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  1. Biospecimens and the Proposed Common Rule, Part 3

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    Biospecimens and the Proposed Common Rule, Part 3

    Jim Gearhart PictureThis 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.

    [ad name=”changes-proposed-common-rule” align=”right”]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: https://www.federalregister.gov/articles/2015/09/08/2015-21756/federal-policy-for-the-protection-of-human-subjects

  2. Possible Next Steps for 21st Century Cures Act: “Advancing Medical Innovation for a Healthier America”

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    Possible Next Steps for 21st Century Cures Act: “Advancing Medical Innovation for a Healthier America”

    Jim Gearhart PictureOn July 10, the House of Representatives sent what it called the 21st Century Cures Act to the Senate. Now the bill, with a wide-ranging list of changes for medical research, is in the hands of the Senate’s HELP (Health, Education, Labor, and Pensions) Committee chaired by Lamar Alexander. Two weeks ago, a report came out that Senator Alexander said could influence his committee’s response to the 21st Century Cures Act. The Bipartisan Policy Center, a think tank founded by four former senators in 2007, released “Advancing Medical Innovation,” which lays out a set of recommendations for reforming medical research and the FDA. Since Senator Alexander said that the BPC’s suggestions could end up in the 21st Century Cures Act, it could be worth a look to see what those suggestions are.

    The BPC’s report focuses on the functioning of the FDA, and has four sections:

    1. Improving the Medical Development Process
    2. Increasing Regulatory Clarity
    3. Strengthening the FDA’s Ability to Carry Out Its Mission
    4. Increasing Investment in Medical Products to Address Unmet and Public Health Needs

    The report echoes many themes and suggestions that appeared in the 21st Century Cures (The BPC also released a table comparing their recommendations with the bill), but it also travels over some new ground. Here are some highlights of what could become law from each section of the report.

    Improving the Medical Development Process

    Site-Match-Skyscraper-245x262Both 21st Century Cures and the BPC report call for a greater reliance on clinical data for new drug approvals. Like 21st Century Cures, the BPC report recommends using information from medical practice for approving new indications. The BPC adds to this idea, calling for a change to the FDA’s established Phase I – III approval process. The report endorses a move away from relying solely on randomized, controlled trials to including studies that replicate clinical treatments, using “populations where care is provided under more typical settings.”

    The report includes a packet of recommendations about publicizing off-label uses of medicines. In presenting the report, former Senator (and surgeon) William Frist said that drug sponsors know what off-label uses work and that clinicians deserve to hear about them. The BPC’s report suggests a framework where pharmaceutical companies can provide, “truthful, non-misleading and scientific” data about alternate uses of approved treatments. Senator Frist insisted that current restrictions on those communications were dated and unnecessary.

    The BPC report also called for a greater use of biomarkers and patient-reported outcomes, again showing a parallel with themes prominent in 21st Century Cures.

    Increasing Regulatory Clarity

    The BPC offered a series of suggestions for better defining who should have responsibilities over what at the FDA. A major topic here, as in the 21st Century Cures Bill, was limiting the regulation of health-related software. The FDA should have very little oversight of health apps, the BPC report. Just as 21st Century Cures set boundaries for what programs should fall under the FDA’s jurisdiction, the BPC says the fewer restrictions on new programming the better.

    The BPC report took aim at one new area: the FDA’s regulatory framework around combination products. The report said a product that uses both a device and a drug to work (such as artery stents or asthma inhalers) faces confounding guidance about which FDA division should review it. To accelerate approvals, and to ensure the United States remains competitive, the BPC calls for updating and simplifying these regulations.

    Strengthening the FDA’s Ability to Carry Out Its Mission

    This section recommended changing the compensation rules for the FDA in order to improve recruitment and retention. It also called for new guidelines around when and how FDA personnel interact with the private sector (such as at conferences).

    Increasing Investment in Medical Products to Address Unmet and Public Health Needs

    Like the 21st Century Cures Act, the BPC report calls for increased attention to developing new antibiotics. It reinforces the bill’s call for less restrictive boundaries around making experimental treatments available to patients. The BPC also recommends new routes for approving what it calls “dormant therapies.”


    It will be interesting to see in the coming months how many of these policy suggestions make it into the next iteration of the 21st Century Cures bill. It stands to reason that those areas of intersection with the current bill – such as monitoring of health IT programs and the use of ‘real-world’ data for approving additional indications – have a good chance of making it through.


    BPC Press Release

    C-span video of Lamar Alexander’s speech

  3. Apple’s ResearchKit Could Change How We Study

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    Apple’s ResearchKit Could Change How We Study

    QIRB-jim-gearhart-blog2Earlier this month, Apple announced ResearchKit, an app-builder that could change fundamentally how research teams gather data and communicate with participants. After exploring the five studies that are showcasing the ResearchKit, it strikes me that this software toolkit can support medical research in at least three ways:

    – It could enable medical studies to reach unprecedented numbers of users/participants
    – It can make it much easier to create and administer electronic consent forms
    – It could help transform smart devices into participant study tools

    When Apple announced ResearchKit, it also released a packet of apps that came from it. The apps are for five studies run by respected research institutions. These studies help demonstrate the potential of ResearchKit and the iPhone:

    • Mount Sinai’s Icahn School of Medicine worked with LifeMap Solutions to create Asthma Health, which is studying patterns of asthma symptoms. Among other plans, the study aims to match up a participant’s report of symptom severity with the air quality at that location at that moment.
    • Massachusetts General Hospital has designed GlucoSuccess to help manage diabetes symptoms and study how personal habits affect glucose levels.
    • Stanford has MyHeart Counts, which track how personal habits affect cardiovascular health. MyHeart Counts monitors daily activities, tracks behavior through surveys, and correlates that data with reported cardiovascular health. (I enrolled in this one, as I was eligible.)
    • Sage Bionetworks and the University of Rochester are studying Parkinson’s Disease with mPower. This study uses the iPhone’s accelerometer and touch screen to assess participants’ balance and dexterity.
    • In a collaboration with the Dana-Farber Cancer Institute, Penn Medicine, and UCLA’s Jonsson Comprehensive Cancer Center, Sage Bionetworks also has created Share the Journey, a program to track the daily impact of breast cancer.

    Judging from these first five examples, the ResearchKit can provide a straightforward template for creating study-related apps. According to Apple’s Technical Overview, ResearchKit has three modules for a study app: conducting surveys; completing tasks on the iPhone; and managing informed consent. These inaugural studies have all three modules on clear display.

    The five apps look similar and essentially follow the same workflow. They have introductory screens that cover study procedures, eligibility requirements, risks and benefits. They guide the user/study volunteer through an informed consent process and confirm eligibility. Then they settle into the data-gathering part of the study. Three of the studies include videos that reinforce the essential study information. From what I’ve seen so far, the ResearchKit can lead to new ways to conduct research. Here are some possibilities:
    [ad name=”social-media-research” align=”right”]

    Huge Number of Participants

    Apple’s promotional video touted the potential to bring more volunteers into a study than ever before. Indeed, the cardiovascular study MyHeart Counts exceeded its target of 10,000 participants within 24 hours of Apple’s announcement. The Parkinson’s study, mPower, attracted four times the volunteers as any similar study had before. A large chunk of those numbers likely came from the excitement of the product launch, but even a fraction of those enrollment numbers would represent an impressive recruitment program.

    Electronic Informed Consent

    Interest in eConsent is growing in the area of clinical research. Some tools are available on the market, more studies are starting to try electronic consent, and the FDA just released draft guidance on using them. It looks like the ResearchKit will offer a way to create and offer eConsents with relative ease. Videos, interactive screens, and comprehension tests are all possible. For documentation, each of the studies delivers a PDF of the consent, and Apple promises electronic signatures will be available.

    Participant Study Tools

    The iPhone (and other devices, if Apple makes good on its promise to release the ResearchKit as open source) could become a portable monitoring device, just by utilizing the features it already contains (i.e., accelerometer, touch screen, GPS, microphone, camera). This could simplify data gathering on a wide range of studies, and help realize the potential of BYOD (bring your own device) convenience in research.

    Of course, these are the first days of ResearchKit, with questions and uncertainties remaining. In an upcoming post I’ll take a closer look at some of the issues, mainly from the perspective of an IRB.

  4. Week in Review

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  5. Week in Review

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  6. Gamification & Clinical Research: Some Serious Fun

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    Gamification & Clinical Research:
    Some Serious Fun

    This is the first in a series of three blogs in a series about gamification in clinical research.

    Jim Gearhart ImageIn a number of blogs, we’ve looked at ways we might improve communication about clinical trials: We have seen how the FDA and the NIH encourage us to improve informed consent. We have considered how mobile and portable devices might affect clinical research. Last week, we reported on how animated shorts online can share scientific knowledge.

    So what other tools might be out there? How about video games?

    Many of us might consider video games as little more than diversions; others see them as opportunities. The idea of applying game design to projects in the workplace – a concept known as gamification – has produced some intriguing results in health care and research. The industrious bloggers and thinkers at Lilly Clinical Open Innovation (Lilly COI) have been following the possibilities of gamification for a while. One of their posts includes an interview with game design thinker Professor Kevin Werbach.

    gamingFor Werbach, gamification’s potential comes from “finding the fun in what you have to do.” Gamification aims to increase engagement in a task or knowledge about a subject by appealing to our basic curiosity, our response to challenges, and our sense of fun. “We’re all gamers,” Werbach said. His definition of a game expands beyond video versions to include any experience with rules, an objective, and – maybe most importantly – an outcome that is important to the player. Werbach used an example from Microsoft to show gamification’s potential. According to Werbach, Microsoft utilized game design to inspire its global workforce to help double-check more than 500,000 “Are you sure you want to continue?”-type dialog boxes in dozens of languages.

    Here are a few examples of how gamification is finding fun in health care and research.

    Medical Devices, Now with Game Mode

    Device company Avacen boasts that it has the first medical device with an “internal game mode.” Game Mode on the AVACEN 100 enlivens an arthritis therapy session by awarding points for accurate use; tracking high scores; and flashing performance-based comments from “Super! That’s how it’s done” to “Yay! You got the new low score!”

    At the Orthodontist: Arrive on Time, “Like” your Orthodontist, Earn Points and Prizes

    A local orthodontist runs a points reward system. Throughout treatment, patients receive points like frequent flyer miles and can use them in online for prizes. Punctuality earns extra points, as do referrals and Likes on Facebook. This past week, the office held a Halloween-candy-for-points exchange.

    Clinical Trial Simulator GameClini-Trial: Can We Discover How to Fly?

    A London healthcare center developed a video game to introduce the ideas of clinical trials. In Clini-Trial, a volunteer signs up to test a drug that might make people fly. The game guides the volunteer through the clinical trial basics of screening, randomization, and participation. The deliberately low-resolution graphics recall early video games such as Mario Brothers.


    Destination Discovery: What Does it Take to Approve a Medicine?

    Lilly COI tries its hand at gamification with Destination Discovery. This virtual board game aims to share the value of medical research and the complexities of discovery.

    Foldit: Solve a Puzzle, Inspire Research

    Foldit provides a series of complex three-dimensional puzzles for a player to solve. The difference is that these puzzles reflect the structures of proteins, and solving them can provide inspiration for exploring medical solutions. The program’s creator found that with Foldit gamers could produce possible solutions faster and with more variety than did computer simulations.

    The Paper Kingdom: Face Your Fears, Defeat a Dragon

    The Paper Kingdom aims to reassure children and adolescents about participating in a clinical trial. The interactive mystery game has a fantasy theme, where an adventurer dispatches monochromatic baddies with infusions of color; dispels myths about clinical trials; and confronts a dragon.

    Check back soon for related blogs, where I test my puzzle-solving skills in Foldit, and my kids and I pursue adventure in the Paper Kingdom.