81 FR 64922 - NIH Policy on the Dissemination of NIH-Funded Clinical Trial Information
DEPARTMENT OF HEALTH AND HUMAN SERVICES
National Institutes of Health Federal Register Volume 81, Issue 183 (September 21, 2016)
National Institutes of Health
Federal Register Volume 81, Issue 183 (September 21, 2016)
| Page Range | 64922-64928 | |
| FR Document | 2016-22379 |
[Federal Register Volume 81, Number 183 (Wednesday, September 21, 2016)] [Notices] [Pages 64922-64928] From the Federal Register Online [www.thefederalregister.org] [FR Doc No: 2016-22379] ----------------------------------------------------------------------- DEPARTMENT OF HEALTH AND HUMAN SERVICES National Institutes of Health NIH Policy on the Dissemination of NIH-Funded Clinical Trial Information AGENCY: National Institutes of Health, Department of Health and Human Services. ACTION: Notice. ----------------------------------------------------------------------- SUMMARY: The National Institutes of Health (NIH) is issuing this policy to promote broad and responsible dissemination of information from NIH- funded clinical trials through ClinicalTrials.gov. The policy establishes the expectation that all investigators conducting clinical trials funded in whole or in part by the NIH will ensure that these trials are registered at ClinicalTrials.gov, and that results information of these trials is submitted to ClinicalTrials.gov. DATES: This policy will take effect January 18, 2017. FOR FURTHER INFORMATION CONTACT: For information about the policy, please contact the NIH Office of Science Policy at [email protected]. SUPPLEMENTARY INFORMATION: The policy is complementary to the statutory and regulatory reporting requirements. These are section 402(j) of the Public Health Service Act, as amended by Title VIII of the Food and Drug Administration (FDA) Amendments Act of 2007 (FDAAA), and the regulation Clinical Trial Registration and Results Information Submission, at 42 CFR part 11. Hereafter, we refer to section 402(j) as the statute and 42 CFR part 11 as the rule or regulation. On November 19, 2014, and in tandem with the publication of the Notice of Proposed Rulemaking (NPRM) on Clinical Trial Registration and Results Submission, the NIH issued a complementary draft policy for public comment on the Dissemination of NIH-funded Clinical Trial Information [Ref. 1, 2]. The draft policy proposed that all NIH-funded awardees and investigators conducting clinical trials, funded in [[Page 64923]] whole or in part by the NIH, regardless of study phase, type of intervention, or whether they are subject to the statutory registration and results information submission requirements, would be expected to ensure that those clinical trials are registered and results information is submitted to ClinicalTrials.gov. It further stated that submission of the same type of registration and results information would be expected and in the same timeframes as the trials subject to the statute, and that this information would be made publicly available through the ClinicalTrials.gov Web site. The NIH received approximately 240 public comments on its proposed policy. The comments came from a range of stakeholders including researchers, academic/research institutions, medical practitioners, patients, patient/disease advocacy groups, scientific/professional societies and associations, device manufacturers, trade associations, not-for-profit non-governmental organizations, and the general public [Ref. 3]. The NIH appreciated the public interest in the proposed policy and the time made and effort taken by stakeholders to provide comments. The NIH carefully considered those comments in the development of the final policy. In the next section, we provide an overview of the comments on the proposed policy. Because those in compliance with the policy would be expected to follow specific provisions of the rule, a number of commenters on the policy reiterated comments that they submitted to the docket in response to the NPRM [Ref. 4]. Since these comments are discussed at length in the preamble of the rule, we are limiting the discussion of comments here primarily to those that identified issues specific to the policy, such as its scope, applicability, and impact on NIH-funded awardees and investigators. Overview of the Public Comments A significant majority of the public comments were supportive of the proposed NIH policy and of its application to the full range of NIH-funded clinical trials. Most commenters appreciated the impetus behind the policy and agreed that it was important to provide ways other than journal publication for clinical trial results to be disseminated and made publicly available to researchers, health care providers, and patient communities. They recognized that increased availability of information from NIH-funded clinical trials would help researchers by informing the design and development of their future studies, address the needs of patients and healthcare providers seeking information about NIH-funded trials, and serve the public's interest by preventing duplication of unsafe and unsuccessful trials and mitigating publication bias. They also agreed that improving the availability of clinical trial information will strengthen the public's trust in biomedical research as well as assure volunteers that their participation in clinical trials has advanced knowledge on human health and disease. A number of commenters also suggested that the policy is particularly appropriate because NIH-funded clinical trials are supported by public funding, and recipients of those funds have a special obligation to ensure that the nation's investment is maximized. A number of comments from academic investigators and stakeholder organizations were supportive of the policy and its goals. Others, however, disagreed with the policy, suggesting that it was ill-advised and/or unnecessary. These commenters suggested that the benefit of greater transparency was outweighed by the burden and cost of the policy to those who conduct clinical trials and that the NIH had not made a sufficient case for the policy or that it was not evidence- based. Some commenters suggested that the NIH should simply encourage investigators to be more transparent or that the NIH's public access policy made the policy unnecessary since it requires NIH-funded investigators to make their published articles publicly available through PubMed Central. Scope and Applicability of the Policy. Although the majority of commenters fully supported the scope of the policy, i.e., that it should apply to NIH-funded clinical trials of FDA-regulated drugs regardless of phase, small feasibility studies of devices, and trials of interventions not regulated by FDA, including surgical and behavioral interventions, there were comments suggesting that the scope was too narrow, or conversely, too broad. One commenter suggested that the policy ought to encompass more detailed summary results, such as Clinical Study Reports, as well as de-identified individual patient-level data. One commenter suggested that the NIH should consider extending the policy to preclinical in vivo (laboratory) animal studies because the arguments for the registration and required reporting of preclinical in vivo (laboratory) animal studies are similar to those of human clinical trials. Some commenters suggested that the policy should be retroactive and apply to clinical trials that are underway as of the policy's effective date as well as those that have already been completed as of the effective date. On the other hand, there were other comments suggesting that the policy should not apply to phase 1 or so called phase 0 trials, pilot trials designed to examine the feasibility of an approach, trials mounted by an investigator at a small organization, or trials that are unable to enroll a statistically significant number of participants. One suggested that even pilot trials that reach their enrollment target should not be expected to submit results information because the results might be more misleading than helpful. Another proposed that reporting on phase 1 clinical trials should be limited to adverse events information because these trials are designed to assess safety rather than efficacy, and reporting non-safety outcomes could be misleading. Another suggested that clinical trials not covered under the statute should not submit adverse event information unless a regulatory authority or equivalent body has first performed an analysis of the event in order to prevent public misunderstanding. Another commenter suggested that submission of data from early phase research could divert limited research resources and time from phase 3 studies. Another suggested that only information about phase 3 clinical trials should be included in ClinicalTrials.gov because information about early stage trials could confound, rather than enhance, public understanding of human health and could, thereby, inadvertently adversely affect patient safety. One commenter suggested that the policy should apply only to the registration of clinical trials, not the submission of results information. This commenter asserted that registration information was sufficient because any interested party could follow up with an investigator to learn more about the trial and because submission of registration information takes a fraction of the time needed to submit results information. There were a few commenters who took issue with the application of the policy to trials that are only partially funded by the NIH. They asserted that the policy would entail the disclosure of confidential commercial information and that the NIH's authority to do so is limited to a trial that is wholly NIH-funded and involves a product with research and development costs wholly government-funded. A few other commenters suggested that the policy should exclude clinical trials that use NIH-supported infrastructure, but involve no NIH funds. [[Page 64924]] NIH Definition of Clinical Trial. Some commenters addressed the NIH definition of clinical trial, which is key to determining the policy's applicability. There was support for the breadth of the definition, i.e., encompassing all interventional studies with biomedical outcomes (e.g., pharmacokinetic and behavioral outcomes, as well as health- related outcomes). One commenter, however, thought more elaboration on the definition was needed to clarify the meaning of ``health-related biomedical or behavioral outcomes.'' They thought that without such specificity, the definition might be interpreted to exclude studies that contain valuable information for public health research, science, and clinical medicine. Commenters believed that addressing this issue would be vital to ensure a common understanding that the NIH policy applies to all clinical trials involving a biomedical or behavioral intervention. Another suggested that a study involving only one participant should not be considered a clinical trial since a trial with a sample size of one would not provide any valid data to share with the public. Some commenters noted that the wording of the NIH definition was not identical to the wording of the definition of clinical trial in the proposed rule or to how other organizations, e.g., the World Health Organization (WHO), International Committee of Medical Journal Editors (ICMJE), and Centers for Medicare & Medicaid Services (CMS), use the term. They were concerned that investigators would have difficulty understanding their obligations under the policy and under the rule and in meeting requirements of others. They called for reconciliation of any actual or apparent differences in the definitions. A commenter urged the NIH to issue guidance to help determine whether a study is a clinical trial under the definition and to clarify how disagreements in the matter would be resolved and communicated. Results Information Submission Timeline. A few commenters raised concerns about the proposed rule's timeline for reporting results information, asserting that 12 months after the primary completion date of the clinical trial (i.e., the date of final data collection for the primary outcome measure) is too soon, particularly for NIH-funded academic investigators. These commenters suggested that academic investigators will have more difficulty meeting the timeframe because they must also spend time teaching, fulfilling clinical care responsibilities, and writing grant applications. Another commenter suggested that a 12-month timeframe would also be more challenging for academic investigators because, unlike industry investigators, they generally cannot count on support from a central administrative service to help them carry out their reporting responsibilities. Decentralization of information in academic centers would also present a particular challenge to those covered by the NIH policy, according to another commenter, who also suggested that the mobility of new investigators may make it difficult to meet timelines. These commenters urged the NIH to allow a longer submission timeframe, e.g., 18 or 24 months. A few noted that providing more time would also give investigators time to prepare journal publications, and one also expressed concern about the possibility that journal editors will begin to consider submission of results information to ClinicalTrials.gov as prior publication, which could thwart journal publication altogether. Structured Results Data Elements. A few commenters suggested that the data submission structure, which is determined by the provisions of the statute, does not work well for clinical trial types that will be covered only the policy, e.g., phase 1 trials of drugs/biologics, small feasibility device studies, trials of social and behavioral interventions, or those with non-standard designs. These commenters thought that other fields would need to be added to the ClinicalTrials.gov to enable investigators to report data elements for those trials appropriately and accurately. They also suggested increasing the character limit on data fields to allow for more careful and nuanced explanations. Commenters also suggested that if the ClinicalTrials.gov cannot accommodate these types of trials, investigators should be exempted from the policy. One commenter requested that an additional data element should be included to allow an investigator to indicate that the trial's hypothesis had been confirmed. Protecting Privacy. One commenter raised a concern about the policy's impact on the privacy of clinical trial participants suggesting that it might be easy to re-identify participants in many NIH-funded pilot studies with small sample sizes. The commenter pointed to the five percent threshold for non-serious adverse events and site location information as the data elements creating the vulnerability. The commenter urged the NIH to allow an investigator to obtain a waiver from results information submission where participant privacy was at risk. Compliance Issues. The proposed policy noted that compliance with the policy would be a term and condition of award and that non- compliance may provide a basis for enforcement actions, including termination. A few commenters discussed the importance of compliance. One suggested that the NIH should take compliance records into account when considering future applications for funding. They suggested that such an approach could be more effective than terminating funding of a current grant since most of the research may already be completed. Another thought that making compliance a term and condition of award was important and that it would incentivize good behavior and help change attitudes about the value of enhancing availability of clinical trial information. Other commenters raised concerns about the costs that will be incurred by NIH-funded academic institutions to ensure that clinical investigators are following the policy. They suggested institutions will need to provide more administrative support and other resources to help investigators comply and that this would be difficult given the indirect cost cap of 26 percent. Commenters urged the NIH to allow the time and effort required for ClinicalTrials.gov compliance to be included as a direct cost on NIH grants. Another commenter suggested that the increased results information submissions brought on by the NIH policy will stretch the NIH's capabilities and that it will be important for the NIH to ensure that sufficient resources are available to manage high volume data uploads and customer service requests. NIH Policy The NIH considered all the comments received on the proposed policy as well as those that were submitted in response to the NPRM. There was overwhelming support for both the proposed policy and the NPRM, particularly among concerned citizens, scientific societies, medical practitioners, and individual scientists. There were also concerns expressed, particularly in the comments from academic commenters. We appreciate those concerns and understand that the policy will create additional work for many investigators. However, we believe that the work should not be seen as a burden, but, rather, an inherent part of an investigator's commitment to the advancement of science. The benefits will, in the long run, accrue to the investigators as well as to the public, patients, and the enterprise as a whole because transparency will improve [[Page 64925]] future research designs and maximize the public's investment--and their trust--in research. Equally important, it will help investigators fulfill the ethical obligation they have to clinical trial participants, namely to ensure that the findings from their participation contribute to generalizable knowledge and the advancement of public health. As we noted in the preamble to the proposed policy, a fundamental premise of all NIH-funded research is that the results of such work must be disseminated in order to contribute to the general body of scientific knowledge and, ultimately, to the public health. The NIH awardees have always been expected to make the results of their activities available to the research community and to the public at large because it is intrinsic to the scientific process. In research involving human beings, moreover, scientists also have an ethical obligation to ensure that the burden and risk that volunteers assume by participating in research comes to something, at the very least by ensuring that others are aware of the study and that its findings contribute to the advancement of human health. We disagree with commenters who suggested that there is no need for coverage of certain types of trials, such as early exploratory trials, small trials, trials assessing only safety, or trials that terminate before reaching enrollment targets. The benefits of transparency and the need to fulfill the ethical obligation to participants is as relevant to these types of trials as to any other type. We were also not persuaded that the timeframe for results information submission should be longer for academic investigators because of their competing responsibilities or that they should be allowed more time to publish their results in a journal. The timeframe of 12 months from the primary completion date should provide enough time for investigators to organize their data and submit results information. We are also confident that academic institutions can develop central support services as necessary to assist investigators should they need it. We also believe that 12 months represents an appropriate balance between investigators' interests and the interests of the public in having access to the results of a publicly funded trial. In addition, it will be possible to delay results information submission for up to two years beyond the initial deadline with a certification that regulatory approval of the trial product is being sought. Some commenters suggested that a policy on clinical trial information dissemination is not needed because it duplicates other NIH policies. This policy is certainly in keeping with our principles, longstanding expectations, and other policies as well as the more recent broad policy call for scientific agencies to increase public access to scientific data [Ref. 5]. However, it does not duplicate any other NIH policy, nor does any other NIH policy accomplish what this one will. Some commenters also contended that this policy is not necessary because the results of clinical trials will be published or because they can be obtained via direct requests to the trial's principal investigator. In fact, research has shown that the results of a significant portion of clinical trials are not published or published in a timely manner. For example, a 2012 study of NIH-funded clinical trials found that after a median of 51 months following trial completion, 32 percent were unpublished [Ref. 6]. A more recent study of the trial publication rate among 51 U.S. academic medical centers found that 43 percent of their clinical trials were unpublished two years after the trial was completed [Ref. 7]. While the ability to seek results information from the original investigator is useful to facilitate collaborations, to access individual-level data, and to gain insights from those who conducted the trial, it is not a surefire way to increase access to trial results nor is it efficient or transparent, particularly for the public. We believe that the public availability of clinical trial results information will be beneficial to all parties in the long run, including those who are covered by this policy. All investigators stand to benefit from this policy. For example, science may progress more quickly because investigators will be able to learn from trials to which they otherwise would not have had access because they were unpublished. In addition, the public availability of results information helps investigators design trials and Institutional Review Boards (IRBs) review proposed trials, by allowing them to weigh the proposed study's risks and benefits against a more complete evidence base than is currently available through the scientific literature [Ref. 8]. Submission and posting of results information will also help investigators avoid repeating trials on interventions that have been found to be unsafe or unsuccessful while also providing access to information that may help verify findings. For all of these reasons, we have not changed the essential contours of the policy. In terms of scope, the policy still applies to all NIH-funded awardees and investigators conducting clinical trials funded in whole or in part by the NIH regardless of study phase, type of intervention, or whether they are subject to the statute and to the rule. It clarifies that the policy is an expectation, that applicants and offerors are required to submit a plan outlining how they will meet the policy's expectations, and, that upon receipt of an award, an awardee will be obligated to adhere to their plan through the terms and conditions of the award. The required plan can be a brief statement explaining whether the applicant/offeror intends to register and submit results information to ClinicalTrials.gov as outlined in the policy or to meet the expectations in another manner. It is important to remember that an NIH-funded clinical trial that meets the definition of an applicable clinical trial is subject to the regulation and, therefore, register and submission of results information to ClinicalTrials.gov is a requirement. The policy applies to both the extramural and intramural programs. For the NIH extramural program, the policy applies to applications for funding including for grants, other transactions, and contracts submitted on or after the policy's effective date that request support for the conduct of a clinical trial that is initiated on or after the policy's effective date. This means that the policy does not apply to clinical trials in ongoing, non-competing awards, but that it will apply if the grantee submits a competing renewal application that includes a new clinical trial, i.e., a clinical trial initiated on or after the effective date of the policy. For the intramural program, the policy applies to clinical trials initiated on or after the policy's effective date. The policy's effective date is January 18, 2017. The policy clarifies that a clinical trial that uses NIH-supported infrastructure, but does not receive NIH funds to support its conduct, is not subject to the policy. The policy outlines the responsibilities for NIH-funded investigators according to whether the trial is covered by the policy only or also the rule. For those covered by the policy only, NIH-funded awardees and investigators will be expected to submit the same registration and results information in the same timeframes as those subject to the statute and rule. The timeline for registration is not later than 21 calendar days after the enrollment of the first participant. The standard timeline for results information is not later than one year after the trial's primary completion date, but the policy also allows for delayed submission of results information in certain [[Page 64926]] circumstances for up to two additional years for trials of products regulated by the FDA that are unapproved, unlicensed, or uncleared or for trials of products for which approval of a new use is being sought. Although the policy does not apply to NIH-funded clinical trials initiated before the effective date, we encourage all ongoing NIH- funded clinical trials to follow it. It is also critical for investigators conducting NIH-funded applicable clinical trials that are subject to the statute and rule to be sure they are in compliance with those requirements. The policy continues to use the NIH definition of ``clinical trial'' as proposed in the draft policy to determine which research studies are covered by the policy. This definition was developed in 2014 to reflect the NIH research mission and the scope of clinical trials within the NIH portfolio. With regard to the concern expressed by a public commenter that the phrase ``health-related biomedical or behavioral outcomes'' might be too narrow, we note that the definition considers biomedical and behavioral outcomes to be health-related outcomes in interventional studies that meet the other components of the definition. Also, regarding the concern that the wording of the definitions of clinical trial in this policy and the rule differ, this is so mainly in reference to outcomes, i.e., the NIH definition explicitly references behavioral outcomes whereas the definition in the rule encompasses them within the term ``health related.'' These distinctions are not significant in terms of defining what is covered by the NIH policy. All NIH-funded clinical trials, whether they are assessing biomedical or behavioral outcomes or whether they are employing an FDA regulated product, are covered by the policy. An NIH- funded clinical trial assessing a behavioral intervention that is not regulated by the FDA would meet both definitions of clinical trial, and, thereby, be covered by the policy. However, such a trial would not be subject to the rule because it does not meet the rule's definition of ``applicable clinical trial.'' Guidance available on the NIH's Web site can help awardees and investigators understand whether a research study is a clinical trial for purposes of the NIH policy (see first Web site listed below). Questions should be directed to the NIH program staff. To understand whether an NIH-funded clinical trial is also subject to the statute and the rule, awardees and investigators should look to the rule's definition of ``applicable clinical trial.'' NIH-funded awardees and investigators will be expected to follow the provisions of the rule in terms of when they register their trials, what information they provide as part of the registration process, when they submit their results information, and what results information is submitted. All of the alternate approaches in the rule will also be available to those covered by the policy, e.g., for delayed posting of device registration information, delayed submission of results information for trials involving unapproved products or products for which a new use is sought, extensions for good cause, and waivers that might be needed for privacy or national security reasons. With regard to the concern that ClinicalTrials.gov is not set up to accept NIH-funded trials that are small or exploratory in nature or involve behavioral interventions, it is important to note that the ClinicalTrials.gov does accommodate the submission of all trial types and that a variety of study and trial types have been entered into ClinicalTrials.gov since its inception. In addition, ClinicalTrials.gov has resources available to assist investigators in navigating the registration and results information submission processes. These resources will continue to be updated over time to be responsive to investigators' needs and the evolving clinical research enterprise. Therefore, it should not be necessary for a clinical investigator of an NIH-funded clinical trial to seek an exemption from the policy for reasons related to the capacity of ClinicalTrials.gov to accommodate all types of clinical trials. Registration and results information submission to ClinicalTrials.gov complements publication of trial results in peer- reviewed scientific journals. Information submitted to ClinicalTrials.gov is displayed in a structured way and includes a complete list of all pre-specified outcome measures and all adverse events. Journal articles, on the other hand, typically focus on a select set of outcome measures and adverse events and include background and discussion of the implications of the results. Information submitted to ClinicalTrials.gov undergoes a quality control review whereas journal articles will be peer reviewed. With regard to the concern that submission of results could make journal publication more difficult or impossible, the ICMJE has stated that submission of summary results to ClinicalTrials.gov will not be considered prior publication and will, thus, not interfere with journal publication [Ref. 9]. We encourage all NIH-funded investigators to publish the results of their studies in peer-reviewed journals. We have no doubt that this policy will be beneficial for the research community as well as the public generally, but we recognize that adhering to it will be a new obligation. We will provide additional guidance to facilitate implementation and help awardees and investigators understand the policy as well as the tasks described in the rule that they will be expected to undertake. In terms of the costs of complying with the policy, grantees are permitted to charge the salaries of administrative and clerical staff as a direct cost [Ref. 10]. Such staff could assist investigators in meeting their responsibilities under the policy. In addition, administrative costs can be covered through indirect cost recovery. We intend for this policy to benefit all communities who seek information about NIH-funded clinical trials, and we are confident that the benefits of transparency will become evident soon after the policy is implemented. We plan to evaluate the implementation and impact of the policy from the perspective of those who comply with it as well as from the perspective of ClinicalTrials.gov users, including patients, providers, and investigators. We look forward to engaging with NIH-funded investigators and awardees as they work to meet the expectations of this important public policy. Information to assist applicants, offerors, and investigators is available at the following Web sites. The NIH will continue to add guidance materials to these sites as the policy's implementation continues.http://osp.od.nih.gov/office-clinical-research-and-bioethics-policy/clinical-research-policy/clinical-trials https://clinicaltrials.gov/ct2/manage-recs http://grants.nih.gov/clinicaltrials_fdaaa/faq.htm The NIH policy is set forth below. References 1. National Institutes of Health, U.S. Department of Health and Human Services, NIH request for public comments on the proposed NIH policy on dissemination of NIH-funded clinical trial information. NIH Guide for Grants and Contracts. 2014 Nov 19. Available from https://grants.nih.gov/grants/guide/notice-files/NOT-OD-15-019.html. Also published in Fed Regist. 2015 Feb 13; 80(30):8096-98. Available from https://www.federalregister.gov/articles/2015/02/13/2015-02994/announcement-of-a-draft-nih-policy-on-dissemination-of-nih-funded-clinical-trial-information. 2. National Institutes of Health, U.S. [[Page 64927]] Department of Health and Human Services, Notice of Proposed Rulemaking on Clinical Trials Registration and Results Submission. Fed Regist. 2014 Nov 21;79(225):69566-69680. Available from https://www.federalregister.gov/articles/2015/02/13/2015-02990/clinical-trials-registration-and-results-submission. 3. A compilation of public comments on the draft NIH Policy on Dissemination of NIH-Funded Clinical Trial Information is available at: http://osp.od.nih.gov/sites/default/files/resources/Clinical%20Trials%20Dissemination%20Policy%20Combined%20Comments_2.0.pdf. 4. U.S. Department of Health and Human Services, National Institutes of Health, National Library of Medicine. Clinical Trials Registration and Results Submission. [Internet]. 2011 [cited 2016 September 1]. Available from: https://www.regulations.gov/docket?D=NIH-2011-0003. 5. NIH Data Sharing Policy (https://grants.nih.gov/grants/policy/data_sharing/); NIH Public Access Policy (https://publicaccess.nih.gov/policy.htm or https://publicaccess.nih.gov/); NIH Genomic Data Sharing Policy (https://gds.nih.gov/03policy2.html); Increasing Access to the Results of Federally Funded Scientific Research (https://www.whitehouse.gov/sites/default/files/microsites/ostp/ostp_public_access_memo_2013.pdf). 6. Ross et al., BMJ. 2012 Jan 3;344:d7292. http://www.bmj.com/content/bmj/344/bmj.d7292.full.pdf. 7. Chen et al., BMJ. 2016 Feb 17;352:i637 http://www.bmj.com/content/bmj/352/bmj.i637.full.pdf. 8. Berlin, JA, et al., Bumps and Bridges on the Road to Responsible Sharing of Clinical Trial Data. Clinical Trials. 2014;11:7-12. 9. ICMJE [Internet]. International Committee of Medical Journal Editors; 2016. Clinical trial registration; 2011 [cited 2016 Aug 5]; [about 2 screens]. Available from: http://www.icmje.org/recommendations/browse/publishing-and-editorial-issues/clinical-trial-registration.html and http://www.icmje.org/about-icmje/faqs/clinical-trials-registration/. 10. 45 CFR 75.413(c) and Chapter 8.1.1.6, Direct Charging Salaries of Administrative and Clerical Staff. NIH Grants Policy Statement. http://grants.nih.gov/grants/policy/nihgps/HTML5/section_8/8.1_changes_in_project_and_budget.htm. NIH Policy on Dissemination of NIH-Funded Clinical Trial Information Purpose The National Institutes of Health (NIH) Policy on Dissemination of NIH-funded Clinical Trial Information establishes the expectation that all NIH-funded awardees and investigators conducting clinical trials, funded in whole or in part by the NIH, will ensure that their NIH- funded clinical trials are registered at, and that summary results information is submitted to, ClinicalTrials.gov for public posting.\1\ The purpose of the policy is to promote broad and responsible dissemination of information from NIH-funded clinical trials through ClinicalTrials.gov. Disseminating this information supports the NIH mission to advance the translation of research results into knowledge, products, and procedures that improve human health. --------------------------------------------------------------------------- \1\ ClinicalTrials.gov is operated by the National Library of Medicine within the NIH. --------------------------------------------------------------------------- This policy is complementary to requirements in the Clinical Trial Registration and Results Information Submission regulation at 42 CFR part 11, hereinafter referred to as the regulation.\2\ Clinical trials that are subject to the regulation are, in general, clinical trials of drug, biological, and device products regulated by the Food and Drug Administration (FDA), except phase 1 trials of drug and biological products and small feasibility studies of device products. A pediatric post-market surveillance study of a device product required by the FDA is also subject to the regulation. Clinical trials subject to the regulation are generally called ``applicable clinical trials.'' Applicable clinical trials are required to be registered in ClinicalTrials.gov not later than 21 calendar days after the enrollment of the first participant. Results information from those trials generally must be submitted not later than one year after the trial's primary completion date. Submission of results information can be delayed in certain circumstances for up to two additional years for trials of products regulated by the FDA that are unapproved, unlicensed, or uncleared or for trials of products for which approval, licensure, or clearance of a new use is being sought. --------------------------------------------------------------------------- \2\ The Clinical Trial Registration and Results Information Submission regulation at 42 CFR part 11 was issued in the Federal Register in September 2016. The regulation implements section 402(j) of the Public Health Service Act. --------------------------------------------------------------------------- Scope and Applicability This policy applies to all NIH-funded clinical trials regardless of study phase, type of intervention, or whether they are subject to the regulation. For example, NIH-funded phase 1 clinical trials of an FDA- regulated product are covered by this policy as are clinical trials studying interventions not regulated by the FDA, such as behavioral interventions. As such, the policy encompasses all NIH-funded clinical trials, including applicable clinical trials subject to the regulation. All NIH-funded clinical trials will be expected to register and submit results information to ClinicalTrials.gov. This policy applies to clinical trials funded in whole or in part through the NIH extramural and intramural programs. For the NIH extramural program, the policy applies to applications for funding including for grants, other transactions, and contracts submitted on or after the policy's effective date that request support for the conduct of a clinical trial that is initiated on or after the policy's effective date. For the NIH intramural program, the policy applies to clinical trials initiated on or after the policy's effective date. This policy does not apply to a clinical trial that uses NIH- supported infrastructure but does not receive NIH funds to support its conduct. Responsibilities As part of their applications or proposals, applicants and offerors seeking NIH funding will be required to submit a plan for the dissemination of NIH-funded clinical trial information that will address how the expectations of this policy will be met. NIH-funded awardees and investigators conducting clinical trials funded in whole or in part by the NIH will be required to comply with all terms and conditions of award, including following their plan for the dissemination of NIH-funded clinical trial information. Consistent with those terms and conditions, the responsibilities of such awardees and investigators will fall within one of the three categories. The category depends on whether, under the regulation, the clinical trial is also an ``applicable clinical trial'' and the awardee or investigator is the ``responsible party.'' 1. If the NIH-funded clinical trial is an applicable clinical trial under the regulation and the awardee or investigator is the responsible party, the awardee or investigator will ensure that all regulatory requirements are met. 2. If the NIH-funded clinical trial is an applicable clinical trial under the regulation but the awardee or investigator is not the responsible party, the awardee or investigator will coordinate with the responsible party to ensure that all regulatory requirements are met. 3. If the NIH-funded clinical trial is not an applicable clinical trial under the regulation, the awardee or investigator will be responsible for carrying out the tasks and meeting the timelines described in regulation. Such tasks include registering the clinical trial in ClinicalTrials.gov and submitting results information to ClinicalTrials.gov. [[Page 64928]] In addition, informed consent documents for clinical trials within all three categories are to include a specific statement relating to posting of clinical trial information at ClinicalTrials.gov. Each NIH-funded clinical trial should have only one entry in ClinicalTrials.gov that contains its registration and results information. Awardees and investigators need not and should not create a separate record of the applicable clinical trial to comply with this policy. The NIH will publicly post registration information and results information in ClinicalTrials.gov. Definitions Clinical Trial. For purposes of this policy, a ``clinical trial'' means ``a research study in which one or more human subjects are prospectively assigned to one or more interventions (which may include placebo or other control) to evaluate the effects of those interventions on health-related biomedical or behavioral outcomes.'' \3\ This definition encompasses phase 1 trials of FDA-regulated drug and biological products, small feasibility studies of FDA-regulated device products, and studies of any intervention not regulated by the FDA, e.g., behavioral interventions. This definition of ``clinical trial'' \4\ is broader than the term ``applicable clinical trial'' as defined in the regulation.\5\ --------------------------------------------------------------------------- \3\ Further information about this definition is available from the NIH Office of Science Policy at http://osp.od.nih.gov/office-clinical-research-and-bioethics-policy/clinical-research-policy/clinical-trials. \4\ Note that the regulation also includes a definition of ``clinical trial.'' That definition is ``a clinical investigation or a clinical study in which human subject(s) are prospectively assigned, according to a protocol, to one or more interventions (or no intervention) to evaluate the effect(s) of the intervention(s) on biomedical or health related outcomes'' (see 42 CFR 11.10 (a)). For the purposes of this policy, the regulatory definition and the definition in this policy are treated as synonymous. \5\ In the regulation, applicable clinical trial is defined as an applicable device clinical trial or an applicable drug clinical trial. The regulation defines an applicable device clinical trial to mean, in part, ``a prospective clinical study of health outcomes comparing an intervention with a device product subject to section 510(k), 515, or 520(m) of the Federal Food, Drug, and Cosmetic Act (21 U.S.C. 360(k), 21 U.S.C. 360e, 21 U.S.C. 360j(m)) against a control in human subjects (other than a small clinical trial to determine the feasibility of a device product, or a clinical trial to test prototype device products where the primary outcome measure relates to feasibility and not to health outcomes).'' The regulation defines an applicable drug clinical trial to mean, in part, ``a controlled clinical investigation, other than a phase 1 clinical investigation, of a drug product subject to section 505 of the Federal Food, Drug, and Cosmetic Act (21 U.S.C. 355) or a biological product subject to section 351 of the Public Health Service Act (42 U.S.C. 262), where ``clinical investigation'' has the meaning given in 21 CFR 312.3 (or any successor regulation) and ``phase 1'' has the meaning given in 21 CFR 312.21 (or any successor regulation).'' --------------------------------------------------------------------------- Responsible Party. In the policy, the awardee or the investigator is responsible for meeting the expectations of this policy. In the regulation, a ``responsible party'' means, in part, ``with respect to a clinical trial, the sponsor of the clinical trial, as defined in 21 CFR 50.3 (or any successor regulation); or the principal investigator of such clinical trial if so designated by a sponsor, grantee, contractor, or awardee, so long as the principal investigator is responsible for conducting the trial, has access to and control over the data from the clinical trial, has the right to publish the results of the trial, and has the ability to meet all of the requirements under [42 CFR part 11] for the submission of clinical trial information.'' \6\ --------------------------------------------------------------------------- \6\ See 42 CFR 11.10 (a) and 42 CFR 11.4. --------------------------------------------------------------------------- Primary Completion Date. In the policy, this term has the same meaning as the term ``primary completion date'' in the regulation, which is ``the date that the final subject was examined or received an intervention for the purposes of final collection of data for the primary outcome, whether the clinical trial concluded according to the pre-specified protocol or was terminated.'' \7\ --------------------------------------------------------------------------- \7\ See the complete definition at 42 CFR 11.10 (a). --------------------------------------------------------------------------- Registration Information. In the policy, this term has the same meaning as the term ``registration information'' in the regulation. In the regulation, registration information consists of descriptive information, recruitment information, location and contact information, and administrative data.\8\ --------------------------------------------------------------------------- \8\ See 42 CFR 11.10 (b) and 42 CFR 11.28 for the specific data elements. --------------------------------------------------------------------------- Results Information. In the policy, this term has the same meaning as the term ``results information'' in the regulation. In the regulation, results information includes participant flow, demographic and baseline characteristics, outcomes and statistical analyses, adverse events, the protocol and statistical analysis plan, and administrative information.\9\ --------------------------------------------------------------------------- \9\ See 42 CFR 11.28 for complete results information and specific data elements. --------------------------------------------------------------------------- Compliance If the clinical trial is NIH-funded in whole or in part, expectations for clinical trial registration and summary results submission will be included in the terms and conditions of the award. Failure to comply with the terms and conditions of the NIH award may provide a basis for enforcement actions, including termination, consistent with 45 CFR 75.371 and/or other authorities, as appropriate. If the NIH-funded clinical trial is also an applicable clinical trial, non-compliance with the requirements specified in 42 U.S.C. 282(j) and 42 CFR part 11 may also lead to the actions described in 42 CFR 11.66. Effective Date This policy is effective January 18, 2017. Date: September 12, 2016. Francis S. Collins, Director, National Institutes of Health. [FR Doc. 2016-22379 Filed 9-16-16; 11:15 am] BILLING CODE 4140-01-P
![64922 Federal Register / Vol. 81, No. 183 / Wednesday, September 21, 2016 / Notices
Name of Committee: Center for Scientific Place: InterContinental Chicago Hotel, 505 93.333, Clinical Research, 93.306, 93.333,
Review Special Emphasis Panel; Cellular North Michigan Avenue, Chicago, IL 60611. 93.337, 93.393–93.396, 93.837–93.844,
Aspects of Diabetes and Obesity. Contact Person: James W. Mack, Ph.D., 93.846–93.878, 93.892, 93.893, National
Date: October 13, 2016. Scientific Review Officer, Center for Institutes of Health, HHS)
Time: 3:00 p.m. to 5:00 p.m. Scientific Review, National Institutes of Dated: September 15, 2016.
Agenda: To review and evaluate grant Health, 6701 Rockledge Drive, Room 4154,
applications. MSC 7806, Bethesda, MD 20892, (301) 435– David Clary,
Place: National Institutes of Health, 6701 2037, mackj2@csr.nih.gov. Program Analyst, Office of Federal Advisory
Rockledge Drive, Bethesda, MD 20892 Name of Committee: Oncology 1-Basic Committee Policy.
(Telephone Conference Call). Translational Integrated Review Group; [FR Doc. 2016–22665 Filed 9–20–16; 8:45 am]
Contact Person: Elaine Sierra-Rivera, Ph.D., Cancer Molecular Pathobiology Study BILLING CODE 4140–01–P
Scientific Review Officer, EMNR IRG, Center Section.
for Scientific Review, National Institutes of Date: October 19–20, 2016.
Health, 6701 Rockledge Drive, Room 6182 Time: 8:00 a.m. to 5:00 p.m. DEPARTMENT OF HEALTH AND
MSC 7892, Bethesda, MD 20892, 301 435– Agenda: To review and evaluate grant
2514, riverase@csr.nih.gov. applications.
HUMAN SERVICES
Name of Committee: Center for Scientific Place: Ritz-Carlton Hotel, 1700 Tysons
Boulevard, McLean, VA 22102.
National Institutes of Health
Review Special Emphasis Panel; RFA–AI–
16–024: Sustained-Release Anti-HIV Contact Person: Manzoor Zarger, Ph.D.,
Scientific Review Officer, Center for NIH Policy on the Dissemination of
Products. NIH-Funded Clinical Trial Information
Date: October 14, 2016. Scientific Review, National Institutes of
Time: 1:00 p.m. to 4:00 p.m. Health, 6701 Rockledge Drive, Room 6208, AGENCY: National Institutes of Health,
Agenda: To review and evaluate grant MSC 7804, Bethesda, MD 20892, (301) 435–
2477, zargerma@csr.nih.gov. Department of Health and Human
applications. Services.
Place: National Institutes of Health, 6701 Name of Committee: Center for Scientific
Review Special Emphasis Panel; ACTION: Notice.
Rockledge Drive, Bethesda, MD 20892
(Virtual Meeting). Musculoskeletal, Oral and Skin Sciences
AREA Review. SUMMARY: The National Institutes of
Contact Person: Shiv A. Prasad, Ph.D.,
Date: October 19, 2016. Health (NIH) is issuing this policy to
Scientific Review Officer, Center for
Scientific Review, National Institutes of Time: 9:00 a.m. to 5:00 p.m. promote broad and responsible
Health, 6701 Rockledge Drive, Room 5220, Agenda: To review and evaluate grant dissemination of information from NIH-
MSC 7852, Bethesda, MD 20892, 301–443– applications. funded clinical trials through
5779, prasads@csr.nih.gov. Place: National Institutes of Health, 6701 ClinicalTrials.gov. The policy
Rockledge Drive, Bethesda, MD 20892, establishes the expectation that all
Name of Committee: Biological Chemistry (Virtual Meeting).
and Macromolecular Biophysics Integrated Contact Person: Aftab A. Ansari, Ph.D., investigators conducting clinical trials
Review Group; Synthetic and Biological Scientific Review Officer, Center for funded in whole or in part by the NIH
Chemistry B Study Section. Scientific Review, National Institutes of will ensure that these trials are
Date: October 19–20, 2016. Health, 6701 Rockledge Drive, Room 4108, registered at ClinicalTrials.gov, and that
Time: 8:00 a.m. to 6:00 p.m. MSC 7814, Bethesda, MD 20892, 301–237– results information of these trials is
Agenda: To review and evaluate grant 9931, ansaria@csr.nih.gov. submitted to ClinicalTrials.gov.
applications. Name of Committee: Center for Scientific
Place: Hyatt Regency Bethesda, One DATES: This policy will take effect
Review Special Emphasis Panel; BD2K Open January 18, 2017.
Bethesda Metro Center, 7400 Wisconsin Educational Resources for Data Science
Avenue, Bethesda, MD 20814. (R25). FOR FURTHER INFORMATION CONTACT: For
Contact Person: Michael Eissenstat, Ph.D., Date: October 19, 2016. information about the policy, please
Scientific Review Officer, BCMB IRG, Center Time: 11:00 a.m. to 4:00 p.m. contact the NIH Office of Science Policy
for Scientific Review, National Institutes of Agenda: To review and evaluate grant at clinicaltrials.disseminationpolicy@
Health, 6701 Rockledge Drive, Room 4166, applications.
MSC 7806, Bethesda, MD 20892, 301–435–
mail.nih.gov.
Place: National Institutes of Health, 6701
1722, eissenstatma@csr.nih.gov. Rockledge Drive, Bethesda, MD 20892, SUPPLEMENTARY INFORMATION: The policy
Name of Committee: Integrative, (Virtual Meeting). is complementary to the statutory and
Functional and Cognitive Neuroscience Contact Person: Craig Giroux, Ph.D., regulatory reporting requirements.
Integrated Review Group; Scientific Review Officer, BST IRG, Center These are section 402(j) of the Public
Neuroendocrinology, Neuroimmunology, for Scientific Review, National Institutes of Health Service Act, as amended by Title
Rhythms and Sleep Study Section. Health, 6701 Rockledge Drive, Room 5150, VIII of the Food and Drug
Date: October 19–20, 2016. Bethesda, MD 20892, 301–435–2204, Administration (FDA) Amendments Act
Time: 8:00 a.m. to 6:00 p.m. girouxcn@csr.nih.gov.
Agenda: To review and evaluate grant
of 2007 (FDAAA), and the regulation
Name of Committee: Center for Scientific
applications. Clinical Trial Registration and Results
Review Special Emphasis Panel; SBIB
Place: Pier 5 Hotel, 711 Eastern Avenue, Clinical Pediatric and Fetal Applications. Information Submission, at 42 CFR part
Baltimore, MD 21202. Date: October 19, 2016. 11. Hereafter, we refer to section 402(j)
Contact Person: Michael Selmanoff, Ph.D., Time: 11:00 a.m. to 5:00 p.m. as the statute and 42 CFR part 11 as the
Scientific Review Officer, Center for Agenda: To review and evaluate grant rule or regulation.
Scientific Review, National Institutes of applications. On November 19, 2014, and in
Health, 6701 Rockledge Drive, Room 5164, Place: National Institutes of Health, 6701 tandem with the publication of the
MSC 7844, Bethesda, MD 20892, 301–435– Rockledge Drive, Bethesda, MD 20892, Notice of Proposed Rulemaking (NPRM)
1119, mselmanoff@csr.nih.gov. (Virtual Meeting). on Clinical Trial Registration and
mstockstill on DSK3G9T082PROD with NOTICES
Name of Committee: Biological Chemistry Contact Person: Songtao Liu, MD,
Scientific Review Officer, Center for
Results Submission, the NIH issued a
and Macromolecular Biophysics Integrated
Scientific Review, National Institutes of complementary draft policy for public
Review Group; Macromolecular Structure
and Function D Study Section. Health, 6701 Rockledge Dr., Rm 5108, comment on the Dissemination of NIH-
Date: October 19, 2016. Bethesda, MD 20817, 301–435–3578, funded Clinical Trial Information [Ref.
Time: 8:00 a.m. to 6:00 p.m. songtao.liu@nih.gov. 1, 2]. The draft policy proposed that all
Agenda: To review and evaluate grant (Catalogue of Federal Domestic Assistance NIH-funded awardees and investigators
applications. Program Nos. 93.306, Comparative Medicine; conducting clinical trials, funded in
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![Federal Register / Vol. 81, No. 183 / Wednesday, September 21, 2016 / Notices 64923
whole or in part by the NIH, regardless healthcare providers seeking effective date as well as those that have
of study phase, type of intervention, or information about NIH-funded trials, already been completed as of the
whether they are subject to the statutory and serve the public’s interest by effective date.
registration and results information preventing duplication of unsafe and On the other hand, there were other
submission requirements, would be unsuccessful trials and mitigating comments suggesting that the policy
expected to ensure that those clinical publication bias. They also agreed that should not apply to phase 1 or so called
trials are registered and results improving the availability of clinical phase 0 trials, pilot trials designed to
information is submitted to trial information will strengthen the examine the feasibility of an approach,
ClinicalTrials.gov. It further stated that public’s trust in biomedical research as trials mounted by an investigator at a
submission of the same type of well as assure volunteers that their small organization, or trials that are
registration and results information participation in clinical trials has unable to enroll a statistically
would be expected and in the same advanced knowledge on human health significant number of participants. One
timeframes as the trials subject to the and disease. A number of commenters suggested that even pilot trials that
statute, and that this information would also suggested that the policy is reach their enrollment target should not
be made publicly available through the particularly appropriate because NIH- be expected to submit results
ClinicalTrials.gov Web site. funded clinical trials are supported by information because the results might be
The NIH received approximately 240 public funding, and recipients of those more misleading than helpful. Another
public comments on its proposed funds have a special obligation to proposed that reporting on phase 1
policy. The comments came from a ensure that the nation’s investment is clinical trials should be limited to
range of stakeholders including maximized. adverse events information because
researchers, academic/research A number of comments from these trials are designed to assess safety
institutions, medical practitioners, academic investigators and stakeholder rather than efficacy, and reporting non-
patients, patient/disease advocacy organizations were supportive of the safety outcomes could be misleading.
groups, scientific/professional societies policy and its goals. Others, however, Another suggested that clinical trials not
and associations, device manufacturers, disagreed with the policy, suggesting covered under the statute should not
trade associations, not-for-profit non- that it was ill-advised and/or submit adverse event information unless
governmental organizations, and the unnecessary. These commenters a regulatory authority or equivalent
general public [Ref. 3]. The NIH suggested that the benefit of greater body has first performed an analysis of
appreciated the public interest in the transparency was outweighed by the the event in order to prevent public
proposed policy and the time made and burden and cost of the policy to those misunderstanding. Another commenter
effort taken by stakeholders to provide who conduct clinical trials and that the suggested that submission of data from
comments. The NIH carefully NIH had not made a sufficient case for early phase research could divert
considered those comments in the the policy or that it was not evidence-
limited research resources and time
development of the final policy. In the based. Some commenters suggested that
from phase 3 studies. Another suggested
next section, we provide an overview of the NIH should simply encourage
that only information about phase 3
the comments on the proposed policy. investigators to be more transparent or
clinical trials should be included in
Because those in compliance with the that the NIH’s public access policy
ClinicalTrials.gov because information
policy would be expected to follow made the policy unnecessary since it
about early stage trials could confound,
specific provisions of the rule, a number requires NIH-funded investigators to
rather than enhance, public
of commenters on the policy reiterated make their published articles publicly
understanding of human health and
comments that they submitted to the available through PubMed Central.
Scope and Applicability of the Policy. could, thereby, inadvertently adversely
docket in response to the NPRM [Ref. 4].
Since these comments are discussed at Although the majority of commenters affect patient safety.
length in the preamble of the rule, we fully supported the scope of the policy, One commenter suggested that the
are limiting the discussion of comments i.e., that it should apply to NIH-funded policy should apply only to the
here primarily to those that identified clinical trials of FDA-regulated drugs registration of clinical trials, not the
issues specific to the policy, such as its regardless of phase, small feasibility submission of results information. This
scope, applicability, and impact on NIH- studies of devices, and trials of commenter asserted that registration
funded awardees and investigators. interventions not regulated by FDA, information was sufficient because any
including surgical and behavioral interested party could follow up with an
Overview of the Public Comments interventions, there were comments investigator to learn more about the trial
A significant majority of the public suggesting that the scope was too and because submission of registration
comments were supportive of the narrow, or conversely, too broad. information takes a fraction of the time
proposed NIH policy and of its One commenter suggested that the needed to submit results information.
application to the full range of NIH- policy ought to encompass more There were a few commenters who
funded clinical trials. Most commenters detailed summary results, such as took issue with the application of the
appreciated the impetus behind the Clinical Study Reports, as well as de- policy to trials that are only partially
policy and agreed that it was important identified individual patient-level data. funded by the NIH. They asserted that
to provide ways other than journal One commenter suggested that the NIH the policy would entail the disclosure of
publication for clinical trial results to be should consider extending the policy to confidential commercial information
disseminated and made publicly preclinical in vivo (laboratory) animal and that the NIH’s authority to do so is
available to researchers, health care studies because the arguments for the limited to a trial that is wholly NIH-
mstockstill on DSK3G9T082PROD with NOTICES
providers, and patient communities. registration and required reporting of funded and involves a product with
They recognized that increased preclinical in vivo (laboratory) animal research and development costs wholly
availability of information from NIH- studies are similar to those of human government-funded. A few other
funded clinical trials would help clinical trials. Some commenters commenters suggested that the policy
researchers by informing the design and suggested that the policy should be should exclude clinical trials that use
development of their future studies, retroactive and apply to clinical trials NIH-supported infrastructure, but
address the needs of patients and that are underway as of the policy’s involve no NIH funds.
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![Federal Register / Vol. 81, No. 183 / Wednesday, September 21, 2016 / Notices 64925
future research designs and maximize duplicates other NIH policies. This investigators conducting clinical trials
the public’s investment—and their policy is certainly in keeping with our funded in whole or in part by the NIH
trust—in research. Equally important, it principles, longstanding expectations, regardless of study phase, type of
will help investigators fulfill the ethical and other policies as well as the more intervention, or whether they are subject
obligation they have to clinical trial recent broad policy call for scientific to the statute and to the rule. It clarifies
participants, namely to ensure that the agencies to increase public access to that the policy is an expectation, that
findings from their participation scientific data [Ref. 5]. However, it does applicants and offerors are required to
contribute to generalizable knowledge not duplicate any other NIH policy, nor submit a plan outlining how they will
and the advancement of public health. does any other NIH policy accomplish meet the policy’s expectations, and, that
As we noted in the preamble to the what this one will. upon receipt of an award, an awardee
proposed policy, a fundamental premise Some commenters also contended will be obligated to adhere to their plan
of all NIH-funded research is that the that this policy is not necessary because through the terms and conditions of the
results of such work must be the results of clinical trials will be award. The required plan can be a brief
disseminated in order to contribute to published or because they can be statement explaining whether the
the general body of scientific knowledge obtained via direct requests to the trial’s applicant/offeror intends to register and
and, ultimately, to the public health. principal investigator. In fact, research submit results information to
The NIH awardees have always been has shown that the results of a ClinicalTrials.gov as outlined in the
expected to make the results of their significant portion of clinical trials are policy or to meet the expectations in
activities available to the research not published or published in a timely another manner. It is important to
community and to the public at large manner. For example, a 2012 study of remember that an NIH-funded clinical
because it is intrinsic to the scientific NIH-funded clinical trials found that trial that meets the definition of an
process. In research involving human after a median of 51 months following applicable clinical trial is subject to the
beings, moreover, scientists also have an trial completion, 32 percent were regulation and, therefore, register and
ethical obligation to ensure that the unpublished [Ref. 6]. A more recent submission of results information to
burden and risk that volunteers assume study of the trial publication rate among ClinicalTrials.gov is a requirement.
by participating in research comes to 51 U.S. academic medical centers found The policy applies to both the
something, at the very least by ensuring that 43 percent of their clinical trials extramural and intramural programs.
that others are aware of the study and were unpublished two years after the For the NIH extramural program, the
that its findings contribute to the trial was completed [Ref. 7]. While the policy applies to applications for
advancement of human health. ability to seek results information from funding including for grants, other
We disagree with commenters who the original investigator is useful to transactions, and contracts submitted on
suggested that there is no need for facilitate collaborations, to access or after the policy’s effective date that
coverage of certain types of trials, such individual-level data, and to gain request support for the conduct of a
as early exploratory trials, small trials, insights from those who conducted the clinical trial that is initiated on or after
trials assessing only safety, or trials that trial, it is not a surefire way to increase the policy’s effective date. This means
terminate before reaching enrollment access to trial results nor is it efficient that the policy does not apply to clinical
targets. The benefits of transparency and or transparent, particularly for the trials in ongoing, non-competing
the need to fulfill the ethical obligation public. awards, but that it will apply if the
to participants is as relevant to these We believe that the public availability grantee submits a competing renewal
types of trials as to any other type. We of clinical trial results information will application that includes a new clinical
were also not persuaded that the be beneficial to all parties in the long trial, i.e., a clinical trial initiated on or
timeframe for results information run, including those who are covered by after the effective date of the policy. For
submission should be longer for this policy. All investigators stand to the intramural program, the policy
academic investigators because of their benefit from this policy. For example, applies to clinical trials initiated on or
competing responsibilities or that they science may progress more quickly after the policy’s effective date. The
should be allowed more time to publish because investigators will be able to policy’s effective date is January 18,
their results in a journal. The timeframe learn from trials to which they 2017. The policy clarifies that a clinical
of 12 months from the primary otherwise would not have had access trial that uses NIH-supported
completion date should provide enough because they were unpublished. In infrastructure, but does not receive NIH
time for investigators to organize their addition, the public availability of funds to support its conduct, is not
data and submit results information. We results information helps investigators subject to the policy.
are also confident that academic design trials and Institutional Review The policy outlines the
institutions can develop central support Boards (IRBs) review proposed trials, by responsibilities for NIH-funded
services as necessary to assist allowing them to weigh the proposed investigators according to whether the
investigators should they need it. We study’s risks and benefits against a more trial is covered by the policy only or
also believe that 12 months represents complete evidence base than is also the rule. For those covered by the
an appropriate balance between currently available through the policy only, NIH-funded awardees and
investigators’ interests and the interests scientific literature [Ref. 8]. Submission investigators will be expected to submit
of the public in having access to the and posting of results information will the same registration and results
results of a publicly funded trial. In also help investigators avoid repeating information in the same timeframes as
addition, it will be possible to delay trials on interventions that have been those subject to the statute and rule. The
results information submission for up to found to be unsafe or unsuccessful timeline for registration is not later than
mstockstill on DSK3G9T082PROD with NOTICES
two years beyond the initial deadline while also providing access to 21 calendar days after the enrollment of
with a certification that regulatory information that may help verify the first participant. The standard
approval of the trial product is being findings. timeline for results information is not
sought. For all of these reasons, we have not later than one year after the trial’s
Some commenters suggested that a changed the essential contours of the primary completion date, but the policy
policy on clinical trial information policy. In terms of scope, the policy still also allows for delayed submission of
dissemination is not needed because it applies to all NIH-funded awardees and results information in certain
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circumstances for up to two additional NIH-funded awardees and NIH-funded investigators to publish the
years for trials of products regulated by investigators will be expected to follow results of their studies in peer-reviewed
the FDA that are unapproved, the provisions of the rule in terms of journals.
unlicensed, or uncleared or for trials of when they register their trials, what We have no doubt that this policy will
products for which approval of a new information they provide as part of the be beneficial for the research
use is being sought. registration process, when they submit community as well as the public
Although the policy does not apply to their results information, and what generally, but we recognize that
NIH-funded clinical trials initiated results information is submitted. All of adhering to it will be a new obligation.
before the effective date, we encourage the alternate approaches in the rule will We will provide additional guidance to
all ongoing NIH-funded clinical trials to also be available to those covered by the facilitate implementation and help
follow it. It is also critical for policy, e.g., for delayed posting of awardees and investigators understand
investigators conducting NIH-funded device registration information, delayed the policy as well as the tasks described
applicable clinical trials that are subject submission of results information for in the rule that they will be expected to
to the statute and rule to be sure they trials involving unapproved products or undertake. In terms of the costs of
are in compliance with those products for which a new use is sought, complying with the policy, grantees are
requirements. extensions for good cause, and waivers permitted to charge the salaries of
The policy continues to use the NIH that might be needed for privacy or administrative and clerical staff as a
definition of ‘‘clinical trial’’ as proposed national security reasons. direct cost [Ref. 10]. Such staff could
With regard to the concern that assist investigators in meeting their
in the draft policy to determine which
ClinicalTrials.gov is not set up to accept responsibilities under the policy. In
research studies are covered by the
NIH-funded trials that are small or addition, administrative costs can be
policy. This definition was developed in
exploratory in nature or involve covered through indirect cost recovery.
2014 to reflect the NIH research mission
behavioral interventions, it is important We intend for this policy to benefit all
and the scope of clinical trials within
to note that the ClinicalTrials.gov does communities who seek information
the NIH portfolio. With regard to the
accommodate the submission of all trial about NIH-funded clinical trials, and we
concern expressed by a public
types and that a variety of study and are confident that the benefits of
commenter that the phrase ‘‘health-
trial types have been entered into transparency will become evident soon
related biomedical or behavioral
ClinicalTrials.gov since its inception. In after the policy is implemented. We
outcomes’’ might be too narrow, we note addition, ClinicalTrials.gov has
that the definition considers biomedical plan to evaluate the implementation and
resources available to assist impact of the policy from the
and behavioral outcomes to be health- investigators in navigating the
related outcomes in interventional perspective of those who comply with it
registration and results information as well as from the perspective of
studies that meet the other components submission processes. These resources
of the definition. Also, regarding the ClinicalTrials.gov users, including
will continue to be updated over time to patients, providers, and investigators.
concern that the wording of the be responsive to investigators’ needs
definitions of clinical trial in this policy We look forward to engaging with
and the evolving clinical research NIH-funded investigators and awardees
and the rule differ, this is so mainly in enterprise. Therefore, it should not be
reference to outcomes, i.e., the NIH as they work to meet the expectations of
necessary for a clinical investigator of this important public policy.
definition explicitly references an NIH-funded clinical trial to seek an
behavioral outcomes whereas the Information to assist applicants,
exemption from the policy for reasons offerors, and investigators is available at
definition in the rule encompasses them related to the capacity of
within the term ‘‘health related.’’ These the following Web sites. The NIH will
ClinicalTrials.gov to accommodate all continue to add guidance materials to
distinctions are not significant in terms types of clinical trials.
of defining what is covered by the NIH these sites as the policy’s
Registration and results information implementation continues.
policy. All NIH-funded clinical trials, submission to ClinicalTrials.gov
whether they are assessing biomedical • http://osp.od.nih.gov/office-
complements publication of trial results
or behavioral outcomes or whether they clinical-research-and-bioethics-policy/
in peer-reviewed scientific journals.
are employing an FDA regulated clinical-research-policy/clinical-trials
Information submitted to • https://clinicaltrials.gov/ct2/
product, are covered by the policy. An ClinicalTrials.gov is displayed in a
NIH-funded clinical trial assessing a manage-recs
structured way and includes a complete • http://grants.nih.gov/clinicaltrials_
behavioral intervention that is not list of all pre-specified outcome fdaaa/faq.htm
regulated by the FDA would meet both measures and all adverse events. Journal
definitions of clinical trial, and, thereby, The NIH policy is set forth below.
articles, on the other hand, typically
be covered by the policy. However, such focus on a select set of outcome References
a trial would not be subject to the rule measures and adverse events and 1. National Institutes of Health, U.S.
because it does not meet the rule’s include background and discussion of Department of Health and Human
definition of ‘‘applicable clinical trial.’’ the implications of the results. Services, NIH request for public
Guidance available on the NIH’s Web Information submitted to comments on the proposed NIH policy
site can help awardees and investigators ClinicalTrials.gov undergoes a quality on dissemination of NIH-funded clinical
understand whether a research study is control review whereas journal articles trial information. NIH Guide for Grants
a clinical trial for purposes of the NIH will be peer reviewed. With regard to and Contracts. 2014 Nov 19. Available
policy (see first Web site listed below). the concern that submission of results from https://grants.nih.gov/grants/guide/
mstockstill on DSK3G9T082PROD with NOTICES
Questions should be directed to the NIH could make journal publication more notice-files/NOT-OD-15-019.html. Also
program staff. To understand whether published in Fed Regist. 2015 Feb 13;
difficult or impossible, the ICMJE has
80(30):8096–98. Available from https://
an NIH-funded clinical trial is also stated that submission of summary www.federalregister.gov/articles/2015/
subject to the statute and the rule, results to ClinicalTrials.gov will not be 02/13/2015-02994/announcement-of-a-
awardees and investigators should look considered prior publication and will, draft-nih-policy-on-dissemination-of-
to the rule’s definition of ‘‘applicable thus, not interfere with journal nih-funded-clinical-trial-information.
clinical trial.’’ publication [Ref. 9]. We encourage all 2. National Institutes of Health, U.S.
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![Federal Register / Vol. 81, No. 183 / Wednesday, September 21, 2016 / Notices 64927
Department of Health and Human registered at, and that summary results submit results information to
Services, Notice of Proposed Rulemaking information is submitted to, ClinicalTrials.gov.
on Clinical Trials Registration and ClinicalTrials.gov for public posting.1 This policy applies to clinical trials
Results Submission. Fed Regist. 2014 The purpose of the policy is to promote funded in whole or in part through the
Nov 21;79(225):69566–69680. Available NIH extramural and intramural
from https://www.federalregister.gov/
broad and responsible dissemination of
articles/2015/02/13/2015-02990/clinical- information from NIH-funded clinical programs. For the NIH extramural
trials-registration-and-results- trials through ClinicalTrials.gov. program, the policy applies to
submission. Disseminating this information supports applications for funding including for
3. A compilation of public comments on the the NIH mission to advance the grants, other transactions, and contracts
draft NIH Policy on Dissemination of translation of research results into submitted on or after the policy’s
NIH-Funded Clinical Trial Information is knowledge, products, and procedures effective date that request support for
available at: http://osp.od.nih.gov/sites/ that improve human health. the conduct of a clinical trial that is
default/files/resources/Clinical%20 This policy is complementary to initiated on or after the policy’s effective
Trials%20Dissemination%20Policy%20 requirements in the Clinical Trial date. For the NIH intramural program,
Combined%20Comments_2.0.pdf. Registration and Results Information the policy applies to clinical trials
4. U.S. Department of Health and Human
Services, National Institutes of Health,
Submission regulation at 42 CFR part initiated on or after the policy’s effective
National Library of Medicine. Clinical 11, hereinafter referred to as the date.
Trials Registration and Results regulation.2 Clinical trials that are This policy does not apply to a
Submission. [Internet]. 2011 [cited 2016 subject to the regulation are, in general, clinical trial that uses NIH-supported
September 1]. Available from: https:// clinical trials of drug, biological, and infrastructure but does not receive NIH
www.regulations.gov/docket?D=NIH- device products regulated by the Food funds to support its conduct.
2011-0003. and Drug Administration (FDA), except
5. NIH Data Sharing Policy (https:// Responsibilities
phase 1 trials of drug and biological
grants.nih.gov/grants/policy/data_ products and small feasibility studies of As part of their applications or
sharing/); NIH Public Access Policy device products. A pediatric post- proposals, applicants and offerors
(https://publicaccess.nih.gov/policy.htm seeking NIH funding will be required to
or https://publicaccess.nih.gov/); NIH
market surveillance study of a device
product required by the FDA is also submit a plan for the dissemination of
Genomic Data Sharing Policy (https://
gds.nih.gov/03policy2.html); Increasing subject to the regulation. Clinical trials NIH-funded clinical trial information
Access to the Results of Federally subject to the regulation are generally that will address how the expectations
Funded Scientific Research (https:// called ‘‘applicable clinical trials.’’ of this policy will be met. NIH-funded
www.whitehouse.gov/sites/default/files/ Applicable clinical trials are required to awardees and investigators conducting
microsites/ostp/ostp_public_access_ be registered in ClinicalTrials.gov not clinical trials funded in whole or in part
memo_2013.pdf). later than 21 calendar days after the by the NIH will be required to comply
6. Ross et al., BMJ. 2012 Jan 3;344:d7292. enrollment of the first participant. with all terms and conditions of award,
http://www.bmj.com/content/bmj/344/ Results information from those trials including following their plan for the
bmj.d7292.full.pdf.
generally must be submitted not later dissemination of NIH-funded clinical
7. Chen et al., BMJ. 2016 Feb 17;352:i637
http://www.bmj.com/content/bmj/352/ than one year after the trial’s primary trial information.
bmj.i637.full.pdf. completion date. Submission of results Consistent with those terms and
8. Berlin, JA, et al., Bumps and Bridges on information can be delayed in certain conditions, the responsibilities of such
the Road to Responsible Sharing of circumstances for up to two additional awardees and investigators will fall
Clinical Trial Data. Clinical Trials. years for trials of products regulated by within one of the three categories. The
2014;11:7–12. the FDA that are unapproved, category depends on whether, under the
9. ICMJE [Internet]. International Committee unlicensed, or uncleared or for trials of regulation, the clinical trial is also an
of Medical Journal Editors; 2016. Clinical products for which approval, licensure, ‘‘applicable clinical trial’’ and the
trial registration; 2011 [cited 2016 Aug awardee or investigator is the
or clearance of a new use is being
5]; [about 2 screens]. Available from:
sought. ‘‘responsible party.’’
http://www.icmje.org/recommendations/
browse/publishing-and-editorial-issues/
1. If the NIH-funded clinical trial is an
Scope and Applicability applicable clinical trial under the
clinical-trial-registration.html and http://
www.icmje.org/about-icmje/faqs/ This policy applies to all NIH-funded regulation and the awardee or
clinical-trials-registration/. clinical trials regardless of study phase, investigator is the responsible party, the
10. 45 CFR 75.413(c) and Chapter 8.1.1.6, type of intervention, or whether they are awardee or investigator will ensure that
Direct Charging Salaries of subject to the regulation. For example, all regulatory requirements are met.
Administrative and Clerical Staff. NIH NIH-funded phase 1 clinical trials of an 2. If the NIH-funded clinical trial is an
Grants Policy Statement. http:// FDA-regulated product are covered by applicable clinical trial under the
grants.nih.gov/grants/policy/nihgps/ this policy as are clinical trials studying regulation but the awardee or
HTML5/section_8/8.1_changes_in_ investigator is not the responsible party,
interventions not regulated by the FDA,
project_and_budget.htm.
such as behavioral interventions. As the awardee or investigator will
NIH Policy on Dissemination of NIH- such, the policy encompasses all NIH- coordinate with the responsible party to
Funded Clinical Trial Information funded clinical trials, including ensure that all regulatory requirements
applicable clinical trials subject to the are met.
Purpose 3. If the NIH-funded clinical trial is
regulation. All NIH-funded clinical
The National Institutes of Health not an applicable clinical trial under the
mstockstill on DSK3G9T082PROD with NOTICES
trials will be expected to register and
(NIH) Policy on Dissemination of NIH- regulation, the awardee or investigator
funded Clinical Trial Information 1 ClinicalTrials.gov is operated by the National will be responsible for carrying out the
establishes the expectation that all NIH- Library of Medicine within the NIH. tasks and meeting the timelines
2 The Clinical Trial Registration and Results
funded awardees and investigators described in regulation. Such tasks
Information Submission regulation at 42 CFR part
conducting clinical trials, funded in 11 was issued in the Federal Register in September
include registering the clinical trial in
whole or in part by the NIH, will ensure 2016. The regulation implements section 402(j) of ClinicalTrials.gov and submitting results
that their NIH-funded clinical trials are the Public Health Service Act. information to ClinicalTrials.gov.
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![64928 Federal Register / Vol. 81, No. 183 / Wednesday, September 21, 2016 / Notices
In addition, informed consent Responsible Party. In the policy, the 45 CFR 75.371 and/or other authorities,
documents for clinical trials within all awardee or the investigator is as appropriate. If the NIH-funded
three categories are to include a specific responsible for meeting the expectations clinical trial is also an applicable
statement relating to posting of clinical of this policy. In the regulation, a clinical trial, non-compliance with the
trial information at ClinicalTrials.gov. ‘‘responsible party’’ means, in part, requirements specified in 42 U.S.C.
Each NIH-funded clinical trial should ‘‘with respect to a clinical trial, the 282(j) and 42 CFR part 11 may also lead
have only one entry in sponsor of the clinical trial, as defined to the actions described in 42 CFR
ClinicalTrials.gov that contains its in 21 CFR 50.3 (or any successor 11.66.
registration and results information. regulation); or the principal investigator
Awardees and investigators need not of such clinical trial if so designated by Effective Date
and should not create a separate record a sponsor, grantee, contractor, or This policy is effective January 18,
of the applicable clinical trial to comply awardee, so long as the principal 2017.
with this policy. investigator is responsible for Date: September 12, 2016.
The NIH will publicly post conducting the trial, has access to and
registration information and results Francis S. Collins,
control over the data from the clinical
information in ClinicalTrials.gov. Director, National Institutes of Health.
trial, has the right to publish the results
of the trial, and has the ability to meet [FR Doc. 2016–22379 Filed 9–16–16; 11:15 am]
Definitions
all of the requirements under [42 CFR BILLING CODE 4140–01–P
Clinical Trial. For purposes of this part 11] for the submission of clinical
policy, a ‘‘clinical trial’’ means ‘‘a trial information.’’ 6
research study in which one or more Primary Completion Date. In the DEPARTMENT OF HEALTH AND
human subjects are prospectively policy, this term has the same meaning HUMAN SERVICES
assigned to one or more interventions as the term ‘‘primary completion date’’
(which may include placebo or other National Institutes of Health
in the regulation, which is ‘‘the date that
control) to evaluate the effects of those the final subject was examined or
interventions on health-related National Center for Advancing
received an intervention for the Translational Sciences; Notice of
biomedical or behavioral outcomes.’’ 3 purposes of final collection of data for
This definition encompasses phase 1 Closed Meeting
the primary outcome, whether the
trials of FDA-regulated drug and clinical trial concluded according to the Pursuant to section 10(d) of the
biological products, small feasibility pre-specified protocol or was Federal Advisory Committee Act, as
studies of FDA-regulated device terminated.’’ 7 amended (5 U.S.C. App.), notice is
products, and studies of any Registration Information. In the hereby given of the following meeting.
intervention not regulated by the FDA, policy, this term has the same meaning The meeting will be closed to the
e.g., behavioral interventions. This as the term ‘‘registration information’’ in public in accordance with the
definition of ‘‘clinical trial’’ 4 is broader the regulation. In the regulation, provisions set forth in sections
than the term ‘‘applicable clinical trial’’ registration information consists of 552b(c)(4) and 552b(c)(6), Title 5 U.S.C.,
as defined in the regulation.5 descriptive information, recruitment as amended. The contract proposals and
information, location and contact the discussions could disclose
3 Further information about this definition is
information, and administrative data.8 confidential trade secrets or commercial
available from the NIH Office of Science Policy at
http://osp.od.nih.gov/office-clinical-research-and- Results Information. In the policy, property such as patentable material,
bioethics-policy/clinical-research-policy/clinical- this term has the same meaning as the and personal information concerning
trials. term ‘‘results information’’ in the individuals associated with the contract
4 Note that the regulation also includes a
regulation. In the regulation, results proposals, the disclosure of which
definition of ‘‘clinical trial.’’ That definition is ‘‘a
clinical investigation or a clinical study in which
information includes participant flow, would constitute a clearly unwarranted
human subject(s) are prospectively assigned, demographic and baseline invasion of personal privacy.
according to a protocol, to one or more characteristics, outcomes and statistical
interventions (or no intervention) to evaluate the Name of Committee: National Center for
analyses, adverse events, the protocol
effect(s) of the intervention(s) on biomedical or Advancing Translational Sciences Special
health related outcomes’’ (see 42 CFR 11.10 (a)). For
and statistical analysis plan, and Emphasis Panel; TRND2.
the purposes of this policy, the regulatory definition administrative information.9 Date: October 13, 2016.
and the definition in this policy are treated as Time: 11:30 a.m. to 6:30 p.m.
synonymous.
Compliance
Agenda: To review and evaluate contract
5 In the regulation, applicable clinical trial is
If the clinical trial is NIH-funded in proposals.
defined as an applicable device clinical trial or an whole or in part, expectations for Place: National Institutes of Health, Room
applicable drug clinical trial. The regulation defines
an applicable device clinical trial to mean, in part, clinical trial registration and summary 1087, 6701 Democracy Blvd., Bethesda, MD
‘‘a prospective clinical study of health outcomes results submission will be included in 20892 (Telephone Conference Call).
comparing an intervention with a device product the terms and conditions of the award. Contact Person: Victor Henriquez, Ph.D.,
subject to section 510(k), 515, or 520(m) of the Failure to comply with the terms and Scientific Review Officer, Office of Scientific
Federal Food, Drug, and Cosmetic Act (21 U.S.C. Director, National Center for Advancing
360(k), 21 U.S.C. 360e, 21 U.S.C. 360j(m)) against conditions of the NIH award may
Translational Sciences (NCATS), National
a control in human subjects (other than a small provide a basis for enforcement actions, Institutes of Health, 6701 Democracy Blvd.,
clinical trial to determine the feasibility of a device including termination, consistent with Democracy 1, Room 1080, Bethesda, MD
product, or a clinical trial to test prototype device
products where the primary outcome measure
20892–4878, 301–451–2405, henriquv@
mstockstill on DSK3G9T082PROD with NOTICES
meaning given in 21 CFR 312.3 (or any successor mail.nih.gov.
relates to feasibility and not to health outcomes).’’
regulation) and ‘‘phase 1’’ has the meaning given in
The regulation defines an applicable drug clinical (Catalogue of Federal Domestic Assistance
21 CFR 312.21 (or any successor regulation).’’
trial to mean, in part, ‘‘a controlled clinical 6 See 42 CFR 11.10 (a) and 42 CFR 11.4. Program Nos. 93.859, Pharmacology,
investigation, other than a phase 1 clinical
investigation, of a drug product subject to section
7 See the complete definition at 42 CFR 11.10 (a). Physiology, and Biological Chemistry
505 of the Federal Food, Drug, and Cosmetic Act 8 See 42 CFR 11.10 (b) and 42 CFR 11.28 for the Research; 93.350, B—Cooperative
(21 U.S.C. 355) or a biological product subject to specific data elements. Agreements; 93.859, Biomedical Research
section 351 of the Public Health Service Act (42 9 See 42 CFR 11.28 for complete results and Research Training, National Institutes of
U.S.C. 262), where ‘‘clinical investigation’’ has the information and specific data elements. Health, HHS)
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Document Created: 2016-09-21 01:30:59
Document Modified: 2016-09-21 01:30:59
| Category | Regulatory Information | |
| Collection | Federal Register | |
| sudoc Class | AE 2.7: GS 4.107: AE 2.106: | |
| Publisher | Office of the Federal Register, National Archives and Records Administration | |
| Section | Notices | |
| Action | Notice. | |
| Dates | This policy will take effect January 18, 2017. | |
| Contact | For information about the policy, please contact the NIH Office of Science Policy at [email protected] | |
| FR Citation | 81 FR 64922 |
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