We have read with significant concern that our paper¹ has been cited in Volume 10, Issue 6 (June 2021) in a manuscript titled “Ethical issues concerning a pay-to-participate stem cell study” authored by Turner and Snyder.² While we recognize and welcome the need for dialog and academic discussion in the field of regenerative medicine, particularly from a bioethical perspective, our study was not a pay-to-participate study. In fact, we went to great effort to ensure that the treatments were completely funded by the sponsor. In our diligent management of conflicts of interest and bioethics, we obtained the Institutional Review Board (IRB) advice to include in the informed consent and on ClinicalTrials.gov an estimate of out-of-pocket expenses the subject may incur for transportation, lodging, and meals, none of which are expenses of the treatment, but are expenses incurred by subjects in most trials. It is regrettable that our study was misrepresented by the authors, especially since we clarified this issue during the peer-review process with this journal.

During the peer-review process of this journal (answer to Q15 of the Lead Reviewer in the first revision, along with a link to clinicaltrials.gov³) and, later on, in a communication with the Editor dated February 16, 2021, we clarified that our study treatments were not paid for by participants. Our answer has not changed: the subjects of this trial did not pay for treatment, as is clearly stated in our protocol. Items not paid for by the participants include prestudy exams, drugs, delivery of drugs, medical services for treatment or follow-up, statistical analysis, study documentation, utilities or rent, employees and support personnel for the clinic during the trial, recruitment, data management, clinic facility fees, physician time, medical staff, clinical trial insurance cost, 24/7 medical assistance, subject coordinators, or the independent CRO services in conducting the trial. These costs were entirely covered by the study sponsor, not in any way by the subjects.

The U.S. $7200 that appears on clinicaltrials.gov³ was an amount estimated to cover incidental, nontreatment-related costs such as transportation, lodging, meals, and other logistics expenses (maximum U.S. $1800 per visit × 4 visits = $7200). These expenses were incurred by participants from third parties, not the sponsor; and they were in no way expenses of conducting the study or administering the therapy, as mentioned above. This separation of logistic expenses from study expenses was clearly established in the protocol. It was communicated to the guardians of the participants during recruitment to fully inform them and make them aware that they would incur those expenses.

It is unreasonable to consider payment of incidental expenses by participants in a clinical study as a breach of scientific integrity. In virtually every study conducted, participants incur some expenses, like those for transportation to the study site or food on the way to or from treatment, phone expenses, loss of wages, and the list goes on. If participant payment of these incidental expenses adversely affects the integrity of the science of a study, then most all of the peer-reviewed literature on medical research in even our most prestigious journals would be discredited. How does payment of these incidental expenses adversely affect the scientific integrity of the study? Bioethics call for management and transparency of any potential or perceived conflicts of interest to ensure the scientific integrity of the study.

For transparency, this cost for other expenses was always publicly available on clinicaltrials.gov.³ We indicated the clinicaltrials.gov identifier in the manuscript, and we linked to it in the cover letter of the first round of revisions, which satisfied the reviewers. We have been always transparent about this information. We hope this sufficiently clarifies that subjects did not have to pay to “participate” in this trial neither from our perspective, nor from that described in another article⁴ in the same issue as Turner and Snyder's.

Regarding any potential conflicts of interest, these were clearly indicated in the appropriate section of the article¹: “N.H.R. and J.P.R. declared leadership position, patent holder, and shareholders of MediStem Panama and the Stem Cell Institute. M.L.H. declared research funding as subinvestigator for Stem Cell Institute. I.M., N.A. declared leadership position with MediStem Panama. G.F., C.L. declared leadership position with Stem Cell Institute. M.M. declared leadership position and stock ownership with MediStem Panama. N.N. declared research funding from MediStem Panama.” This information is available along with the article and was in no way withheld during the peer-review stage or after publication.

To manage conflicts of interest, our Clinical Trials Department is staffed by researchers who are not involved with commercial activities. All meetings for the preparation of this article were approached with utmost objectivity, from a research perspective, and with no “direct-to-consumer marketing and sale of putative stem cell treatments and (…) a financial interest in continuing to sell such products”² ulterior motives. Moreover, there was no bias in classifying adverse events as “related to treatment”—some of the events recorded (1) are as benign as ant or mosquito bites and rashes, (2) respond to clinical issues noted prior to treatment, or (3) were deemed to be unrelated to treatment by licensed medical professionals. We stand by the medical integrity of our researchers and the research in this study. At the request of one of the reviewers (Q11 by the Lead Reviewer), we did include all events deemed related to the study. The peer-reviewing process for this article was exhaustive and included numerous clarifications that were invaluable in transparently, concisely, and clearly communicating the methods, results, and conclusions of this study.

Finally, our study conclusions were well supported by the data. We have maintained a cautious tone in reporting all findings of this study and have called for larger studies to be conducted with this approach (“Although encouraging, the results of this study should therefore be taken as indicative of trends and signals that should be further explored in larger, double-blind, placebo-controlled studies.”—bolded for emphasis)¹ As stated in the conclusions,¹ the administration of umbilical cord-derived mesenchymal stem cells was well tolerated with no serious adverse events in a reduced sample size (only 10 completed the full study) of young patients with ASD, of which a percentage showed some improvement signals in cytokine levels and in the Childhood Autism Rating Scale (CARS) and Autism Treatment Evaluation Checklist (ATEC) scores. We have upheld scientific and medical professionalism in acknowledging the limitations of this study in the article, particularly highlighting the involvement of the parents in assessing any amelioration, and also noting the small sample size which calls for caution when approaching statistical significance issues.¹

Our aim with this article was to evaluate the safety of umbilical cord-derived mesenchymal stem cells (UC-MSC) administration with the purpose of contributing to the many ongoing clinical studies of MSC administration worldwide. Our ultimate purpose is to see better funded, better designed, larger, placebo-controlled trials utilizing UC-MSCs, thereby allowing elucidation of their potential mechanisms of action.

We stand firm that our study was conducted with scientific integrity that transparency and potential conflicts of interest were properly managed with independent oversight by those without conflict of interest that the methods and results support the limited conclusions, and that our article contributes to the corpus of MSC research and to the still unresolved biomolecular etiology of autism spectrum disorder. We remain committed to scientific pursuit of potential novel therapies for the many children who suffer from this debilitating disorder. We have been committed to transparency and academic discussion from the start of the submission process of this article, and we hope this letter is conducive to a cordial, fact-based debate between interested parties.

我们非常关切地阅读了我们的论文¹已在第 10 卷第 6 期（2021 年 6 月）中被引用，该手稿由 Turner 和 Snyder 撰写，题为“关于付费参与干细胞研究的伦理问题”。²虽然我们承认并欢迎在再生医学领域进行对话和学术讨论的必要性，特别是从生物伦理学的角度来看，但我们的研究并不是一项有偿参与的研究。事实上，我们竭尽全力确保治疗完全由赞助商资助。在我们对利益冲突和生物伦理的勤勉管理中，我们获得了机构审查委员会 (IRB) 的建议，以在知情同意书和 ClinicalTrials.gov 上包括受试者可能因交通、住宿、和膳食，这些都不是治疗费用，而是大多数试验中受试者的费用。很遗憾，我们的研究被作者歪曲了，特别是因为我们在与该期刊的同行评审过程中澄清了这个问题。

在本期刊的同行评审过程中（对第一版中首席评审员 Q15 的回答，以及到 Clinicaltrials.gov 的链接³)，后来，在 2021 年 2 月 16 日与编辑的沟通中，我们澄清说，我们的研究治疗不是由参与者支付的。我们的答案没有改变：该试验的受试者没有支付治疗费用，正如我们的方案中明确规定的那样。参与者未支付的项目包括研究前检查、药物、药物递送、治疗或随访的医疗服务、统计分析、研究文件、水电费或租金、试验期间诊所的雇员和支持人员、招聘、数据管理、诊所设施费用、医生时间、医务人员、临床试验保险费用、24/7 医疗援助、受试者协调员或进行试验的独立 CRO 服务。这些费用完全由研究赞助商承担，而不是由受试者承担。

^{出现在clinicaltrials.gov 3}上的7200 美元估计用于支付与治疗无关的杂费，例如交通、住宿、膳食和其他后勤费用（每次就诊最多1800 美元×4 次就诊=7200 美元）。这些费用是由第三方的参与者产生的，而不是赞助商；如上所述，它们绝不是进行研究或进行治疗的费用。协议中明确规定了后勤费用与研究费用的分离。在招募过程中向参与者的监护人传达了这一信息，以充分告知他们并让他们知道他们会承担这些费用。

将临床研究参与者支付的附带费用视为违反科学诚信是不合理的。在几乎所有进行的研究中，参与者都会产生一些费用，例如前往研究地点的交通费用或往返治疗途中的食物费用、电话费用、工资损失等等。如果参与者支付这些杂费会对研究的科学完整性产生不利影响，那么即使是我们最负盛名的期刊上的大多数医学研究同行评审文献都会被抹黑。这些杂费的支付如何对研究的科学完整性产生不利影响？生物伦理学要求对任何潜在或感知到的利益冲突进行管理和透明化，以确保研究的科学完整性。

为透明起见，其他费用的成本始终在临床试验.gov 上公开。³我们在手稿中注明了clinicaltrials.gov 标识符，并在第一轮修订的cover letter 中链接到它，这让审稿人感到满意。我们一直对这些信息保持透明。我们希望这充分阐明，无论从我们的角度来看，还是从与 Turner 和 Snyder 的同一期的另一篇文章⁴中描述的角度来看，受试者都不必为“参与”该试验付费。

关于任何潜在的利益冲突，这些在第¹条的适当部分中明确指出：“NHR 和 JPR 宣布领导地位、专利持有人以及 MediStem Panama 和干细胞研究所的股东。MLH 宣布为干细胞研究所提供研究资助。IM, NA 宣布在 MediStem Panama 担任领导职务。GF、CL 宣布在干细胞研究所担任领导职务。MM 宣布在 MediStem Panama 担任领导职务和持股。NN 宣布从 MediStem Panama 获得研究资金。” 此信息与文章一起提供，在同行评审阶段或发表后绝不会隐瞒。

为了管理利益冲突，我们的临床试验部门配备了不参与商业活动的研究人员。从研究的角度来看，为撰写本文而召开的所有会议都是以最大的客观性进行的，并且没有“直接面向消费者营销和销售推定的干细胞治疗以及（……）继续销售此类产品的经济利益” ²别有用心。此外，将不良事件归类为“与治疗相关”没有任何偏见——记录的一些事件（1）与蚂蚁或蚊虫叮咬和皮疹一样良性，（2）对治疗前注意到的临床问题有反应，或（ 3) 被有执照的医疗专业人员认为与治疗无关。我们支持我们研究人员的医疗诚信和本研究中的研究。应一位评审员的要求（首席评审员的 Q11），我们确实包括了所有被认为与研究相关的事件。本文的同行评审过程非常详尽，包括许多澄清，这些澄清对于透明、简洁和清晰地传达本研究的方法、结果和结论非常宝贵。

最后，我们的研究结论得到了数据的充分支持。我们在报告本研究的所有发现时保持谨慎的态度，并呼吁使用这种方法进行更大规模的研究（“尽管令人鼓舞，但本研究的结果应被视为应进一步探索的趋势和信号在更大的、双盲、安慰剂对照研究中。”——粗体表示强调）¹如结论中所述，¹在减少年轻 ASD 患者的样本量（仅 10 人完成了完整研究）中，脐带来源的间充质干细胞的给药耐受性良好，没有出现严重的不良事件，其中一定百分比显示细胞因子水平和在儿童自闭症评定量表 (CARS) 和自闭症治疗评估清单 (ATEC) 分数。我们坚持科学和医学专业精神，在文章中承认这项研究的局限性，特别强调父母参与评估任何改善情况，并注意到在处理统计显着性问题时需要谨慎的小样本量。¹

我们这篇文章的目的是评估脐带间充质干细胞 (UC-MSC) 给药的安全性，目的是为全球许多正在进行的 MSC 给药临床研究做出贡献。我们的最终目的是看到利用 UC-MSC 获得更好资助、更好设计、更大、安慰剂对照的试验，从而阐明其潜在的作用机制。

我们坚信，我们的研究是在科学诚信的情况下进行的，透明度和潜在的利益冲突在没有利益冲突的人的独立监督下得到妥善管理，方法和结果支持有限的结论，并且我们的文章有助于 MSC 的语料库研究和仍未解决的自闭症谱系障碍的生物分子病因学。我们仍然致力于为许多患有这种使人衰弱的疾病的儿童寻找潜在的新疗法。从本文提交过程开始，我们就一直致力于透明度和学术讨论，我们希望这封信有助于相关各方之间进行亲切的、基于事实的辩论。