How to Solve Diseases with Existing Drugs

My blog guests this week are Amy Conn, Bruce Bloom, and Clare Thibodeaux from Cures Within Reach. Disclosure: I am a member of their Advisory Board, and think that testing older drugs for rare diseases is brilliant!

The power of repurposing

What if the latest treatment for cancer, diabetes or thousands of other unsolved diseases was already available?

Although this might sound too good to be true, “repurposing” existing drugs could make this a reality. Repurposing takes any drug, device or nutriceutical, already approved in one disease, and tests it in a different disease to quickly and affordably improve more patients’ lives.

cures within reach infographicCurrently more than 500 million people worldwide suffer from diseases that lack effective treatments. As a result, global health care costs are growing and patients are suffering. Yet new drug discovery can take 10-15 years and can cost over $2 billion. This process is too long and costly for many patients who needs a solution today.

Instead, repurposing leverages prior investments by finding new uses for “old” drugs. This means repurposed treatments can reach patients in about 3 years and for less than $500,000.

Testing for repurposing sometimes means they are first tested in tissue samples or animal models in laboratories to find accurate dosing. If this pre-clinical research is done, the drug can quickly move into human trials. In some cases, it moves into human trials immediately.

How do repurposing ideas happen?

Repurposing is not a new concept. Doctors often prescribe medications ‘off-label’ when they think the patient may benefit. This happens when there is no approved treatment for a specific medical condition.

  • In fact, 1 in 5 prescriptions (21.3%) written in the United States are for off-label use. The range varies widely, based on the medical condition or patient group. For instance off-label use can be as high as 7 in 10 children for pediatric illnesses, because sponsors don’t typically focus on them. Here is a table with common off-label prescriptions.

Repurposing research can take off-label prescribing a step further by confirming clinical observations through a clinical trial. The data from these trials can then be published in scientific journals, and shared with other doctors to become part of standard treatment.

Other sources

  • Patients also contribute insights when they describe how a drug or supplement that they are taking for one issue impacts a different disease or diagnosis (i.e. “my asthma drug seems to be helping my eczema”).
  • Ideas also come from laboratory scientists, who connect the dots between newly discovered disease information and existing compounds.
  • And in our emerging world of big data, informatics engines can comb through scientific literature to find existing ideas and generate new ideas suitable for immediate testing.

Who pays for repurposing research?

Sometimes, pharmaceutical companies finance repurposing projects.

A case in point: ViagraViagra_in_Pack

Originally tested as a drug for angina, sildenafil failed. Instead, it was repositioned into the Pfizer blockbuster Viagra for erectile dysfunction after patients mentioned this side effect. Sildenafil was still under patent protection and the market was huge, making it a lucrative endeavor. This drug was later repurposed by Pfizer a second time in a different dosage under the name Revatio for pulmonary arterial hypertension.

Too many are orphans

Many repurposed opportunities are based on generic drugs that are often inexpensive and widely available. These characteristics make them ideal candidates for repurposing for patients, but industry doesn’t often pursue them, since there is no clear path to profit. This is where philanthropy plays an important role.

Cures Within Reach (CWR) is a global non-profit dedicated to repurposing research

CWR focuses on improving patient outcomes in any disease with repurposed treatments, while addressing larger needs around global collaboration, and the creation of alternative financial incentives for repurposing.

Successful repurposing

Key In Lock Showing Forbidden Information And Privacy

Since 2010, 13 repurposing projects that Cures Within Reach supported have made a clinical impact. One such project involved repurposing sirolimus, a generic drug originally used to reduce organ transplant rejection, to treat a rare and deadly childhood disease called autoimmune lymphoproliferative syndrome (ALPS).

Children with ALPS carry a genetic mutation that causes some of their white blood cells to multiply and crowd out other types of blood cells. They suffer from enlarged lymph nodes and spleens, increased infections and anemia. Some patients can spend up to 10 days a month in the hospital receiving treatment, placing physical, emotional and financial burdens on patients and their family.

CWR funded research that helped prove that sirolimus produced a lasting positive response in patients, leading to fewer hospitalizations, greatly lowered medical costs and improved quality of life. This result happened in 3 years for about $250,000. Sirolimus has since been repurposed in 5 more childhood autoimmune diseases with similar results.

Ready for more successes with CureAcceleratorTM

Philanthropic funding was critical to this high-impact repurposing research. There are many more opportunities like this one, in which a small “investment” can create a life-saving repurposed treatment.

To find important repurposing opportunities CWR asks:cure accelerator logo

  • How can we help repurposing researchers connect with strong funding streams?
  • Are there financial models other than traditional philanthropy that can help scale this research?

To answer these questions, CWR created an online crowd-sourced platform in 2015 called CureAccelerator.™ Check us out, and watch for another post soon about CureAccelerator.

Repurposing is an important healthcare strategy, both in terms of patient impact and cost savings. As scientists and clinicians learn more about the mechanisms and molecular targets of diseases, repurposing will play an even larger role. The key stakeholders in repurposing, from funders to researchers to patient advocates to industry, all need to work together to drive new “old” treatments to patients.

Learn more about repurposing drugs here.

Make Clinical Trials Better for Patients

There are many reasons why clinical trials don’t work well. A major one is not making them useful or interesting to patients.

I had high hopes when I heard about the recent clinical trial protocol (plan) template from the U.S. Food & Drug Administration (FDA) and the National Institutes of Health (NIHJoint Leadership Council (JLC). Unfortunately, it looks like they just took the traditional clinical trial approaches and set up a template for them.

We can insert PATIENT-centered research now!scales-research-patients

This is OUR CHANCE to include patient-oriented recommendations, not just assistance for researchers and regulators. Please read this post, and make your own comments by 11:59p Eastern on April 17th.

Change the clinical trial protocol template

The template covers phase 2 or phase 3 protocols with investigational new drug (IND) or investigational device exemption (IDE) applications. Here is some background information, in case you’re interested.

“Our goal is to provide an organized way for creative investigators to describe their plans so that others can understand them.”

– Dr. Pamela McInnes, Deputy Director, NIH NCATS

While the FDA/NIH want better organized and consistent plans from researchers so they can review them faster, there is no discussion on how to create BETTER trials for PATIENTS. Since everyone else is focusing on their own interests, we need to bring up PATIENT NEEDS!

Belmont triangleHere are my submitted comments. Please, please, PLEASE take ~30 minutes RIGHT NOW to make your own points (or use mine) and send them in.

My comments – make yours by midnight, April 17!

There are broader issues to discuss, but this is not the place. For now, here is the information I sent to the NIH and FDA Request for Public Comment on Draft Clinical Trial Protocol Template for Phase 2 and 3 IND/IDE Studies on April 16th:

As President of Patient Advocates In Research (PAIR), I have worked with translational, clinical, epidemiological, and healthcare delivery researchers for over 20 years. I offer these comments, based on that experience. These suggestions only touch the surface of far-reaching changes that should be taken to change to a patient-focused clinical trial system. I would be happy to discuss them in more detail with your Joint Leadership Council.

After reading the proposed template, I am not sure how it supports newer approaches to clinical trials, such as those that combine phase 2 with other phases. There is also no discussion about how to make clinical trials more patient-focused. This is an opportunity to actually change the way clinical trials are developed so that they address PATIENT needs, not just those of researchers and regulators. Please consider how this template can satisfy your requirements, focus on patient population needs, and support new approaches to study design as science advances. For example, including explanations or encouraging examples of bucket trials and other newer designs would be useful.

Rather than separate my comments into your categories, I have created a list of overall suggestions, and have indicated when my comments apply to certain protocol sections.

  • First, PLEASE STOP using the words “subject” and “subjects” when referring to people who may or may not be study participants. It should be replaced by “human research participant,” “trial participant,” or another less derogatory term through the entire template. As an example, this term is actually used incorrectly in the Statement of Compliance (p.vi), since the association that conducts the accreditation (AAHRPP) calls it “Human Research Protection Programs,” NOT “Human Subjects Protection Programs.”
  • Include a required, numbered section for some type of Patient Reported Outcomes (PRO) with the study population. This should be included in the Schematic of Study Design (p.viii) and as a complete explanation of the type of PRO that will be implemented. If it is determined this is not possible for some reason, an explanation should be included in the protocol that will be formally reviewed by NIH/FDA.
  • The template is oriented almost exclusively toward drugs. Where applicable, additional information for devices and behavioral interventions should also be included.
  • Good references (pp.a-b) are included to point investigators to useful resources for protocol development, but it might help to categorize them by type of information.
  • A statement should be added to the List of Abbreviations (p.v) so that any and all acronyms used in the protocol will be added to this list.
  • Consider a limit on the number of secondary endpoints allowed. Many secondary endpoints add no value whatsoever for patients, and often add complexity to clinical trials in an attempt to salvage an uninteresting agent or device that will not improve patient outcomes. Your designation on the Protocol Summary (p.vii) of “Important Secondary Endpoints” illustrates this point. No ‘unimportant’ secondary endpoints should be included in a protocol!
  • In the Protocol Summary (p. viii), please add any diagnostics that will be used and whether or not these are being developed concurrently, or are commercially available.
  • Again, replace the word “subject” on the Schematic of Study Design (pp.viii-xi) with a more appropriate and accurate term, such as “research participant.” Examples of biologic testing procedures for concurrent development and/or for eligibility should also be listed, as well as PRO parameters and timing, as mentioned above.
  • Under Key Roles (p.1), there are sometimes designated patient advocates/representatives who play a formal role in the leadership of the protocol. This role should also be mentioned on this page to encourage investigators to include patient advocates. The research nurse assigned to the protocol for the sponsor and site should also be listed  since they are critical not only to the protocol, but also to study participants.
  • A required section in 2.1 Background Information (p.1) of the protocol template should include information about the patient population being studied. Examples that include patient needs and issues will help investigators think more about how to meet patient needs. It should also include what treatment options patients normally have.
  • In 2.2 Rationale, please state that investigators should include a statement on how patient outcomes may be improved by their intervention or study hypotheses.
  • In 3 Objectives and Responses and 4 Study Design and Endpoints (p.3), please require a clear explanation of why a non-inferiority design might have been chosen, that it fits the ethical constructs of studying the appropriate population (e.g. sicker patients instead of healthier), and describes how they will minimize the percentage allowed to be worse than standard treatment. A concern is that non-inferiority designs are misunderstood, and can lower the accepted standard over time without sufficient vigilance by FDA and NIH. Superiority trials should be encouraged and preferred. If a superiority trial is not be possible,  an explanation should be included for formal FDA/NIH review before accepting the clinical trial design.
  • In 4.1 Description of the Study Design (p.3), please add “adaptive design” and other newer design methods in the ‘description (e.g.)’ to encourage investigators to include these designs in their trials. It is also important to encourage crossover and treatment switching for patients where possible. The Center for Medical Technology Policy (CMTP) and its international working group are publishing guidelines in May 2016 to help investigators include appropriate treatment switching. It would also be useful to encourage dose escalation in the same patient when possible if this study design is being used.
  • In 4.2 Study Endpoints (p.3), please add PRO to the ‘e.g. examples’ so investigators will use them in appropriate situations to help determine study endpoints.
  • In 5 Study Enrollment and Withdrawal (p.4), please remind investigators to be as inclusive as possible to better reflect the general population, and to limit test and trial procedures to those that are required to reach study endpoints, rather than traditional convention. Many eligibility criteria become boilerplate items, rather than appropriate criteria for each specific clinical trial. Also, please state that an explanation to justify a limit on reproductive status is required, so that it is treated appropriately, rather than as a traditional exclusion criteria.
  • In 5.3 Strategies for Recruitment and Retention (p.6), please add a section that encourages the return of results to trial participants. This could include how incidental or individual results may be returned, as well as how aggregate results will be disseminated to study participants, their doctors, and the general public. In addition, it is worthwhile to develop plans for the targeted patient population(s), site staff, and referral physicians. This presents a more comprehensive approach to recruitment that has a better chance of succeeding than past approaches.
  • In 5.5 Premature Termination or Suspension of Study (p.7), please add a section that describes how this information will be disseminated to all study participants and their doctors.
  • In 6.2 Study Agent Accountability Procedures (p.10), please include a requirement that explains how study participants will receive the agent/device after the trial has been completed.
  • In 7 Study Procedures and Schedule (p.11), there should also be a statement of how study data will be associated with the study participant’s medical records (both paper or electronic) during the trial and in the future, and if any medical records will be used in data collection. Procedures should include safeguards and privacy protections for all data, biospecimens, images, and other procedures. Data sharing procedures and policies should also be stated explicitly.
  • In 7.3.1 Screening (p.13), it is also important to have investigators describe how they will inform potential participants of their eligibility, including how any test results that determine eligibility will be shared.
  • In 7.3.3 Follow-up (p.14), procedures to update study participants on the trial status and findings should also be included in addition to an expectation of what follow-up visits will entail. It would also be useful to show how they can describe the ability to use local labs and clinics for procedures to make follow-up visits more convenient for study participants.
  • In 7.3.4 Final Study Visit (p.15), the investigator should also describe the information that will be given to the study participant, along with resources that will be available to them. Some of these can be collected and distributed by FDA/NIH so investigators won’t have to re-invent them for each trial.
  • In 7.5 Concomitant Medications, Treatments, and Procedures (p.16), investigators should also ask study participants about any supplements or other complementary/alternative therapies they may use since these have the potential to confound clinical trial data. This should be included on case report forms and tracked throughout the trial.
  • 8.1 Specification of Safety Parameters (p.18) should also include the way that study participants and others will be alerted to SAEs and Unanticipated Problems (UP). It should also require the collection of PROs to ensure comprehensive data collection.
  • In 10.4 Description of Statistical Methods (p.31), please include adaptive and Bayesian statistical examples to encourage their use. Methods for treatment switching should also be described.
  • 11 Source Documents and Access to Source Data/Documents (p.36) should include a description of how study participants’ medical records (all of them) will be validated since multiple records may exist and/or not include comprehensive information. It should also list how study participants will be updated about data sources, and how trial data will be shared with others.
  • 13.3 Informed Consent Process (p.38) should also include the description of plain language and a resource list for health literacy and numeracy principles. It would also be useful for FDA/NIH to create a repository of good informed consent examples of processes and forms for investigators.
  • 14.5 Publication and Data Sharing (p.45) should include a section on how data will be shared, and when types of data will be available to multiple stakeholders, including the trial participants.

Patients ARE the (end)Point of Clinical Trials

CT Arena post on Feb conference 2016Back in February, I spoke at the 2016 Arena International Outsourcing Clinical Trials West Coast Conference on “Patient Centricity” – a topic they gave me, along with some rather ambiguous objectives. I changed it to “Patients ARE the Endpoint” because it is time to get real about why the clinical trial industry exists in the first place.

Yu Ping Yen from Dance Biopharm joined me in the 30 minute session, and detailed diabetes patient interactions after I introduced patient-focused concepts. You can see from the slides how tough it was to present so much information in a 30 minute time slot!

Arena International also asked me to pen a summary about the session, which now resides on the Clinical Trials Arena site. Somewhat chagrined that the title still includes the centricity word, though! Come on, what does that mean, really? Slide1

My hope is that all patient representatives (whether they speak of their own experience or broaden their talks to cover endemic patient issues) speak clearly and succinctly about what patients need and want, and why we need to be in the development process from beginning to end. Maybe then, the clinical trial industry will focus on patients instead of just products.

Oops! Don’t Buy Chocolate Milk for Concussions

No, really. This is a real thing, created by money. Oops, I meant to say, created by researchers and institutions with MAJOR conflicts of interest. Why post it? Well, while this is the most blatant example we’ve seen in a long time, it happens every day, even to well-meaning researchers.

silhouette arrow to dollar signFACT: research is a money game. If your proposal piques the interest of a funder (e.g.  government (public), private foundations, commercial companies), you get to do your research. Researchers are eternally grateful because, otherwise, they have to find a new career. Many proposals are worthwhile and survive rigorous grant review (including serious peer review) to qualify as “good science.” This one didn’t…

Note: always be wary of overly-enthusiastic researchers

The chocolate milk story shows how urban legends are founded, and never die. This story came to light because it was PUBLICIZED without the necessary data from the Public Relations or Press Release (PR) office, not PUBLISHED (as in a scientific journal).

While I always hope for the best in research, skepticism is a good thing. Why are good scientists inherently skeptical? Because researchers can quickly lose their objectivity and tout success based on hope, not on facts. In the worst cases like this one, their ‘hope’ can turn to hype, fame and/or fortune. It takes constant vigilance by each scientist, and the whole research system, to make sure facts lead to relevant conclusions instead of ego.

Unfortunately, news aggregators, like prnewswire.com, also spread false hype without question. By the way, University of Maryland (U MD) has since removed the press release since the ‘scandal’ began.

“There are real consequences to PR spin of health research.”

Andrew Holtz, Yoni Freedhoff, & Kathlyn Stone, HealthNewsReview.org reviewers

In this case, consequences for people included mass purchases of this particular chocolate milk by school athletic departments, as reported by Quartz and others. Unfortunately, the sugar content is very high, leading to other issues involved in dietary studies (see the post Quality Diet Research Needed for more on this). Consequences for U MD aren’t done yet.

Concussion/milk study: fact or fiction? Cow - dairy

But I digress – let’s get back to the study. HealthNewsReview.org first commented on a U MD press release (PR), giving it a 1 out of 5 rating on January 5th, 2016 (that’s bad). They couldn’t get any study information (data) because it had not been published.

This was picked up by other news sites later in January, such as Stat News and NYMagazine Science of Us, claiming more bizarre issues with the study. The only reason Retraction Watch wasn’t involved – the study was never published.

“…a scandal that touches on vital issues of scientific ethics, the collision of money and research, and the lightning-quick pace at which pseudoscience can lead vulnerable people astray. And it all boils down to a simple question: How the hell could the University of Maryland have allowed this to happen?”

Jessie Singal, Science of Us

Then, on April 1st (no joke), CBS News reported that U MD “disavowed” the study and would give back the $228,910 to the company who sells the milk and sponsored the study. I learned about it from this Huffington Post sketch.

All of this adds to other examples of concussion research conflicts in which the National Football League (N.F.L.) is embroiled, as reported by The New York Times.

But Deb, You Don’t Do Concussions!

Web research

True, I usually cover research in cancers and infectious diseases. So? This deals with a universal research issue that impacts millions of patients and people. Seriously!

Research is often done well, by researchers who care and follow ethical principles. Even the good ones with whom I’ve served on countless committees and review panels, however, can let ego, opportunity, and fame trump true objectivity. Many are also led down conflicted paths by their institutions who smell money, and are willing to give undue influence to sponsors in return.

Frankly, we need set Standard Operating Procedures (SOPs) for these kinds of conflicts for ALL academic research institutions (after all, that’s what standard actually implies). For instance, don’t do it in the first place. But, when a conflict is discovered:

  1. Give the money back (in process).
  2. Recall the erroneous information (check).
  3. Fire the researchers involved (not yet).
  4. Publicize the error and steps taken to resolve the problem through the SAME CHANNELS + others (not yet).
  5. Share the data so others can learn from it (not yet). Doesn’t matter if it’s bogus or not – everyone can learn and take steps to make sure it doesn’t happen again.

Health/medical researchers and their institutions/companies HAVE to understand that their work impacts lives. They MUST start policing their own, or others will do it for them.Important Stamp Shows Critical Information Or Documents

The references I listed in this article aren’t hard to find. It takes some effort, but it should represent the least amount of effort we all put into study results to make sure the claims match the data. So, thanks HealthNewsReview.org and others!

Got research? Do it right, or suffer the consequences.

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.

Getting Real about Patients & Clinical Trials

I’ve been asked countless times to write about patients and clinical trials. Guess it’s time to share what I’ve learned, along with other patient advocates, as we work beside researchers in the proverbial trenches. Just so happens that this post coincides with April Fool’s Day – hope that’s not an omen!

Why this series?

This is the first in a series on Patients & Clinical Trials (CT). Why? Because clinical trials are really the only tried & true way we get new diagnostics, treatments, and preventive approaches to people. For all diseases and health conditions.

But the research system isn’t very good at it, even after 70+ years. It’s not for lack of trying – BILLIONs have been spent on tweaking existing structures, but perplexing problems persist.

Heads up on CT activities

Other themes will also emerge, based on over 20 years of changing research and medicine culture (or at least trying to). In the meantime, here are some of my activities in the CT world:

Event Inscription on Sign

Other activities:information-orange-circle_fkMzuUIu_L

  • The California Technology Assessment Forum (CTAF), part of ICER, released their recommendations from the February meeting for new drugs in diabetes and asthma.
  • CTTI just released materials from an expert meeting about the issues surrounding FDA streamlined approvals for new antibiotic drug development. A summary will be posted soon. You can also read a past post called Antibiotic Resistance – It’s Complicated!
  • Cures Within Reach focuses on ways that existing drugs can be used for other purposes. More from this group in a guest blog post here soon!
  • Two DCIS studies are being funded by PCORI to help answer treatment questions for this pre-cancer, and learn how women feel about them. You can also read a past post called When is ‘Carcinoma’ Not Cancer?
  • The Center for Medical Technology Policy (CMTP) is working on recommendations to allow patients to switch treatments in a clinical trial if their cancers keep growing.
  • The Metastatic Breast Cancer Alliance (MBCA) is creating a summary of their February meeting from the Research Task Force to Advance Progress.
  • The NC ProCESS project on prostate cancer has convened a patient advisory board to help communicate effectively with prostate survivors in their study.
  • Two groups I’m working with (MRCT and the NCI NCTN Biospecimen Banks) are discussing how to handle the challenges of giving individual research results to patients.

You can also read past CT posts about:

There are many other clinical trial happenings – these are just some of the ones in which I’m involved! Yes, it’s heavy on cancer, but remember that cancers cover the gamut from rare diseases to millions of people.

Updates will be posted regularly. Let me know what you’d like to hear about. TTFN.

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.