Tag: Collaboration

Building Better Clinical Trials through Enhanced Stewardship and Transparency

Posted on

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
Blog Roll

Next Steps on Research Using Animal Embryos Containing Human Cells

Posted on

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
Blog Roll

Accelerating Clinical Research by Streamlining Multi-Site Review of Human Subjects Research

Posted on

Research involving human participants is key to improving public health and advancing medicine. Oversight of such research by institutional review boards (IRBs) both protects research participants  and promotes ethical science.  IRB review and approval is a critical step in initiating the start of a research project and for multi-site studies, NIH is taking an important step to help streamline the process.

Today, NIH is issuing the NIH Policy on the Use of a Single Institutional Review Board (IRB) for Multi-Site Research (sIRB Policy) in both the Federal Register and the NIH Guide to Grants and Contracts.  The sIRB policy establishes the expectation that a single IRB of record will be used to conduct ethical reviews for domestic sites of multi-site, non-exempt human subjects research protocols that are funded by NIH.   The goal is to promote effective IRB review of multi-site research proposals while eliminating the unnecessary repetition of those reviews across sites.  In developing the policy, NIH considered input from a range of stakeholders who commented on a 2014 draft version. The comments are discussed in the preamble to the final policy, and a compilation of the public comments are available on the NIH Office of Science Policy (OSP) website.

This move to a single IRB model also presents a unique opportunity to harmonize the standards and agreements used in clinical research. The NIH National Center for Advancing Translational Sciences (NCATS), through its Clinical and Translational Science Awards (CTSA) Program, convened experts across the nation to develop a “single IRB reliance model” for multi-site clinical studies. This model, the NCATS “Streamlined, Multisite, Accelerated Resources for Trials” (or “SMART”) IRB Reliance Platform, provides investigators and clinical research review networks with a flexible and user-friendly toolkit.  Several CTSA-supported institutions have already adopted this platform leading the goal to have all CTSA institutions use the SMART IRB Reliance Platform. More information about SMART IRB is available on the NCATS website.

To give the research community ample time to prepare for this change, the NIH is providing a long lead time before the policy takes effect on May 25, 2017.  In addition to the SMART IRB Reliance Platform, guidance on implementation of the sIRB policy is available, such as how costs may be charged to NIH awards. Information and resources, such as FAQs, will be posted to the NIH OSP website, as they are developed. NIH will continue to add information to this page prior to the policy implementation date.

We look forward to working with our stakeholders to facilitate implementation, and welcome input on additional information or clarifications that may be helpful.  We also encourage you to read a statement published today by NIH Director Francis Collins on the importance of this issue.

For further questions or additional information about the policy, we invite you to contact us at [email protected].

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, June 21, 2016

Dr. Mike Lauer
NIH Deputy Director for Extramural Research
Blog Roll

Emerging Biotechnologies and the Role of the NIH RAC

Posted on

Next week, we mark the 40th anniversary of the first publication of the NIH Guidelines governing experiments using recombinant DNA. On June 23rd, 1976, former NIH Director Dr. Donald Frederickson announced that all NIH funded and conducted research involving recombinant DNA would be expected to follow the NIH Guidelines, noting both the great potential benefits that could arise from this new technology and the lack of certainty about the risks.

We have come a long way in 40 years, and the use of recombinant DNA is ubiquitous in research, medicine, and many other aspects of our daily lives. Recently, the NIH announced revisions to the NIH Guidelines that included amending the criteria and process for how human gene transfer protocols would be selected for review by the Recombinant DNA Advisory committee (RAC), limiting in depth review and public discussion only for exceptional cases.

Just such an exceptional case comes before the RAC during their meeting this week. During the June 21-22 meeting, the RAC will review a protocol involving the first-in-human use of gene editing via CRISPR/Cas9 technology.  This T cell immunotherapy protocol involves the use of CRISPR/Cas9 to edit two genes in T cells also modified to express T cell receptors targeting myeloma, melanoma, and sarcoma tumor cells.  Consideration of this study underlines the purpose of changing the RAC process: to better use the collective breadth of experience of the RAC members in reviewing gene transfer trials and novel technologies that pose unknown risks, exactly as described by Dr. Frederickson four decades ago.

Researchers in the field of gene transfer are excited by the potential of utilizing CRISPR/Cas9 to repair or delete mutations that are involved in numerous human diseases in less time and at a lower cost than earlier gene editing systems.  While the application of new gene editing technologies in this field has great potential to improve human health, it is not without concerns.  In a previous statement, NIH Director, Dr. Francis Collins, reiterated NIH’s commitment to support innovations in biomedical research in a fashion that reflects well-established scientific and ethical principles.  Having a body such as the RAC available to publicly discuss the scientific, safety, and ethical implications of such cutting-edge experiments helps to ensure we are living up to that commitment.

As the application of biotechnology innovations moves closer to the clinical realm, we are confident that the changes we have made to the NIH Guidelines will enable the RAC to devote its full resources to where they are most needed. And as science continues to evolve, we will strive for parallel evolution in our policies to make oversight of research commensurate with the risks involved.

I encourage you to either attend the upcoming RAC meeting in person, or through the NIH Videocast to learn more about the exciting advances being made in the field of gene transfer.  Information about the RAC meeting, including an agenda and the meeting location can be found on the OSP website.

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

Blog Roll