Saskia Hendriks, MD, PhD (1), Steven D Pearson, MD (2)
(1) Department of Bioethics, Clinical Center, National Institutes of Health, Bethesda, Maryland
(2) Institute for Clinical and Economic Review, Boston, Massachusetts
Over the past several decades, many innovative reproductive techniques have been rapidly adopted in clinical practice based on case reports of success instead of undergoing a formal regulatory review. After broad adoption, organizing formal research to evaluate safety and effectiveness becomes difficult. Thus, the lack of regulatory review may expose patients, unborn children, and society to risks and unnecessary health system and personal costs. As innovation continues to accelerate, the need for a more robust regulatory framework to evaluate clinical risks and benefits will grow. Additionally, policy makers will need to explore how to evaluate the broader social and ethical implications of these techniques.
We argue that the current criteria used by the FDA to determine when full regulatory review is needed are inadequate. Regulatory review of safety, effectiveness, and social impact should become the default in reproductive medicine, with only a few exceptions. To support this argument, we borrow from conceptual work in surgery to establish a framework for determining when new reproductive techniques should receive regulatory oversight. Full regulatory oversight should be required unless a new reproductive technique: 1) presents no more than minimal safety issues beyond those of existing techniques; 2) presents no risk of reducing live birth rates compared to the standard of care; and 3) does not raise concerns of societal harms. By expanding regulatory oversight, reproductive medicine can continue to innovate, whilst safeguarding the best interests of patients today and of society in the future.
Innovation is critical in advancing health. Over recent decades, however, significant innovative reproductive techniques have been rapidly adopted based only on case or cohort reports of success without a regulatory process to evaluate the risks and benefits (1-5).
Examples are numerous, including preimplantation genetic testing for aneuploidy
(PGT-A), which is costly but was ultimately found not to improve live birth rates (6). As innovation in reproductive techniques continues to accelerate, the need for a robust regulatory framework to evaluate their risks and benefits for patients will grow. Additionally, policy makers will need to explore how to evaluate the broader social and ethical implications of these techniques for society (4, 5).
The current United States (US) regulatory framework for reproductive techniques uses criteria that fail to capture all the techniques that should receive rigorous regulatory oversight. Formal regulatory review of safety, effectiveness, and social impact should become the default in reproductive medicine, with only a few exceptions. To support this argument, in this paper we will borrow important elements from conceptual work in the surgical domain to describe a framework for determining when new reproductive techniques should receive regulatory oversight and then present the basic outlines of the oversight needed.
Current Regulatory Landscape
Even for germline genome modification, the US does not have specific federal prohibitions that extend beyond limitations in funding. The limited regulatory oversight of reproductive techniques is exercised by the Food and Drug Administration (FDA) through a rule related to human cellular and tissue-based products (HCT/Ps), defined as: “articles containing or consisting of human cells or tissues that are intended for implantation, transplantation, infusion, or transfer into a human recipient” (7).
The rule effectively assigns one of two levels of regulation for reproductive techniques based on a single criterion: whether HCT/Ps are “minimally” or “more-than-minimally” manipulated (7). Techniques that are judged to involve minimal manipulation receive review that only requires the registration of facilities, following the guidelines for handling tissues, and screening for communicable diseases. More-than-minimally manipulated HCT/Ps are regulated with the same level of scrutiny as drugs and biologics. This includes a requirement for preclinical data and formal protocols for clinical studies to demonstrate safety and effectiveness before introduction of the technique into non-research settings.
The FDA defined minimal manipulation as ‘processing [that] does not alter the relevant biological characteristics of cells or tissues’ (8). Reproductive techniques such as ICSI were judged not to alter the relevant biological characteristics of cells and were thus assigned to the low level of regulation, requiring no assessment of safety and effectiveness.
To date not a single reproductive technique has gone through the higher level of regulatory scrutiny at the FDA, but two disruptive techniques are now being developed that the FDA has flagged as involving “more-than-minimal” manipulation: mitochondrial replacement therapy and germline genome editing (9) (Edited 5-17-2019: Of note, the FDA is currently prohibited by congress to use its funds to review submissions in which a human embryo is intentionally modified to include a heritable genetic modification [H.R. 1625], so any such review could only take place after this prohibition is lifted in a future budget exercise). Possibly, in vitro gametogenesis will also be classified as “more-than-minimal” manipulation (10). But we believe that this approach to identifying techniques for more rigorous regulatory review is inadequate, and that virtually all emerging reproductive techniques should receive greater review prior to introduction.
The Need for Full Regulatory Review
Experts have argued that dissemination of new health care interventions without rigorous regulatory review exposes patients to additional risks, renders patients veritable unwitting research subjects, and often involves unnecessary financial and personal costs (1-5). Rapid adoption of new interventions also makes it difficult to recruit clinicians and patients for randomized clinical trials. Although most clinics report the results of their clinical care to the Society for Assisted Reproductive Technology and/or the CDC, the incomplete and observational nature of the data make rigorous assessment of clinical effectiveness difficult (11, 12). In the surgical realm, various criteria have been proposed for identifying new techniques that merit full regulatory oversight (13). Applying these criteria to reproductive techniques would suggest that virtually all novel techniques should require full regulatory oversight (Supplementary Table 1).
Several characteristics of reproductive medicine accentuate the need for rigorous regulatory oversight. First, infertile patients are often desperate to try new approaches, as creating a family is of key importance in many peoples’ lives, and an inability to do so can cause substantial psychological and societal burdens (14). Compounding this vulnerability is the risk that special interests and commercial pressures in this field may drive clinicians’ treatment choices, potentially leading to exploitation of patients (5). For example, commercial incentives have likely played a role in the widespread adoption of the earliest iteration of PGT-A (using a cleavage stage biopsy and fluorescence in situ hybridization (FISH)), which after a decade turned out to reduce live birth rates (6).
Furthermore, intended parents, potential future children, and even the wider community, all have interests in appropriately introducing new reproductive techniques. For example, the early embryo’s environment (e.g. culture media) can affect birth weight and lead to increased long-term disease risks (e.g. cardiovascular problems) (15, 16). And for the community, reproduction has a complex interaction with core personal and social values that often leads reproductive techniques to present important questions related to societal implications and ethical concerns.
Given all these features of reproductive techniques, many clinical and policy experts have called for greater regulation to prevent premature dissemination of future techniques (1-5, 17). We concur with these arguments and extend them to propose that the default should be for all novel reproductive techniques to undergo full regulatory review. The related policy challenge is to define the narrow set of new techniques for which the current lighter regulatory process is sufficient.
Criteria for Light Regulatory Oversight
To address concerns regarding the risks for individual patients as well as broader social impact, we propose full regulatory oversight should be required unless a new reproductive technique meets all three of the following criteria: (1) it presents no more than “minimal” safety issues beyond those of currently used techniques; (2) it presents no risk of reducing live birth rates compared to the standard of care; and (3) it does not raise concerns of societal harms. Below, we describe these criteria in more detail.
Safety issues Identifying safety issues requires considering risks for both the intended parents and their potential future offspring. To judge the risks for the intended parents, we propose that the FDA assess a new technique’s risks that are additional to the risks of existing alternatives in reproductive medicine. If these additional risks are judged to be minimal, no full review would be required. For example, a minor variation to an existing technique (e.g. mock embryo transfer) will, in many cases, not add more than minimal safety issues as compared to the currently accepted technique.
To evaluate the risk to future offspring, we propose that only techniques that do not change the handling of gametes or embryos present no more than “minimal” safety issues. A narrow definition is prudent since we are not yet at a point of epigenetics and embryology where we can reliably predict what effects interventions will have (3, 18). It is thus reasonable to assume that anything we do, or fail to do, in how we deal with gametes and embryos (i) may affect the embryo, and (ii) may pose a potential significant risk (19). As 1.5% of US children are born after ART (20), the potential impact is significant. Of note, even when techniques are introduced into clinical practice after reassuring results from clinical trials, the FDA may frequently wish to require clinics to maintain long-term registries to be able to pick up and act on potential adverse health outcomes that appear later in life (3).
Risk of reducing live birth rates
This criterion allows light regulation only for techniques that do not present the risk of being less effective in achieving the primary outcome of interest for patients – live births (21). Minor variations on standard techniques should not present this risk. For example, there is no conceivable mechanism through which a dummy embryo transfer could reduce live birth rates. In contrast, using this criterion, the second iteration of PGT-A (using a blastocyst stage biopsy followed by comprehensive chromosome screening) would have been identified as potentially decreasing live birth rates, based on knowledge available at the time of its introduction (6).
Though challenging, identifying techniques that do not present ethical dilemmas or concerns about societal consequences values should be possible. For example, IVF “add-ons” like embryo glue do not present new social concerns.
The FDA may operationalise distinguishing between light and heavy regulation by assessing dossiers submitted by clinicians for light regulation, using these three criteria. Table 1 displays how these criteria could be applied to several future and recently introduced reproductive techniques to determine the extent of required regulation. Over time, the FDA will likely develop internal guidance on how to calibrate each criterion.
Procedures for Full Regulatory Review
For the vast majority of novel reproductive techniques that do not meet the criteria for light review, full review of safety, effectiveness and social impact should be required.
The review of safety and effectiveness should resemble the procedure and requirements for review of novel medications. However, it may be tailored to acknowledge differences in introducing reproductive techniques rather than drugs. For example, although they should be carefully assessed, randomized controlled trials might not be necessary for techniques attending to issues with low spontaneous recovery rates (e.g. when a woman born without a uterus gives birth after a uterus transplant) (22). The proposed framework for the evaluation of surgical techniques may provide inspiration (23).
Unlike existing pathways for regulatory review of safety and effectiveness, there is no model at the FDA for reviewing social impact and moral acceptability (24). To address this, we suggest two courses of action. First, a conceptual framework for assessing the social issues specific to reproduction should be developed, including a list of relevant considerations (e.g. potential for effects on our species). Second, the FDA should install a specialized interdisciplinary and objective advisory group to debate these issues. Having a special advisory committee to the FDA would offer the advantage of field-specific expertise like other countries’ statutory commissions (e.g. HFEA in the United Kingdom) but in a format that better fits the US socio-political context (25).
Potential Concerns About Regulation
Any expansion of regulatory oversight should be mindful of potential negative consequences. First, clinical trials can take years to complete, and regulatory review can prolong the time before all patients have access to the new technique. For example, the median time for New Drug Application approval was 7.8 months in 2016 (26). Second, the expense of clinical trials may deter the development of novel techniques. Finally, oversight may politicize medical issues. Taken together, expansion of oversight could slow down the progress of, and access to, innovations that turn out to be beneficial for patients.
Ideally, we too prefer self-regulation over formal regulatory oversight (4, 27). However, self-regulation is unlikely to be effective (1-3, 5). Professional associations (e.g. ASRM or SART) may not want this regulatory role. ASRM performs repeated reviews of new therapies to classify them as experimental or established medical practice, but ASRM stipulates that designation as experimental does not mean IRB approval is required and that their classification “is not intended to be the only approved standard of practice or to dictate an exclusive course of treatment”(28). Correspondingly, gynaecologists have been found to prefer an independent committee over their own professional association in this role (17). Furthermore, professional associations lack enforcement mechanisms (2). Attempts by surgical associations to increase formal clinical trial evaluation of new techniques, for example, suffered from low compliance rates (29). As such, we suggest the likely benefits of expanded regulatory oversight of novel reproductive techniques would outweigh the drawbacks.
Today, nearly all reproductive techniques are allowed to be clinically introduced in the US without formal research or independent review. This may expose patients, unborn children, and society to risks and may involve unnecessary costs. We therefore propose that the FDA should change their criteria so that almost all reproductive techniques be required to undergo a rigorous, independent and objective review of safety, effectiveness, and potential societal repercussions. Moving to an expanded regulatory approach would ensure that reproductive medicine can continue to innovate, whilst safeguarding the best interests of patients today and of our society in the future.
The views expressed are the authors’ own and do not necessarily reflect those of the National Institutes of Health, the Department of Health and Human Services, or the United States government.
Both authors have significantly contributed to the conception and the drafting of this paper.
We thank Dr. D. Wendler for reviewing the manuscript.
Clinical Center, Department of Bioethics, National Institutes of Health Intramural Research Program.
Conflict of Interest
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