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  1. 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

  2. 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.

  3. 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.

  4. 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: