Attachment B - Deceased Donor Intervention Research 45 CFR part 46

Issues Surrounding Deceased Donor Intervention Research under 45 CFR part 46

OHRP has asked SACHRP to consider whether and how certain provisions of the HHS regulations for human subjects research protections apply to research involving interventions conducted on organs from deceased donors^[1] before they are transplanted into living recipients. Building on the conclusions of the  2017 Consensus Study Report of the National Academy of Medicine (NAM), entitled “Opportunities for Organ Donor Intervention Research: Saving Lives by Improving the Quality and Quantity of Organs for Transplantation” (hereinafter NAM Report)^[2], SACHRP is asked to form recommendations on the questions below.

In the course of extensive discussions on this topic, issues were raised by SACHRP that are related to but potentially outside the scope of the specific questions, or that expand the context of the questions.  These issues are noted both before and at the end of this document.

OHRP has determined that deceased organ donors are not human subjects under the HHS regulations. The NAM report concluded that recipients of organs^[3] that have been subjected to research interventions, and in whom transplanted organs are now being studied for their function, efficacy, and safety, should be treated as research subjects. While the NAM Report addressed numerous issues affecting deceased donor intervention research (DDIR), the specific charge to SACHRP addresses only certain questions and recommendations affecting human subjects research protections under HHS jurisdiction. Specifically, when individuals are identified as needing an organ transplant, a two-part conversation process begins.  The precise contours of this process vary across transplant centers, but are generally similar in intent. The first part of the two-part conversation begins when a patient and health care provider discuss whether the patient should become a transplant candidate.  This first conversation usually includes some standardized education about transplantation and the candidate role. Discussion about transplant continues periodically with the health care team throughout the time during which the patient waits for an organ offer. That waiting time can vary from days to years.

In the first conversation, individuals are told about the process of organ transplantation, including the clinical risks. Individuals are also told about the potential availability of organs that may carry a risk of infection (formerly categorized as “increased risk” organs), and organs that may have a lower likelihood of functioning well or may have a shorter lifespan than most (called “non-standard” or “marginal” organs).  Potential recipients may decide at any time that they do not wish to receive offers of such organs. They are also free to change their minds at any time. During this first conversation, individuals could also be told about the potential availability of DDIR organs, given general information about DDIR and what participating in DDIR would entail for organ recipients, and perhaps could also be told about current IRB-approved research interventions on such organs. Individuals could decide that they do not want to receive offers of DDIR organs, but could change their minds at any time while awaiting transplant.

Transplantation does not occur until after the second step, which is the organ offer call.  This conversation takes place immediately before the transplant, when a suitable organ is offered to a potential recipient and that individual decides whether or not to accept that organ.  This second step is the only opportunity to obtain informed consent for a research intervention, as consent has traditionally been interpreted. In most situations, there will be only 30 minutes to an hour for the transplant surgeon, the facility and the potential recipient to determine, respectively, that an offered organ is clinically appropriate, surgical resources are available, and the organ is acceptable.

SACHRP has been advised that the request from OHRP has been prompted by the understanding that there is a lack of professional consensus in the community, and a lack of standardized practice, with respect to the application of the HHS regulations for human subjects research protections to research involving deceased donor organs that have been or will be manipulated and subsequently implanted in living human recipients. The diversity of practice probably arises from differing perspectives in the research, transplant, and ethics communities about how the requirements of the HHS protection of human subjects regulations apply to such research, the overlap between clinical practice and research, and the complex and novel ethical and practical considerations inherent in this unique context.

In January of 2019, OHRP requested that SACHRP explore this issue by responding to ten specific questions. The expectation is that SACHRP’s recommendations will inform HHS action, including issuance of guidance concerning the proper application of the HHS regulations for human subjects research protections to DDIR and whether a Secretarial waiver^[4] of certain regulatory requirements may be necessary with respect to such research.

A. The Unique Context of DDIR

In the process of learning about the ethical, regulatory, and practical challenges posed by this unique research context and responding to these ten questions, SACHRP has considered and discussed how the system and circumstances of organ transplantation affect a wide range of issues posed both by 45 CFR 46.116 and by the ethical bedrock on which the Common Rule is based.

Research involving manipulation of donor organs and their subsequent use in transplant recipients has several unusual structural characteristics. These include:

• The research involves two interventions (manipulation of the donor organ and transplant) that are separated in space and time, meaning that the primary research team may not be involved in the intervention on the living human participant. As a corollary, the individuals with whom the participant/transplant recipient interacts may only be involved in the research to the extent that it offers a clinical alternative to the patient.
• The lack of well-defined sites: while the deceased donor intervention may take place at a small number of institutions, transplant of the manipulated organ may occur at any of the over 250 transplant hospitals in the United States;
• A recipient’s decision to accept a manipulated organ must be made under severe time constraints. There are parallels for this kind of decision-making in other research settings, but in those settings the constraints are usually dictated by a patient’s clinical circumstances (e.g., research involving individuals with an acute MI or stroke). In DDIR the constraints arise from the limited window of viability for the donor organ.
• Although time constraints limit both the ability to convey sufficient information and sufficient opportunity to discuss and consider research participation, individuals on the transplant waiting list are a well-defined population who typically have frequent interactions with the healthcare delivery system. These circumstances provide other opportunities to support informed decision-making, opportunities that are absent in other clinical circumstances in which some IRBs have approved time-constrained research decision-making.
• The choice facing the potential participant in DDIR is unusually stark. Whatever the research-related risk, saying “no” to an organ offer generally means returning to an unstable and typically worsening clinical situation with no certainty of when another offer will be made. This decision stands in contrast to other time-constrained decisions, where the potential participant may generally choose between a research intervention and standard-of-care treatment, both of which are available at the time of the decision.
• The reality of the decision facing a potential participant (not whether or not to participate in research versus receiving standard-of-care treatment, but whether or not to receive a potentially life-saving organ by becoming a research subject) carries a heightened ethical obligation to make the decision-making process as clear and straightforward as possible for the potential recipient/participant.
• Individual research proposals cannot be considered outside the context of the organ transplant system as a whole. Donated organs are a scarce resource, and approving a particular research study may mean that organs are not available for other research, or, if DDIR becomes more common, for transplant as unmanipulated organs. Further, manipulation of donors has an impact on organs that are not the focus of the research: so-called “off target” organs.  DDIR thus may also implicate a broader group of potential recipients who will be human subjects, but are not the primary subjects of the research.
• The structural reality that DDIR must be managed as a scarce resource for the public good also has ethical implications. Ethical review in this setting must go beyond balancing risks of harm and potential benefits for individual participants and focus on the benefits to society from the production of generalizable knowledge, thus expanding consideration of individual DDIR studies to include their impact on the organ transplantation landscape as a whole.

We first respond to the ten questions, and then offer recommendations based on our responses.

B. Responses to Questions

IRB Approval and Informed Consent when transplant candidates are considered human subjects for DDIR:

Question 1. If the two-part process proposed by the NAM for seeking informed consent from transplant candidates offered organs as part of DDIR studies were implemented, would the information provided to a transplant candidate in the second part of such a process (at the time a specific organ that was subject to a research intervention is offered) substantially differ from, or be significantly more time-consuming to share than, the information routinely provided to a transplant candidate when offered an organ as part of clinical practice? Does this change if the organs are coming from high-risk donors?

Discussion: 

SACHRP has been provided with information from representatives from HRSA as well as external consultants at numerous meetings of the Committee and of the SACHRP subcommittees from June 2019 through March 2020. Notable points included the following: while currently there are only a limited number of IRB-approved studies relating to deceased donor organs that will be transplanted into living human recipients, the expectation is that the number of such studies will increase significantly over time. In addition, there was discussion that the length of time a harvested organ remains viable differs depending on the organ (e.g., heart, lung or kidney). Finally, both the gravity of the situation facing individuals on transplant waiting lists and the time constraints mean that the decision-making process (often conducted by telephone) that takes place when a DDIR organ is being offered could be less than optimal.

SACHRP discussed whether the first step in the NAM-described two-part process could include a discussion of currently approved IRB protocols that could be applicable to that individual, as well as a general discussion of what types of future intervention research might be approved. However, transplant representatives noted that the initial conversation could take place years before the actual transplant and that new protocols could be approved in the interim period. SACHRP discussed the desirability of a communication system such as a single website that could provide prospective transplant recipients with information on IRB-approved protocols. Representatives of the transplant community were divided as to the practicality of creating and effectively maintaining such a resource. Even were such a central resource available, SACHRP had concerns about placing the obligation to be informed on potential research participants, who might not be in a position to keep up with ongoing research, and even if they were vigilant, might not have learned about or be able to recall particulars if offered an organ from any specific study. Thus, the first step in the NAM process could provide potential recipients/participants with education about DDIR in general, but could not reliably provide relevant information about particular research in advance of the organ offer itself.

While clinical consent to receive an organ from a high risk donor provides many parallels to DDIR, differences between what has been deemed adequate for clinical as compared to research consent led SACHRP to conclude that research consent in this context would be expected to require more time and discussion than has usually been allotted for clinical consent.

Question 2. Should an IRB’s approval of DDIR be affected by circumstances specific to organ transplantation, including the following factors: (i) the time period available to a transplant candidate to accept or reject an organ offer; (ii) whether a transplant candidate is likely to die without a transplant or alternative treatments exist (e.g., dialysis for patients with end stage renal disease); (iii) the likelihood that transplant candidates will receive other organ offers, including offers of organs not subject to the same interventions; and (iv) the fact that any organ offered for transplantation, whether subject to a research intervention or not, must be individually accepted by a transplant candidate? Please explain.

Discussion:

SACHRP considers that an IRB’s approval of deceased donor intervention research (DDIR) will be affected as follows:

(i) the time period available to a transplant candidate to accept or reject an organ offer:

Yes, because this will affect the informed consent content and process.

(ii) whether a transplant candidate is likely to die without a transplant or alternative treatments exist (e.g., dialysis for patients with end stage renal disease):

IRBs routinely approve research in which the prospective participants have no standard of care options and may be facing death. The likelihood of death should not affect the IRB’s approval of the research, except in so far as it may compromise an individual’s decision-making at the time consent is sought. Individuals on the transplant list are at risk of death from their underlying condition; the offer of a research organ may provide an early opportunity for intervention, and refusal should not change their priority on the transplant list. Thus, a refusal of a DDIR organ does not change an individual’s risk of death from where it stood before the research offer, and it should not be considered a risk of the research (unlike any risk of death that may arise from the research intervention on the organ). That being said, there is never a guarantee of an organ offer, and the IRB must acknowledge that a prospective participant’s decisions will be significantly affected by the choice between acceptance of an immediate and potentially life-saving offer and deciding to continue to wait. This is particularly true because for many DDIR protocols, the risks of harm from participation, although greater than minimal, may well be lower than the risks of death or increased disability arising from waiting longer for a standard organ.

(iii) the likelihood that transplant candidates will receive other organ offers, including offers of organs not subject to the same interventions:   

This could affect an individual’s decision whether to accept a DDIR organ. It is an important aspect of consideration of alternatives to participating in research. However, it is not clear how the availability or unavailability of other organs should affect the IRB’s approval determination. Certainly, individuals who are unlikely to timely receive another organ offer will be motivated to accept a research organ. As in (ii), this should not affect the IRB’s approval of the research but will need to be considered in the process of obtaining informed consent.

Should DDIR become more common, it is also possible that approval of a research study could affect the supply of unmanipulated organs. That is, growth in approved DDIR could decrease the general availability of standard, unmanipulated organs, thus decreasing the likelihood that anyone on the transplant list would be offered a non-research organ.  The potential for such an impact must be evaluated by the IRB or a committee charged with scientific review in the context of organ transplantation.

(iv) the fact that any organ offered for transplantation, whether subject to a research intervention or not, must be individually accepted by a transplant candidate:

It is not clear what this question is intended to mean, nor why this circumstance should be regarded as specific to organ transplantation. Clinical consent (i.e., individual acceptance) is required for any surgical intervention unless there are circumstances that make it impractical or impossible, and affirmative research consent is required before a participant receives a research intervention – a requirement that is subject to even more restrictive constraints than apply to clinical consent. The challenge to IRB approval of DDIR arises from the particular context of this organ offer process, rather than from the requirement that an offer be accepted or declined.

Question 3. How practicable would it be for investigators to implement the two-step consent process proposed by the NAM? Specifically, is the second step of the proposed consent process feasible to implement given that it would occur at the time the organ is being offered to the transplant candidate?

Discussion:

The step one discussion of DDIR is practicable by any standard, because it can feasibly be added to existing general education about transplantation. This general education discussion, which begins when potential transplant recipients are in the process of committing to wait for an organ, already includes education about organs that, for various reasons, might be less desirable than standard organs (they might pose a risk of infecting the recipient, or might be expected not to last as long as a standard organ, or might not be as likely to be successfully transplanted). Potential recipients are educated generally about the reasons an organ might be designated as nonstandard and are told that they can choose not to receive some or all such offers but may change their decisions at any time. Similarly, general education about DDIR organs and about being a research subject in DDIR could easily be provided during the step one discussion, and that information could be revisited and updated during clinical visits while the potential recipient is waiting for an organ offer.

When any organ is offered, including any nonstandard organ, information about that specific organ is provided in the step two organ offer discussion. This second step, which occurs at the time of organ offer, is severely time constrained and made under circumstances that could be construed as unduly influential, or even coercive, because the possibly life-saving clinical offer of an organ is contingent on agreement to participate in research.^[5] Further, this step is likely to be conducted over the telephone by a transplant coordinator who is not an investigator on the DDIR protocol, raising additional barriers to provision of sufficient "opportunity to discuss and consider" participation. For all these reasons, it would be difficult for this step alone to meet traditional ethical and regulatory requirements for information, comprehension and voluntariness, but consent regulations require that, absent regulatorily specified exceptional circumstances, potential participants be informed of the particulars of a specific research protocol at the time they must decide whether or not to participate. Thus, it is this problematic second step in the process described in the NAM report that must satisfy the regulatory requirements for consent. It may be practicable for clinicians or investigators to have the conversation that constitutes the second step in the NAM process, but the IRB will face real difficulty in determining that this conversation, while adequate for clinical consent, fulfills the regulatory requirements for research informed consent as usually interpreted.

Question 4.  Would the two-step process, taken as a whole, satisfy the regulatory criteria for informed consent? If not, what would need to be included, and what circumstances would make regulatory compliance challenging?

Discussion:

Based upon the information provided to SACHRP, it is unlikely that the two-step consent process as a whole could meet the requirements for research informed consent, except in unusual circumstances when the first conversation takes place at a time when the research intervention is known and it is clear that a specific organ would be offered to a specific recipient. The step one process could include considerable information about what it means to be a research subject, how that differs from receiving treatment, and what accepting a DDIR organ means for recipients (including mandatory use of clinical data for research purposes, the possibility that recipients might be asked to consider agreeing to additional data-gathering interventions solely for research purposes, the DDIR currently underway, and a general description of the kinds of DDIR that could begin in the future and potentially be the source of offered organs).  Nonetheless, as noted in Question 3, step two is fundamental to the DDIR informed consent process and presents challenges to the usual interpretation of the consent regulations.

Waiver or Alteration of Informed Consent when transplant candidates are considered human subjects for DDIR:

Question 5. Should an IRB’s consideration of waiver of informed consent in DDIR be affected by the circumstances specific to organ transplantation, including the factors listed in question #2?

Discussion:

In order for an IRB to grant a waiver or alteration of any or all of the elements of informed consent, the IRB must find the following:

(i) The research involves no more than minimal risk to the subjects; (ii) The research could not practicably be carried out without the requested waiver or alteration; (iii) If the research involves using identifiable private information or identifiable biospecimens, the research could not practicably be carried out without using such information or biospecimens in an identifiable format; (iv) The waiver or alteration will not adversely affect the rights and welfare of the subjects; and (v) Whenever appropriate, the subjects or legally authorized representatives will be provided with additional pertinent information after participation.

The question asks whether the factors listed in question number 2 will affect the IRB’s consideration of waiver or alteration of informed consent. Those factors are:

(i) the time period available to a transplant candidate to accept or reject an organ offer; (ii) whether a transplant candidate is likely to die without a transplant or alternative treatments exist (e.g., dialysis for patients with end stage renal disease); (iii) the likelihood that transplant candidates will receive other organ offers, including offers of organs not subject to the same interventions; and (iv) the fact that any organ offered for transplantation, whether subject to a research intervention or not, must be individually accepted by a transplant candidate?

If the research is minimal risk research, meaning that: “the probability and magnitude of physical or psychological harm anticipated in the research are not greater in and of themselves than those ordinarily encountered in daily life, or in routine medical, dental, or psychological examinations,”  then the factors noted above should not affect the decision to waive or alter research informed consent.

Question 6. How should an IRB determine whether waiver or alteration of informed consent will not adversely affect the rights and welfare of transplant recipients?

Discussion:

IRBs routinely approve waivers and alterations of informed consent and make determinations that a waiver will not adversely affect the rights and welfare of participants. As in all research, the answer is dependent upon the context. If the research is truly minimal risk research, then the IRB would be expected to use its usual criteria and processes to determine that the rights and welfare of transplant recipients are not adversely affected.

Question 7. If it is not practicable to get consent for a study that is not greater than minimal risk, is it permissible to waive consent under 45 CFR 46.116(e) or (f)?

Discussion:

If the research is minimal risk research, the IRB finds that it is not practicable to obtain consent, and the research meets the other criteria for waiver or alteration, then a waiver or alteration of consent would be appropriate. In determining whether it is practicable to obtain consent, IRBs often base their decision on the availability of potential participants and the opportunity to have an interaction with a clinician or investigator. In the context of DDIR, there must be such an interaction to document clinical consent, and this necessary interaction might suggest that it is practicable to get consent and that a waiver is therefore inappropriate. Although typically a circumstances when there is an opportunity for interaction would not meet the impracticability component of the waiver provisions, DDIR presents unique circumstances in which consent is not practicable despite the opportunity for interaction, as argued in SACHRP’s response to questions 3, 4 and 8. This concern is the basis for the recommendation that a Secretarial waiver be required. If such a waiver is required for research that presents greater than minimal risk because obtaining adequate consent is generally not practicable, that same reasoning should justify the determination that it is not practicable to obtain consent when the research presents no greater than minimal risk.

Department or Agency Waivers of Regulatory Requirements:

Question 8. Is a Secretarial waiver necessary or appropriate for any DDIR? If so, please describe the scope of such a waiver, including which regulatory requirements should be waived, and whether the waiver should include alternate procedures to be followed for the conduct of the research. Would such waiver be necessary or appropriate if informed consent were required for all DDIR (i.e., if an IRB determined that the current regulatory requirements would not allow informed consent to be waived or altered for such research)?

Discussion:

SACHRP believes that a Secretarial waiver is both necessary and appropriate for research on deceased donor organs where those organs will be transplanted into living individuals, because the step one consent conversation is not sufficient to meet the regulatory requirements for research informed consent and the step two consent conversation is likely to be time-constrained and raise other issues of understanding and voluntariness. In particular, it may not be possible to satisfy the regulatory criteria that: (1) key information and all basic elements be conveyed in a way that facilitates understanding (.116(a)5 and (b)), and (2) participants have sufficient opportunity to discuss and consider participation in the research in circumstances that minimize the possibility of coercion or undue influence (.116(a)(2)).

The NAM Report described the two-step consent process from an ethically informed perspective, but without the regulatory perspective that SACHRP necessarily brings.  From a  regulatory perspective, only step two of the process constitutes a regulatory opportunity to consent (see Question 3). The first step is essentially general education about and a decision whether to receive an offer of a manipulated organ. The second step is consent to participate in a specific DDIR protocol as a research subject. In this context, SACHRP does not have concerns about the step one conversation, in which the recipient is introduced to the idea and implications of receiving an organ on which there has been a research intervention.

Since the particular research is not likely to be known at the time of the step one discussion, the step two discussion needs to satisfy all of the elements of consent. In other words, the discussion at the time of organ offer constitutes the research consent, from the perspective of the usual interpretation of the regulations. Accordingly, since the step two process alone is unlikely to be consistent with this usual interpretation, the Secretary could waive the requirement at 45 CFR 46.116(a)(2) that: “An investigator shall seek informed consent only under circumstances that provide the prospective subject or the legally authorized representative sufficient opportunity to discuss and consider whether or not to participate and that minimize the possibility of coercion or undue influence” and also the required elements of consent at 45 CFR 46.116(b). Provision of such a waiver would be conditioned on satisfying 45 CFR 46.116(a)(5)(i), the requirement for a concise and focused presentation of key information, which would be presented as part of the step two discussion, and on the preparation of a complete consent form, satisfying 45 CFR 46.116(b), which would be made available to the transplant recipient after the step two discussion but as soon as possible, and no later than upon arrival at the transplant center.

In the few cases where the details of specific research are known before the organ offer, and there is thus an opportunity to discuss these with potential participants, a Secretarial waiver of the same provisions described above could be conditioned on the same requirements for presenting key information during step two, but also on satisfying the 45 CFR 46.116(b) required elements of consent as part of the step one process.

Question 9. The NAM report recommended three independent but affiliated and cooperative structures.  One is a single IRB, which could be a central IRB or an IRB of record, with enough scientific, ethical, and regulatory expertise to address organ donor intervention research.  A second recommended central structure is the Donor Research Oversight Committee (D-ROC). A third recommended structure consists of one or more data and safety monitoring boards with the appropriate expertise to oversee the conduct of DDIR. Does SACHRP believe these structures would help improve the quality of the system of human research protection programs for DDIR?

Discussion:

SACHRP agrees that these three entities -- the single IRB, the D-ROC, and the DSMB(s) -- would help improve the quality of the system of human research protection programs for DDIR. In particular, the D-ROC would be an appropriate group to assess the impact of DDIR on the availability of unmanipulated organs.  It is also worth noting that, unless and until the number of DDIR studies increases greatly, a single standing DSMB might be well-positioned to assist in assessing the progress and effects of DDIR on transplantation overall.

SACHRP regards a single, central IRB with a national scope as an important source of standardization and consistency in DDIR, but notes that in order adequately to protect patient-subjects who are transplant recipients, the single IRB must be well-equipped for broad and comparative consideration of ethical and regulatory issues as well as transplantation science. (For instance, it will be important for the single IRB to distinguish between minimal risk as a regulatory criterion and a clinical determination that the risk posed by a particular DDIR protocol presents minimal incremental risk in the context of the risks posed by transplantation of standard organs.) The single IRB may also be best positioned to incorporate the perspectives of transplant recipients and experienced research subjects into its protocol reviews on an ongoing basis. Lastly, DDIR is likely to constitute only a small proportion of the reviews of conducted by an existing IRB. A single IRB will be necessary to ensure consistent interpretation of risk and benefit in this unique circumstance, and to promote a single understanding of the ethical requirements for such research in both the research and transplant recipient communities.

While SACHRP strongly supports the establishment of these entities, the committee also recognizes that developing a single, national IRB as well as the D-ROC and DSMB, will take time and resources. The committee also notes that most, if not all, DDIR protocols will require single IRB review under the Common Rule. Accordingly, until such time as these entities are established, all of the recommendations in this report should apply to the single reviewing IRB, regardless of its location. Importantly, all DDIR research should go through the national or other single IRB, regardless of whether or not it is deemed to be minimal risk. The decision not to require establishment of central oversight and management acknowledges the importance of this research, but should not be interpreted as lessening the need to establish these entities, which should be proceed as quickly as possible.

Question 10. Should these structures of IRB oversight also address research in which transplant recipients receive non-targeted organs (organs from donors that were subject to research interventions that were targeted only toward other organs in the same donor prior to procurement)?

Discussion:

Yes. SACHRP would very much welcome more information about non-targeted organs in order to improve our understanding of the issue of consent in this context, but in general non-targeted organs appear to raise essentially the same issues as targeted organs. Whether non-targeted organs are affected by research interventions on targeted organs seems highly context-specific, but in many cases, the only interventions on a research participant will be (1) the receipt of a manipulated organ; (2) additional sample and data collection. Given that the risks associated with (1) are the major risks of the protocol, and that recipients of non-targeted organs would be exposed to these same risks, it would be consistent to consider them research participants except in circumstances in which the intervention is known not to affect the non-targeted organ.

C. Recommendations

(1) The three independent, affiliated, centralized, and cooperative structures recommended in the NAM report – the single IRB, the D-ROC, and either a standing DSMB or a study-specific DSMB for each protocol – should be created. A single national IRB to review all DDIR protocols will promote completeness, consistency, and regulatory compliance, and maximize attention to respect for persons, beneficence, and justice in DDIR under the unique constraints of organ transplantation. 

Until such time as these entities are established, the following recommendations should be implemented by the single IRB for each DDIR protocol wherever possible.  Some recommendations (e.g., the development of standardized educational information about DDIR and the creation of a website and hotline for protocol-specific information) may be implemented centrally by the appropriate entities.  Finally, SACHRP trusts it is clear that, although these recommendations focus almost exclusively on the consent form and process in DDIR, any IRB reviewing a DDIR protocol must determine its compliance with all of the regulatory criteria for approval of research.

(2) Secretarial Waiver Required:

While SACHRP recognizes that, in practice, some IRBs approve individual protocols that recognize consent discussions conducted under extreme time constraints to be compliant with the regulations, SACHRP does NOT equate DDIR decision-making with that more general context.  Instead, our goals are (1) to standardize decision-making policy and practice in an important developing research area that has the unique features we have described and (2) to do so in a manner that maximizes autonomy and reasoned decision-making for an identified cohort of potential patient-subjects.  (It is our hope that some of our recommendations may be adaptable to the broader context of time-constrained decision-making in general, but that is not our goal here.)

SACHRP believes it will be difficult to find that DDIR presents no more than minimal risk to participating organ recipients but recognizes that this determination should be made by the IRB on a study-by-study basis. Except in the rare case where the IRB determines that the research presents no greater than minimal risk and subsequently waives the requirement to obtain informed consent, the time constraints of the organ offer call require the following conditions to be deemed adequate in terms of both regulatory compliance and ethics:

1. a Secretarial waiver of 45 CFR 46.116(a)(2) and (b) at the time of the organ offer consent process is necessary,
2. 45 CFR 46.116(a)(5)(i) is NOT waived. Because of the time constraints, the development of a clear and robust key information summary that satisfies 45 CFR 46.116(a)(5)(i) is essential.
3. Most importantly, this key information summary must be used during the organ offer call.  Conveying key information about the DDIR study is central to the consent process during that call.  For each DDIR protocol, a telephone consent script based on the key information summary must be prepared for use at the time of organ offer.  This oral version of the key information summary can convey a minimally acceptable amount of meaningful information that can fit the time constraints of the call.  An opportunity to ask questions must also be included (and may be answered, at least in part, by using the key information summary and other parts of the complete consent form as a reference- see (D), below).  The research consent process during the organ offer call should adhere to the model provided in 46.117(b)(2) for witnessed oral presentation of key information. Training in use of the consent scripts and provision of access to further resources to respond to potential recipients’ questions must be mandatory and completed before any organ is offered from the relevant protocol.
4. An information form to be given to the recipient that fully satisfies the requirements at 45 CFR 46.116 for consent forms must be prepared by study PIs and approved by the single IRB for use by the transplant center during the organ offer call (step two of the two-part process described in the NAM report) and to be provided to the recipient after arrival at the transplant center.  Recipients should review and sign the form to attest to its receipt and presentation at the first practical opportunity, but are not required to do so before surgery. The Secretarial Waiver is required in recognition that the decision to accept an organ must be made at the time of the organ offer call. 
5. AND the following recommendations must be implemented and followed as conditions of the waiver.

The recommendations that follow are both independent recommendations and requirements for use of the Secretarial waiver.

(3) In the initial education session and subsequent clinical interactions before receiving an organ offer (collectively step one of the two-part process described in the NAS report), potential transplant recipients are told about high risk or non-standard organs and about why it is reasonable to offer such organs.  Potential recipients consider whether they would be willing to receive offers of such organs and are free to decide that they do not wish to be offered non-standard organs.  While they wait for an organ offer, the health care team may seek to persuade them of the benefits of accepting a non-standard organ, and they may change their minds and agree to accept an offer of a non-standard organ at any time, but they may also decide to persist in waiting for a standard organ.  Similarly, potential recipients should be told about DDIR organs, given standardized general education about DDIR, about how acceptance of a DDIR organ would make a recipient a research subject and what that would mean in this context, examples of some current trials, and a brief explanation of what will happen when offered such an organ.  Potential transplant recipients should be afforded the opportunity to state that they do not wish to receive offers of DDIR organs; they should be informed that they may change their minds at any time, and they should be offered the opportunity to do so at any time while awaiting an organ offer.  The team may seek to persuade them of the benefits of considering an offer of a DDIR organ, but potential recipients remain free either to refuse to be offered a DDIR organ or to agree to consider such an offer.

 (4) Standardized education about DDIR for potential transplant recipients should be approved by the single IRB that has been established to review DDIR at a national level.

 (5) Standardized education about DDIR for transplant teams, especially for transplant surgeons, coordinators, and any other personnel likely to interact with recipients offered DDIR organs, should be approved by the single IRB and made mandatory for personnel at all transplant centers likely to be provided with a DDIR organ.

 (6) The following additional resources must be developed and periodically updated so that potential recipients who choose to do so can stay apprised of current DDIR protocols and so that any potential recipient may ask questions of personnel knowledgeable about particular DDIR protocols:

• A website, designed with the principles of accessibility and health literacy, that provides a synopsis of approved and active DDIR protocols
• A telephone hotline, accessible at all hours, that can answer potential participant questions about particular protocols in the context of an organ offer.  Such a resource could help to ameliorate the problem that the transplant team offering a DDIR organ might know only the broadest details of the particular protocol applicable to that organ, and thus might not be able to answer specific questions.

 (7) Additional protections similar to those offered by the emergency exception to informed consent – for instance, consultation with the community of potential transplant recipients about particular DDIR protocols before they are implemented – may be considered and encouraged or required by the single IRB, as may other means of sharing experiences in effectively implementing the requirements of the Secretarial waiver.

Justification for Secretarial Waiver

SACHRP believes that the above recommendations are consistent with the principles of the Belmont Report.

Respect for Persons and Beneficence:

SACHRP is confident that an ethically appropriate balance of respecting and supporting autonomous decision-making and maximizing the potential for transplant recipients to benefit from what is learned through DDIR is achieved by:

1. the oral provision of key information during the organ offer call to potential transplant recipients about the particular DDIR protocol that has manipulated the organ being offered, which is
2. preceded by required information about DDIR in general and the implications of receiving a DDIR organ and being a DDIR subject, by the opportunity to opt out of DDIR organ offers, and by periodic opportunities to learn about ongoing DDIR studies, and which is
3. followed by provision of a consent form that fulfills all the requirements of 45 CFR 46.116.

Although in most instances there will be insufficient time during the organ offer call to consider and discuss all of the elements of consent enumerated in 45 CFR 46.116(b), there will be enough time to briefly consider and discuss key information as provided in 45 CFR 46.116(a)(5), thereby providing potential transplant recipients with a minimally sufficient opportunity to decide whether to accept a DDIR organ, and thus enroll in the relevant research, without jeopardizing that recipient’s potential to benefit from receipt of the offered organ and still preserving the organ’s availability to benefit another potential recipient should the first offer be refused.  SACHRP’s conditions for the Secretarial waiver are therefore consistent with respect for persons and beneficence.

Justice:

SACHRP heard presentations from the transplant community suggesting that the decentralized management and oversight of the organ transplant process is a barrier to successful and equitable implementation of DDIR. In particular, transplant centers and organ procurement organizations may have concerns that DDIR could pose unacceptable ethical, reputational, and compliance risks, with the result that many are currently reluctant to participate in such research.

The unwillingness of the community to broadly embrace DDIR has several consequences. First, it makes this research more difficult to do, delaying much needed innovation that could expand the pool of useable organs. Second, trials that are conducted may be less generalizable, given the systematically limited pool of participants. Finally, selective participation raises concerns about justice. Should DDIR validate an intervention that improves organ viability or increases the pool of useable organs, all individuals needing organ transplant will benefit, but the burden of the research would be borne by recipients at the relatively small number of sites that take the institutional risk to conduct such research. 

It is SACHRP's hope that our recommendations will help allay some of the concerns about the ethics and compliance aspects of this research. As with all research, each protocol must be reviewed for ethics and participant protections, but the Committee believes that there is nothing inherently unethical about DDIR as a whole. In addition, central oversight and management of the organ transplant enterprise would ensure fair distribution of research burdens and generalizable results and would help assuage concerns about individual institutional exposure^[6].

For these reasons, satisfying the conditions of the Secretarial waiver as set forth in our recommendations constitute alternative procedures that are consistent with the principles of the Belmont Report.

D. Additional Considerations

FDA-Regulated DDIR:

SACHRP has also considered that a Secretarial waiver will only apply to HHS-funded research and not to FDA-regulated DDIR, although many, if not most, DDIR protocols will seek to develop FDA-approved interventions to extend or improve the viability of transplantable organs. Unlike the Common Rule, the FDA regulations do not allow for a Secretarial waiver of any of their provisions, instead providing two existing exceptions to the requirements for informed consent: 21 CFR 50.23 provides for research consent when an individual is unable to give consent, time is not sufficient to obtain consent from their legally authorized representative, and participation in research offers the best clinical choice in a life-threatening situation; 21 CFR 50.24 provides for planned emergency research in a population of interest. In this latter circumstance, the ability to obtain voluntary informed consent is constrained by the situation but that constraint is anticipated as part of the research design.

SACHRP does not believe that DDIR fits the intent of 21 CFR 50.24, because the potential subjects of DDIR do not lack decision-making capacity and do not meet the specified criteria in 21 CFR 50.24(a)(1), and completely forgoing all individual consent discussion is neither contemplated nor justifiable in DDIR. The FDA crafted specific exceptions to the general informed consent requirements because the Agency believed that those general requirements were not satisfied in the two situations described at 21 CFR 50.23 and 50.24, and SACHRP has recommended that a Secretarial Waiver is necessary to satisfy those same general provisions. Accordingly, it is likely that the FDA will find that rulemaking is necessary to conduct DDIR in a manner that is compliant with its regulations. In order to avoid further delays and barriers to the conduct of this important research, SACHRP recommends that the FDA signal its use of enforcement discretion in this area pending final rulemaking, as it did during the rulemaking to allow waivers of informed consent.

Conclusion

SACHRP commends the transplant community for its diligence and conscientiousness in ensuring that transplant recipients are adequately protected when receiving an organ on which a research intervention has been conducted, and for the significant progress that has been made in setting the stage for implementing the NAM recommendations and our follow-up recommendations contained herein. DDIR raises important issues at the complicated intersection of clinical and research consent, and addressing these issues productively could significantly improve the organ transplantation landscape.  We also believe that this effort could serve as a model or starting point for considering other research contexts that present challenges in learning healthcare systems and similar settings.

SACHRP is ready to assist HRSA and the transplant community in further developing and implementing our recommendations to satisfy regulatory requirements and to protect the rights and welfare of transplant recipients considering offers of DDIR organs.