A recently published analysis1 of comments on biospecimen research submitted in response to the 2011 Advance Notice of Proposed Rulemaking (ANPRM)2 indicates institutional review boards and researchers are facing a series of “tradeoffs” that will likely carry over in the next iteration of the human research Common Rule.
The NPRM3 was published on Sept. 8, 2015, and some of the same issues and questions may be forthcoming in a new round of public comments. The previous ANPRM identified biospecimen research as a key area for consideration of regulatory revisions.
Though emphasizing she was still reviewing the NPRM, study co-author Gail E. Henderson, PhD, professor in the Department of Social Medicine at the University of North Carolina School of Medicine in Chapel Hill, says it appears many of the themes have carried over in the updated proposed regulation.
“Despite the fact that our study is based on analyzing comments from the earlier ANPRM, I think they are really still relevant to how people are going to be responding to the NPRM,” Henderson tells IRB Advisor. “Generally speaking, the kind of tradeoffs that we identified are very likely to still be evident in comments on the NPRM.”
Indeed, the overall goal in both versions is to enhance protections for research participants while improving the efficiency of IRB review of research studies. Using a random number generator tool, Henderson and colleagues selected 300 of the 1,126 public comments submitted in response to the ANPRM and available in the open record. They searched the randomly selected comments for keywords such as “biospecimen,” “tissue,” and “biobank.” After some further exclusions per the study protocol, they ended up with 109 comments for the full analysis. Overall, the comments responded to biospecimen research issues on at least one of the study’s four focus points:
• mandated written consent,
• the current system permitting a waiver of consent,
• the use of a standardized general consent form, and
• the inherent identifiability of biospecimens.
“It was kind of painstaking to get that random sample,” Henderson says, “but because it is a random sample, it is representative of [the total comments submitted about biospecimens].”
There were more comments in the random sample about mandated written consent and the current system of permitting a waiver of consent, with 87 and 81 comments respectively. ANPRM issues on a standardized general consent form were the subject of 67 comments and identifiability of biospecimens was addressed by 60 comments. IRB members, university officials, and scientists writing on behalf of their organizations were the authors of most of the comments, the authors report.
One of the more controversial proposals in the ANPRM called for mandated written informed consent from individuals for any use of their biospecimens, regardless of their identifiability and the original purpose for which they were obtained, the authors stated. As a tradeoff, the ANPRM proposed an open-ended consent form that would allow biospecimens to be used for future unspecified research. Respondent views on the mandated consent for specimens were reflected in 87 comments. Of these, nine offered full support, nine offered qualified support, and 69 were opposed. The majority of responding IRBs and scientific perspective groups opposed mandated consent, whereas the majority of those in a much smaller patient/advocacy perspective group supported this consent approach. The most common argument for mandated informed consent cited the inherent identifiability of biospecimens. As one commenter observed, “We will be as ethical as possible by explaining upfront that with today’s technology biospecimens are inherently at increased risk for breach of privacy due to today’s and future technology,” the authors reported.
Logistical quagmire
Again, the majority of the comments opposed mandated consent, warning that it would be “a logistical quagmire,” that it would create “an unfunded mandate on research enterprises,” and “profoundly impede clinical research for biomarkers and basic science studies.”
“Our study found that two responses were very highly correlated,” Henderson says. “If you opposed mandated consent you tended to support continuing with the current system of being able to waive consent for this kind of research, under the current rules of our system.”
In general, the NPRM did not give much ground on consent, but did provide tradeoffs similar to those Henderson and colleagues observed in the ANPRM. An executive summary of the NPRM states that the proposed regulation would “improve informed consent by increasing transparency and by imposing stricter new requirements regarding the information that must be given to prospective subjects, and the manner in which it is given to them, to better assure that subjects are appropriately informed before they decide to enroll in a research study.”
The NPRM would generally require informed consent for the use of stored biospecimens in secondary research (i.e., leftover blood samples), even if the investigator is not being given information that could identify the research subject. That consent would generally be obtained by means of a broad consent for future, unspecified research with the biospecimens.
Indeed, the NPRM proposes to do away with “unduly long [consent] documents” in favor of forms that highlight the key information. “To assure that these rules do indeed change current practices, there will be a one-time posting requirement for the consent forms for clinical trials, so that anyone drafting a consent form will do so knowing that it will eventually be subject to public scrutiny,” the NPRM states.
Short form, future use?
However, in comments in the ANPRM study, some questioned the idea of simplifying and shortening consent forms that apparently will grant future unspecified uses for research.
“To me one of the most interesting comments that we got was, ‘If you are really concerned about respecting the autonomy of individual participants, these short consents are silly. This isn’t consent to future unspecified use — who can understand what that really means?’” Henderson says. “I think the motive is good — the balancing, the tradeoffs, and the attempt to make it less burdensome. Yet when you get to one of those really short forms there is some question about the extent people can really understand [what they are consenting to]. Now I will say I have colleagues who think a short form can be created that can identify the most important elements. But that was one of the more interesting comments we got. People said, ‘I think consent is important and I am not in favor of this.’”
Regarding the current consent waiver system, 70 of the 81 comments in the ANPRM study were strongly supportive of a waiver of consent for research with deidentified biospecimens. Comments in support of the current waiver system argued that it worked well and facilitated research in a manner that did not unduly violate the rights or welfare of research participants. Using the example of tissue banks, several commenters pointed out that access to resources that operate under the current waiver provisions is essential to research. As one individual noted, “[I]t is not possible to know how a researcher will want to use specimens in the future, and it may be impractical to go back and get consent,” the authors reported.
However, it appears the NPRM was not persuaded by this sentiment, as it proposes to “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.”
“It sounds like they are really cracking down on that,” Henderson says. “In fact, it’s very similar. They are saying, ‘OK, maybe in really unusual circumstances you might be allowed to [waive consent], but we are going to be very careful about allowing that.’ Essentially, I think it is very similar to the ANPRM.”
In making waiver of consent “rare,” researchers and IRBs could presumably face more work in documentation and review of protocols that were heretofore waived. “That is certainly a conclusion you could draw from our study,” she says. “But I have been told that the NPRM has proposed a very gradual process of implementing these changes as far as biospecimen research is concerned. And of course, if you had collected specimens previously, you don’t have to go back [and get consent] unless you are proposing new and different uses for them. Prior work can be grandfathered in.”
Also, in yet another tradeoff, the NPRM proposes a provision that could make the waiver of consent less critical — excluding low-risk trials from IRB review.
“Research that poses greater risk to subjects should receive more oversight and deliberation than less risky research,” the NPRM states. “…Cumbersome and outdated regulatory standards overwhelm and distract institutions, IRBs, and investigators in ways that stymie efforts to appropriately address the real risks and benefits of research. The result of these types of changes, as the NPRM proposes to implement them, is that some studies that currently require IRB review would now become exempt. Some that are currently exempt would specifically be declared as outside the scope of the regulations (‘excluded’), and thus would not require any administrative or IRB review.”
The NPRM proposes to expedite this process by creating a Web-based “decision tool” that will be used to determine whether a research trial is low risk enough to be exempt from IRB review.
Concerning the issue of identifying specimens, genetic research advances are raising questions about whether biospecimens can ever be truly deidentified. The NPRM has a section dealing with “storing or maintaining biospecimens and identifiable private information for future, unspecified secondary research studies, or conducting such studies, when a broad consent template…is used, information and biospecimen privacy safeguards are followed, and limited IRB approval of the consent process used is obtained.”
Sixty comments analyzed in the ANPRM addressed whether a human biospecimen ought to “be considered identifiable in and of itself.” Of the comments, 15 stated that biospecimens should be considered identifiable, and 44 respondents said they should not. The most interesting finding regarding responses related to identifiability is that virtually all comments that included rationales acknowledged that specimens could be identifiable with proper conditions in place, the authors note.
“Genetic research [is advancing so rapidly] the landscape is not the same as it was for the ANPRM,” Henderson says. “On the other hand, the ANPRM took this on because there were scientific publications that demonstrated that it was possible — if you worked at it — to identify somebody without too much genetic information. The NPRM is saying the same thing in my view. To a certain extent, I think people will have similar responses.”
REFERENCES
- Cardigan RJ, Nelson DK, Henderson GE, et al. Public Comments on Proposed Regulatory Reforms That Would Impact Biospecimen Research: The Good, the Bad, and the Puzzling. IRB: Ethics & Human Research 2015;37(5):1-10.
- The Department of Health and Human Services and the Food and Drug Administration. Human subjects research protections: Enhancing protections for research subjects and reducing burden, delay, and ambiguity for investigators. Advance notice of proposed rulemaking. Fed Reg 2011; 76(143):44512-44531. http://1.usa.gov/1MWLFMx.
- U.S. Department of Health and Human Services. NPRM 2015 – Summary: http://1.usa.gov/1M8BSW2.
A recently published analysis of comments on biospecimen research submitted in response to the 2011 Advance Notice of Proposed Rulemaking indicates institutional review boards and researchers are facing a series of “tradeoffs” that will likely carry over in the next iteration of the human research Common Rule.
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