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by Jim Gearhart

Biospecimens and the Proposed Common Rule, Part 3

This is the third blog of three about how the recent Notice of Proposed Rule-Making (NPRM) for the Common Rule foresees changing the ethical framework around biospecimen research. Biospecimens are samples of human blood, tissue, or other biological material that researchers could use in investigations, and this blog looks at how the proposed Common Rule would govern the collection, storage, and eventual use of those biospecimens in future research.

To review, the first blog of this series discussed the NPRM’s changed definition of research, to say that research on a biospecimen should be considered the ethical equivalent of research on the person who donated it. The second blog looked at how this definition affected many of the NPRM’s new rules (it generally creates more protections around biospecimens). Now we’re moving on to the prospect of saving biological samples for future studies.

The NPRM sets itself a difficult task here. It starts by declaring research on a biospecimen is the effective equivalent of research on the donor. Then it proposes to construct a regime where it’s acceptable and practical to store those samples until someone is ready to experiment on them. A core ethical guideline for research involving people is that every study participant must understand the research study in question and every participant must enroll voluntarily. One challenge is to gather meaningful enough informed consent to use the biospecimen for whatever research purpose it serves, whenever that research happens.

The NPRM proposes to solve this by front-loading the consent and decision-making. That way, when it comes time to use the samples, the NPRM foresees that the research could be exempt from further Common Rule oversight. It will require as comprehensive consent as possible when the sample is collected, and a robust set of safeguards around the storage of those samples. It is a carefully-built structure, but one that relies heavily on resources that do not yet exist.

Collection of Biospecimens for Future Research

How will future researchers ensure that a specimen came from someone who understood and agreed to the possible uses of that sample? The NPRM has an answer to this question, and it is called a broad consent for future secondary use. (The broad consent is mentioned all over the NPRM, but the core discussion happens at §§__.116 and __.117(b)) The drafters of the NPRM reason that a carefully managed consent process at the very beginning can preempt quandaries about permissions for use later on.

  • “Broad” indicates that this process gives permission for multiple, unspecified purposes.
  • “Consent” implies that any permission to use the biospecimens is voluntary and informed.
  • “Future” acknowledges that the specimen will be stored and that a researcher or an institution cannot predict exactly how the specimen might be used.
  • “Secondary” reflects that these uses are in addition to the reason the samples were collected in the first place.

The requirements for this consent process would differ from the usual research consents. A broad consent for future use would require some but not all of the standard elements that the NPRM is proposing for research. Here are the core elements that the NPRM wants to carry over to a broad future use consent:

  • A description of forseeable risks or discomfort
  • A description of any anticipated benefits
  • A description of confidentiality of records
  • Contact information in case of research-related injury.
  • A statement whether the biospecimens will be used for commercial profit and, if so, whether the subject would receive a share of the profits.
  • A statement whether the donor will receive any information about significant clinical findings (Later on, we’ll see that for future biospecimen research this answer most likely will be no).
  • A statement that the subject has the opportunity to receive or not receive requests to donate additional samples or participate in other studies.

The NPRM then adds a handful of consent requirements that are specific to collecting biospecimens for future use. The broad consents would have to include:

  • What type of research might be conducted on the biospecimens
  • Which, when, and how samples will be collected;
  • Which, when, and how samples will be stored;
  • For how long specimens might be collected (with a maximum of 10 years)
  • How long investigators could access the stored specimens
  • A statement that agreeing to donation, storage, and future use is voluntary, with no penalty for refusal.
  • A statement whether the participant could find out how donated specimens were used.
  • A statement whether the biospecimens will be shared with other institutions or organizations.
  • A statement whether the biospecimens might be identifiable
  • A list of institutions which might access or use the biospecimens (while acknowledging that such information might change)

The drafters of the NPRM argue that these elements will explain enough so potential donors can make an informed, voluntary decision. And along with creating this list of new requirements, the NPRM also promises to help manage them. The NPRM states that the Department of Health and Human Services (DHHS) will create a consent template that meets all of these new criteria. If anyone uses that template, then an IRB will not need to review the document. Any changes to the template, however, would prompt a need for IRB approval. So the NPRM would increase protections through a new consent process with one hand, and try to make that process easier with another.

Storage of Biospecimens (Biorepositories)

The NPRM highlights two primary ethical concerns with biorepositories (i.e., how/where biospecimens are stored): managing identifiability and meeting the terms of a donor’s consent. Adequate safeguards are the key; the NPRM says that a biorepository must protect specimens from “intentional or unintentional use, release, or disclosure” to anyone other than those qualified to use them. Wrapped up in those safeguards is the directive that a biorepository do everything that the broad consent promised to do while storing someone’s biospecimens. The NPRM avoids mentioning specific guidelines, however, other than to say that DHHS will issue and update standards for biorepositories to follow, and that another option is to adhere to HIPAA’s security guidelines in 45 CFR 164.

Under these proposals the NPRM sees a limited role for IRB oversight of biorepositories. It has created a Common Rule exemption category for biorepositories, §__.104(f)(1)(i), and exemption in this case would include limited IRB review with no continuing review. And in the future world of the NPRM, an online tool will complete the exemption determinations.

Here, then are the steps so far for collecting and storing biospecimens for future research:

  1. Receive limited IRB review and approval for storage. The NPRM suggests that qualifying biorepositories will not require continuing review ( §__. 109(f)(1)(iii)) and that two IRB criteria should apply to them (§__. 111(a)(9)). Specifically, the IRB should determine that
    1. The procedures for obtaining broad consent for collecting specimens are conducted properly; and
    2. Biorepository procedures still meet the required protection standards after any changes are made.
  2. Obtain informed consent for the collection, storage, and use of biospecimens, preferably by using the broad consent template that the NPRM says DHHS will provide (§__.116);
  3. Apply qualifying standards for the protection of biospecimens, preferably by meeting the guidelines that the NPRM says DHHS will provide (§__.105)); and
  4. Secure an exemption determination, preferably by using the determination tool that the NPRM says DHHS will provide (§__.104(c));

While these directions fall short of requiring a formal IRB review of biorepositories, the NPRM does give IRBs the authority to find that a biorepository’s safeguards are inadequate. This suggests that an IRB should be aware of the safeguards and agree that they are adequate (§__.109(a)(7)).

Once its broad consent process is in operation and biorepositories are following its set of safeguards, the NPRM will consider that protections are then appropriate enough for researchers to study the biospecimens without direct oversight of the Common Rule. The future research at that point would be exempt.

Future Use of Biospecimens in Clinical Research

If a researcher or institution does everything according to the NPRM’s plan, then the research that eventually takes place will not need a separate consent process or IRB review (§__.104(f)(2)(i) and (ii)). That is to say, future secondary use of biospecimens would be exempt from Common Rule oversight if

  • The biospecimen was collected through the broad consent process;
  • The donor actually consented to use of biospecimens for research (documentation of this cannot be waived);
  • Biospecimen storage provided all of the protections required by regulations and expected by the donor; and
  • The research activity itself falls within the categories of the NPRM’s new Common Rule (which can include excluded or exempt activities)

One final requirement is that the future researcher cannot plan to return any clinically significant findings to donors. Doing so would imply that the investigator could and in some cases would identify the source of the biospecimens, which raises all sorts of complications which this framework wants to avoid). With all of those pieces in place, the NPRM concludes that future secondary research on biospecimens could be exempt from Common Rule oversight, and it promises to develop a tool that will make that determination.

That is a short(ish) overview of the NPRM’s framework for future biospecimen research. And this discussion assumes the easiest path for many decision points (such as keeping samples unidentifiable, agreeing not to return results, using the standard broad consent template, etc.). Any deviations would prompt additional requirements.

Overall, the NPRM’s proposed schema aims to balance the protection of participants who offer biological samples up for research with the practicalities of preparing for future research. The NPRM wants to say that secondary research on biospecimens can be exempt from oversight and still ethically acceptable with a broad consent when samples are collected, a rigorous set of rules around storage, and some limited IRB review. No problem. Once all of the tools exist.

LINK to Proposed Common Rule Changes Contained in the NPRM

The NPRM in the Federal Register:

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