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  1. Returning Individual Research Results: The Five Questions You Should Ask

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    Should research participants receive the results of tests that occur as part of a study? Not long ago the presumed answer was no; returning individual results seemed impractical and participants had no reason to expect to learn anything about their own health through the study. Expectations, however, are evolving, and the standard answer to that question might be, too.

    At this year’s SCOPE Summit conference, Kinetiq’s Executive Vice President James Riddle chaired a keynote discussion about returning individual results. The presentation urged sponsors, CROs, investigators, and IRBs to address questions of returning individual results during study design, instead of after a study begins. To continue the discussion started at SCOPE, this blog reviews some ethical and regulatory fundamentals regarding the return of individual test results to research participants.

    Ethical Issues

    People now can access—and demand—more health information about themselves than ever before. Increased access to electronic health records, a proliferation of wearable health monitors, the popularity of personal genetic tests, and the availability of medical information online has fostered our appetite for individualized and patient-centric health information. This has implications for human research, too, where research participants may want personal results from the tests they undergo.

    The crux of whether to provide those results typically lies in the healthcare/research dichotomy. Unlike clinical care, where the focus is on what benefits the patient, research focuses on contributions to generalizable knowledge. A research study may not present any direct benefit to a participant, and study-related tests may not be designed for individual results. A study objective such as preserving a study’s blind actually may work against providing an individual’s results. Ethical justifications for non-disclosure include the duty to avoid harm by providing results of uncertain value, and contributing to the “therapeutic misconception” that individual care is a researcher’s main concern.

    At the same time, other ethical principles can favor the return of individual results. The principle of respect for persons suggests that participants are equitable partners in the success of research and also suggest an investigator should inform participants of medical findings incidentally discovered during the course of the study that require action to avoid harm, and similar arguments can be made for providing planned research test results. Another justification—the principle of reciprocity, which originates from the duty to respect persons–acknowledges participants as partners in the research enterprise who are entitled to choose whether they receive potentially useful test results. When assessing whether it is appropriate to return individual research test results, sponsors, CROs, investigators, and IRBs can consider several questions:

    1. Do the test results have clinical or reproductive significance, and is the test result clinically actionable?

    There may be an ethical obligation to provide individual test results if an effective intervention is available for the discovered condition and if that intervention could prevent serious harm.

    2. Has the test’s analytic and clinical validity been established?

    If the accuracy of the test is unknown, there may be limited benefit and potential harm in releasing the results. A major consideration is the test’s analytic validity (specificity and sensitivity) and clinical validity (causal association between finding and condition).

    The Centers for Medicare & Medicaid Services (CMS) regulates laboratory testing through the Clinical Laboratory Improvement Amendments of 1988 (CLIA). The CLIA program ensures that clinical labs meet standards for accuracy and reliability. Research laboratories, however, can be “excepted” from CLIA certification requirements if they do not report patient-specific results “for the diagnosis, prevention, or treatment of any disease or impairment of, or the assessment of the health of individual patients.” Using a non-CLIA laboratory for research therefore might preclude the return of a participant’s individual results from a non-CLIA certified research laboratory, or increase the risks associated with providing test results of uncertified accuracy and reliability.

    3. What is the magnitude of potential harm if the results are not disclosed?

    Even if some test results are not clinically actionable, the results might reveal the potential of a serious medical condition. Participants might value that knowledge.

    4. Does the informed consent process discuss the possibility of disclosing test results?

    As of January 2019, informed consent documents for research conducted under the Common Rule must state whether participants will receive clinically relevant research results. (See for example, 45 CFR 46.116(c)(8).)

    5. Does disclosing the test results comply with applicable law?

    Some regulatory issues related to providing individual research test results are discussed below.

    In a 2017 editorial, the Journal of the American Medical Association (JAMA) argued that at least one study should have returned individual results. JAMA criticized the study of testosterone’s effect on anemia because it did not include a mechanism for alerting participants to a possible worsening of anemia. In this case, the study plan itself complicated the possibility of returning results, as the anemia test results were blinded, analyzed away from the study sites, and found after the study procedures had ended.

    Ideally, researchers and IRBs will prospectively establish plans for returning results and document that plan in the protocol and consent forms. In some cases, however, the question whether a specific result should be returned can arise after a study begins. This raises another set of questions for consideration:

    • Was the participant given the option of receiving test results?
    • If given an option, did the participant choose to receive results?
    • Was the consent form silent on the issue of returning results?
    • Did the consent state that no results would be disclosed?

    Researchers also should consider whether disclosing results complies with applicable law.

    Regulatory Issues

    As mentioned above, the 2018 Requirements of the Common Rule necessitate that the informed consent document state whether results will be returned. Other than that, the federal human subject protection regulations are largely silent regarding the return of individual results. The rules do, however, indirectly affect the issue.

    Regulatory requirements related to informed consent state that the consent process must provide adequate information to a potential subject about the reasonably foreseeable risks and benefits of the research. Participants must also be told of any significant new findings developed during the course of the research that might relate to their willingness to continue participation. Some research test results, both planned test results and incidental findings, could be viewed as a benefit or risk of the study and thus the possibility of such findings and any policy for their return needs to be disclosed in the consent discussion and in the consent form.

    The Health Insurance Portability and Accountability Act (HIPAA) Privacy Rule also impacts the regulatory question of when test results should be returned to research participants. The Privacy Rule establishes standards for protecting the privacy of individually identifiable health information and confers specific rights on individuals, including the right to access and amend certain health information. Generally, if research test results are included in a participant’s medical record or otherwise used to make decisions about them, those results become part of the designated record set and subject to an individual’s right of access. In other words, if a participant requested access to those test results, an entity covered by HIPAA would be obligated to provide them. While the Privacy Rule does not involve IRBs in the process of reviewing and honoring an individual’s request to access research test results, IRBs, institutions, and investigators should understand this right and ensure that the protocol and informed consent documents do not contain information contrary to the Privacy Rule.

    It is important to note some regulatory uncertainty regarding the interaction between the Privacy Rule and the CLIA laboratory requirements mentioned earlier. Recent amendments to both rules broaden an individual’s ability to access laboratory test reports directly, but some commentators interpret these revisions as conflicting with each other. Specifically, if a research laboratory is a HIPAA-covered entity and research test results are considered part of the designated record set, then participants have a legal right to receive these results. But if this same research laboratory is excused from CLIA requirements, it cannot comply with the Privacy Rule’s access provisions without violating the prohibition against returning individual results from a non-CLIA certified laboratory.

    Several factors can influence whether the HIPAA and CLIA regulations actually conflict. For example, there is ambiguity regarding the scope of research laboratory test results that would be considered part of a designated record set. It is also unclear whether CMS interprets providing test results per an individual’s request under the Privacy Rule as a violation of the CLIA regulations.

    Learn more about HIPAA and CLIA considerations for research—and earn continuing education credits–through an on-demand webinar by Kinetiq, the research and technology consulting division of Quorum.


    It no longer seems enough to say the returning of results is impractical, or that the study design precludes it. As patient access to individual health information increases, more research participants will expect to see their research test results, including exploratory tests that may have un-established accuracy and reliability. The traditional stance prohibiting the return of individual research results is arguably evolving into a “translational research” model where researchers have a limited duty to provide results to their participants. SACHRP’s 2018 memo to the Secretary of Health and Human Services suggests how norms around returning results may be evolving:

    “SACHRP believes that there should be due consideration of whether to return individual research results during the design, conduct, and oversight of research, with a general but rebuttable presumption towards disclosure.”

    As the SCOPE Summit keynote presentation suggested, sponsors, CROs, investigators, and IRBs should work together to ensure that any decision regarding the return of individual results minimizes risks and maximizes benefits to the participant.

  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. 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.

  4. Experiments in the Emergency Room

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    QIRB-jim-gearhart-blog2The Seattle Times recently ran an article with an interesting contrast to Facebook’s no-information, no-consent experiment on news feeds. The writer discussed a Seattle hospital’s plans to conduct an experiment on ER patients without necessarily telling them. The experiment will test the effectiveness of a drug solution on bleeding around the brain. Once the study starts (sometime in the next few months), anyone arriving at Harborview Medical Center’s ER with a head injury could be a part of it. The patients may not be conscious, and the doctors may not have time to conduct the lengthy informed consent process that’s normally required for medical experiments. To learn whether the treatment works means skipping that core tenet of research on human subjects.

    Where is the tie-in to the Facebook study? At first glance, Harborview’s plan resembles the much-publicized Facebook move, but with more serious consequences. Facebook didn’t tell any users that it was manipulating news feeds to see how we would react, and at Harborview the ER staff could administer a drug with an experimental use without notifying us while we’re possibly helpless. What is the deletion of happy or unhappy language compared to that?

    One difference in Harborview’s case is that somebody’s watching. A whole host of somebodies, actually. Some of this study’s funding comes from federal agencies, which means it must meet their ethical guidelines. And the research is happening at the hospital of a public university, so state and school jurisdictions are additional layers of potential oversight. Each level has requirements for ensuring any research is ethical – coming down to the researchers and the university’s ethics review board. To conduct research in the emergency room, the ethical path is narrow and restrictive. In comparison, Facebook only had an internal vetting process.

    emergency_running_hallwayThe prospect of experimenting on someone without explicit permission sets off all kinds of alarms, but in the case of the emergency room, it also could be the only way to find out what works. This experiment is testing the effectiveness of Tranxemia, a solution that is FDA-approved for other situations. Tranxemia has a solid history of doing better than other treatments in reducing blood loss during heart surgery, dental surgery, and difficult deliveries. Harborview (and others) want to see whether Tranxemia can do the same for bleeding in the brain.

    How do we learn the best treatments without comparisons? Can we risk someone’s life to find out? What if that risk could save future lives, or even the life of the person involved?  These questions are hard, the risks high, but the potential benefits are life-saving. A few years ago, another ER study tested several methods of CPR and illustrated which ones helped the most.

    To allow this kind of study, regulators and ethicists face extensive requirements. In summary:

    • They need to be certain the proposed method is the only way to test the question
    • They need to be certain the study sponsor will watch the results closely
    • In lieu of seeking consent before treatment, they require an outreach program to the community

    QIRB_drug_syringeHarborview has allocated $34,000 to conduct a survey, make announcements, issue flyers, and hold meetings. Since bicyclists are some of the most likely to visit the ER for head injuries, the hospital is teaming up with a local bike club to publicize the experiment. If someone be a part of the study, the hospital will provide a bracelet. One could argue whether or not these measures are adequate notification to the community, and that argument is the ethics committee’s job.

    But again, compare those efforts to how Facebook handled notification about its study. Facebook said nothing about the study at the time of its launch, and later retrofitted the company’s Terms of Use language to match what it did.

    For me, the fundamental difference between Harborview’s approach and Facebook’s is respect. “Respect for persons” has been a fundamental element of human research ethics for over 35 years, and the regulations codify ways researchers can honor it. The guidance for emergency room research is strict because not obtaining prior consent suggests a lack of respect. To balance that out, the hospital must follow all of the necessary steps:

    1. Prove there’s a lack of alternatives
    2. Demonstrate a clear possibility of benefit
    3. Let the community know
    4. And an independent group—one with members who are not beholden to the hospital—has to agree with the plan

    And what about Facebook? The social media provider tweaked our news feeds without telling us. When compared with treating head injuries, the stakes with Facebook are nowhere near as high. But Facebook deliberately manipulated information to see how people would react, and did nothing to alert people that they were being manipulated, let alone asking their permission. To me, nothing about that demonstrates respect.

  5. Learning from 2013 Warning Letters to IRBs

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    Institutional Bulletin vol 4,  issue 2

    In the recent edition of our sister publication, The Quorum Forum, we discussed reflecting on the past year as a means to formulate possible improvements to IRB procedures.  A review of FDA warning letters to IRBs from 2013 provides an opportunity to evaluate your IRB procedures and policies and evaluate them against the regulatory requirements for IRBs. If you are interested in the specifics, FDA warning letters are posted publicly on the FDA website, here.

    The handful of warning letters issued to IRBs list several failings that may seem straightforward; however, it is worthwhile to review the issues FDA raised and evaluate your own IRB procedures and policies. This exercise can help to ensure that each of these regulatory requirements is met.

    For ease of reference covering the points noted in warning letters, Quorum Review has developed a checklist for your use:


    Another important point to consider is whether the study file provides adequate documentation that the above-referenced procedural requirements are followed. Once procedures have been identified that meet the regulatory requirements, it would be prudent to self-audit study files to ensure the documentation in the files clearly records that the IRB is following procedures and fulfilling regulatory obligations. 

    In addition, to procedural failings, the FDA warning letters addressed a lack of appropriate documentation in IRB minutes. Again, it may be worthwhile to review examples of recent minutes to ensure the following information is documented in minutes appropriately.

    For your convenience, Quorum Review has developed a checklist for Board minutes: