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Reinventing the Clinical Trial: Start at Ground Level

If each of us humans is a snowflake, unique in our genomic makeup, where’s my snowflake medicine? I asked that question from the platform at the ePharma Summit in New York in 2013, and have yet to get an answer. The challenge for the bioscience industry is, I believe, the classic randomized clinical trial. That design goes through four phases:

  • Phase 1: a small group of people are given the drug under study evaluate its safety, determine a safe dosage range, and identify side effects
  • Phase 2: a larger group is given the drug to evaluate its efficacy and safety in a larger population
  • Phase 3: large groups – plural – of people are given the drug to confirm its effectiveness, monitor side effects, compare it to other commonly-used treatments, and collect information that will allow the drug /treatment to be used safely
  • Phase 4: the drug is marketed while study continues to assess long-term effects and efficacy

Of course, before they even get to Phase 1, there have to be both the idea for the new treatment, and animal studies to determine what the substance or compound under study might do to a mouse or a monkey.

Science isn’t easy. The phrase “trial and error” came out of science labs, with many trials running up against the error wall by Phase 2. Since bioscience companies can sink about $1 billion-with-a-B into getting just one drug to market, it seems that the traditional clinical trial has turned into a pathway to NOT making scientific discoveries that can benefit humankind.

Then there’s the whole “who’s in charge here?” question. Clinical trials are now a global effort, with US and European pharma companies testing new treatments in Latin America, Russia, and China to gain traction in those emerging markets while simultaneously developing me-too drugs for their domestic markets. So, who’s in charge, the US Food and Drug Administration (FDA)? The European Medicines Agency (EMEA)? A player to be named later? The answer to the question seems to be “all of the above,” which adds to the complexity of the clinical trial process.

As digital technology has made data easier to collect and share, it would seem that clinical trials would be a great place to start intersecting with the quantified-self movement. The shift to electronic health records, the widening adoption of all sorts of health tracking devices, and the rise of (relatively) cheap genomic sequencing should signal an ability to identify conditions, and populations, eager to participate in clinical investigations. But so far, it hasn’t.

What might challenge that stasis? In November 2013, three major pharma companies – Novartis, Pfizer, and Eli Lilly – announced via the White House’s website that they had joined together in a clinical open innovation effort. That page on the White House’s site is gone now – changes in Presidential administrations will do that – but here’s a direct quote from that announcement:

“In order to connect patients and researchers, Novartis, Pfizer and Eli Lilly and Company, are partnering in the U.S. to provide a new platform to improve access to information about clinical trials. The platform will enhance clinicaltrials.gov and will provide more detailed and patient-friendly information about the trials, including a machine readable ‘target health profile’ to improve the ability of healthcare software to match individual health profiles to applicable clinical trials. As part of the project, patients can search for trials using their own Blue Button data.”

Five years later, and we’re still stuck on the slow train when it comes to really reinventing the clinical trial.

I’m one of a growing group of people who think that the entire life-sciences process chain needs to be re-tooled for the 21st century. In my view, the best place to start that re-tool is at ground level, with the patients and clinicians who deal with challenging medical conditions daily. If a doctor has a number of patients who might benefit from some clinical study, why isn’t there an easy way to find a researcher looking into that condition? If a patient has an idea for a clinical investigation into his or her illness or condition, why can’t they find a researcher who’s interested in the same condition to team up and start a science project?

I can only hope that the regulatory agencies involved in life science oversight (hello, FDA!) can move beyond the aftermath of Thalidomide – for which epic disaster we’re still paying a price when it comes to the timeline for drug approval in the US – and toward a process of “all deliberate speed” that doesn’t forsake speed for deliberation. Both are necessary, neither should be more heavily weighted than the other.

We all can, and should, take part in scientific exploration into human life, and human health. Got an idea for a clinical trial? Share that idea in the patient communities you hang out in, and ask your tribe to help you bring that trial to life. To quote Arthur Ashe, “Start where you are. Use what you have. Do what you can.”

We’ve got to start somewhere, right?

Health Insurance and Cancer: Your Mileage (and Coverage) May Vary

Financial toxicity is the phrase used to describe the impact of the cost of treatment on patients. The NIH describes financial toxicity as “problems a patient has related to the cost of treatment.” No matter what kind of health coverage plan you have, if you get a cancer diagnosis you’ll quickly discover all the things you’ll have to pay for, from co-pays on chemotherapy infusion drugs to the intricacies of “co-insurance,” where an insurer will pay a percentage, usually 70-80%, of the cost, with the patient responsible for the remaining percentage.

Financial toxicity isn’t limited to cancer – ask any person with diabetes who relies on insulin to stay alive about that – but the cost of cancer treatments is high, and rising higher. Cancer patients are put in the position of having to decide whether they’ll get the treatment their oncology team prescribes, or if they’ll put it off until they have the money for it. Patient assistance programs at pharmaceutical companies can offer some help, but there is no guarantee that a patient assistance program for a specific cancer drug will help everyone who can’t afford the drug.

An NPR piece covered this last year, framing the story around a man with advanced lung cancer whose oncologist prescribed a new drug, Alecensa, for his treatment. Alecensa’s annual list-price cost is $159,000, with Medicare patients like the man in the NPR piece paying $3,200 per calendar year. The patient in the story was prescribed the drug in late 2016, but decided to forego filling the prescription until January 2017, to avoid having to pay $6,400 within 60 days for the treatment.

This is part of a pattern of cost shifting across the health payment landscape. Premiums for private insurance rose 170% from 1999 to 2011, far higher than the average increase in wages in the same time frame. Prescription co-pays also rose dramatically with the introduction of tiered drug coverage plans that passed more cost to the patient. For example, from 2000 to 2012, the proportion of individuals with a drug plan that had three tiers increased from 27% to 63%.

Exacerbating the immediate financial anxiety of negotiating for a treatment that could mean the difference between life and death, there’s the impact of medical bills on a patient’s long-term financial health. A Consumer Financial Protection Bureau report in 2014 revealed that almost 20% of credit reports had medical debt reported on them. In 2016, the Commonweath Fund noted that, “As of late 2016, 28 percent of U.S. adults ages 19 to 64 who were insured all year were underinsured — or an estimated 41 million people. […] Half (52%) of underinsured adults reported problems with medical bills or debt and more than two of five (45%) reported not getting needed care because of cost.”

I’ll put a face on this issue by introducing you to a friend of mine, Linnea Olson, who has been successfully beating Stage IV lung cancer for over a decade. Linnea has insurance coverage under COBRA, which is costly, but helps keep her alive by covering the costs of treatment that aren’t covered by the clinical trials she’s been part of over the years. She recently got a notice that her insurance had been terminated – the story on that is here, on her blog – which put her in the “high anxiety” zone, to say the least. That post is a very clear example of how financial toxicity impacts someone with cancer. Her situation lit fires across the cancer patient activist community, launching a campaign to get her coverage back. Four days later, she received word that her coverage had been reinstated. She shared that news publicly on her blog, too.

My point here is that this should not be way Americans are expected to deal with a cancer diagnosis – by facing the fight of their life while their financial lives are laid waste. The costs of treatment shouldn’t be the first thing someone has to think of when facing a life-threatening illness. The patient community is in sync on that. The oncology clinical community agrees that treatment costs, and financial toxicity, are in need of clearer discussion. The American Society of Clinical Oncology published a report in 2017 that included a recommendation that discussion of treatment cost and coverage “would […] facilitate rational discussions of efforts to use more cost-efficient regimens, use less expensive alternatives, or perhaps forego extremely expensive and toxic options that have little chance to provide meaningful benefit.”

I recommend that we keep advocating for more transparency in insurance coverage, and in the in-clinic discussion of the costs and benefits of cancer treatments. It also couldn’t hurt to advocate that our elected representatives craft legislation that makes that transparency a requirement, not an option.

Show Me the Evidence

A habit of basing convictions upon evidence, and of giving to them only that degree or certainty which the evidence warrants, would, if it became general, cure most of the ills from which the world suffers. ~ Bertrand Russell 

If you follow science and medicine headlines – which I do – you’ll find yourself wondering which headlines to believe, and which to discount. Do I believe that cancer has been cured after seeing that headline in a newspaper? No, because the headline usually skips mentioning that the “cure” was “in mice,” and only a couple of mice. But what about a headline that says a new screening protocol can catch a cancer that’s usually not discovered until it’s metastatic?

Prescription? Follow the evidence.

That prescription can be a challenge, since wading through the science behind the headlines isn’t a short and easy process. But you’re up to that challenge, since there’s a handy-dandy “How to Read Scientific Papers” post to help you navigate the science.

However, I’m not going to just say “go forth, and read science!” Here are two resources to help you figure out what’s real, and what’s just a shiny object, when it comes to the evidence behind medical treatments.

  • Cochrane Crowd is a new project from the folks at Cochrane, the global collaborative with the mission to systematically review the scientific studies that medical evidence is based on – Crowd puts you on the systematic review team. They have training modules to get you up to speed on understanding how to assess scientific studies:
    • Treatments can harm
    • Anecdotes are unreliable
    • Expert opinion alone is not enough
    • The role of comparison
    • Comparing like with like
    • The role of blinding
    • Size matters
  • Health Evidence is a database created and maintained by McMaster University in Canada, where anyone can search for evidence reviews, which are rated on a color scale. Wrapped around this database are a “how to use this” video tutorial, ongoing webinars, a comprehensive glossary (pack a lunch!), and workshops on using evidence in public health policy and decision-making.

If you’re new to the evidence based medicine discussion, I’d recommend starting with Cochrane Crowd, since that’s aimed at getting the public involved in evaluating the evidence alongside professional scientists. The presentation of information is laid out in slices, with the initial 7 training modules leading you into a couple of interactive training sessions with clinical trial , where you’ll

Health Evidence is a deeper dive, aimed at a professional audience, but presented in a way that anyone who can read at an 8th grade level can understand, and use.

Evidence is what the work of science is – forming a hypothesis, testing that hypothesis, and then proving or disproving it. Making the leap from “one mouse now has no tumors after we did this experiment on it” to “we’ve cured cancer!” is one that gets turned into clickbait headlines almost daily. But that linguistic leap does not represent actual scientific advancement.

Science is the slow, steady testing and retesting that happens in studies and trials across the globe. Once those studies and trials are complete, and reported in journals, the work continues to review those results against studies that look to replicate the results of the initial experiments. Then come the systematic reviews of all those experiments, and the assessment of whether what they’ve presented is evidence … or more questions that need to be answered. One mouse without tumors does not human medical evidence make.

Science is a process, and it’s always under review. The more of us who get involved, the more evidence will be proven, with less airtime given to unproven false promises. Get involved, because your life just might depend on it.

Patient-Centered Research: Is That a Thing?

Medical care is based on research. That was true in the time of Hippocrates, and it’s true in our 21st century lives. The scientific questioning that leads people to start experimenting and investigating something is as old as human intelligence – we’re a curious species, always trying to figure out the “why” on pretty much everything around us. Historically, the research that led to medical discovery has viewed people – the ones most often called “patients” or “subjects” in medical research – as just that: subjects in an experiment. That thinking has shifted over the last half century, though, particularly in light of the story of Henrietta Lacks, and the efforts of her family to have her recognized for the scientific contributions that are her “immortal HeLa cells” legacy.

Which brings me to my topic, patient-centered research, and the question of if that’s even actually a thing in 2018. I had two experiences recently that had me thinking of two aphorisms – or what the 21st century calls “memes”:

  • YMMV – Your Mileage May Vary, meaning that what you experience in a situation might not be what the guy next to you experiences in the same situation;
  • Objects in mirror are closer than they appear – a warning label that is engraved on side-view mirrors on cars in the US, Canada, India, Nepal, and Saudi Arabia.

My two recent experiences, one at a workshop meeting organized by the Robert Wood Johnson Foundation and AcademyHealth titled “Moving Patient-Centered Care Forward: How Do We Get There,” the other at the wrap-up meeting for a PCORI research project, “Defining a Roadmap for Patient Engagement in Imaging CER” (CER = Comparative Effectiveness Research), gave me some strong signals that the research community is waking up to the power of co-design, and people/patient inclusion in all aspects of medical research.

The RWJF/AcademyHealth workshop was framed around a series of four questions that asked how people/patients and medical providers could team up to make patient-centered care, and research into patient-centered care, a reality. The workshop was researcher and policy wonk heavy, with a patient-voice cohort of a dozen people. When I asked why it was still taking so long to get research discoveries implemented at the point of care, there was some pushback from the research folks, who thought I was saying that research should stop once something was known.

This reaction, which expresses frustration with the person/patient community for not “getting it” that research is a never-ending process – nothing in science is ever 100% known, everything is under constant review and challenge, which is how science works – is very frustrating to me, and to every other person/patient who is invited to participate in discussions like this. Person/patient-centered research that includes actual persons (the ones called patients) in the research process is something the patient community celebrates. What we WANT, though, is to see discoveries arrive in clinics and communities, not lie dormant in journals, where those discoveries become grist for more science, but not for actual practice. We’re looking to short-circuit Max Planck’s statement, “A new scientific truth does not triumph by convincing its opponents and making them see the light, but rather because its opponents eventually die, and a new generation grows up that is familiar with it.” The only way to ensure the patient community, and the research community, can communicate well with each other without misunderstandings is to spend more time in each other’s company, at workshops like this, learning how to avoid what I call “the lost in translation effect.” That’s the YMMV thing I referred to up-post.

My experience with the PCORI-funded research project, and the wrap-up meeting I attended the same week as the RWJF/AcademyHealth workshop, was the one where the object (patient-centered research as an actual thing) in the mirror was pretty darn close: co-designed and implemented research was visible, and the communication between the research team and the patient-voice team was less fraught with lost-in-translation. Since the group had spent more than a year working on this project together, the communication kinks had been worked out over time, and we understood each other’s point of view well. The lost-in-translation stuff we encountered early in the project actually helped inform our work, and our insights in how to better co-design research based on our experience.

The PCORI project was an example of what I was asking for at the RWJF/AcademyHealth meeting: include people-commonly-called-patients in the DESIGN of research projects and activities. Then enlist us to participate in the implementation, the analysis of study results, and the public dissemination of results – THAT approach will drive wider, faster adoption of new discoveries and processes. An additional benefit will be to start eroding public distrust of science as something that “elites” do, that the average human is somehow seen only as a lab subject.

So hey, research and policy folks – work on having people/patients on your team from the very beginning. In fact, if you want to kick off some from-a-new-perspective discovery, ask patient communities to help you create your research question, and define your null hypothesis. Amazing stuff could ensue!

(Self)Knowledge = (Em)Power(ment)

“Promise me you’ll always remember: You’re braver than you believe, and stronger than you seem, and smarter than you think.” – A. A. Milne

Finding yourself sitting on an exam table, or lying in a hospital bed, can be scary. Annual well-check visits to your primary care doc are one thing, but if one of those visits starts you on a journey through the maze of treating a diagnosis of cancer, or Parkinson’s, or [insert name of life-changing condition here], you find yourself feeling pretty overwhelmed.

My mantra has long been “be your own best advocate.” I learned this from my parents, who were e-patients long before that term was even coined. When I started my own cancer treatment journey ten years ago, I sprang into self-advocacy mode even before I had a confirmed diagnosis. I asked questions, worked to understand the answers, pressed for clarification when I needed it, on a “lather, rinse, repeat” cycle throughout the months between mammogram the end of active treatment; that process continues to today.

Since I just got my 10 Year Cancer-versary mammogram today (January 11, 2018), I figured my January PEN post would be a great place to share some of my how-to on being your own best healthcare advocate.

Let’s start with the basics, questions you can ask in any healthcare setting when a nurse or doctor outlines an issue, and a treatment plan for that issue, with you. This is straight from the Institute for Healthcare Improvement and the National Patient Safety Foundation – they call it Ask Me 3:

  1. What is my main problem?
  2. What do I need to do?
  3. Why is it important for me to do this?

This will work for anything from an upper respiratory infection to a badly sprained ankle to a hypertension diagnosis. It helps you learn more about the issue at hand, and opens up a dialogue where you can add information about your medical history, your family history, your preferences about medical treatment, and any concerns you have about treatment outcomes and side effects. e-Patient Health Literacy 101, if you will. The Ask Me 3 program link above includes some really superb health literacy materials, too. I encourage you to read through them, and to share them with your family and your community. I’m all about “the more you know” in healthcare.

If you want some e-Patient Health Literacy 201 questions to take to your next doctor’s appointment, I put together a handout I call the Must Ask List. I use this one-sheet constantly, at healthcare events where I’m invited to speak and in webinars where I share my thinking on patient engagement, health literacy, and health system innovation. Please feel free to use and share it – if you have questions you’d like to see added to it, let me know.

It takes a village to change the world. In the global village working to improve human health, it’s critical that we all share what we’ve learned, and look to learn from others with expertise in both the getting, and the giving, of medical care.

Doctors + patients x knowledge sharing = health and healthcare system improvement at light speed.

That’s my formula, and I’m sticking to it!