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The Institutional DURC Policy – One Year Later: An Invitation for Stakeholder Input

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Maximizing the benefits of life sciences research while minimizing the potential risks associated with conducting that research is an important and ongoing topic of conversation within the science policy community. For example, developing lifesaving treatments for infectious diseases often requires working directly with infectious pathogens. This presents inherent risks to lab workers, which can be managed with proper biocontainment and safety practices. Scientific information can also pose risks if communicating the research involves findings that could be misused for nefarious purposes.

All research has some “dual use” potential, but so-called dual use research of concern (DURC) is legitimate research with the greatest potential for generating information that could be misused and result in significant harmful consequences. Recognizing the need for oversight of DURC, the U.S. government issued two policies aimed at managing risks associated with this small universe of research. One policy, issued in 2012 focuses on the responsibilities of federal funding agencies to identify DURC and manage risks accordingly. The other, and the focus of this blog, was issued in 2014 and focuses on the responsibilities of research institutions. Together, these complementary policies establish a system of shared responsibility for DURC oversight among federal funding agencies, institutions, and researchers.

Prior to the institutional DURC Policy’s 2015 implementation date, the U.S. government held a workshop to engage stakeholders and address questions. Now, just over a year later, the U.S. Government is interested in learning more about how researchers and institutions are implementing the Policy. What are the challenges being encountered? Are there best practices for identifying DURC or managing risks? To help answer these and other questions, the National Science Advisory Board for Biosecurity (NSABB) is being asked to help the U.S. Government further solicit feedback by hosting a series of regional stakeholder meetings. These meetings will focus on how institutions are implementing the DURC policy and what challenges they are facing.

The NSABB will discuss this new task at its next full Board meeting, a teleconference on November 4th, 2016 from 12:00 pm – 3:00 pm ET. This teleconference is open to the public and time will be reserved on the agenda for public comments. If you can’t participate on Nov. 4th, there will be additional opportunities to engage the NSABB to discuss the institutional DURC policy in the coming months. Additionally, we invite interested stakeholders to submit comments to the NSABB at any time by emailing [email protected].

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Improving Visibility of NIH-Supported Clinical Trial Activities and Results Information

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In a separate post today, we provide an overview of the various reforms the NIH is leading to enhance our stewardship of clinical trials. In this post we’d like to focus a bit more on our efforts to broadly disseminate clinical trial availability and results information.

Timely dissemination of clinical trial results information has been a problem, one that has been documented more than once, and that appears to apply to NIH- as well as non-NIH funded trials. To realize the benefits of a clinical trial, the findings must be available to the public as soon as possible after the trial has concluded. This is not only responsible use of taxpayer dollars for publicly funded trials, but also fulfills our responsibility to the individuals who volunteered in these studies with an understanding that their participation would contribute to advancing medical knowledge. Today, NIH announced a new policy that will complement a new federal regulation, referred to here as the Final Rule, also released today, to improve the accessibility of information on clinical trial availability and on the outcomes and results of completed trials.

As you likely know, to carry out the laws passed by Congress, federal agencies issue regulations that govern the activities of the agency and the applicable community. The “Final Rule” announced today by the U.S. Department of Health and Human Services is the federal regulation that implements requirements in the Food and Drug Administration Amendments Act of 2007 (FDAAA) for registering and reporting clinical trials on ClinicalTrials.gov. Clinical trials that are subject to this federal regulation are, in general, 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. Pediatric post-market surveillances of device products, required by the FDA, are also subject to the regulation.

In addition, NIH issued a policy today that complements the Final Rule and sets the same reporting expectations for all NIH-funded clinical trials whether or not they are subject to the regulation (to include, for example, phase 1 studies of FDA regulated products as well as studies of interventions not regulated by FDA, e.g., behavioral interventions.)Both the NIH policy and the Final Rule will take effect January 18, 2017.

The Final Rule and NIH policy will provide greater clarity and robust enforcement provisions that we anticipate will result in rapid increases in the percentage of trials that are registered and that will promote timely dissemination of main results information through ClinicalTrials.gov. Investigators and sponsors who fail to comply with the regulation will be subject to civil monetary penalties assessed by FDA. In addition, NIH will restrict clinical trial funding to grantee institutions if the agency is unable to verify adequate registration and results information reporting from all trials funded at that institution. Failure to comply with the NIH policy in accordance with the terms and conditions of an NIH award can also have consequences, including suspension of funding.

In addition to the Final Rule and NIH policy, NIH has made available a number of resources to help explain the changes, and will be rolling out more over the upcoming months. Resources available now include:

As described in the NIH Guide Notice, for the NIH extramural program, the NIH 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 NIH policy applies to clinical trials initiated on or after the policy’s effective date.

Any grant application or contract proposal submitted on or after the policy’s effective date (January 18, 2017) must include a plan describing how awardees will ensure the appropriate dissemination of NIH-funded clinical trial information. The contents of this plan may vary, depending on whether the NIH clinical trial falls under the Final Rule (referred to as an “applicable clinical trial”), and whether the awardee or investigator is a “responsible party” as defined in the Final Rule (42 CFR Part 11). For more details, please read the NIH Policy on Dissemination of NIH-Funded Clinical Trial Information and the Final Rule published today.

We certainly encourage the broad dissemination of results information from all trials, both through ClinicalTrials.gov and peer-reviewed published results, even prior to the NIH policy’s effective date. Please join us in our efforts to maximize the federal investment in clinical trials as well as maximizing the impact of the contributions of the patient volunteers who are so critical to helping advance human health as a whole.

Dr. Mike Lauer is the NIH Deputy Director for Extramural Research and blogs about NIH research funding policies and data at his blog, Open Mike.

Dr. Mike Lauer
NIH Deputy Director for Extramural Research
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Building Better Clinical Trials through Enhanced Stewardship and Transparency

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NIH is the largest public funder of clinical trials in the United States. As stewards of this research enterprise, we have been actively listening and discussing how to overcome hurdles and  shortcomings that we, and others in the research community, have identified. If you’ve been following the conversation, you’ll know that NIH already has implemented some key reforms to enhance clinical trial stewardship. Today, in a Viewpoint Essay published in the Journal of the American Medical Association (JAMA), we provide an overview of how these reforms, and new initiatives, fit in to the broader picture of building a better clinical trial enterprise through better stewardship, accountability, and transparency.

Figure 1 illustrates the clinical trial “lifespan”, and key opportunities for improving the quality and efficiency of clinical trials – opportunities that translate into more innovative and robust clinical trial design, and accelerated discoveries that will advance human health. NIH is leading a multi-faceted effort that addresses shortcomings and challenges throughout this lifespan, including the application and award process; the scientific review of trial applications; post-award management and oversight; sharing of trial data; and dissemination of research results information to the public.

Some key highlights from our essay:

  • Good clinical practice training. New NIH policies issued today establish Good Clinical Practice (GCP) training expectations – effective January 1, 2017 — for investigators involved in NIH-supported trials, as well as for NIH staff who design, oversee, manage, or conduct clinical trials. There are many providers of GCP training, and institutions have the flexibility to choose the training program that is the best fit with their existing programs (some universities already include GCP in their institutional training requirements, for example).
  • Changes to clinical trial applications. A new NIH policy issued today requires that the research community submit grant applications requesting support for clinical trials in response to clinical trial-specific funding opportunity announcements (FOAs). This policy is targeted to apply to applications submitted for due dates on or after September 27, 2017. This change will allow NIH to readily identify proposed clinical trials, to ensure that key pieces of trial-specific information are submitted with each application, and to ensure that trial-specific review criteria are uniformly applied. To give NIH institutes and centers flexibility across their different scientific areas, each NIH IC will be developing clinical trial FOAs that address their research funding priorities and strategic goals. There will be commonalities across FOAs, in that all clinical trial applications will need to contain key clinical trial-specific elements, such as protocol information. This change will mean that you will no longer be able to submit an application requesting support for a clinical trial on one of our parent announcements. You will need to identify an FOA that clearly invites clinical trial applications. We will publish reminders in the NIH Guide and NIH Extramural Nexus. Read today’s NIH Guide Notice for more information.
  • Enhancing clinical trial registration and summary results information reporting. A new HHS regulation released today specifies requirements for clinical trial registration and summary results information reporting. NIH also issued a policy today that complements the federal regulation and sets the same reporting expectations for all NIH-funded clinical trials whether or not they are subject to the regulation (to include, for example, phase 1 studies of FDA regulated products as well as studies of interventions not regulated by FDA, e.g., behavioral interventions.) Read more in a New England Journal of Medicine paper authored by NIH staff, and we’ve also written more about this change in a separate blog post published today.
  • Use of a single institutional review board for multi-site studies. This NIH policy, issued in June 2016, will streamline and expedite institutional review board (IRB) review of clinical trials conducted across multiple sites. The policy establishes the expectation that a single IRB will be used for multi-site research as of May 25, 2017. (Read an earlier Under the Poliscope post describing this change.)
  • Clinical trial protocol template. To expedite both NIH and federal regulatory oversight processes, NIH, in collaboration with FDA, is developing a clinical trial protocol template for phase 2 and 3 Investigational New Drug (IND)/Investigational Device Exemption (IDE) clinical trials. NIH plans to encourage its use as a way to organize and standardize key details that should be included in clinical trial protocols. NIH is reviewing public comments and working toward an updated version of the template this fall and plans to develop an electronic clinical trial protocol template thereafter.

We encourage you to read our JAMA article, and the articles linked from this blog, for more information. We will continue to harmonize the establishment, conduct, and follow-through of clinical trials research in the upcoming months and years. As described in the JAMA article, clinical trials have evolved and improved over time, resulting in impressive advances, but there are still challenges that we must address. The suite of complementary activities described here intends to help fulfill our mission of improving health through scientific discovery, while preserving the public trust in research through efficient and transparent clinical trials.

Dr. Mike Lauer is the NIH Deputy Director for Extramural Research and blogs about NIH research funding policies and data at his blog, Open Mike.

Posted by Dr. Carrie D. Wolinetz, September 16, 2016

Dr. Mike Lauer
NIH Deputy Director for Extramural Research
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Next Steps on Research Using Animal Embryos Containing Human Cells

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Biomedical researchers have created and used animal models containing human cells for decades to gain valuable insights into human biology and disease development. For example, human tumor cells are routinely grown in mice to study cancer disease processes and to evaluate potential treatment strategies. To advance regenerative medicine, it is common practice to validate the potency of pluripotent human cells – which can become any tissue in the body – through introducing them into rodents.

With recent advances in stem cell and gene editing technologies, an increasing number of researchers are interested in growing human tissues and organs in animals by introducing pluripotent human cells into early animal embryos. Formation of these types of human-animal organism, referred to as “chimeras”, holds tremendous potential for disease modeling, drug testing, and perhaps eventual organ transplant. However, uncertainty about the effects of human cells on off-target organs and tissues in the chimeric animals, particularly in the nervous system, raises ethical and animal welfare concerns.

Currently, the 2009 NIH Guidelines for Human Stem Cell Research specifically prohibit introducing human pluripotent cells into nonhuman primate blastocysts and the breeding of animals into which human pluripotent cells may have contributed to the germ line (egg or sperm cells).  Given the direction of the science, however, NIH felt that it was an appropriate time to consider whether further policy provisions regarding other chimera models were needed before making funding decisions. Therefore, as I wrote about last fall, NIH instituted a funding moratorium in September 2015 (NOT-OD-15-158) for research proposing to introduce human pluripotent cells into animal embryos prior to gastrulation stage—the beginning of development of the three germ layers.

Since the moratorium was issued, NIH has reviewed the state of the science and also convened a workshop in November 2015 to bring together leading experts in the field of chimera research and animal welfare.  Today, NIH has published in the Federal Register and the NIH Guide to Grants and Contracts a proposal to make two changes to our policy in this area, for which we are seeking public comment (a table summarizing the proposed changes also appears at the end of the blog to assist stakeholders.) First, NIH is establishing an internal NIH steering committee to provide programmatic input to NIH Institute and Center Directors in making funding decisions for two areas of research in which:

  1. human pluripotent cells are introduced into non-human vertebrate embryos, up through the end of gastrulation stage, with the exception of non-human primates, which would only be considered after the blastocyst stage, or
  2. human cells are introduced into post-gastrulation non-human mammals (excluding rodents), where there could be either a substantial contribution or a substantial functional modification to the animal brain by the human cells.

NIH is seeking public comment on the proposed scope of the chimera research to be considered by the NIH steering committee. The committee will focus on the experimental design and likely nature of the chimeric animal model. The committee’s work will be independent of the peer review process. This committee will also monitor new developments in this field and provide analysis and advice to NIH leadership as needed.

NIH is also seeking comment on modifications to the NIH Guidelines for Human Stem Cell Research, where we propose to slightly expand the current prohibition on the introduction of human pluripotent cells into non-human primate embryos to include the preblastocyst stage, and to clarify that NIH will not fund research involving the breeding of animals where the introduction of any type of human cell may result in human egg or sperm development.

These actions are consistent with recently updated guidelines from the International Society for Stem Cell Research (ISSCR), which suggest that a specialized review of certain types of chimera research is appropriate. The ISSCR guidelines also contain useful suggestions of best practices for experimental design, which I encourage the research community to consider.

I am confident that these proposed changes will enable the NIH research community to move this promising area of science forward in a responsible manner. I encourage those interested in this field to to add their voice by utilizing the public comment form. While NIH awaits public comment, the moratorium on NIH funding for such research (NOT-OD-15-158) will remain in effect.

Frequently Asked Questions on Chimera Proposal

Draft Chimera Policy Framework

Key Embryonic Stages of Development

Fertilized Egg → Preblastocyst (Morula) → Blastocyst  → Gastrula

Current Stem Cell Prohibitions Proposed Stem Cell Expanded Prohibitions
Proposed Expansion of NIH Guidelines for Human Stem Cell Research
Nonhuman primate embryos No human embryonic stem cells or iPS cells (derived from adult tissues) into non-human primate blastocyst-stage embryos Expanded to include the restriction on earlier stage (pre-blastocyst) of non-human primate embryos
Breeding No breeding of animals where the introduction of human hESC or iPS cells may contribute to germ line (i.e. make human egg or sperm) Expanded to no breeding of animals where any human cells may contribute to germ line
Early Embryos Neural Contribution/Effect
Proposed Scope of Chimera Research Considered by new NIH Steering Committee
Research in which human pluripotent cells are introduced into non-human vertebrate embryos, up through end of gastrulation stage*

*Note that NIH will not fund research introducing human pluripotent cells into non-human primate embryos through the blastocyst stage, per stem cell guidelines, but committee would consider introduction of human cells into non-human primate gastrula stage embryos.

 Research in which human cells are introduced into post-gastrulation non-human mammals (excluding rodents) where there could be:

  • substantial contribution to animal brain or
  • substantial functional modification to animal brain
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