The Office for Human Research Protections (OHRP) has posted a series of six webinarsexplaining the recent Notice of Proposed Rulemaking (NPRM) regarding revisions to the Common Rule (the federal policy for human subjects protection). The presentations by policy experts can be viewed anytime; they cover the following topics:
Overview of the NPRM
Exclusions and exemptions
Informed consent
IRB review and operations
Research with biospecimens
Secondary research use of data
For more information on the NPRM, visit the OHRP website. The deadline for comments on the proposed revision has been extended to January 6, 2016.
A new series of 12 articlespublished in a special issue of the journal Clinical Trials addresses ethical and regulatory challenges particular to pragmatic clinical research. Pragmatic clinical trials are designed to efficiently provide answers to important clinical questions, yet they present special challenges in conforming to the ethical and regulatory guidelines that were developed for more traditional clinical research. The special issue describes these challenges and begins to outline possible solutions that will protect the rights and welfare of research participants while allowing pragmatic clinical trials to gather much-needed evidence for informing healthcare decisions. An introductory article is followed by 11 articles addressing individual topics, such as alteration of informed consent, privacy, gatekeepers, and defining minimal risk research. The effort was funded by the NIH Health Care Systems Research Collaboratory, with additional support from the Patient-Centered Outcomes Research Institute (PCORI), and involved diverse groups of stakeholders, including researchers, patient advocates, bioethicists, and regulatory experts. Robert M. Califf, MD, and Jeremy Sugarman, MD, MPH, were editors of the special issue.
The U.S. Department of Health and Human Services(HHS) and 15 other federal departments and agencies have announced proposed revisions to modernize, strengthen, and make more effective the Federal Policy for the Protection of Human Subjects that was promulgated as a Common Rule (45 CFR 46, Subpart A) in 1991. A Notice of Proposed Rulemaking (NPRM) was published in the Federal Register on September 8, 2015 (see the press release).
The NPRM seeks comment on proposals to better protect human subjects involved in research, while facilitating valuable research and reducing burden, delay, and ambiguity for investigators. Comments must be received no later than the extended deadline of 5 pm on January 6, 2016. Visit the HHS page for a summary of the proposed changes and instructions on submitting or browsing comments.
Webinars are availableexplaining the changes proposed in the NPRM, and a town hall meeting is planned to be held in Washington, DC, in October.
Among the major changes being proposed in order to better protect research subjects and help build public trust are modifications to rules affecting patient informed consent. With regard to informed consent in general (such as consent to participate in a clinical trial), the rules would be significantly tightened to ensure that the process becomes more meaningful. Consent forms in particular would be affected. A common complaint about informed consent forms is that they are often unduly lengthy and cumbersome, with important information often buried and hard to find. Under the proposed changes, such documents would need to be streamlined in ways that provide appropriate details about the research that is most relevant to a person’s decision to participate in the study, such as information a reasonable person would want to know, and present that information in a way that highlights the key information.
The proposed modifications are designed to continue to uphold the ethical principlesupon which the Common Rule is based, as applied to the current social, cultural, and technological environment. In brief, the most significant changes proposed in the NPRM include:
Improve informed consent by increasing transparency and by imposing stricter new requirements regarding the information that must be given to prospective subjects.
Generally require informed consent for the use of stored biospecimens in secondary research.
Exclude from coverage under the Common Rule certain categories of activities that should be deemed not to be research, are inherently low risk, or where protections similar to those usually provided by IRB review are separately mandated.
Add additional categories of exempt research to accommodate changes in the scientific landscape and to better calibrate the level of review to the level of risk involved in the research.
Change the conditions and requirements for waiver or alteration of consent such that waiver of consent for research involving biospecimens (regardless of identifiability) will occur only in very rare circumstances.
Mandate that U.S. institutions engaged in cooperative research rely on a single IRB for that portion of the research that takes place within the United States, with certain exceptions.
Eliminate the continuing review requirement for studies that undergo expedited review and for studies that have completed study interventions and are merely analyzing data or involve only observational follow-up in conjunction with standard clinical care.
Extend the scope of the policy to cover all clinical trials, regardless of funding source, conducted at a U.S. institution that receives federal funding for non-exempt human subjects research.
As part of a project that examined the degree to which sponsors of clinical research are complying with federal requirements for the reporting of clinical trial results, the Clinical Trials Transformation Initiative (CTTI) and the authors of the study are making the primary dataset used in the analysis available to the public. The full analysis dataset, study variables, and data definitions are available as Excel worksheets from the CTTI website and on the Living Textbook’s Tools for Research page.
A persistent problem facing the clinical research enterprise is the difficulty of negotiating the terms of contracts under which clinical trials will be performed at individual clinical research sites. For many research centers, the process is complex and protracted, and can often contribute to substantial delay in study start-up.
However, the Clinical and Translational Science Award (CTSA) Master Contracts Working Group has recently developed a possible solution—the Accelerated Clinical Trial Agreement, or ACTA. The ACTA provides a standardized template for contracts between site investigators and study sponsors, one with the potential to expedite contracting and make the start-up process for clinical trials more efficient.
A new analysis of data from the ClinicalTrials.gov website shows that despite federal laws requiring the public reporting of results from clinical trials, most research sponsors fail to do so in a timely fashion—or, in many cases, at all. The study, published in the March 12, 2015 issue of the New England Journal of Medicine, was conducted by researchers at Duke University and supported by the NIH Collaboratory and the Clinical Trials Transformation Initiative (CTTI). The study’s authors examined trial results as reported to ClinicalTrials.gov and evaluated the degree to which research sponsors were complying with a federal law that requires public reporting of findings from clinical trials of medical products regulated by the U.S. Food and Drug Administration (FDA).
“We thought it would be a great idea to see how compliant investigators are with results reporting, as mandated by law,” said lead author Dr. Monique Anderson, a cardiologist and assistant professor of medicine at Duke University.
Monique L. Anderson, MD. Photo courtesy of Duke Medicine.
Using a publicly available database developed and maintained at Duke by CTTI, the authors were able to home in on trials registered with ClinicalTrials.gov that were highly likely to have been conducted within a 5-year study window and to be subject to the Food and Drug Administration Amendments Act (FDAAA). This federal law, which was enacted in 2007, includes provisions that obligate sponsors of non-phase 1 clinical trials testing medical products to report study results to ClinicalTrials.gov within 12 months of the trial’s end. It also describes allowable exceptions for failing to meet that timeline.
However, when the authors analyzed the data, they found that relatively few studies overall—just 13 percent—had reported results within the 12-month period prescribed by FDAAA, and less than 40 percent had reported results at any time between the enactment of FDAAA and the 5-year benchmark.
“We were really surprised at how untimely the reporting was—and that more than 66 percent hadn’t reported at all over the 5 years [of the study interval],” said Dr. Anderson, noting that although prior studies have explored the issue of results reporting, they have until now been confined to examinations of reporting rates at 1 year.
Another unexpected result was the finding that industry-sponsored studies were significantly more likely to have reported timely results than were trials sponsored by the National Institutes of Health (NIH) or by other academic or government funding sources. The authors noted that despite a seemingly widespread lack of compliance with both legal and ethical imperatives for reporting trial results, there has so far been no penalty for failing to meet reporting obligations, even though FDAAA spells out punishments that include fines of up to $10,000 per day and, in the case of NIH-sponsored trials, loss of future funding.
“Academia needs to be educated on FDAAA, because enforcement will happen at some point. There’s maybe a sense that ‘this law is for industry,’ but it applies to everyone,” said Anderson, who points out that this study is being published just as the U.S. Department of Health and Human Services and the NIH are in the process of crafting new rules that deal specifically with ensuring compliance with federal reporting laws.
According to Anderson, increased awareness of the law, coupled with stepped-up enforcement and infrastructure designed to inform researchers about their reporting obligations, have the potential to improve compliance with both the letter and the spirit of the regulations. “I think reporting rates will skyrocket after the rulemaking,” she says.
In the end, Anderson notes, reporting clinical trials results in order to contribute to scientific and medical knowledge is as much an ethical obligation for researchers as a legal one: “It’s something we really promise to every patient when they enroll on a trial.”
On March 9, 2015, the U.S. Food and Drug Administration (FDA) issued draft guidance on the Use of Electronic Informed Consent in Clinical Investigations (document opens as a PDF). In a question-and-answer format, the guidance provides recommendations for investigators, sponsors, and institutional review boards (IRBs) on the use of electronic media and processes to obtain informed consent for FDA-regulated clinical investigations of medical products, including human drug and biological products, and medical devices, and combinations thereof.
Electronic informed consent, or eIC, refers to the use of electronic systems and processes to convey information related to the study and to obtain and document informed consent. Electronic media formats may include text, graphics, audio, video, podcasts, and interactive websites, biological recognition devices, and card readers. Use of electronic systems may allow for rapid notification to study participants of any amendments pertaining to the informed consent, promote timely entry of eIC data into the study database, and allow for timely collection of the informed consent data from remote locations.
The guidance provides answers to these questions:
How should the information in the eIC be presented to the subject?
How and where may the eIC process be conducted?
How and when should questions from subjects be answered?
What steps may be taken to facilitate the subject’s understanding of the information being presented?
What steps may be taken to ensure that new or additional information is conveyed to the subject during the course of the clinical investigation?
Does FDA allow the use of electronic signatures to document eIC?
What special considerations should be given to the use of eIC for pediatric studies?
Should subjects receive a copy of their eIC and have easy access to the material and information presented to them in their eIC?
What steps can be taken to help ensure confidentiality of the information once eIC is obtained?
Can HIPAA authorizations for research, which are frequently combined with informed consent documents, be obtained electronically?
What are the IRB’s responsibilities in the eIC process?
What eIC documentation does FDA require for submission with applications?
What steps can be taken to ensure the system archives the documents appropriately?
What materials or documents will FDA require during an inspection?
The comment period ends May 7, 2015. Users can submit electronic comments using the docket number HHS-OPHS-2015-0002 at the Federal eRulemaking Portal: http://www.regulations.gov.
Guidance documents represent the FDA’s current thinking on particular topics and are used by stakeholders to understand the agency’s interpretation of regulations and policies.
There are approximately 3,000 guidance documents available on the site, which can be searched by keyword or filtered by date issued, FDA organizational unit, subject, draft or final status, and comment period.
The search feature was implemented in January 2015 in response to site visitor feedback.
The compilation includes direct links to many of the laws, regulations, and guidelines, and serves as a resource for researchers, institutional review boards (IRBs), research sponsors, and others involved in human subjects research worldwide.
The 2015 edition includes hundreds of updates, including the addition of six new countries (Ghana, Guinea, Liberia, Malaysia, Saudi Arabia, and Sierra Leone).
Access the 2015 compilation here
Content is organized in the following topics:
1. General
2. Drugs and Devices
3. Research Injury
4. Privacy/Data Protection
5. Human Biological Materials
6. Genetic
7. Embryos, Stem Cells, and Cloning
On November 19, 2014, the U.S. Department of Health and Human Services issued a Notice of Proposed Rulemaking (NPRM), which proposes regulations to implement reporting requirements for clinical trials that are subject to Title VIII of the Food and Drug Administration Amendments Act of 2007 (FDAAA). According to FDA Commissioner Margaret A. Hamburg, MD:
This proposed rule would close an important gap, making additional information about clinical studies of investigational drugs, medical devices, and biological products available to the public. It would help eliminate unnecessary duplicative trials, advance biomedical innovation, and provide the public with a much richer understanding about the clinical trials for these products.
Further details are in a summary of proposed changes. Notable changes from current requirements and practice include:
A streamlined approach for determining which trials are subject to the proposed regulations and who is responsible for submitting required information.
Expansion of the set of trials subject to summary results reporting to include trials of unapproved products.
Additional data elements that must be provided at the time of registration (not later than 21 days after enrolling the first participant) and results submission (generally not later than 12 months after completion).
Clarified procedures for delaying results submission when studying an unapproved, unlicensed, or uncleared product or a new use of a previously approved, licensed, or cleared product and for requesting extensions to the results submission deadline for good cause.
More rapid updating of several data elements to help ensure that users of ClinicalTrials.govhave access to accurate, up-to-date information about important aspects of a clinical trial.
Procedures for timely corrections to any errors discovered by the responsible party or by the Agency as it processes submissions prior to posting.
A 