A Clinical Trial Failed Patients

Something horrible happened – a clinical trial failed, causing one unexpected death and seriously injuring 5 people. And instead of dealing with a dysfunctional research system, “experts” are spouting off on their own. The few articles written to date focus on the drug (aka the money), not on what people want to know.

My Initial Thoughts

high wire climbing in the wood

ClinicalTrialsArena asked me to comment, due to my unique expertise that straddles the patient and research worlds. After researching the topic,* here are my concerns – most of which have not been discussed yet.

This poses a much larger question – why am I the one bringing these up?

Fact 1: Something really bad happened – the first 6 people to get “repeated higher doses” died or were seriously damaged. This is a clear sign of system failure (e.g. approval, protocol, procedures, formulation, PharmcoDynamics).

Fact 2: A phase 1 clinical trial means it is the first time a drug is studied this way in people. 127 people in the trial is far larger than classic phase 1, and most don’t have placebos. Isn’t this more like a phase 2, or the new-fangled phase 1-2 trial? If so, what happened to the rules?

Fact 3: The drug showed activity in laboratory dishes and animals first. We don’t know what mouse-realtesting was done, or for how long. How realistic are the animal models, and how closely do they relate to humans?

Fact 4: Existing articles stress the need for more ‘transparency’ to share the drug’s molecular structure. Patients want honesty first, which in this case may mean, who screwed up?

Fact 5: I’m a big believer (and trail blazer) in presenting trial results, but that’s when we have results. NOT during an ongoing, active clinical trial. Why aren’t we calling for the protocol to be publicly published immediately?

medical_1000006456-120613intFact 6: Healthy volunteers joined this trial after reading an ‘informed consent’ form about its procedures and risks, and they were paid well. Why isn’t the consent form (for every trial) publicly available once the trial is approved?

Fact 7: In the U.S., the Institutional Review Board (IRB) would be shut down and investigated before any new trials could be opened.

Fact 8: A thorough investigation on all parts of this system failure is obvious. This, too, should be open and as public as soon as possible, and at all times.

Fact 9: Risk is an inherent part of clinical trials because risk is part of everyday life. Even when rules are followed, bad things can still happen. Patients aren’t stupid, so there is no need to shut down other clinical trials.

A Setback for Other Clinical Trials?

Amazing we even have to ask this question, right? Of course it will!

Only other researchers may think their trial will be ok because, oh let’s see, because that trial was different – yes, that’s it! That trial (take your pick):

  •  was in a different disease
  •  was in a different country
  •  was run by a company I don’t know
  •  had a different study design
  •  was a horrible accident that would never happen to me
  •  add your own excuse

But patients won’t care about any of that. They’ll steer away from danger or discomfort. And let’s face it, anything called a “clinical trial” isn’t comforting. And as far as whether the rule were (or weren’t) followed – that doesn’t matter either. The rules in the case of a clinical trial include the protocol, of course.

I am firmly in the patient/participant camp. Some may call this a bias, but I consider it the only worthwhile endpoint. I know patients want better answers NOW, and I know people in research deal daily with regulations and hubris.

There was clearly a system failure here, and people needlessly paid too high a price. Let’s find out why and make the pieces work together so people won’t worry about needlessly putting their lives on the line.

* Online information (as of 1/21/16) about the French clinical trial from a Portuguese company is located on Facebook, at #clinicaltrials on Twitter, and is listed in articles from:

All content © 2016 by Deborah Collyar unless otherwise specified. All rights reserved. Permission is granted to use short quotes provided a link back to this page and proper attribution is given to me as the original author.

Clinical Trial Patient Summaries Win!

Congratulations to the MRCT Center of Brigham and Women’s Hospital and Harvard and team for winning the 2015 Award for Excellence in Human Research Protection from the Health Improvement Institute! The winning project recommends ways to write public summaries after a clinical trial is over.

Why Is This Important?

  • People join clinical trials (research studies) so researchers can learn if new treatments, tests, procedures, or other things work better than what is now offered to patients.
  • People who join the trial are research participants, and contribute a great deal – sometimes their very lives.
  • Participants are told they’ll learn important things about the study, but they rarely receive a summary of what happened during the trial. Until now (hopefully).

Thanks, Europe!

The European Medical Agency (EMA) created a new rule that says ALL clinical trial sponsors must create a public summary within 1 year after a clinical trial is closed (6 months for trials with children). This rule scared sponsors (aka drug companies, government, and private funders), so the MRCT Center assembled a Return of Results (ROR) Working Group (WG) to help.

Why did it take a government regulation to make this happen, you might ask?
Oh, they must have been busy with things more important than telling people what happened (sigh).

What is the Return of Results (ROR) Project?

sign direction expect-result made in 2d softwareThe MRCT Center ROR project focuses on patient needs (for a change!), instead of just the research system. This means including principles about plain language, health literacy, and how to explain numbers (numeracy) – making sense of clinical trial results for normal people.

The ROR project includes:

  • A Guidance Document: how to set up a process to create patient summaries.
  • A Toolkit: with helpful templates, non-promotional language, and checklists.

We studied a few groups who actually create clinical trial result summaries, like CISCRP and the Alliance for Clinical Trial in Oncology (disclosure – I run the summary project there).

The Award

“The award program recognizes submissions that our judging panel determines have demonstrated excellence in promoting the well-being of human research participants.”

– Dr. Peter G. Goldschmidt, President and Founder of Health Improvement Institute

Quite a mouthful, but nice recognition! They agree the ROR Project puts patients first.

Thanks to All

Thank you

Thank you

As Co-Chair of the MRCT Center ROR Working Group, along with Laurie Myers from Merck, we thank all 53 team members (pp. 2-4) for creating ‘how to’ information for all clinical trial sponsors to create plain language study result summaries for real people. Thanks also to Barbara Bierer, Rebecca Li, and the MRCT staff. We’ll continue to update as new information becomes available.

A Plea to Sponsors

The tools exist, so let’s get started NOW! Don’t wait for the EMA ruling or for the U.S. Food & Drug Administration (FDA) to follow suit. Patients, trial participants and the PUBLIC want these NOW. And some of us can help. Really. Contact me!

After all, it’s the right thing to do AND you really need some goodwill, but that’s another story…

What YOU Can Do

Please ask for a public summary of any clinical trial you want to know about. You can find most trials listed at https://clinicaltrials.gov/. And ask them to stop calling them “lay” summaries (what does that really mean, anyway?).

More information on clinical trial result summaries is in this post.

All content © 2016 by Deborah Collyar unless otherwise specified. All rights reserved. Permission is granted to use short quotes provided a link back to this page and proper attribution is given to me as the original author.

When Clinical Trials Don’t Match Their Data

dart off-centerClinical trials (research studies in people) can help find better treatment, care and prevention for patients. When done well, they answer important questions posed in the protocol (study plan) before the trial starts. Unfortunately, those answers are often not published. Some also don’t have the right study designs, which means the studies won’t tell us what we truly want to know.

The Problem?

…”the international Cochrane Collaboration commonly exclude from evidence 50% to 75% of published studies…”

– Soumerai, Starr, and Majumdar, The Health Care Blog

Why? They don’t meet the basic research design standards that Cochrane relies on to produce reliable results. 1/2 to 3/4 of our clinical trials? Big problem! But it’s only one of the issues.

Why Does This Happen?

Many misalignments help foster these problems. In their article, Soumerai et al show how clinical trialists start with errors that get multiplied as they gather steam, especially when those who will profit spin stories that get picked up by the news media.

“We will show how single, flawed studies, combined with widespread news media attention and advocacy by special interests, can lead to ineffective or unsafe policies.”

– Soumerai, Starr, and Majumdar

John Ioannidis at Stanford has written about this for years, and was recently interviewed by Gary Schwitzer from HealthNewsReview.org (podcast available). John published a seminal paper in 2005 called “Why Most Published Research Findings Are False.” Sorry to say that 10 years later, it is still true and will be until incentives change.

The COMPARE Project has taken on a simple (but not easy) goal – to find out which clinical trials reported on the outcomes (endpoints) that they stated in the protocol (study plan). As of 12/10/2015, the 58 trials they checked had these depressing results:

  • 8 trials (14%) reported the stated outcomes and they didn’t add later outcomes.
    That means they did what they said they would do. Thank you.
  • In the 50 trials (86%) that did NOT report on the stated outcomes,
    • They did NOT report on 306 of the original outcomes.
    • They added 304 different outcomes after they saw the data.
Photo credit: stevendepolo via Foter.com / CC BY

Photo credit: stevendepolo via Foter.com / CC BY

That’s like waiting until everyone turns over their cards before you decide how you want to play! There can be valid reasons for some, but certainly not all, of these changes. Retraction Watch has a good post about this.

To follow up, Ben Goldacre and his team send letters to journals who published the trial results to alert them to errors so they can issue a correction.

…”we entrust journals with an incredibly important job, a huge portion of the knowledge management in medicine and science.  We should be able to expect that journals routinely police something as unambiguous as outcome switching, during the peer review and editing process. Where there are slip-ups, we should be able to expect that those errors are corrected swiftly.”

– Ben Goldacre

Why Does This Matter?

Patients rely on doctors for accurate information that can be used to make critical decisions. Physicians also want this, and often base their decisions that treatments off of these clinical trials. If the evidence isn’t real, it could actually lead to wrong decisions that might actually create harm to patients. And no one wants that, do they?

What are publishers doing about this?

The COMPARE Project is relatively recent, so maybe it just takes publishers longer than expected to publish the team’s letters and then issue corrections. Right?

Old letters in string - deskI mean, it only makes sense that such esteemed journals as the Journal of the American Medical Association (JAMA), The Lancet, the Annals of Internal Medicine (Annals), and the British Medical Journal (BMJ) would take this seriously and correct errors quickly. And they would commit to checking something simple like this for each clinical trial BEFORE it is published. Right?

Millions of patients who count on the accuracy of their publications certainly hope so.

All content © 2015 by Deborah Collyar unless otherwise specified. All rights reserved. Permission is granted to use short quotes provided a link back to this page and proper attribution is given to me as the original author.

Informed about Changes to Research Consents?

Isolated patients need clearer informed consents to engage fully in research.

If not, you’ll be surprised soon. The Common Rule is changing – 1st time since 1991. The US NIH NINR says, “The Common Rule contains regulations that protect individuals who participate in research and is followed by 18 federal agencies.” Translation: these are the rules that apply to informed consent forms that patients sign to join research studies.

Your input (yes, you!) actually matters. Here is what you can do:

  1. Brush up on proposed changes: check out the summary, the full text in Federal Register, the public comments, and start thinking about yours as you read on.
  2. Comment by 1/6/2016 (was 12/7/15 originally) at the Notice of Proposed Rulemaking (NPRM). If you need the docket ID #, it’s HHS-OPHS-2015-0008.
    EDIT: the public comment period has been extended – post your comments before 1/6/2016.
  3. Be sure to remind them to STOP with this ‘research subject’ nonsense! People who join studies are trial participants, not subjects of some self-imposed royalty (or worse). And please ask them to require public study result summaries too.

If you want to post on your own, go for it. If you want to know my thoughts, read on…

“…bold moves to streamline the clinical trial process.”

Quorum Review IRB

Here is a quick summary of the proposed changes:

  • Tighter rules on explaining the study: shorter forms with key points highlighted for better patient understanding. Consent forms will become public. Hopefully, a step forward.
  • A written “broad” consent for all biological samples (e.g. leftover blood, surgery tissue) for any research, now or in the future. This includes samples that don’t have personal information attached, so each person won’t be identified.
  • Linking the level of risk with the type of Institutional Review Board (IRB) review.
    • Less risk = less review. A web-based decision tool will help figure this out.
  • More data security & privacy standards to protect trial participants’ confidentiality.
  • Requiring a single/central IRB for studies done at many sites.
  • Applying the Common Rule to all clinical trials in institutions that get federal funding.
  • Eliminate ongoing (continuing) reviews for some research.
Good review of Medical Ethics!

Good review of Medical Ethics!

For a quick refresher on ethical principles, please see the Belmont Report, and Medical Ethics for Dummies. It will make this much easier! This stuff matters – worth your effort.

So, what’s the big deal?

Many researchers think the new requirement of a written consent for all research samples will hinder medical advances. Until now, they collected samples from everyday medical care to use in research without each patient signing a form that says ‘yes, you can use my sample.’ Many of these samples had patient identifiers removed (called “de-identified” samples).

Translation: people working in the system chose which samples to take, and how use them. Some set up ethical methods, but patients weren’t involved in decisions (i.e., paternalistic).

Here are some arguments from the research perspective about changes (I’m paraphrasing):

  • This will negatively impact sample collections from the past (called “retrospective biobanks”). These samples are valuable because data (e.g., w/5 year follow-up) is useful now instead of waiting another 5 years if we start collecting now.
  • Changes only apply to physical samples, not data. Data also needs careful management to protect people from harm.
  • There is no oversight for the broad consent option, so how will we protect people from misuse? Issues like scarce samples, race and ethnicity, cultural norms, and harms to societal groups are not covered.
  • Changes create extra burden & cost on hospitals and clinics to use a broad consent form. Smaller places may opt out of research, which limits access to some communities.
  • Hesitancy to find patients for consent (or ask them about past samples), and the fear that many patients may not like being contacted.
  • Changes over-emphasize Autonomy (independent choice) vs. Beneficence (maximize benefit while doing no harm) and Justice (people affected should be offered access). See? I told you to check medical ethics first!

In a Perfect World…

This scenario may never happen since middlemen (like institutions) couldn’t make money off the data or samples, as many do now:

Patients would own their own samples, data AND electronic Medical Record (eMR/eHR). Healthcare professionals would interact with patients, but patients would be in total control of everything related to them. Flags in the record could be turned on for Y/N to donating research samples, data, etc.

BTW, how many current eMRs do you have? I’m up to 10 and many are wrong and/or incomplete!

My Take on NPRM Changes

I have worked directly with thousands of researchers for over 20 years, and I respect their dedication and efforts. Some have asked me if I can support their position on NPRM. After much contemplation, I have my own opinions regarding the proposed changes to the Common Rule (as usual). My current thoughts are:

  1. NPRM will change the way research samples are collected. It might reduce the number of samples that researchers have available if it is not explained well. That doesn’t mean, however, that people can’t decide for themselves.
  2. The arguments above represent a system averse to change, not on how to improve the research process and engage patients in new, open ways. Researchers are constrained by the old guard and fear extra burdens from the traditional research system.
  3. Modern social media and communication technologies can help find and engage patients. It takes new mindsets and methods, but old institutions don’t change easily. The NPRM should NOT be viewed in isolation, but rather WITH the rest of healthcare!
  4. Simple, direct plain-language consents can help people understand how samples have been used for years, and how they can continue to contribute to better care today. Some of us who create plain-language patient communications can help.
  5. New regulations (broad consent in this case) frequently allow for continuation (grandfathering) of older collections and procedures.
  6. NPRM must require specific oversight for the broad consent approval process. IRBs or usage committees should not be left out of this process, and a patient communication plan is CRITICAL.
  7. We should definitely include DATA (big, little & in-between) in the requirements. Data standards are desperately needed for research collections, which carry greater potential risk/harm than do body parts. Some groups are writing recommendation reports, but we need widespread action NOW.
  8. Extra burden? Every new initiative is an opportunity to make hospital procedures easier. Right now, patients give separate consents for any procedure they have done in a medical setting. While these are different from research informed consents, they are indistinguishable to most patients.

There are many more points, but I need to wrap up for now. Patients want to be more engaged, and this is an opportunity to better explain how the research community develops new treatments, procedures and tests that help people.

I frequently feel the need to remind ethicists not to “protect patients from themselves.” This is a step in the right direction (as long as they call us trial participants, of course!).

Involving those of us who represent patient voices in the implementation plans will help ensure that this works for patients AND those who serve them.

“…the ethical principle of respect for persons.”

NPRM 2015 Summary

All content © 2015 by Deborah Collyar unless otherwise specified. All rights reserved. Permission is granted to use short quotes provided a link back to this page and proper attribution is given to me as the original author.

Patients want Results. Share Data. Plain & Simple.

It certainly made my week when CT Arena asked me to write a guest post on returning research results to trial participants. It’s the small victories that keep you going, you know?

Creating plain language study result summaries for people is becoming popular these days, thanks to a recent regulation from the European Medicines Agency (EMA). The EMA is similar to the U.S. Food & Drug Administration (FDA). Clinical trial summaries can help patients make better decisions, and show respect to trial participants.

It’s strange to become one of the world’s experts in this field – it’s one of many interests! You can link to the article here. And feel free to contact me for more information – happy to help!

All content © 2015 by Deborah Collyar unless otherwise specified. All rights reserved. Permission is granted to use short quotes provided a link back to this page and proper attribution is given to me as the original author.