A multibillion-dollar research funding bill, like the 21st Century Cures Act, that receives bipartisan Congressional support has been a very rare occurrence these past eight years. Only a handful of U.S. senators voted against the Cures Act. Plus, it was signed on Dec. 13, 2016, by President Barack Obama, who had paid particular attention to promoting and funding research. Those facts might suggest that the 21st Century Cures Act is both popular and a good thing for patients and research participants.
But the bill’s broad popularity and its $4.8 billion in spending for new research at the National Institutes of Health (NIH) might not offset some of the bill’s problems tied to research protection, some critics say.
“We thought this final bill provided an early Christmas present to the pharmaceutical and medical device industries because it contains a number of giveaways to those industries that further weaken the review and approval of drugs and medical devices,” says Michael A. Carome, MD, director of the health research group of Public Citizen in Washington, DC.
“For that reason, we had urged it to be turned down,” he adds. “I think many members of Congress were persuaded to ignore the harmful provisions in exchange for additional funding provided to NIH for research on cancer, brain disorders, precision medicine, and additional funding for the treatment of opioid addiction.”
While funding for those purposes is a good thing, the trade-off was bad for patients, Carome says.
“The $4.8 billion in additional funding is not that huge of an amount because its funding is spread over 10 fiscal years,” he explains. “And there’s no guarantee that the money will be appropriated in future years because each year Congress has to vote to appropriate that money, and it’s possible that Congress won’t appropriate it in a year or two or four years.”
“In general, the 21st Century Cures Act supports simplification of IRB and informed consent processes over protection of research subjects, which raises a number of concerns,” says Michael S. Sinha, MD, JD, MPH, a postdoctoral fellow in the Program on Regulation, Therapeutics, and Law (PORTAL) at Brigham & Women’s Hospital and Harvard Medical School in Boston. Sinha served four years on a rural academic medical center’s IRB and writes about informed consent in clinical and research settings.
Chief among Sinha’s concerns are provisions limiting the scope of local IRBs. The Cures Act encourages the shifting of research protection away from local IRB review toward national or central IRB review in Section 3023, titled “Avoiding Regulatory Duplication and Unnecessary Delays.”
“By limiting the ability of local IRBs to participate, this could result in forum-shopping by clinical sponsors,” Sinha explains.
“The 21st Century Cures Act’s move toward lead institutional review boards limits the ability of local IRBs to have some authority and autonomy over trials within their jurisdiction,” he adds.
Local IRB review, with members from varied backgrounds, can better identify challenges that make local participation less likely, Sinha says.
At his IRB, rural research participants often faced geographic challenges to participation, including commutes of an hour or more to a research site, making routine monitoring logistically challenging.
In recent years, the U.S. Department of Health and Human Services (HHS) proposed changes that also would shift human subject research review more toward central IRBs in its 2011 Advance Notice of Proposed Rulemaking (ANPRM), its 2015 Notice of Proposed Rulemaking (NPRM), and the 2016 Final NIH Policy on the Use of a Single Institutional Review Board for Multisite Research. The new NIH policy, which has a goal of enhancing and streamlining the IRB review process in the context of multisite research, will take effect on May 25, 2017.
Having a local IRB review with board members from varied backgrounds provides a more rounded view and is more likely to identify local concerns, Sinha says.
For example, an IRB connected to a rural community would be more likely to note that rural research subjects would have difficulty making it to twice-weekly monitoring at an urban research site, he explains.
The Cures Act directly encourages the use of a central IRB and is in line with the NIH policy and with NPRM, says David Forster, JD, MA, CIP, chief compliance officer with WIRB-Copernicus Group in Princeton, NJ.
“What’s nice is they say to avoid duplication and unnecessary delays, there should be an emphasis on shared review and similar arrangements,” Forster says. “It’s not a mandate to use a central IRB, but, rather, an encouragement.”
Earlier versions of the Cures Act had language that would have had local IRBs provide information about local attitudes and subjects, but that part was removed in the final bill, Forster notes.
“I think if the congressional act had included language about continuing to use local IRBs for local purpose, it would have taken away from the purpose of NPRM and others,” Forster says.
This omission is one of the parts of the act that troubles Sinha.
“The local IRB I served on had a very good sense of our own patient population and our own patient needs,” Sinha says. “That knowledge of a unique population is lost if you have a centralized IRB making determinations on your behalf.”
Also, the Cures Act eliminates reporting to local IRBs in some situations. “They may not hear about local adverse events and problems in a timely fashion, which would make it very difficult for local IRBs to serve the protective function they’ve been designed to serve,” Sinha says.
Another area of concern involves the Cures Act’s section 3024 on waiving informed consent, Carome and Sinha say.
“This is a situation that has no clear legal precedent or justification,” Sinha says. “We’ve seen legal exemptions for life-threatening situations or when informed consent is not feasible, but now we’re talking about informed consent in a setting where there is no more than minimal risk, yet patients are consentable.”
One problem with this provision is that minimal risk is not well-defined, and it’s not clear who gets to define it, Sinha adds.
“If the pharmaceutical or medical device company is defining risk, they may be more likely to underestimate risk to avoid going through the process of informed consent,” Sinha says.
The Secretary’s Advisory Committee on Human Research Protections (SACHRP) recommended this waiver of consent, Forster says.
“Its most common use will be for research records review,” Forster explains. “The problem with the current FDA framework is that you can only waive consent in an emergency setting, but what is disallowed under the current FDA framework is the waiving of consent for records review.”
While any system can be abused, Forster says he sees this waiver provision as a way to enhance public health by allowing the FDA to obtain more data from sponsors.
“Right now, if a sponsor, for instance, says, ‘We have 20 years of experience in using this implanted hip device and we want to go back and look at all of the records and submit these to the FDA to change our labeling,’ the current FDA rules say you have to get consent from every one of these people or we cannot allow the data,” Forster explains.
The Cures Act’s waiver provision will allow sponsors to obtain the data without informed consent.
“I see that as a huge advantage, especially with the increasing availability of big data,” Forster says.
Informed consent should remain a bulwark of human research protection, Carome says.
“We think most of FDA research involving drugs and medical devices should still be getting informed consent — even with minimal risk,” Carome says. “I think IRBs, generally, wouldn’t grant a waiver for a minimal risk clinical trial, and nor should they.”
A privacy protections provision of the Cures Act also is new, Carome says.
“There’s a provision regarding privacy protections for human research subjects, and this requests the secretary of HHS to issue a certificate of confidentiality,” Carome explains. “The certificate of confidentiality has existed for years, and they were voluntary.”
Researchers involved in studies with sensitive topics, such as drug abuse, where a breach of privacy could damage the research participant’s reputation or lead to criminal prosecution, could request the certificate of confidentiality to protect data even in the event of a legal proceeding, Carome explains.
“Sometimes an IRB that is reviewing research would say to investigators, ‘You need to get one,’” Carome adds. “But this provision, as I read it, would require for any federally funded research involving sensitive identifiable information that they must issue a certificate of confidentiality.”
Non-federally funded research would leave the certificate optional.
Even with the Cures Act’s passage, local IRBs should continue with business as usual, keeping in mind their important role as gatekeepers in terms of clinical research approval and local participation, Sinha notes.
However, Sinha acknowledges that some small IRBs at rural hospitals and medical schools may face pressure to dissolve or to farm out protocol review and monitoring to an independent IRB.
The Cures Act, mirroring recent NIH policy, emphasizes the point that research institutions should use central IRBs as much as possible, Forster says.
“That is a trend that is occurring in the United States, and it has been — for 20 years — moving more toward the European model where central IRBs are the predominant method of IRB review,” Forster says. “I think it will help to change the mindset about IRBs.”
The 21st Century Cures Act's broad popularity and its $4.8 billion in spending for new research at the National Institutes of Health might not offset some of the bill’s problems tied to research protection, some critics say.
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