and clinical translation: The 2016 ISSCR guidelines. Stem Cell Reports. 2016; 6 (6): 787–797. PubMed Abstract | Publisher Full Text | Free Full Text 28. Jasanoff S, Hurlbut JB: A global observatory for gene editing. Nature. 2018; 555 (7697): 435–437. Publisher Full Text 29. Hourd P, Chandra A, Medcalf N, et al. : Regulatory challenges for the manufacture and scale-out of autologous cell therapies. Int. J. Biomed. Health Sci. 2021; 10 (4). 30. Von Tigerstrom B: Revising the regulation of stem cell-based therapies: critical assessment of potential models. Food Drug Law J. 2015; 70 : 315. 31. Zarzeczny A, Atkins H, Illes J, et al. : The stem cell market and policy options: a call for clarity. J. Law Biosci. 2018; 5 (3): 743–758. PubMed Abstract | Publisher Full Text | Free Full Text 32. Turner L: US stem cell clinics, patient safety, and the FDA. Trends Mol. Med. 2017; 23 (7): 583–586. 33. Daley GQ, Hyun I: The International Society for Stem Cell Research (ISSCR) guidelines for stem cell research and clinical translation. Sci. Transl. Med. 2016; 8 : 341–343. 34. Chisholm J, Ruff C, Viswanathan S: Current state of Health Canada regulation for cellular and gene therapy products: potential cures on the horizon. Cytotherapy. 2019; 21 (7): 686–698. PubMed Abstract | Publisher Full Text 35. Bell R: Australian cellular therapy regulations. Cell Therapy: cGMP Facilities and Manufacturing. 2022; pp. 57–71. Publisher Full Text 36. Master Z, Resnik DB: Hype and public trust in science. Sci. Eng. Ethics. 2013; 19 (2): 321–335. PubMed Abstract | Publisher Full Text | Free Full Text 37. Turner L: Preying on public fears and anxieties in a pandemic: Businesses selling unproven and unlicensed “stem cell treatments” for COVID-19. Cell Stem Cell. 2020; 26 (6): 806–810. PubMed Abstract | Publisher Full Text | Free Full Text 38. Hyun I, Lindvall O, Ahrlund-Richter L, et al. : New ISSCR guidelines underscore major principles for responsible translational stem cell research. Cell Stem Cell. 2008; 3 (6): 607–609. PubMed Abstract | Publisher Full Text 39. Caulfield T, McGuire A, Cho M, et al. : Research ethics recommendations for whole-genome research: consensus statement. PLoS Biol. 2008; 6 (3): e73. PubMed Abstract | Publisher Full Text | Free Full Text 40. Werner M, Mayleben T, Bokkelen GV: Autologous cell therapies: the importance of regulatory oversight. Regen. Med. 2012; 7 (6 Suppl): 100–103. PubMed Abstract | Publisher Full Text 41. Tabachnick BG, Fidell LS: Using multivariate statistics. 6th ed.Upper Saddle River: Pearson Education Inc.; 2013. 42. Ogbogu U, Du J, Koukio Y: The involvement of Canadian physicians in promoting and providing unproven and unapproved stem cell interventions. BMC Med. Ethics. 2018; 19 (32): 32. PubMed Abstract | Publisher Full Text | Free Full Text 43. Murdoch B, Zarzeczny A, Caulfield T: Exploiting science? A systematic analysis of complementary and alternative medicine clinic websites’ marketing of stem cell therapies. BMJ Open. 2018; 8 : e019414. PubMed Abstract | Publisher Full Text | Free Full Text 44. Driscoll D, Farnia S, Kefalas P, et al. : Concise review: The high cost of high tech medicine: Planning ahead for market access. Stem Cells Transl. Med. 2017; 6 : 1723–1729. PubMed Abstract | Publisher Full Text | Free Full Text 45. Turner L, Snyder J: Ethical issues concerning a pay-to-participate stem cell study. Stem Cells Transl. Med. 2021; 10 : 815–819. PubMed Abstract | Publisher Full Text | Free Full Text 46. Emanuel EJ, Joffe S, Grady C, et al. : Clinical research: Should patients pay to play? Sci. Transl. Med. 2015; 7 (298): 1–5. Publisher Full Text 47. Wenner DM, Kimmelman J, London AJ: Forum Patient-Funded Trials: Opportunity or Liability? Cell Stem Cell. 2015; 17 (2): 135–137. Publisher Full Text 48. Ogbogu U, Case N: Clinical Use of Autologous Cell-Based Therapies in an Evolving Regulatory Landscape: A Survey of Patient Experiences and Perceptions (Dataset and Survey Questionnaire). [Dataset]. 2023, August 8. Publisher Full Text Footnotes 1 We are grateful to Yann Joly, one of the peer reviewers, for this insight. Comments on this article Comments (0) Version 2 VERSION 2 PUBLISHED 18 Sep 2023 ADD YOUR COMMENT Comment Author details Author details 1 Faculty of Law, University of Alberta, Edmonton, Alberta, T6G2H5, Canada Ubaka Ogbogu Roles: Conceptualization, Data Curation, Formal Analysis, Funding Acquisition, Investigation, Methodology, Project Administration, Resources, Software, Supervision, Validation, Visualization, Writing – Original Draft Preparation, Writing – Review & Editing Nevicia Case Roles: Data Curation, Formal Analysis, Investigation, Methodology, Project Administration, Validation, Visualization, Writing – Original Draft Preparation, Writing – Review & Editing Competing interests No competing interests were disclosed. Grant information This study received funding from the Stem Cell Network. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. Article Versions (2) version 2 Revised Published: 27 Aug 2024, 12:1165 https://doi.org/10.12688/f1000research.141002.2 version 1 Published: 18 Sep 2023, 12:1165 https://doi.org/10.12688/f1000research.141002.1 Copyright © 2024 Ogbogu U and Case N. This is an open access article distributed under the terms of the Creative Commons Attribution License , which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. Download Export To Sciwheel Bibtex EndNote ProCite Ref. Manager (RIS) Sente metrics Views Downloads F1000Research - - PubMed Central info_outline Data from PMC are received and updated monthly. - - Citations open_in_new 0 open_in_new 0 open_in_new SEE MORE DETAILS CITE how to cite this article Ogbogu U and Case N. Clinical use of autologous cell-based therapies in an evolving regulatory landscape: A survey of patient experiences and perceptions [version 2; peer review: 2 approved] . F1000Research 2024, 12 :1165 ( https://doi.org/10.12688/f1000research.141002.2 ) NOTE: If applicable, it is important to ensure the information in square brackets after the title is included in all citations of this article. COPY CITATION DETAILS track receive updates on this article Track an article to receive email alerts on any updates to this article. TRACK THIS ARTICLE Share Open Peer Review Current Reviewer Status: ? Key to Reviewer Statuses VIEW HIDE Approved The paper is scientifically sound in its current form and only minor, if any, improvements are suggested Approved with reservations A number of small changes, sometimes more significant revisions are required to address specific details and improve the papers academic merit. Not approved Fundamental flaws in the paper seriously undermine the findings and conclusions Version 2 VERSION 2 PUBLISHED 27 Aug 2024 Revised Views 0 Cite How to cite this report: Joly Y. Reviewer Report For: Clinical use of autologous cell-based therapies in an evolving regulatory landscape: A survey of patient experiences and perceptions [version 2; peer review: 2 approved] . F1000Research 2024, 12 :1165 ( https://doi.org/10.5256/f1000research.170536.r317354 ) The direct URL for this report is: https://f1000research.com/articles/12-1165/v2#referee-response-317354 NOTE: it is important to ensure the information in square brackets after the title is included in this citation. Close Copy Citation Details Reviewer Report 18 Oct 2024 Yann Joly , McGill University, Montreal, QC, Canada Approved VIEWS 0 https://doi.org/10.5256/f1000research.170536.r317354 I accept this manuscript ... Continue reading READ ALL I accept this manuscript without reservation for indexing. Competing Interests: No competing interests were disclosed. I confirm that I have read this submission and believe that I have an appropriate level of expertise to confirm that it is of an acceptable scientific standard. Close READ LESS CITE CITE HOW TO CITE THIS REPORT Joly Y. Reviewer Report For: Clinical use of autologous cell-based therapies in an evolving regulatory landscape: A survey of patient experiences and perceptions [version 2; peer review: 2 approved] . F1000Research 2024, 12 :1165 ( https://doi.org/10.5256/f1000research.170536.r317354 ) The direct URL for this report is: https://f1000research.com/articles/12-1165/v2#referee-response-317354 NOTE: it is important to ensure the information in square brackets after the title is included in all citations of this article. COPY CITATION DETAILS Report a concern Respond or Comment COMMENT ON THIS REPORT Views 0 Cite How to cite this report: Du L. Reviewer Report For: Clinical use of autologous cell-based therapies in an evolving regulatory landscape: A survey of patient experiences and perceptions [version 2; peer review: 2 approved] . F1000Research 2024, 12 :1165 ( https://doi.org/10.5256/f1000research.170536.r317355 ) The direct URL for this report is: https://f1000research.com/articles/12-1165/v2#referee-response-317355 NOTE: it is important to ensure the information in square brackets after the title is included in this citation. Close Copy Citation Details Reviewer Report 10 Sep 2024 Li Du , University of Macau, Macau, China Approved VIEWS 0 https://doi.org/10.5256/f1000research.170536.r317355 I would like to express my thanks for the authors' ... Continue reading READ ALL I would like to express my thanks for the authors' explanations and revisions. I am satisfied with this revised version. Competing Interests: No competing interests were disclosed. I confirm that I have read this submission and believe that I have an appropriate level of expertise to confirm that it is of an acceptable scientific standard. Close READ LESS CITE CITE HOW TO CITE THIS REPORT Du L. Reviewer Report For: Clinical use of autologous cell-based therapies in an evolving regulatory landscape: A survey of patient experiences and perceptions [version 2; peer review: 2 approved] . F1000Research 2024, 12 :1165 ( https://doi.org/10.5256/f1000research.170536.r317355 ) The direct URL for this report is: https://f1000research.com/articles/12-1165/v2#referee-response-317355 NOTE: it is important to ensure the information in square brackets after the title is included in all citations of this article. COPY CITATION DETAILS Report a concern Respond or Comment COMMENT ON THIS REPORT Version 1 VERSION 1 PUBLISHED 18 Sep 2023 Views 0 Cite How to cite this report: Joly Y. Reviewer Report For: Clinical use of autologous cell-based therapies in an evolving regulatory landscape: A survey of patient experiences and perceptions [version 2; peer review: 2 approved] . F1000Research 2024, 12 :1165 ( https://doi.org/10.5256/f1000research.154413.r292492 ) The direct URL for this report is: https://f1000research.com/articles/12-1165/v1#referee-response-292492 NOTE: it is important to ensure the information in square brackets after the title is included in this citation. Close Copy Citation Details Reviewer Report 03 Jul 2024 Yann Joly , McGill University, Montreal, QC, Canada Approved with Reservations VIEWS 0 https://doi.org/10.5256/f1000research.154413.r292492 This manuscript presents an interesting study of patient experiences and perceptions of autologous cell-based therapy (ACBT) procedures. The piece is clear and well written it is informative of the type of patients interested in these procedures in North America, and ... Continue reading READ ALL This manuscript presents an interesting study of patient experiences and perceptions of autologous cell-based therapy (ACBT) procedures. The piece is clear and well written it is informative of the type of patients interested in these procedures in North America, and about the procedures themselves. The context information provided, while succinct, is recent and accurate. It is surprising to me that the authors did not choose to collect a minimal set of demographic information about their respondents, age range, sex, education level, for example, which would have provided a much richer dataset. In the same vein, it is unclear whether they retained the information about countries of origin (U.S., Canada). If they did, it was not included in the analysis parameters they used. Given that the survey was anonymous, were the authors able to filter out potential duplicates? (Participants that may have responded twice or more to the questionnaire). Were respondents compensated for their responses or was the contribution non remunerated? I would have also liked to have more information on whether the quantitative data obtained was statistically significant or sufficiently representative of the U.S./Canadian population of patients seeking ACBT. This seems unlikely and it would be important to disclose this study limitation. In the discussion section, the authors make the most of their data providing interesting interpretations and inferences for their results. I have some reserve about the positive inference made by the authors about international practices during the clinical encounter. The fact that service providers participating in a generally fraudulent practice, can speak to some of its basic regulatory and mechanistic concepts with customers is hardly reassuring, it simply makes their otherwise false representations more believable to them. The findings about the (growing?) importance of the pay-to-participate type of stem cell clinical trials and, that of reimbursement payments for ACBT procedures are much more interesting and warrant further exploration. In sum a good short manuscript, to keep up with the fraudulent stem cell businesses ethical challenge. The study itself make for a good pilot that could be further developed to be used more widely. If so, please make sure to collect some demographic data with the responses. This manuscript presents an interesting study of patient experiences and perceptions of autologous cell-based therapy (ACBT) procedures. The piece is clear and well written it is informative of the type of patients interested in these procedures in North America, and about the procedures themselves. The context information provided, while succinct, is recent and accurate. It is surprising to me that the authors did not choose to collect a minimal set of demographic information about their respondents, age range, sex, education level, for example, which would have provided a much richer dataset. In the same vein, it is unclear whether they retained the information about countries of origin (U.S., Canada). If they did, it was not included in the analysis parameters they used. Given that the survey was anonymous, were the authors able to filter out potential duplicates? (Participants that may have responded twice or more to the questionnaire). Were respondents compensated for their responses or was the contribution non remunerated? I would have also liked to have more information on whether the quantitative data obtained was statistically significant or sufficiently representative of the U.S./Canadian population of patients seeking ACBT. This seems unlikely and it would be important to disclose this study limitation. In the discussion section, the authors make the most of their data providing interesting interpretations and inferences for their results. I have some reserve about the positive inference made by the authors about international practices during the clinical encounter. The fact that service providers participating in a generally fraudulent practice, can speak to some of its basic regulatory and mechanistic concepts with customers is hardly reassuring, it simply makes their otherwise false representations more believable to them. The findings about the (growing?) importance of the pay-to-participate type of stem cell clinical trials and, that of reimbursement payments for ACBT procedures are much more interesting and warrant further exploration. In sum a good short manuscript, to keep up with the fraudulent stem cell businesses ethical challenge. The study itself make for a good pilot that could be further developed to be used more widely. If so, please make sure to collect some demographic data with the responses. Is the work clearly and accurately presented and does it cite the current literature? Yes Is the study design appropriate and is the work technically sound? Partly Are sufficient details of methods and analysis provided to allow replication by others? Partly If applicable, is the statistical analysis and its interpretation appropriate? Yes Are all the source data underlying the results available to ensure full reproducibility? Yes Are the conclusions drawn adequately supported by the results? Yes Competing Interests: No competing interests were disclosed. Reviewer Expertise: Law, bioethics and public policy in modern medicine I confirm that I have read this submission and believe that I have an appropriate level of expertise to confirm that it is of an acceptable scientific standard, however I have significant reservations, as outlined above. Close READ LESS CITE CITE HOW TO CITE THIS REPORT Joly Y. Reviewer Report For: Clinical use of autologous cell-based therapies in an evolving regulatory landscape: A survey of patient experiences and perceptions [version 2; peer review: 2 approved] . F1000Research 2024, 12 :1165 ( https://doi.org/10.5256/f1000research.154413.r292492 ) The direct URL for this report is: https://f1000research.com/articles/12-1165/v1#referee-response-292492 NOTE: it is important to ensure the information in square brackets after the title is included in all citations of this article. COPY CITATION DETAILS Report a concern Author Response 27 Aug 2024 Ubaka Ogbogu , Faculty of Law, University of Alberta, Edmonton, T6G2H5, Canada 27 Aug 2024 Author Response Reviewer: This manuscript presents an interesting study of patient experiences and perceptions of autologous cell-based therapy (ACBT) procedures. The piece is clear and well written it is informative of the ... Continue reading Reviewer: This manuscript presents an interesting study of patient experiences and perceptions of autologous cell-based therapy (ACBT) procedures. The piece is clear and well written it is informative of the type of patients interested in these procedures in North America, and about the procedures themselves. The context information provided, while succinct, is recent and accurate. It is surprising to me that the authors did not choose to collect a minimal set of demographic information about their respondents, age range, sex, education level, for example, which would have provided a much richer dataset. Response: We initially considered collecting demographic information but decided against it for two main reasons. First, to minimize the risk of “survey fatigue” and to improve response rates and data quality, we shortened the questionnaire to focus solely on questions directly related to our research objectives. Survey fatigue is a well-documented issue, particularly during the COVID-19 pandemic [1-5]. Second, while demographic data could provide insights into how demographic variables influence perceptions, we determined that our research questions could be answered without it. Additionally, our analysis did not rely on demographic factors or treat the responses as representative of any specific population of patients seeking ACBT. However, we acknowledge the reviewer’s point and will incorporate demographic information in future studies on this topic. Reviewer: In the same vein, it is unclear whether they retained the information about countries of origin (U.S., Canada). If they did, it was not included in the analysis parameters they used. Response: We did not collect information regarding the country of origin, as it was not necessary for answering our research question. However, we did gather data on the country where respondents received ACBT, which is detailed in the “Results” section under “Part 1: Summary of Participants’ Experiences.” Reviewer: Given that the survey was anonymous, were the authors able to filter out potential duplicates? (Participants that may have responded twice or more to the questionnaire). Response: Yes, duplicates were filtered out by Qualtrics and through manual screening. We have already mentioned this process in the Methods section of the paper. Additionally, we noted in the Limitations section that “we removed any likely bot or duplicate responses from our analysis.” Reviewer: Were respondents compensated for their responses or was the contribution non remunerated? Response: Survey respondents were entered into a lottery draw for a chance to win a $50 CAD gift card. This incentive was approved by the University of Alberta Research Ethics Board. One respondent received the incentive. We already noted the lottery draw in the Limitations section, but we have also updated the Methods section to clearly note the incentive. Reviewer: I would have also liked to have more information on whether the quantitative data obtained was statistically significant or sufficiently representative of the U.S./Canadian population of patients seeking ACBT. This seems unlikely and it would be important to disclose this study limitation. Response: We have included a statement in the Limitations section to address this comment. The statement reads: “The quantitative data reported in this study is not sufficiently representative of the population of patients seeking ACBT in the U.S. and Canada. Therefore, the data should not be interpreted as generalizable to this population.” Reviewer: In the discussion section, the authors make the most of their data providing interesting interpretations and inferences for their results. I have some reserve about the positive inference made by the authors about international practices during the clinical encounter. The fact that service providers participating in a generally fraudulent practice, can speak to some of its basic regulatory and mechanistic concepts with customers is hardly reassuring, it simply makes their otherwise false representations more believable to them. Response: We are grateful to the reviewer for this observation. We have added a statement in the Discussion section to acknowledge the comment. Reviewer: The findings about the (growing?) importance of the pay-to-participate type of stem cell clinical trials and, that of reimbursement payments for ACBT procedures are much more interesting and warrant further exploration. Response: We are grateful to the reviewer for this observation and will keep it in mind for further exploration. Reviewer: In sum a good short manuscript, to keep up with the fraudulent stem cell businesses ethical challenge. The study itself make for a good pilot that could be further developed to be used more widely. If so, please make sure to collect some demographic data with the responses. Response: Noted. We will endeavour to address this comment in future studies. Thank you! References Lavrakas, P. J. (2008). Respondent fatigue. In Encyclopedia of Survey Research Methods (pp. 743-743). SAGE Publications, Inc., https://doi.org/10.4135/9781412963947 . Galesic, M., & Bosnjak, M. (2009). Effects of Questionnaire Length on Participation and Indicators of Response Quality in a Web Survey. The Public Opinion Quarterly , 73 (2), 349–360. http://www.jstor.org/stable/25548084 Herzog, A. R., & Bachman, J. G. (1981). Effects of Questionnaire Length on Response Quality. The Public Opinion Quarterly , 45 (4), 549–559. http://www.jstor.org/stable/2748903 Jeong, D., Aggarwal, S., Robinson, J., Kumar, N., Spearot, A., & Park, D. S. (2023). Exhaustive or exhausting? Evidence on respondent fatigue in long surveys. Journal of Development Economics , 161 , 102992. De Koning, R., Egiz, A., Kotecha, J., Ciuculete, A. C., Ooi, S. Z. Y., Bankole, N. D. A., ... & Kanmounye, U. S. (2021). Survey fatigue during the COVID-19 pandemic: an analysis of neurosurgery survey response rates. Frontiers in surgery , 8 , 690680. Reviewer: This manuscript presents an interesting study of patient experiences and perceptions of autologous cell-based therapy (ACBT) procedures. The piece is clear and well written it is informative of the type of patients interested in these procedures in North America, and about the procedures themselves. The context information provided, while succinct, is recent and accurate. It is surprising to me that the authors did not choose to collect a minimal set of demographic information about their respondents, age range, sex, education level, for example, which would have provided a much richer dataset. Response: We initially considered collecting demographic information but decided against it for two main reasons. First, to minimize the risk of “survey fatigue” and to improve response rates and data quality, we shortened the questionnaire to focus solely on questions directly related to our research objectives. Survey fatigue is a well-documented issue, particularly during the COVID-19 pandemic [1-5]. Second, while demographic data could provide insights into how demographic variables influence perceptions, we determined that our research questions could be answered without it. Additionally, our analysis did not rely on demographic factors or treat the responses as representative of any specific population of patients seeking ACBT. However, we acknowledge the reviewer’s point and will incorporate demographic information in future studies on this topic. Reviewer: In the same vein, it is unclear whether they retained the information about countries of origin (U.S., Canada). If they did, it was not included in the analysis parameters they used. Response: We did not collect information regarding the country of origin, as it was not necessary for answering our research question. However, we did gather data on the country where respondents received ACBT, which is detailed in the “Results” section under “Part 1: Summary of Participants’ Experiences.” Reviewer: Given that the survey was anonymous, were the authors able to filter out potential duplicates? (Participants that may have responded twice or more to the questionnaire). Response: Yes, duplicates were filtered out by Qualtrics and through manual screening. We have already mentioned this process in the Methods section of the paper. Additionally, we noted in the Limitations section that “we removed any likely bot or duplicate responses from our analysis.” Reviewer: Were respondents compensated for their responses or was the contribution non remunerated? Response: Survey respondents were entered into a lottery draw for a chance to win a $50 CAD gift card. This incentive was approved by the University of Alberta Research Ethics Board. One respondent received the incentive. We already noted the lottery draw in the Limitations section, but we have also updated the Methods section to clearly note the incentive. Reviewer: I would have also liked to have more information on whether the quantitative data obtained was statistically significant or sufficiently representative of the U.S./Canadian population of patients seeking ACBT. This seems unlikely and it would be important to disclose this study limitation. Response: We have included a statement in the Limitations section to address this comment. The statement reads: “The quantitative data reported in this study is not sufficiently representative of the population of patients seeking ACBT in the U.S. and Canada. Therefore, the data should not be interpreted as generalizable to this population.” Reviewer: In the discussion section, the authors make the most of their data providing interesting interpretations and inferences for their results. I have some reserve about the positive inference made by the authors about international practices during the clinical encounter. The fact that service providers participating in a generally fraudulent practice, can speak to some of its basic regulatory and mechanistic concepts with customers is hardly reassuring, it simply makes their otherwise false representations more believable to them. Response: We are grateful to the reviewer for this observation. We have added a statement in the Discussion section to acknowledge the comment. Reviewer: The findings about the (growing?) importance of the pay-to-participate type of stem cell clinical trials and, that of reimbursement payments for ACBT procedures are much more interesting and warrant further exploration. Response: We are grateful to the reviewer for this observation and will keep it in mind for further exploration. Reviewer: In sum a good short manuscript, to keep up with the fraudulent stem cell businesses ethical challenge. The study itself make for a good pilot that could be further developed to be used more widely. If so, please make sure to collect some demographic data with the responses. Response: Noted. We will endeavour to address this comment in future studies. Thank you! References Lavrakas, P. J. (2008). Respondent fatigue. In Encyclopedia of Survey Research Methods (pp. 743-743). SAGE Publications, Inc., https://doi.org/10.4135/9781412963947 . Galesic, M., & Bosnjak, M. (2009). Effects of Questionnaire Length on Participation and Indicators of Response Quality in a Web Survey. The Public Opinion Quarterly , 73 (2), 349–360. http://www.jstor.org/stable/25548084 Herzog, A. R., & Bachman, J. G. (1981). Effects of Questionnaire Length on Response Quality. The Public Opinion Quarterly , 45 (4), 549–559. http://www.jstor.org/stable/2748903 Jeong, D., Aggarwal, S., Robinson, J., Kumar, N., Spearot, A., & Park, D. S. (2023). Exhaustive or exhausting? Evidence on respondent fatigue in long surveys. Journal of Development Economics , 161 , 102992. De Koning, R., Egiz, A., Kotecha, J., Ciuculete, A. C., Ooi, S. Z. Y., Bankole, N. D. A., ... & Kanmounye, U. S. (2021). Survey fatigue during the COVID-19 pandemic: an analysis of neurosurgery survey response rates. Frontiers in surgery , 8 , 690680. Competing Interests: None Close Report a concern Respond or Comment COMMENTS ON THIS REPORT Author Response 27 Aug 2024 Ubaka Ogbogu , Faculty of Law, University of Alberta, Edmonton, T6G2H5, Canada 27 Aug 2024 Author Response Reviewer: This manuscript presents an interesting study of patient experiences and perceptions of autologous cell-based therapy (ACBT) procedures. The piece is clear and well written it is informative of the ... Continue reading Reviewer: This manuscript presents an interesting study of patient experiences and perceptions of autologous cell-based therapy (ACBT) procedures. The piece is clear and well written it is informative of the type of patients interested in these procedures in North America, and about the procedures themselves. The context information provided, while succinct, is recent and accurate. It is surprising to me that the authors did not choose to collect a minimal set of demographic information about their respondents, age range, sex, education level, for example, which would have provided a much richer dataset. Response: We initially considered collecting demographic information but decided against it for two main reasons. First, to minimize the risk of “survey fatigue” and to improve response rates and data quality, we shortened the questionnaire to focus solely on questions directly related to our research objectives. Survey fatigue is a well-documented issue, particularly during the COVID-19 pandemic [1-5]. Second, while demographic data could provide insights into how demographic variables influence perceptions, we determined that our research questions could be answered without it. Additionally, our analysis did not rely on demographic factors or treat the responses as representative of any specific population of patients seeking ACBT. However, we acknowledge the reviewer’s point and will incorporate demographic information in future studies on this topic. Reviewer: In the same vein, it is unclear whether they retained the information about countries of origin (U.S., Canada). If they did, it was not included in the analysis parameters they used. Response: We did not collect information regarding the country of origin, as it was not necessary for answering our research question. However, we did gather data on the country where respondents received ACBT, which is detailed in the “Results” section under “Part 1: Summary of Participants’ Experiences.” Reviewer: Given that the survey was anonymous, were the authors able to filter out potential duplicates? (Participants that may have responded twice or more to the questionnaire). Response: Yes, duplicates were filtered out by Qualtrics and through manual screening. We have already mentioned this process in the Methods section of the paper. Additionally, we noted in the Limitations section that “we removed any likely bot or duplicate responses from our analysis.” Reviewer: Were respondents compensated for their responses or was the contribution non remunerated? Response: Survey respondents were entered into a lottery draw for a chance to win a $50 CAD gift card. This incentive was approved by the University of Alberta Research Ethics Board. One respondent received the incentive. We already noted the lottery draw in the Limitations section, but we have also updated the Methods section to clearly note the incentive. Reviewer: I would have also liked to have more information on whether the quantitative data obtained was statistically significant or sufficiently representative of the U.S./Canadian population of patients seeking ACBT. This seems unlikely and it would be important to disclose this study limitation. Response: We have included a statement in the Limitations section to address this comment. The statement reads: “The quantitative data reported in this study is not sufficiently representative of the population of patients seeking ACBT in the U.S. and Canada. Therefore, the data should not be interpreted as generalizable to this population.” Reviewer: In the discussion section, the authors make the most of their data providing interesting interpretations and inferences for their results. I have some reserve about the positive inference made by the authors about international practices during the clinical encounter. The fact that service providers participating in a generally fraudulent practice, can speak to some of its basic regulatory and mechanistic concepts with customers is hardly reassuring, it simply makes their otherwise false representations more believable to them. Response: We are grateful to the reviewer for this observation. We have added a statement in the Discussion section to acknowledge the comment. Reviewer: The findings about the (growing?) importance of the pay-to-participate type of stem cell clinical trials and, that of reimbursement payments for ACBT procedures are much more interesting and warrant further exploration. Response: We are grateful to the reviewer for this observation and will keep it in mind for further exploration. Reviewer: In sum a good short manuscript, to keep up with the fraudulent stem cell businesses ethical challenge. The study itself make for a good pilot that could be further developed to be used more widely. If so, please make sure to collect some demographic data with the responses. Response: Noted. We will endeavour to address this comment in future studies. Thank you! References Lavrakas, P. J. (2008). Respondent fatigue. In Encyclopedia of Survey Research Methods (pp. 743-743). SAGE Publications, Inc., https://doi.org/10.4135/9781412963947 . Galesic, M., & Bosnjak, M. (2009). Effects of Questionnaire Length on Participation and Indicators of Response Quality in a Web Survey. The Public Opinion Quarterly , 73 (2), 349–360. http://www.jstor.org/stable/25548084 Herzog, A. R., & Bachman, J. G. (1981). Effects of Questionnaire Length on Response Quality. The Public Opinion Quarterly , 45 (4), 549–559. http://www.jstor.org/stable/2748903 Jeong, D., Aggarwal, S., Robinson, J., Kumar, N., Spearot, A., & Park, D. S. (2023). Exhaustive or exhausting? Evidence on respondent fatigue in long surveys. Journal of Development Economics , 161 , 102992. De Koning, R., Egiz, A., Kotecha, J., Ciuculete, A. C., Ooi, S. Z. Y., Bankole, N. D. A., ... & Kanmounye, U. S. (2021). Survey fatigue during the COVID-19 pandemic: an analysis of neurosurgery survey response rates. Frontiers in surgery , 8 , 690680. Reviewer: This manuscript presents an interesting study of patient experiences and perceptions of autologous cell-based therapy (ACBT) procedures. The piece is clear and well written it is informative of the type of patients interested in these procedures in North America, and about the procedures themselves. The context information provided, while succinct, is recent and accurate. It is surprising to me that the authors did not choose to collect a minimal set of demographic information about their respondents, age range, sex, education level, for example, which would have provided a much richer dataset. Response: We initially considered collecting demographic information but decided against it for two main reasons. First, to minimize the risk of “survey fatigue” and to improve response rates and data quality, we shortened the questionnaire to focus solely on questions directly related to our research objectives. Survey fatigue is a well-documented issue, particularly during the COVID-19 pandemic [1-5]. Second, while demographic data could provide insights into how demographic variables influence perceptions, we determined that our research questions could be answered without it. Additionally, our analysis did not rely on demographic factors or treat the responses as representative of any specific population of patients seeking ACBT. However, we acknowledge the reviewer’s point and will incorporate demographic information in future studies on this topic. Reviewer: In the same vein, it is unclear whether they retained the information about countries of origin (U.S., Canada). If they did, it was not included in the analysis parameters they used. Response: We did not collect information regarding the country of origin, as it was not necessary for answering our research question. However, we did gather data on the country where respondents received ACBT, which is detailed in the “Results” section under “Part 1: Summary of Participants’ Experiences.” Reviewer: Given that the survey was anonymous, were the authors able to filter out potential duplicates? (Participants that may have responded twice or more to the questionnaire). Response: Yes, duplicates were filtered out by Qualtrics and through manual screening. We have already mentioned this process in the Methods section of the paper. Additionally, we noted in the Limitations section that “we removed any likely bot or duplicate responses from our analysis.” Reviewer: Were respondents compensated for their responses or was the contribution non remunerated? Response: Survey respondents were entered into a lottery draw for a chance to win a $50 CAD gift card. This incentive was approved by the University of Alberta Research Ethics Board. One respondent received the incentive. We already noted the lottery draw in the Limitations section, but we have also updated the Methods section to clearly note the incentive. Reviewer: I would have also liked to have more information on whether the quantitative data obtained was statistically significant or sufficiently representative of the U.S./Canadian population of patients seeking ACBT. This seems unlikely and it would be important to disclose this study limitation. Response: We have included a statement in the Limitations section to address this comment. The statement reads: “The quantitative data reported in this study is not sufficiently representative of the population of patients seeking ACBT in the U.S. and Canada. Therefore, the data should not be interpreted as generalizable to this population.” Reviewer: In the discussion section, the authors make the most of their data providing interesting interpretations and inferences for their results. I have some reserve about the positive inference made by the authors about international practices during the clinical encounter. The fact that service providers participating in a generally fraudulent practice, can speak to some of its basic regulatory and mechanistic concepts with customers is hardly reassuring, it simply makes their otherwise false representations more believable to them. Response: We are grateful to the reviewer for this observation. We have added a statement in the Discussion section to acknowledge the comment. Reviewer: The findings about the (growing?) importance of the pay-to-participate type of stem cell clinical trials and, that of reimbursement payments for ACBT procedures are much more interesting and warrant further exploration. Response: We are grateful to the reviewer for this observation and will keep it in mind for further exploration. Reviewer: In sum a good short manuscript, to keep up with the fraudulent stem cell businesses ethical challenge. The study itself make for a good pilot that could be further developed to be used more widely. If so, please make sure to collect some demographic data with the responses. Response: Noted. We will endeavour to address this comment in future studies. Thank you! References Lavrakas, P. J. (2008). Respondent fatigue. In Encyclopedia of Survey Research Methods (pp. 743-743). SAGE Publications, Inc., https://doi.org/10.4135/9781412963947 . Galesic, M., & Bosnjak, M. (2009). Effects of Questionnaire Length on Participation and Indicators of Response Quality in a Web Survey. The Public Opinion Quarterly , 73 (2), 349–360. http://www.jstor.org/stable/25548084 Herzog, A. R., & Bachman, J. G. (1981). Effects of Questionnaire Length on Response Quality. The Public Opinion Quarterly , 45 (4), 549–559. http://www.jstor.org/stable/2748903 Jeong, D., Aggarwal, S., Robinson, J., Kumar, N., Spearot, A., & Park, D. S. (2023). Exhaustive or exhausting? Evidence on respondent fatigue in long surveys. Journal of Development Economics , 161 , 102992. De Koning, R., Egiz, A., Kotecha, J., Ciuculete, A. C., Ooi, S. Z. Y., Bankole, N. D. A., ... & Kanmounye, U. S. (2021). Survey fatigue during the COVID-19 pandemic: an analysis of neurosurgery survey response rates. Frontiers in surgery , 8 , 690680. Competing Interests: None Close Report a concern COMMENT ON THIS REPORT Views 0 Cite How to cite this report: Du L. Reviewer Report For: Clinical use of autologous cell-based therapies in an evolving regulatory landscape: A survey of patient experiences and perceptions [version 2; peer review: 2 approved] . F1000Research 2024, 12 :1165 ( https://doi.org/10.5256/f1000research.154413.r223427 ) The direct URL for this report is: https://f1000research.com/articles/12-1165/v1#referee-response-223427 NOTE: it is important to ensure the information in square brackets after the title is included in this citation. Close Copy Citation Details Reviewer Report 15 Dec 2023 Li Du , University of Macau, Macau, China Approved with Reservations VIEWS 0 https://doi.org/10.5256/f1000research.154413.r223427 The research is well-structured and written. It offers a unique viewpoint from patients who underwent the ACBT about their experience and comprehension of ACBT regulation’s legal aspects. I recommend accepting it for publication. However, I have two concerns regarding the ... Continue reading READ ALL The research is well-structured and written. It offers a unique viewpoint from patients who underwent the ACBT about their experience and comprehension of ACBT regulation’s legal aspects. I recommend accepting it for publication. However, I have two concerns regarding the discussion section where the authors discuss payment reimbursement for ACBT and improvements for clinical trials and regulations. The authors’ assertion that insurers perceive ACBT as beneficial in the reimbursement section does not appear well-supported by the results. More explanation is needed to support this point. For improving regulations, safety is typically a fundamental principle for clinical trial regulations. Authors should further elaborate on this issue, explaining why the authors raised this concern. For example, are there regulations that place safety to a secondary role, or have certain regulations been improperly interpreted or enforced, thereby diminishing the importance of safety in favor of other considerations? Is the work clearly and accurately presented and does it cite the current literature? Yes Is the study design appropriate and is the work technically sound? Yes Are sufficient details of methods and analysis provided to allow replication by others? Yes If applicable, is the statistical analysis and its interpretation appropriate? Partly Are all the source data underlying the results available to ensure full reproducibility? Yes Are the conclusions drawn adequately supported by the results? Yes Competing Interests: No competing interests were disclosed. Reviewer Expertise: biotechnology law and policy I confirm that I have read this submission and believe that I have an appropriate level of expertise to confirm that it is of an acceptable scientific standard, however I have significant reservations, as outlined above. Close READ LESS CITE CITE HOW TO CITE THIS REPORT Du L. Reviewer Report For: Clinical use of autologous cell-based therapies in an evolving regulatory landscape: A survey of patient experiences and perceptions [version 2; peer review: 2 approved] . F1000Research 2024, 12 :1165 ( https://doi.org/10.5256/f1000research.154413.r223427 ) The direct URL for this report is: https://f1000research.com/articles/12-1165/v1#referee-response-223427 NOTE: it is important to ensure the information in square brackets after the title is included in all citations of this article. COPY CITATION DETAILS Report a concern Author Response 22 Mar 2024 Ubaka Ogbogu , Faculty of Law, University of Alberta, Edmonton, T6G2H5, Canada 22 Mar 2024 Author Response We are grateful to the reviewer for the positive feedback and for the comments on the article. We have provided responses addressing the reviewer's comments below, as follows: Reviewer ... Continue reading We are grateful to the reviewer for the positive feedback and for the comments on the article. We have provided responses addressing the reviewer's comments below, as follows: Reviewer comment: The authors’ assertion that insurers perceive ACBT as beneficial in the reimbursement section does not appear well-supported by the results. More explanation is needed to support this point. Our response: Thank you for this feedback. In the discussion section we suggested that insurers view ACBT as beneficial based on the finding that some participants are receiving reimbursement for treatment expenses from public and private health insurers. Generally, a criterion that health insurers (and health technology assessment reviews that inform reimbursement decisions) consider in deciding whether to reimburse the cost of a health intervention or drug is whether it provides a clinical benefit that is superior or comparable to existing treatment options (CADTH 2020; Nagase et al 2019). While it is not the only criteria (others include survival gains, cost and cost-effectiveness, clinical safety, improvement in surrogate outcomes, etc.), we use the notion of "beneficial" to link the finding that insurers are reimbursing ACBT costs to the notion that they do so because they believe, among other things, that it offers relative clinical benefit. We hope this explanation clarifies. Reviewer comment: For improving regulations, safety is typically a fundamental principle for clinical trial regulations. Authors should further elaborate on this issue, explaining why the authors raised this concern. For example, are there regulations that place safety to a secondary role, or have certain regulations been improperly interpreted or enforced, thereby diminishing the importance of safety in favor of other considerations? Our response: We have not raised the issue of safety as a "concern" in the discussion. Rather, we discussed the finding that safety emerged as a major theme of concern for the participants in the study (so, it was raised by the participants, not us) and we then reflected that this suggests a need to prioritize and address those safety concerns through future regulations. However, we note, in agreement with the reviewer, that it may be necessary to examine the extent to which extant regulations advance or fail to advance safety in the context of clinical trials of ACBT, and how safety regulations operate in practice or are perceived. This work, though important, is outside the scope of the current study. We are presently conducting other empirical studies with regulators and ACBT trialists where we examine how extant regulations, including safety regulations, shape and influence clinical trials and clinical uses of ACBT, and their perceptions of such regulations. We believe the results of the in progress study will answer some of the questions posed by the reviewer regarding the role that safety regulations play, and how they are perceived, within the context of ACBT clinical trials. Citations: CADTH (Canada's Drug and Health Technology Agency), Procedures for CADTH Reimbursement Reviews, January 2024, https://www.cadth.ca/sites/default/files/Drug_Review_Process/CADTH_Drug_Reimbursement_Review_Procedures.pdf Nagase, F.N.I., Stafinski, T., Sun, J. et al. Factors associated with positive and negative recommendations for cancer and non-cancer drugs for rare diseases in Canada. Orphanet J Rare Dis 14 , 127 (2019). https://doi.org/10.1186/s13023-019-1104-7 We are grateful to the reviewer for the positive feedback and for the comments on the article. We have provided responses addressing the reviewer's comments below, as follows: Reviewer comment: The authors’ assertion that insurers perceive ACBT as beneficial in the reimbursement section does not appear well-supported by the results. More explanation is needed to support this point. Our response: Thank you for this feedback. In the discussion section we suggested that insurers view ACBT as beneficial based on the finding that some participants are receiving reimbursement for treatment expenses from public and private health insurers. Generally, a criterion that health insurers (and health technology assessment reviews that inform reimbursement decisions) consider in deciding whether to reimburse the cost of a health intervention or drug is whether it provides a clinical benefit that is superior or comparable to existing treatment options (CADTH 2020; Nagase et al 2019). While it is not the only criteria (others include survival gains, cost and cost-effectiveness, clinical safety, improvement in surrogate outcomes, etc.), we use the notion of "beneficial" to link the finding that insurers are reimbursing ACBT costs to the notion that they do so because they believe, among other things, that it offers relative clinical benefit. We hope this explanation clarifies. Reviewer comment: For improving regulations, safety is typically a fundamental principle for clinical trial regulations. Authors should further elaborate on this issue, explaining why the authors raised this concern. For example, are there regulations that place safety to a secondary role, or have certain regulations been improperly interpreted or enforced, thereby diminishing the importance of safety in favor of other considerations? Our response: We have not raised the issue of safety as a "concern" in the discussion. Rather, we discussed the finding that safety emerged as a major theme of concern for the participants in the study (so, it was raised by the participants, not us) and we then reflected that this suggests a need to prioritize and address those safety concerns through future regulations. However, we note, in agreement with the reviewer, that it may be necessary to examine the extent to which extant regulations advance or fail to advance safety in the context of clinical trials of ACBT, and how safety regulations operate in practice or are perceived. This work, though important, is outside the scope of the current study. We are presently conducting other empirical studies with regulators and ACBT trialists where we examine how extant regulations, including safety regulations, shape and influence clinical trials and clinical uses of ACBT, and their perceptions of such regulations. We believe the results of the in progress study will answer some of the questions posed by the reviewer regarding the role that safety regulations play, and how they are perceived, within the context of ACBT clinical trials. Citations: CADTH (Canada's Drug and Health Technology Agency), Procedures for CADTH Reimbursement Reviews, January 2024, https://www.cadth.ca/sites/default/files/Drug_Review_Process/CADTH_Drug_Reimbursement_Review_Procedures.pdf Nagase, F.N.I., Stafinski, T., Sun, J. et al. Factors associated with positive and negative recommendations for cancer and non-cancer drugs for rare diseases in Canada. Orphanet J Rare Dis 14 , 127 (2019). https://doi.org/10.1186/s13023-019-1104-7 Competing Interests: No competing interests were disclosed. Close Report a concern Respond or Comment COMMENTS ON THIS REPORT Author Response 22 Mar 2024 Ubaka Ogbogu , Faculty of Law, University of Alberta, Edmonton, T6G2H5, Canada 22 Mar 2024 Author Response We are grateful to the reviewer for the positive feedback and for the comments on the article. We have provided responses addressing the reviewer's comments below, as follows: Reviewer ... Continue reading We are grateful to the reviewer for the positive feedback and for the comments on the article. We have provided responses addressing the reviewer's comments below, as follows: Reviewer comment: The authors’ assertion that insurers perceive ACBT as beneficial in the reimbursement section does not appear well-supported by the results. More explanation is needed to support this point. Our response: Thank you for this feedback. In the discussion section we suggested that insurers view ACBT as beneficial based on the finding that some participants are receiving reimbursement for treatment expenses from public and private health insurers. Generally, a criterion that health insurers (and health technology assessment reviews that inform reimbursement decisions) consider in deciding whether to reimburse the cost of a health intervention or drug is whether it provides a clinical benefit that is superior or comparable to existing treatment options (CADTH 2020; Nagase et al 2019). While it is not the only criteria (others include survival gains, cost and cost-effectiveness, clinical safety, improvement in surrogate outcomes, etc.), we use the notion of "beneficial" to link the finding that insurers are reimbursing ACBT costs to the notion that they do so because they believe, among other things, that it offers relative clinical benefit. We hope this explanation clarifies. Reviewer comment: For improving regulations, safety is typically a fundamental principle for clinical trial regulations. Authors should further elaborate on this issue, explaining why the authors raised this concern. For example, are there regulations that place safety to a secondary role, or have certain regulations been improperly interpreted or enforced, thereby diminishing the importance of safety in favor of other considerations? Our response: We have not raised the issue of safety as a "concern" in the discussion. Rather, we discussed the finding that safety emerged as a major theme of concern for the participants in the study (so, it was raised by the participants, not us) and we then reflected that this suggests a need to prioritize and address those safety concerns through future regulations. However, we note, in agreement with the reviewer, that it may be necessary to examine the extent to which extant regulations advance or fail to advance safety in the context of clinical trials of ACBT, and how safety regulations operate in practice or are perceived. This work, though important, is outside the scope of the current study. We are presently conducting other empirical studies with regulators and ACBT trialists where we examine how extant regulations, including safety regulations, shape and influence clinical trials and clinical uses of ACBT, and their perceptions of such regulations. We believe the results of the in progress study will answer some of the questions posed by the reviewer regarding the role that safety regulations play, and how they are perceived, within the context of ACBT clinical trials. Citations: CADTH (Canada's Drug and Health Technology Agency), Procedures for CADTH Reimbursement Reviews, January 2024, https://www.cadth.ca/sites/default/files/Drug_Review_Process/CADTH_Drug_Reimbursement_Review_Procedures.pdf Nagase, F.N.I., Stafinski, T., Sun, J. et al. Factors associated with positive and negative recommendations for cancer and non-cancer drugs for rare diseases in Canada. Orphanet J Rare Dis 14 , 127 (2019). https://doi.org/10.1186/s13023-019-1104-7 We are grateful to the reviewer for the positive feedback and for the comments on the article. We have provided responses addressing the reviewer's comments below, as follows: Reviewer comment: The authors’ assertion that insurers perceive ACBT as beneficial in the reimbursement section does not appear well-supported by the results. More explanation is needed to support this point. Our response: Thank you for this feedback. In the discussion section we suggested that insurers view ACBT as beneficial based on the finding that some participants are receiving reimbursement for treatment expenses from public and private health insurers. Generally, a criterion that health insurers (and health technology assessment reviews that inform reimbursement decisions) consider in deciding whether to reimburse the cost of a health intervention or drug is whether it provides a clinical benefit that is superior or comparable to existing treatment options (CADTH 2020; Nagase et al 2019). While it is not the only criteria (others include survival gains, cost and cost-effectiveness, clinical safety, improvement in surrogate outcomes, etc.), we use the notion of "beneficial" to link the finding that insurers are reimbursing ACBT costs to the notion that they do so because they believe, among other things, that it offers relative clinical benefit. We hope this explanation clarifies. Reviewer comment: For improving regulations, safety is typically a fundamental principle for clinical trial regulations. Authors should further elaborate on this issue, explaining why the authors raised this concern. For example, are there regulations that place safety to a secondary role, or have certain regulations been improperly interpreted or enforced, thereby diminishing the importance of safety in favor of other considerations? Our response: We have not raised the issue of safety as a "concern" in the discussion. Rather, we discussed the finding that safety emerged as a major theme of concern for the participants in the study (so, it was raised by the participants, not us) and we then reflected that this suggests a need to prioritize and address those safety concerns through future regulations. However, we note, in agreement with the reviewer, that it may be necessary to examine the extent to which extant regulations advance or fail to advance safety in the context of clinical trials of ACBT, and how safety regulations operate in practice or are perceived. This work, though important, is outside the scope of the current study. We are presently conducting other empirical studies with regulators and ACBT trialists where we examine how extant regulations, including safety regulations, shape and influence clinical trials and clinical uses of ACBT, and their perceptions of such regulations. We believe the results of the in progress study will answer some of the questions posed by the reviewer regarding the role that safety regulations play, and how they are perceived, within the context of ACBT clinical trials. Citations: CADTH (Canada's Drug and Health Technology Agency), Procedures for CADTH Reimbursement Reviews, January 2024, https://www.cadth.ca/sites/default/files/Drug_Review_Process/CADTH_Drug_Reimbursement_Review_Procedures.pdf Nagase, F.N.I., Stafinski, T., Sun, J. et al. Factors associated with positive and negative recommendations for cancer and non-cancer drugs for rare diseases in Canada. Orphanet J Rare Dis 14 , 127 (2019). https://doi.org/10.1186/s13023-019-1104-7 Competing Interests: No competing interests were disclosed. Close Report a concern COMMENT ON THIS REPORT Comments on this article Comments (0) Version 2 VERSION 2 PUBLISHED 18 Sep 2023 ADD YOUR COMMENT Comment keyboard_arrow_left keyboard_arrow_right Open Peer Review Reviewer Status info_outline Alongside their report, reviewers assign a status to the article: Approved The paper is scientifically sound in its current form and only minor, if any, improvements are suggested Approved with reservations A number of small changes, sometimes more significant revisions are required to address specific details and improve the papers academic merit. Not approved Fundamental flaws in the paper seriously undermine the findings and conclusions Reviewer Reports Invited Reviewers 1 2 Version 2 (revision) 27 Aug 24 read read Version 1 18 Sep 23 read read Li Du , University of Macau, Macau, China Yann Joly , McGill University, Montreal, Canada Comments on this article All Comments (0) Add a comment Sign up for content alerts Sign Up You are now signed up to receive this alert Browse by related subjects keyboard_arrow_left Back to all reports Reviewer Report 0 Views copyright © 2024 Joly Y. This is an open access peer review report distributed under the terms of the Creative Commons Attribution License , which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. 18 Oct 2024 | for Version 2 Yann Joly , McGill University, Montreal, QC, Canada 0 Views copyright © 2024 Joly Y. This is an open access peer review report distributed under the terms of the Creative Commons Attribution License , which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. format_quote Cite this report speaker_notes Responses (0) Approved info_outline Alongside their report, reviewers assign a status to the article: Approved The paper is scientifically sound in its current form and only minor, if any, improvements are suggested Approved with reservations A number of small changes, sometimes more significant revisions are required to address specific details and improve the papers academic merit. Not approved Fundamental flaws in the paper seriously undermine the findings and conclusions I accept this manuscript without reservation for indexing. Competing Interests No competing interests were disclosed. I confirm that I have read this submission and believe that I have an appropriate level of expertise to confirm that it is of an acceptable scientific standard. reply Respond to this report Responses (0) Joly Y. Peer Review Report For: Clinical use of autologous cell-based therapies in an evolving regulatory landscape: A survey of patient experiences and perceptions [version 2; peer review: 2 approved] . F1000Research 2024, 12 :1165 ( https://doi.org/10.5256/f1000research.170536.r317354) NOTE: it is important to ensure the information in square brackets after the title is included in this citation. The direct URL for this report is: https://f1000research.com/articles/12-1165/v2#referee-response-317354 keyboard_arrow_left Back to all reports Reviewer Report 0 Views copyright © 2024 Du L. This is an open access peer review report distributed under the terms of the Creative Commons Attribution License , which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. 10 Sep 2024 | for Version 2 Li Du , University of Macau, Macau, China 0 Views copyright © 2024 Du L. This is an open access peer review report distributed under the terms of the Creative Commons Attribution License , which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. format_quote Cite this report speaker_notes Responses (0) Approved info_outline Alongside their report, reviewers assign a status to the article: Approved The paper is scientifically sound in its current form and only minor, if any, improvements are suggested Approved with reservations A number of small changes, sometimes more significant revisions are required to address specific details and improve the papers academic merit. Not approved Fundamental flaws in the paper seriously undermine the findings and conclusions I would like to express my thanks for the authors' explanations and revisions. I am satisfied with this revised version. Competing Interests No competing interests were disclosed. I confirm that I have read this submission and believe that I have an appropriate level of expertise to confirm that it is of an acceptable scientific standard. reply Respond to this report Responses (0) Du L. Peer Review Report For: Clinical use of autologous cell-based therapies in an evolving regulatory landscape: A survey of patient experiences and perceptions [version 2; peer review: 2 approved] . F1000Research 2024, 12 :1165 ( https://doi.org/10.5256/f1000research.170536.r317355) NOTE: it is important to ensure the information in square brackets after the title is included in this citation. The direct URL for this report is: https://f1000research.com/articles/12-1165/v2#referee-response-317355 keyboard_arrow_left Back to all reports Reviewer Report 0 Views copyright © 2024 Joly Y. This is an open access peer review report distributed under the terms of the Creative Commons Attribution License , which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. 03 Jul 2024 | for Version 1 Yann Joly , McGill University, Montreal, QC, Canada 0 Views copyright © 2024 Joly Y. This is an open access peer review report distributed under the terms of the Creative Commons Attribution License , which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. format_quote Cite this report speaker_notes Responses (1) Approved With Reservations info_outline Alongside their report, reviewers assign a status to the article: Approved The paper is scientifically sound in its current form and only minor, if any, improvements are suggested Approved with reservations A number of small changes, sometimes more significant revisions are required to address specific details and improve the papers academic merit. Not approved Fundamental flaws in the paper seriously undermine the findings and conclusions This manuscript presents an interesting study of patient experiences and perceptions of autologous cell-based therapy (ACBT) procedures. The piece is clear and well written it is informative of the type of patients interested in these procedures in North America, and about the procedures themselves. The context information provided, while succinct, is recent and accurate. It is surprising to me that the authors did not choose to collect a minimal set of demographic information about their respondents, age range, sex, education level, for example, which would have provided a much richer dataset. In the same vein, it is unclear whether they retained the information about countries of origin (U.S., Canada). If they did, it was not included in the analysis parameters they used. Given that the survey was anonymous, were the authors able to filter out potential duplicates? (Participants that may have responded twice or more to the questionnaire). Were respondents compensated for their responses or was the contribution non remunerated? I would have also liked to have more information on whether the quantitative data obtained was statistically significant or sufficiently representative of the U.S./Canadian population of patients seeking ACBT. This seems unlikely and it would be important to disclose this study limitation. In the discussion section, the authors make the most of their data providing interesting interpretations and inferences for their results. I have some reserve about the positive inference made by the authors about international practices during the clinical encounter. The fact that service providers participating in a generally fraudulent practice, can speak to some of its basic regulatory and mechanistic concepts with customers is hardly reassuring, it simply makes their otherwise false representations more believable to them. The findings about the (growing?) importance of the pay-to-participate type of stem cell clinical trials and, that of reimbursement payments for ACBT procedures are much more interesting and warrant further exploration. In sum a good short manuscript, to keep up with the fraudulent stem cell businesses ethical challenge. The study itself make for a good pilot that could be further developed to be used more widely. If so, please make sure to collect some demographic data with the responses. This manuscript presents an interesting study of patient experiences and perceptions of autologous cell-based therapy (ACBT) procedures. The piece is clear and well written it is informative of the type of patients interested in these procedures in North America, and about the procedures themselves. The context information provided, while succinct, is recent and accurate. It is surprising to me that the authors did not choose to collect a minimal set of demographic information about their respondents, age range, sex, education level, for example, which would have provided a much richer dataset. In the same vein, it is unclear whether they retained the information about countries of origin (U.S., Canada). If they did, it was not included in the analysis parameters they used. Given that the survey was anonymous, were the authors able to filter out potential duplicates? (Participants that may have responded twice or more to the questionnaire). Were respondents compensated for their responses or was the contribution non remunerated? I would have also liked to have more information on whether the quantitative data obtained was statistically significant or sufficiently representative of the U.S./Canadian population of patients seeking ACBT. This seems unlikely and it would be important to disclose this study limitation. In the discussion section, the authors make the most of their data providing interesting interpretations and inferences for their results. I have some reserve about the positive inference made by the authors about international practices during the clinical encounter. The fact that service providers participating in a generally fraudulent practice, can speak to some of its basic regulatory and mechanistic concepts with customers is hardly reassuring, it simply makes their otherwise false representations more believable to them. The findings about the (growing?) importance of the pay-to-participate type of stem cell clinical trials and, that of reimbursement payments for ACBT procedures are much more interesting and warrant further exploration. In sum a good short manuscript, to keep up with the fraudulent stem cell businesses ethical challenge. The study itself make for a good pilot that could be further developed to be used more widely. If so, please make sure to collect some demographic data with the responses. Is the work clearly and accurately presented and does it cite the current literature? Yes Is the study design appropriate and is the work technically sound? Partly Are sufficient details of methods and analysis provided to allow replication by others? Partly If applicable, is the statistical analysis and its interpretation appropriate? Yes Are all the source data underlying the results available to ensure full reproducibility? Yes Are the conclusions drawn adequately supported by the results? Yes Competing Interests No competing interests were disclosed. Reviewer Expertise Law, bioethics and public policy in modern medicine I confirm that I have read this submission and believe that I have an appropriate level of expertise to confirm that it is of an acceptable scientific standard, however I have significant reservations, as outlined above. reply Respond to this report Responses (1) Author Response 27 Aug 2024 Ubaka Ogbogu, Faculty of Law, University of Alberta, Edmonton, T6G2H5, Canada Reviewer: This manuscript presents an interesting study of patient experiences and perceptions of autologous cell-based therapy (ACBT) procedures. The piece is clear and well written it is informative of the type of patients interested in these procedures in North America, and about the procedures themselves. The context information provided, while succinct, is recent and accurate. It is surprising to me that the authors did not choose to collect a minimal set of demographic information about their respondents, age range, sex, education level, for example, which would have provided a much richer dataset. Response: We initially considered collecting demographic information but decided against it for two main reasons. First, to minimize the risk of “survey fatigue” and to improve response rates and data quality, we shortened the questionnaire to focus solely on questions directly related to our research objectives. Survey fatigue is a well-documented issue, particularly during the COVID-19 pandemic [1-5]. Second, while demographic data could provide insights into how demographic variables influence perceptions, we determined that our research questions could be answered without it. Additionally, our analysis did not rely on demographic factors or treat the responses as representative of any specific population of patients seeking ACBT. However, we acknowledge the reviewer’s point and will incorporate demographic information in future studies on this topic. Reviewer: In the same vein, it is unclear whether they retained the information about countries of origin (U.S., Canada). If they did, it was not included in the analysis parameters they used. Response: We did not collect information regarding the country of origin, as it was not necessary for answering our research question. However, we did gather data on the country where respondents received ACBT, which is detailed in the “Results” section under “Part 1: Summary of Participants’ Experiences.” Reviewer: Given that the survey was anonymous, were the authors able to filter out potential duplicates? (Participants that may have responded twice or more to the questionnaire). Response: Yes, duplicates were filtered out by Qualtrics and through manual screening. We have already mentioned this process in the Methods section of the paper. Additionally, we noted in the Limitations section that “we removed any likely bot or duplicate responses from our analysis.” Reviewer: Were respondents compensated for their responses or was the contribution non remunerated? Response: Survey respondents were entered into a lottery draw for a chance to win a $50 CAD gift card. This incentive was approved by the University of Alberta Research Ethics Board. One respondent received the incentive. We already noted the lottery draw in the Limitations section, but we have also updated the Methods section to clearly note the incentive. Reviewer: I would have also liked to have more information on whether the quantitative data obtained was statistically significant or sufficiently representative of the U.S./Canadian population of patients seeking ACBT. This seems unlikely and it would be important to disclose this study limitation. Response: We have included a statement in the Limitations section to address this comment. The statement reads: “The quantitative data reported in this study is not sufficiently representative of the population of patients seeking ACBT in the U.S. and Canada. Therefore, the data should not be interpreted as generalizable to this population.” Reviewer: In the discussion section, the authors make the most of their data providing interesting interpretations and inferences for their results. I have some reserve about the positive inference made by the authors about international practices during the clinical encounter. The fact that service providers participating in a generally fraudulent practice, can speak to some of its basic regulatory and mechanistic concepts with customers is hardly reassuring, it simply makes their otherwise false representations more believable to them. Response: We are grateful to the reviewer for this observation. We have added a statement in the Discussion section to acknowledge the comment. Reviewer: The findings about the (growing?) importance of the pay-to-participate type of stem cell clinical trials and, that of reimbursement payments for ACBT procedures are much more interesting and warrant further exploration. Response: We are grateful to the reviewer for this observation and will keep it in mind for further exploration. Reviewer: In sum a good short manuscript, to keep up with the fraudulent stem cell businesses ethical challenge. The study itself make for a good pilot that could be further developed to be used more widely. If so, please make sure to collect some demographic data with the responses. Response: Noted. We will endeavour to address this comment in future studies. Thank you! References Lavrakas, P. J. (2008). Respondent fatigue. In Encyclopedia of Survey Research Methods (pp. 743-743). SAGE Publications, Inc., https://doi.org/10.4135/9781412963947 . Galesic, M., & Bosnjak, M. (2009). Effects of Questionnaire Length on Participation and Indicators of Response Quality in a Web Survey. The Public Opinion Quarterly , 73 (2), 349–360. http://www.jstor.org/stable/25548084 Herzog, A. R., & Bachman, J. G. (1981). Effects of Questionnaire Length on Response Quality. The Public Opinion Quarterly , 45 (4), 549–559. http://www.jstor.org/stable/2748903 Jeong, D., Aggarwal, S., Robinson, J., Kumar, N., Spearot, A., & Park, D. S. (2023). Exhaustive or exhausting? Evidence on respondent fatigue in long surveys. Journal of Development Economics , 161 , 102992. De Koning, R., Egiz, A., Kotecha, J., Ciuculete, A. C., Ooi, S. Z. Y., Bankole, N. D. A., ... & Kanmounye, U. S. (2021). Survey fatigue during the COVID-19 pandemic: an analysis of neurosurgery survey response rates. Frontiers in surgery , 8 , 690680. View more View less Competing Interests None reply Respond Report a concern Joly Y. Peer Review Report For: Clinical use of autologous cell-based therapies in an evolving regulatory landscape: A survey of patient experiences and perceptions [version 2; peer review: 2 approved] . F1000Research 2024, 12 :1165 ( https://doi.org/10.5256/f1000research.154413.r292492) NOTE: it is important to ensure the information in square brackets after the title is included in this citation. The direct URL for this report is: https://f1000research.com/articles/12-1165/v1#referee-response-292492 keyboard_arrow_left Back to all reports Reviewer Report 0 Views copyright © 2023 Du L. This is an open access peer review report distributed under the terms of the Creative Commons Attribution License , which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. 15 Dec 2023 | for Version 1 Li Du , University of Macau, Macau, China 0 Views copyright © 2023 Du L. This is an open access peer review report distributed under the terms of the Creative Commons Attribution License , which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. format_quote Cite this report speaker_notes Responses (1) Approved With Reservations info_outline Alongside their report, reviewers assign a status to the article: Approved The paper is scientifically sound in its current form and only minor, if any, improvements are suggested Approved with reservations A number of small changes, sometimes more significant revisions are required to address specific details and improve the papers academic merit. Not approved Fundamental flaws in the paper seriously undermine the findings and conclusions The research is well-structured and written. It offers a unique viewpoint from patients who underwent the ACBT about their experience and comprehension of ACBT regulation’s legal aspects. I recommend accepting it for publication. However, I have two concerns regarding the discussion section where the authors discuss payment reimbursement for ACBT and improvements for clinical trials and regulations. The authors’ assertion that insurers perceive ACBT as beneficial in the reimbursement section does not appear well-supported by the results. More explanation is needed to support this point. For improving regulations, safety is typically a fundamental principle for clinical trial regulations. Authors should further elaborate on this issue, explaining why the authors raised this concern. For example, are there regulations that place safety to a secondary role, or have certain regulations been improperly interpreted or enforced, thereby diminishing the importance of safety in favor of other considerations? Is the work clearly and accurately presented and does it cite the current literature? Yes Is the study design appropriate and is the work technically sound? Yes Are sufficient details of methods and analysis provided to allow replication by others? Yes If applicable, is the statistical analysis and its interpretation appropriate? Partly Are all the source data underlying the results available to ensure full reproducibility? Yes Are the conclusions drawn adequately supported by the results? Yes Competing Interests No competing interests were disclosed. Reviewer Expertise biotechnology law and policy I confirm that I have read this submission and believe that I have an appropriate level of expertise to confirm that it is of an acceptable scientific standard, however I have significant reservations, as outlined above. reply Respond to this report Responses (1) Author Response 22 Mar 2024 Ubaka Ogbogu, Faculty of Law, University of Alberta, Edmonton, T6G2H5, Canada We are grateful to the reviewer for the positive feedback and for the comments on the article. We have provided responses addressing the reviewer's comments below, as follows: Reviewer comment: The authors’ assertion that insurers perceive ACBT as beneficial in the reimbursement section does not appear well-supported by the results. More explanation is needed to support this point. Our response: Thank you for this feedback. In the discussion section we suggested that insurers view ACBT as beneficial based on the finding that some participants are receiving reimbursement for treatment expenses from public and private health insurers. Generally, a criterion that health insurers (and health technology assessment reviews that inform reimbursement decisions) consider in deciding whether to reimburse the cost of a health intervention or drug is whether it provides a clinical benefit that is superior or comparable to existing treatment options (CADTH 2020; Nagase et al 2019). While it is not the only criteria (others include survival gains, cost and cost-effectiveness, clinical safety, improvement in surrogate outcomes, etc.), we use the notion of "beneficial" to link the finding that insurers are reimbursing ACBT costs to the notion that they do so because they believe, among other things, that it offers relative clinical benefit. We hope this explanation clarifies. Reviewer comment: For improving regulations, safety is typically a fundamental principle for clinical trial regulations. Authors should further elaborate on this issue, explaining why the authors raised this concern. For example, are there regulations that place safety to a secondary role, or have certain regulations been improperly interpreted or enforced, thereby diminishing the importance of safety in favor of other considerations? Our response: We have not raised the issue of safety as a "concern" in the discussion. Rather, we discussed the finding that safety emerged as a major theme of concern for the participants in the study (so, it was raised by the participants, not us) and we then reflected that this suggests a need to prioritize and address those safety concerns through future regulations. However, we note, in agreement with the reviewer, that it may be necessary to examine the extent to which extant regulations advance or fail to advance safety in the context of clinical trials of ACBT, and how safety regulations operate in practice or are perceived. This work, though important, is outside the scope of the current study. We are presently conducting other empirical studies with regulators and ACBT trialists where we examine how extant regulations, including safety regulations, shape and influence clinical trials and clinical uses of ACBT, and their perceptions of such regulations. We believe the results of the in progress study will answer some of the questions posed by the reviewer regarding the role that safety regulations play, and how they are perceived, within the context of ACBT clinical trials. Citations: CADTH (Canada's Drug and Health Technology Agency), Procedures for CADTH Reimbursement Reviews, January 2024, https://www.cadth.ca/sites/default/files/Drug_Review_Process/CADTH_Drug_Reimbursement_Review_Procedures.pdf Nagase, F.N.I., Stafinski, T., Sun, J. et al. Factors associated with positive and negative recommendations for cancer and non-cancer drugs for rare diseases in Canada. Orphanet J Rare Dis 14 , 127 (2019). https://doi.org/10.1186/s13023-019-1104-7 View more View less Competing Interests No competing interests were disclosed. reply Respond Report a concern Du L. Peer Review Report For: Clinical use of autologous cell-based therapies in an evolving regulatory landscape: A survey of patient experiences and perceptions [version 2; peer review: 2 approved] . F1000Research 2024, 12 :1165 ( https://doi.org/10.5256/f1000research.154413.r223427) NOTE: it is important to ensure the information in square brackets after the title is included in this citation. The direct URL for this report is: https://f1000research.com/articles/12-1165/v1#referee-response-223427 Alongside their report, reviewers assign a status to the article: Approved - the paper is scientifically sound in its current form and only minor, if any, improvements are suggested Approved with reservations - A number of small changes, sometimes more significant revisions are required to address specific details and improve the papers academic merit. Not approved - fundamental flaws in the paper seriously undermine the findings and conclusions Adjust parameters to alter display View on desktop for interactive features Includes Interactive Elements View on desktop for interactive features Competing Interests Policy Provide sufficient details of any financial or non-financial competing interests to enable users to assess whether your comments might lead a reasonable person to question your impartiality. Consider the following examples, but note that this is not an exhaustive list: Examples of 'Non-Financial Competing Interests' Within the past 4 years, you have held joint grants, published or collaborated with any of the authors of the selected paper. You have a close personal relationship (e.g. parent, spouse, sibling, or domestic partner) with any of the authors. You are a close professional associate of any of the authors (e.g. scientific mentor, recent student). You work at the same institute as any of the authors. You hope/expect to benefit (e.g. favour or employment) as a result of your submission. You are an Editor for the journal in which the article is published. Examples of 'Financial Competing Interests' You expect to receive, or in the past 4 years have received, any of the following from any commercial organisation that may gain financially from your submission: a salary, fees, funding, reimbursements. You expect to receive, or in the past 4 years have received, shared grant support or other funding with any of the authors. You hold, or are currently applying for, any patents or significant stocks/shares relating to the subject matter of the paper you are commenting on. Stay Updated Sign up for content alerts and receive a weekly or monthly email with all newly published articles Register with F1000Research Already registered? Sign in Not now, thanks close PLEASE NOTE If you are an AUTHOR of this article, please check that you signed in with the account associated with this article otherwise we cannot automatically identify your role as an author and your comment will be labelled as a “User Comment”. If you are a REVIEWER of this article, please check that you have signed in with the account associated with this article and then go to your account to submit your report, please do not post your review here. If you do not have access to your original account, please contact us . All commenters must hold a formal affiliation as per our Policies . The information that you give us will be displayed next to your comment. User comments must be in English, comprehensible and relevant to the article under discussion. We reserve the right to remove any comments that we consider to be inappropriate, offensive or otherwise in breach of the User Comment Terms and Conditions . Commenters must not use a comment for personal attacks. When criticisms of the article are based on unpublished data, the data should be made available. I accept the User Comment Terms and Conditions Please confirm that you accept the User Comment Terms and Conditions. Affiliation ✕ refresh Please enter your institution. Note: To add your institution or organisation, start typing the name and then select the correct name from the list. Where applicable, the name will appear in both the original language and in English. Do not paste in the name. If the name does not appear in the drop-down list, we will display the information you have entered. ✕ refresh Country/Region * USA UK Canada China France Germany Afghanistan Aland Islands Albania Algeria American Samoa Andorra Angola Anguilla Antarctica Antigua and Barbuda Argentina Armenia Aruba Australia Austria Azerbaijan Bahamas Bahrain Bangladesh Barbados Belarus Belgium Belize Benin Bermuda Bhutan Bolivia Bosnia and Herzegovina Botswana Bouvet Island Brazil British Indian Ocean Territory British Virgin Islands Brunei Bulgaria Burkina Faso Burundi Cambodia Cameroon Canada Cape Verde Cayman Islands Central African Republic Chad Chile China Christmas Island Cocos (Keeling) Islands Colombia Comoros Congo Cook Islands Costa Rica Cote d'Ivoire Croatia Cuba Cyprus Czech Republic Democratic Republic of the Congo Denmark Djibouti Dominica Dominican Republic Ecuador Egypt El Salvador Equatorial Guinea Eritrea Estonia Ethiopia Falkland Islands Faroe Islands Federated States of Micronesia Fiji Finland France French Guiana French Polynesia French Southern Territories Gabon Georgia Germany Ghana Gibraltar Greece Greenland Grenada Guadeloupe Guam Guatemala Guernsey Guinea Guinea-Bissau Guyana Haiti Heard Island and Mcdonald Islands Holy See (Vatican City State) Honduras Hong Kong Hungary Iceland India Indonesia Iran Iraq Ireland Israel Italy Jamaica Japan Jersey Jordan Kazakhstan Kenya Kiribati Kosovo (Serbia and Montenegro) Kuwait Kyrgyzstan Lao People's Democratic Republic Latvia Lebanon Lesotho Liberia Libya Liechtenstein Lithuania Luxembourg Macao Madagascar Malawi Malaysia Maldives Mali Malta Marshall Islands Martinique Mauritania Mauritius Mayotte Mexico Minor Outlying Islands of the United States Moldova Monaco Mongolia Montenegro Montserrat Morocco Mozambique Myanmar Namibia Nauru Nepal Netherlands Antilles New Caledonia New Zealand Nicaragua Niger Nigeria Niue Norfolk Island North Korea North Macedonia Northern Mariana Islands Norway Oman Pakistan Palau Palestinian Territory Panama Papua New Guinea Paraguay Peru Philippines Pitcairn Poland Portugal Puerto Rico Qatar Reunion Romania Russian Federation Rwanda Saint Helena Saint Kitts and Nevis Saint Lucia Saint Pierre and Miquelon Saint Vincent and the Grenadines Samoa San Marino Sao Tome and Principe Saudi Arabia Senegal Serbia Seychelles Sierra Leone Singapore Slovakia Slovenia Solomon Islands Somalia South Africa South Georgia and the South Sandwich Is South Korea South Sudan Spain Sri Lanka Sudan Suriname Svalbard and Jan Mayen Swaziland Sweden Switzerland Syria Taiwan Tajikistan Tanzania Thailand The Gambia The Netherlands Timor-Leste Togo Tokelau Tonga Trinidad and Tobago Tunisia Turkey Turkmenistan Turks and Caicos Islands Tuvalu UK USA Uganda Ukraine United Arab Emirates United States Virgin Islands Uruguay Uzbekistan Vanuatu Venezuela Vietnam Wallis and Futuna West Bank and Gaza Strip Western Sahara Yemen Zambia Zimbabwe Please select your country/region. You must enter a comment. Competing Interests Please disclose any competing interests that might be construed to influence your judgment of the article's or peer review report's validity or importance. Competing Interests Policy Provide sufficient details of any financial or non-financial competing interests to enable users to assess whether your comments might lead a reasonable person to question your impartiality. Consider the following examples, but note that this is not an exhaustive list: Examples of 'Non-Financial Competing Interests' Within the past 4 years, you have held joint grants, published or collaborated with any of the authors of the selected paper. You have a close personal relationship (e.g. parent, spouse, sibling, or domestic partner) with any of the authors. You are a close professional associate of any of the authors (e.g. scientific mentor, recent student). You work at the same institute as any of the authors. You hope/expect to benefit (e.g. favour or employment) as a result of your submission. You are an Editor for the journal in which the article is published. Examples of 'Financial Competing Interests' You expect to receive, or in the past 4 years have received, any of the following from any commercial organisation that may gain financially from your submission: a salary, fees, funding, reimbursements. You expect to receive, or in the past 4 years have received, shared grant support or other funding with any of the authors. You hold, or are currently applying for, any patents or significant stocks/shares relating to the subject matter of the paper you are commenting on. Please state your competing interests The comment has been saved. An error has occurred. Please try again. Cancel Post var lTitle = "Clinical use of autologous cell-based therapies...".replace("'", ''); var linkedInUrl = "http://www.linkedin.com/shareArticle?url=https://f1000research.com/articles/12-1165/v2" + "&title=" + encodeURIComponent(lTitle) + "&summary=" + encodeURIComponent('Read the article by '); var deliciousUrl = "https://del.icio.us/post?url=https://f1000research.com/articles/12-1165/v2&title=" + encodeURIComponent(lTitle); var redditUrl = "http://reddit.com/submit?url=https://f1000research.com/articles/12-1165/v2" + "&title=" + encodeURIComponent(lTitle); linkedInUrl += encodeURIComponent('Ogbogu U and Case N'); var offsetTop = /chrome/i.test( navigator.userAgent ) ? 4 : -10; var addthis_config = { ui_offset_top: offsetTop, services_compact : "facebook,twitter,www.linkedin.com,www.mendeley.com,reddit.com", services_expanded : "facebook,twitter,www.linkedin.com,www.mendeley.com,reddit.com", services_custom : [ { name: "LinkedIn", url: linkedInUrl, icon:"/img/icon/at_linkedin.svg" }, { name: "Mendeley", url: "http://www.mendeley.com/import/?url=https://f1000research.com/articles/12-1165/v2/mendeley", icon:"/img/icon/at_mendeley.svg" }, { name: "Reddit", url: redditUrl, icon:"/img/icon/at_reddit.svg" }, ] }; var addthis_share = { url: "https://f1000research.com/articles/12-1165", templates : { twitter : "Clinical use of autologous cell-based therapies in an evolving.... Ogbogu U and Case N, published by " + "@F1000Research" + ", https://f1000research.com/articles/12-1165/v2" } }; if (typeof(addthis) != "undefined"){ addthis.addEventListener('addthis.ready', checkCount); addthis.addEventListener('addthis.menu.share', checkCount); } $(".f1r-shares-twitter").attr("href", "https://twitter.com/intent/tweet?text=" + addthis_share.templates.twitter); $(".f1r-shares-facebook").attr("href", "https://www.facebook.com/sharer/sharer.php?u=" + addthis_share.url); $(".f1r-shares-linkedin").attr("href", addthis_config.services_custom[0].url); $(".f1r-shares-reddit").attr("href", addthis_config.services_custom[2].url); $(".f1r-shares-mendelay").attr("href", addthis_config.services_custom[1].url); function checkCount(){ setTimeout(function(){ $(".addthis_button_expanded").each(function(){ var count = $(this).text(); if (count !== "" && count != "0") $(this).removeClass("is-hidden"); else $(this).addClass("is-hidden"); }); }, 1000); } close How to cite this report {{reportCitation}} Cancel Copy Citation Details $(function(){R.ui.buttonDropdowns('.dropdown-for-downloads');}); $(function(){R.ui.toolbarDropdowns('.toolbar-dropdown-for-downloads');}); $.get("/articles/acj/141002/170536") new F1000.Clipboard(); new F1000.ThesaurusTermsDisplay("articles", "article", "170536"); $(document).ready(function() { $( "#frame1" ).on('load', function() { var mydiv = $(this).contents().find("div"); var h = mydiv.height(); console.log(h) }); var tooltipLivingFigure = jQuery(".interactive-living-figure-label .icon-more-info"), titleLivingFigure = tooltipLivingFigure.attr("title"); tooltipLivingFigure.simpletip({ fixed: true, position: ["-115", "30"], baseClass: 'small-tooltip', content:titleLivingFigure + " " }); tooltipLivingFigure.removeAttr("title"); $("body").on("click", ".cite-living-figure", function(e) { e.preventDefault(); var ref = $(this).attr("data-ref"); $(this).closest(".living-figure-list-container").find("#" + ref).fadeIn(200); }); $("body").on("click", ".close-cite-living-figure", function(e) { e.preventDefault(); $(this).closest(".popup-window-wrapper").fadeOut(200); }); $(document).on("mouseup", function(e) { var metricsContainer = $(".article-metrics-popover-wrapper"); if (!metricsContainer.is(e.target) && metricsContainer.has(e.target).length === 0) { $(".article-metrics-close-button").click(); } }); var articleId = $('#articleId').val(); if($("#main-article-count-box").attachArticleMetrics) { $("#main-article-count-box").attachArticleMetrics(articleId, { articleMetricsView: true }); } }); var figshareWidget = $(".new_figshare_widget"); if (figshareWidget.length > 0) { window.figshare.load("f1000", function(Widget) { // Select a tag/tags defined in your page. In this tag we will place the widget. _.map(figshareWidget, function(el){ var widget = new Widget({ articleId: $(el).attr("figshare_articleId") //height:300 // this is the height of the viewer part. [Default: 550] }); widget.initialize(); // initialize the widget widget.mount(el); // mount it in a tag that's on your page // this will save the widget on the global scope for later use from // your JS scripts. This line is optional. //window.widget = widget; }); }); } close Error Close Add Reset F1000.MICROSERVICES.AFFILIATION = ''; $(document).ready(function () { $('.js-affiliations-form').each((index, form) => { new AffiliationForm({ formId: form.id, institutionErrorSelector: '.comment-enter-institution', departmentErrorSelector: '.comment-enter-department', placeSelector: '.js-add-comment-place', stateSelector: '.js-add-comment-state', zipCodeSelector: '.js-add-comment-zipcode', countrySelector: '.js-add-comment-country', countryErrorSelector: '.comment-enter-country', }); }); }); $(document).ready(function () { var reportIds = { "292492": 16, "292493": 0, "292494": 0, "292495": 0, "292490": 0, "292491": 0, "292496": 0, "292497": 0, "292498": 0, "292499": 0, "317354": 6, "317355": 7, "317884": 0, "317885": 0, "321854": 0, "317886": 0, "321855": 0, "317887": 0, "317882": 0, "317883": 0, "321860": 0, "223427": 25, "321861": 0, "223426": 0, "321862": 0, "321863": 0, "321856": 0, "317888": 0, "321857": 0, "317889": 0, "321858": 0, "317890": 0, "321859": 0, "317891": 0, "325356": 0, "325357": 0, "325358": 0, "325359": 0, "325354": 0, "325355": 0, "222195": 0, "222194": 0, "325360": 0, "325361": 0, "325362": 0, "325363": 0, "207994": 0, "207993": 0, "207992": 0, }; $(".referee-response-container,.js-referee-report").each(function(index, el) { var reportId = $(el).attr("data-reportid"), reportCount = reportIds[reportId] || 0; $(el).find(".comments-count-container,.js-referee-report-views").html(reportCount); }); var uuidInput = $("#article_uuid"), oldUUId = uuidInput.val(), newUUId = "59d0a6f6-0daa-430e-b0c4-fd59211d8213"; uuidInput.val(newUUId); $("a[href*='article_uuid=']").each(function(index, el) { var newHref = $(el).attr("href").replace(oldUUId, newUUId); $(el).attr("href", newHref); }); }); An innovative open access publishing platform offering rapid publication and open peer review, whilst supporting data deposition and sharing. Browse Gateways Collections How it Works Contact For Developers Cookie Notice Privacy Notice RSS Submit Your Research Follow us © 2012-2026 F1000 Research Ltd. ISSN 2046-1402 | Legal | Partner of Research4Life • CrossRef • ORCID • FAIRSharing R.templateTests.simpleTemplate = R.template(' $text $text $text $text $text '); R.templateTests.runTests(); var F1000platform = new F1000.Platform({ name: "f1000research", displayName: "F1000Research", hostName: "f1000research.com", id: "1", editorialEmail: "[email protected]", infoEmail: "[email protected]", usePmcStats: true }); $(function(){R.ui.dropdowns('.dropdown-for-authors, .dropdown-for-about, .dropdown-for-myresearch');}); // $(function(){R.ui.dropdowns('.dropdown-for-referees');}); $(document).ready(function () { if ($(".cookie-warning").is(":visible")) { $(".sticky").css("margin-bottom", "35px"); $(".devices").addClass("devices-and-cookie-warning"); } $(".cookie-warning .close-button").click(function (e) { $(".devices").removeClass("devices-and-cookie-warning"); $(".sticky").css("margin-bottom", "0"); }); $("#tweeter-feed .tweet-message").each(function (i, message) { var self = $(message); self.html(linkify(self.html())); }); $(".partner").on("mouseenter mouseleave", function() { $(this).find(".gray-scale, .colour").toggleClass("is-hidden"); }); }); Sign In Remember me Forgotten your password? Sign In Cancel Email or password not correct. Please try again Please wait... $(function(){ // Note: All the setup needs to run against a name attribute and *not* the id due the clonish // nature of facebox... $("a[id=googleSignInButton]").click(function(event){ event.preventDefault(); $("input[id=oAuthSystem]").val("GOOGLE"); $("form[id=oAuthForm]").submit(); }); $("a[id=facebookSignInButton]").click(function(event){ event.preventDefault(); $("input[id=oAuthSystem]").val("FACEBOOK"); $("form[id=oAuthForm]").submit(); }); $("a[id=orcidSignInButton]").click(function(event){ event.preventDefault(); $("input[id=oAuthSystem]").val("ORCID"); $("form[id=oAuthForm]").submit(); }); }); If you've forgotten your password, please enter your email address below and we'll send you instructions on how to reset your password. The email address should be the one you originally registered with F1000. Email address not valid, please try again You registered with F1000 via Google, so we cannot reset your password. To sign in, please click here . If you still need help with your Google account password, please click here . You registered with F1000 via Facebook, so we cannot reset your password. To sign in, please click here . If you still need help with your Facebook account password, please click here . Code not correct, please try again Reset password Cancel Email us for further assistance. Server error, please try again. If your email address is registered with us, we will email you instructions to reset your password. If you think you should have received this email but it has not arrived, please check your spam filters and/or contact for further assistance. Please wait... Register $(document).ready(function () { signIn.createSignInAsRow($("#sign-in-form-gfb-popup")); $(".target-field").each(function () { var uris = $(this).val().split("/"); if (uris.pop() === "login") { $(this).val(uris.toString().replace(",","/")); } }); });