Introduction There is currently significant attention to the distribution of final study data and results, both to the subjects who participated in the research and to the public at large. SACHRP has determined that there are four aspects of returning research results to subjects and releasing the results publicly, with overlap of the concepts along a spectrum: Return of incidental findings to subjects Return of individual study results to subjects Return of general study results to subjects Public release of study data SACHRP partially addressed the issue of public release of data in December of 2013 by providing commentary in response to the June 4, 2013, Food and Drug Administration (FDA) Request for Comment relating to the availability of masked and de-identified non-summary safety and efficacy data. While this commentary was focused on the issues presented in the FDA request for comment, it also addressed some of the broader issues associated with the public release of study data. SACHRP plans to address each of the remaining three topics in individual recommendations in order to provide targeted assessments of the ethical, regulatory, and administrative issues raised by each. While there is overlap among the concepts, as shown above in the linear Venn diagram, SACHRP believes that each topic is best addressed individually for clarity. Currently there are several processes being implemented or considered for sharing study data publicly, including but not limited to the direct provision of general study results to research subjects. At the broadest level are public releases of study data in formats such as ClinicalTrials.gov and published medical journal articles. This information is available to subjects just as it is to other members of the public, but does not involve a specific effort to provide the data directly to the subjects, and is generally written for a medical rather than a lay audience. There are also other data sharing proposals where data is shared upon specific request, such as the EMA proposal to enable access to full data sets by interested parties, the FDA proposal to enable access to masked and de-identified non-summary data by interested parties, and the EFPIA and PhRMA “Joint Principles for Responsible Clinical Trial Data Sharing.” The Joint Principles also endorses, as an additional mechanism for transparency, the provision of factual summaries of clinical trial results to research participants. Several companies have initiated programs to share such results. These efforts have been received positively by many entities, such as patient advocacy groups and independent researchers. This document will focus on the return of general research results to the subjects who participated in the research. Subsequent SACHRP recommendations will focus on return of individual results and the return of incidental findings to research subjects. Ethical Foundation The provision of general research results to research subjects is supported by the principles of Respect for Persons and Beneficence. Subjects make an autonomous decision to participate in research, and in so doing help to create scientific knowledge that is valuable to society and to other individuals. One means to provide recognition and appreciation for this contribution is to provide subjects with a summary of the results of the research and interpretation, which helps to build a sense of participation and partnership in the development and makes their experience more fulfilling. In addition, the information may prove valuable for the subjects or their families in making future decisions regarding their health or welfare. For these reasons, this policy has the potential to lead to greater public trust in research and greater willingness by individuals to participate in research, which will increase the development of new knowledge and interventions for the public good. Regulatory Status The HHS, FDA and HIPAA/HITECH regulations are silent regarding the return of general results to research subjects, and neither require nor disallow this activity. Therefore, this SACHRP recommendation is largely extra-regulatory. However, SACHRP believes that the agencies should take steps to promote the return of general results to subjects, due to the value of providing general results to subjects. SACHRP believes that the most important agency action is for FDA to provide clear guidance on how clinical investigators and sponsors can avoid unlawful promotion of medical products when providing general results to subjects, as this would greatly contribute to sponsors’ comfort with providing such results to subjects. SACHRP also encourages FDA and OHRP to address the role of various parties in return of research results. For instance, agency guidance on whether an IRB needs to review the communications of research results to subjects would help the regulated community to efficiently implement such policies. These issues are discussed in greater detail below in the section entitled “SACHRP Recommendations to Federal Agencies on Best Practices to Promote the Return of General Results to Subjects.” Ethical and Administrative Considerations Risks to Subjects or Others One consideration is whether there are potential risks to subjects that result from the provision of general results of research studies. General results will usually not provide a subject with individual knowledge that will be actionable, and are often also available in other formats such as ClinicalTrials.gov and journal articles. However, in rare cases there may be potential for misuse or misunderstanding of the results of the research. For instance, subjects could theoretically receive information that causes them to take inappropriate medical or personal action. For example, a subject might decide to take aspirin for the prevention of heart disease without physician involvement. However, this concern is much more pronounced with the return of individual results or incidental findings. Investigators and sponsors should be aware of the potential for subject misunderstanding of the clinical importance of results, and make clear to subjects the limits of applicability of these general results to individual cases. It may be warranted to recommend that all general results should have a disclaimer that these are not “clinical results” and should not be used to take action without proper guidance from healthcare providers. Additionally, in certain research such as in studies of illegal or socially unacceptable behavior such as illicit drug use or sex work, providing results to subjects might create a risk of a breach of confidentiality, and in small studies with limited numbers of subjects, there might be potential for subjects to identify themselves and other subjects. Investigators and sponsors should consider whether the return of results in these types of research could create risk, and consider whether the risk outweighs the benefits of returning the results. Benefits to Subjects or Others In addition to risks, there may be direct benefit to subjects that result from being provided with the general results of research studies. The information may assist the recipients in future decisions regarding their health or welfare, such as future choices about the use of certain classes of drugs or family planning decisions. In addition, the provision of general results should lead to increased trust and participation in research, and thus support the development of knowledge that is beneficial to others. Inclusion of Plans for Return of Results in Protocol As of the time of this recommendation, many sponsors are in the in the process of developing programs for the return of general results. Therefore, provisions for the return of general results are generally not included in protocols or otherwise prospectively described to government agencies, IRBs, institutions, or investigators at this time. However, as these programs become established, they should be described in protocols and other research documents prospectively, so that the entities involved in research can appropriately plan for the conduct of the program. Prospective disclosure will assist in preparation for the activities, such as maintenance by investigators of subject contact information. The protocol should provide the basic information regarding the program for the release of the data, including what information will be released, who will do so, and when the disclosure is expected to take place. The protocol description should be very general, and does not have to provide the administrative details of the program. However, investigators and institutions should be instructed, whether in the protocol or separately, if there are actions they need to take such as keeping subject contact information readily available after the study is closed. The IRB should also understand if, and how, and for how long, such information is to be retained, and confidentiality assured during that retention period. In addition, or alternatively, institutions and IRBs may wish to request plans from investigators or sponsors for return of results to subjects as part of the IRB submission. However, it is important to stress that return of general results is not required by regulation, and the costs and burden of the release need to be balanced with the benefit that will likely result. Inclusion of Plans for Return of Results Consent Form and Consent Process The intent to provide general research results should be included in the consent form so that subjects are informed of the plan as they consider participation in the research. The consent form should provide the basic information regarding the program for the return of the research results, including a basic description of the information that will be returned, who will do so, and when the disclosure is expected to take place. A brief description will be sufficient. SACHPR is currently working on recommendations regarding the informed consent process, and wants to ensure that this is not interpreted as an issue requiring lengthy disclosure. In research studies involving incapacitated adults, Legally Authorized Representatives (LARs) provide consent for the subjects, and in studies involving children, parents or guardians provide consent for the child. The fact that these populations are included in research should not be a prima facie factor in a sponsor’s decision not to provide general research results. The return of results will provide the same benefits for these populations and their parents, guardians and LARs. When adult subjects regain capacity, or when children reach the age of majority, SACHRP does not recommend re-consent for the return of results as a requirement for providing the results. Generally, when research activities are ongoing, subjects who regain capacity or reach adulthood are asked if they wish to continue participation in the study. However, given the value of the provision of general results, the likely low risk, and the fact that these individuals are no longer research subjects after the study has ended and the results are provided, the administrative burden of attempting to obtain consent solely for the return of the research results due to this change in status is not warranted. The sponsor or other party providing the results to subjects should be able to rely upon the original consent provided by the parent, guardian or LAR. IRB Review One issue that arises in consideration of return of general research results under both HHS and FDA regulations is the role of the IRB. The return of general results may be a planned activity at the time of initial IRB review, or the decision to share results may be made after initial IRB approval but while the study is still open with the IRB, or the decision to share results may be made after the research is closed with the IRB. Consideration of Return of General Results Proposed at Time of Initial IRB Review If there is a plan in place for the return of general research results to subjects at the time the research is provided to the IRB for initial review, the sponsor should describe the plan in the protocol or other study documents, and describe the plan in the consent form. IRBs may wish to proactively solicit this information in the submission forms. However, this is not a regulatory requirement under either FDA or HHS regulations. The reviewing IRB must consider whether the plan to provide general results to subjects will affect the applicable criteria for IRB approval at 21 CFR 56.111 and 45 CFR 46.111, similar to any other component of research. However, SACHRP’s assumption is that the return of general results to subjects will ordinarily not negatively affect the criteria for IRB approval and will unlikely be a cause for deferral or disapproval. Consideration of Return of General Results Proposed After Initial IRB Review, But While Study is Still Open If return of general results is proposed after initial IRB review has occurred, the IRB should review it as a change in research. The IRB should consider whether the change in research changes the acceptability of the criteria for IRB approval of research. The change can be expedited if it is considered not to increase risk or change the risk-benefit relationship. Re-consent is necessary if the new information might affect the willingness of subjects to continue participation. This is most likely to occur in studies with long term follow up, or important interim data. Consideration of Return of General Results Proposed after IRB Review Has Ended and Study is Closed with the IRB An issue that currently arises is whether IRB review is required if the return of general results is initiated and conducted after the study has been closed with the IRB. There are three arguments for the position that research results communications do not need IRB review if the study has been closed with the IRB. The first is that the activity is no longer research and there are no human subjects in the activity. The HHS definition of human subject is an individual about whom an investigator intervenes or interacts to collect data, or about whom an investigator obtains private identifiable information. A research result communication after a study has ended involves none of these conditions. Similarly, the definition of a human subject under the FDA regulations is an individual who is or becomes a participant in research, either as a recipient of the test article or as a control. In this case, the study has ended and has been closed with the IRB, so there is no longer open research and the individuals are no longer subjects in the research. Rather, they are former subjects. The second argument for the IRB not reviewing research result communications after the study is closed is that they are unlikely to affect the criteria for IRB approval. They don’t affect subject recruitment, in that they are not coercive or unduly influential as to the subject’s decision to join or stay in the study. They don’t affect equitable selection of subjects, as both the designed and the actual selection of subjects is a finished issue by this point. The communications don’t affect subject safety monitoring, as the subject has already been exposed to the physical risks. They won’t adversely affect vulnerable subjects. Finally, they enhance the consent process to the extent they extend the consent process with more information after the study has ended. The third argument is that research data is often released publicly on clinicaltrials.gov or in medical journal publication, and IRB review is not required for those activities. The only difference in this case is that these results are sent directly to the subjects. There are three arguments for requiring IRB review even after the study is closed. The first is the possibility of information risks to subjects in the form of a breach of confidentiality, such as revealing that the subject was a participant in the research. As a worst case scenario, a CRO and sponsor could use a postcard with no envelope which says something like “Thank you for your participation in the HIV vaccine trial. The trial showed the vaccine was not effective.” A second risk is that subjects will misinterpret or misunderstand the information they receive, and take an inappropriate action. Finally, it is worth questioning whether an IRB’s duties to subjects completely end once the study is closed with the IRB. For instance, if there were a breach of confidentiality or new risk information important to the subjects, it is likely that the IRB would feel that it had the authority and the duty to take appropriate actions to protect and inform subjects. However, in SACHRP’s opinion, these arguments are not sufficient to make IRB review of return of results a requirement in all cases if the study is closed with the IRB, as addressed in the SACHRP recommendations at the end of this document. However, institutions and sponsors can require IRB review based on internal policies if desired. Furthermore, IRBs can serve as a resource when there are questions about returning results, and in this circumstance can provide consultation or an opinion without having to reopen the study. Finally, SACHRP would like to note that, like subjects, IRB members are often interested to learn of the results of research studies as they normally do not learn of the results. For that reason, sponsors, investigators and institutions may wish consider providing the results to the IRB at the same time as the subject, not for review but to enhance a sense of participation and partnership and to make the IRB process more fulfilling to staff and board members. An Alternative Approach: IRB Review of Standard Processes for Return of General Results rather than Protocol-by-Protocol Review One approach currently used for the regulatory oversight of tissue banks that gather, store and distribute human tissue for research activities is to have IRBs review the processes for gathering, storing, and protecting the privacy confidentiality, as opposed to looking at the collection and storage as part of each individual research protocol utilizing the tissue. If an institution, IRB or sponsor does wish to have oversight, then a similar system of oversight could be applied to data sharing activities, particularly those that occur after a research project is “closed” with the IRB. Under such a system, industry and government sponsors could establish standard procedures for data sharing, and obtain IRB approval and continued oversight of those standard procedures, and then any data sharing and the subsequent analyses done in compliance with the policies would not need individual IRB review. If there were reason to vary from the standard procedures, this could be presented to the IRB as a formal amendment or one-time deviation for prior review and approval. Third Party Review An issue that arises in the consideration of returning general research results is whether a party other than the sponsor and investigator should draft or review the proposed communication in advance of the distribution. Potential third parties could include IRBs, other institutional committees, contracted parties such as honest brokers, or government agencies. The potential benefits of a third party review include an assurance of accuracy, objectivity, understandability, and consistency of the communication. The third party might also assess whether the information provides value to the subject in making future decisions about health care or family or life planning. The third party review does not need to assess whether the communication will be coercive or unduly influential regarding participation in the research, because it will be provided after the individual has finished participation in the research. Third party review could be provided for each proposed communication of general results, or it could be limited to review of a template for providing the results which would then be utilized by the party actually providing the results. The benefits of third party review, as described above, will need to be balanced with the administrative burden. Costs An important consideration in the return of general results to research subjects is the cost. Pilot programs show that it costs a considerable amount to provide the administrative support necessary for the preparation, review, and return of the general results, whether those activities are performed by employees of the sponsor, investigators, or third parties. These costs will generally be borne by the sponsor, but other parties such as investigators and institutions may also incur costs. The costs include re-writing the information in lay language, any third party reviews, the distribution of the information, and the cost of maintaining the contact data of the subjects. At least one sponsor has initiated a pilot program involving the use of a third party to write the communication and distribute it to subjects, and has found that the cost will be difficult to sustain in the long term due to the expense. SACHRP General Recommendations 1. SACHRP believes that the return of general research results, in most cases, is a beneficial activity that has the possibility to enhance public trust in research, enhance willingness for subjects to participate, and will increase the development of new knowledge. Therefore, the return of general research results should be supported by all parties involved in the conduct and oversight of human subjects research, including government agencies, sponsors, institutions, investigators, and IRBs. 2. The return of general research results should be conducted equally with positive, equivocal, and negative research results. Regardless of the study outcome, it is valuable to let subjects know the outcome. If the results are equivocal or negative, the communication should outline that even though the study did not produce scientific knowledge such as the direct development of the medical product that was tested in the research, it has contributed information toward the development of scientific knowledge as a whole. The scientific enterprise depends on the development of knowledge that results from both positive and negative research results. 3. The benefit of returning general results will not be equal across all studies, and in some studies will not be appropriate, or possible, or may not justify the administrative burden and expense. In some studies the results may be of limited interest to subjects. In other studies, it may be impossible to provide results because the subjects are de-identified or anonymous, for example certain tissue banking activities, research conducted under a waiver of consent, exempt studies, and cluster randomized studies. In addition, some studies may be of insufficient scientific rigor to justify the return of results, such as research required of students in order to graduate. Also, in studies of illegal or socially stigmatizing behavior such as illegal drug use or sex work, providing results to subjects might create too great a risk of a breach of confidentiality and subsequent harm. Finally, in small studies with limited numbers of subjects, there might be potential for subjects to identify themselves and other subjects, thus raising superseding concerns about breaches of confidentiality or privacy. 4. SACHRP believes that the return of general research results applies to social and behavioral research as well as biomedical research. The ethical foundation for providing general results applies equally to all research subjects regardless of the nature of the research although, as noted, the factors relevant to this decision must be considered on a protocol by protocol basis. SACHRP Specific Recommendations to Federal Agencies on Best Practices to Promote the Return of General Results to Subjects As noted previously, the HHS, FDA and HIPAA/HITECH regulations are silent regarding the return of general results to research subjects, and none require nor disallow this activity. 1. SACHRP believes that the agencies should take steps to promote the return of general results to subjects, due to the overall benefit of the activity. To this end, the agencies should issue guidance or other forms of communication that describe how regulated parties can return general research results without violating any regulations or guidance. Food and Drug Administration (FDA) The most significant potential regulatory concern of the regulated industry, particularly commercial sponsors and sponsor-investigators, is that return of research results to subjects will be interpreted by the FDA as unlawful pre-approval or off-label promotion of a medical product. Therefore, SACHRP recommends that FDA provide guidance on how sponsors may return research results without putting themselves in jeopardy of violating these prohibitions. As with any guidance, the provision of examples of acceptable and unacceptable communications or practices will assist the regulated community in complying with the FDA’s expectations. The FDA should address the following issues: Which entities, if any, should not be involved in drafting the information to be returned to subjects? Potential entities include the sponsor, investigators, institutions, and third parties such as honest brokers. If FDA were to clarify whether any of those parties are not acceptable, it would assist sponsors in choosing the appropriate party to draft these communications. Which entities, if any, should not be involved in the provision of the results to the subjects? Potential entities include the sponsor, investigators, institutions, and third parties such as honest brokers. If FDA were to clarify whether any of those parties are not acceptable, it would assist sponsors in choosing the appropriate party to provide these communications to subjects. What information, if any, should not be included in summary? If FDA has any concerns about the timing of the release of general results to subjects, knowledge of those concerns would be helpful to sponsors in coordinating the timing. Does FDA have any concerns about the format and medium in which the general results are returned to subjects? Does FDA have any concerns about given types of clinical trials having results returned, such as Phase I? For each of these issues, guidance establishing safe harbors or acceptable practices is desirable. SACHRP’s recommendation is that FDA promote the practice of returning general research results to subjects by providing such safe harbors or acceptable practices. 2. IRB Approval Time Line Considerations: Office for Human Research Protections (OHRP) and Food and Drug Administration (FDA) One issue that arises in consideration of return of general research results under both HHS and FDA regulations is the role of the IRB. SACHRP believes that when the return of general results is planned at the time of initial IRB review, or the decision to share results is made after initial IRB approval but while the study is still open with the IRB, then the activity requires IRB review. The return of general results is a research activity, and should be reviewed by the IRB either at initial review or as a change in research. The reviewing IRB must consider whether the plan to provide general results to subjects will affect the applicable criteria for IRB approval at 21 CFR 56.111 and 45 CFR 46.111, similar to any other component of research. However, SACHRP’s assumption is that the return of general results to subjects will ordinarily not negatively affect the criteria for IRB approval and will unlikely be a cause for deferral or disapproval. However, SACHRP recommends that the agencies issue guidance noting that IRBs do not have to open the study or otherwise review either the plan for the return of general results to subjects, nor the return of results documents that will be provided to the subjects, if the activity is implemented after the study has been closed by the IRB. Additionally, SACHRP recommends that the agencies note that IRBs do not have to review the return of results documents that will be provided to the subjects if those documents are drafted and sent after the study has been closed with the IRB, even if the plan was described in the protocol and consent form. There is not a regulatory requirement to do so. 3. Centers for Medicare & Medicaid Services (CMS) There are not any direct CLIA issues involved in the return of general research results, as no individual results are being provided to subjects. CLIA issues are more of a concern for return of individual results or incidental findings. Conclusion Valuable work on this subject is also being performed by the Multi-Regional Clinical Trials Initiative (MRCT) and the Center for Information & Study on Clinical Research Participation (CISCRP). Both organizations presented information at the SACHRP meeting of June 2014, and both organizations have developed templates for communications of return of results to research subjects. SACHRP would like to thank both organizations and recommend their work on this issue.  Data Sharing Commitments will Enhance Research and Scientific Knowledge, Advance Patient Care and Improve Public Health.