A Place to Teach Old Drugs New Tricks

Due to popular demand, former blog guests Bruce Bloom, and Clare Thibodeaux from Cures Within Reach have returned with another post. This time, they explain how they bring researchers, older drugs, and new funders together to come up with new solutions for patients. Disclosure: I am a member of their Advisory Board, and think this concept is brilliant!
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Time to comment on EU clinical trial result summaries

I just finished my public comments to the EU about the “Summary of Clinical Trial Results for Laypersons.” You can too if you hurry (public comments end on 8/31/16). Here are the instructions. I would appreciate your support on some of the key points listed below.

A bit of background

The European Medical Agency (EMA) issued Regulation (EU) No 536/2014 that does several things, including a requirement for public results summaries for all clinical trials conducted in the European Union (EU). They use the term “laypersons,” which is a real problem that you’ll see below (and further depth at a later time). Annex V of this regulations states 10 requirements.

As you may know, I have led many of the efforts to create clear, useful research summaries for decades now. My comments reflect what I’ve learned, and where problems may appear as these regulations take effect sometime in 2017. Feel free to use any of this information in your own comments (either paraphrased or in total), and share your comments so we can all learn from them. This is our one chance to set the record straight on language and mindsets!

My comments

To the European Commission Unit B4 “Medical products – Quality, Safety and Innovation,”EMA logo

My name is Deborah Collyar, Deborah@tumortime.com, and
I am responding as an individual.

Thank you for allowing public comments on the draft consultation document for “Summary of Clinical Trial Results for Laypersons; Recommendations of the expert group on clinical trials for the implementation of Regulation (EU) No 536/2014 on clinical trials on medicinal products for human use.”

While I am submitting these comments as an individual, I’ve led many efforts in plain language results for decades, with more personal hands-on experience than anyone else to which I am aware. This started with my non-profit, the Clinical Trials Information Project (CTIP), that became a catalyst for U.S. National Cancer Institute improvements (Physician Data Query (PDQ), cancer.gov, and eventually clinicaltrials.gov). As co-chair of the Cancer and Leukemia Group B Committee on Advocacy, Research Communication, Ethics, and Disparities (and now Vice Chair of the Alliance for Clinical Trials in Oncology Publications Committee), I created a process that has produced over 40 public study result summaries. I am also co-chair of the MRCT Center of Brigham and Women’s and Harvard Return of Results Working Group (which the consultation document references), and am directing Health Literacy Missouri’s (HLM) new Plain Language Research Summary service. I have also created many patient advocate opportunities to work directly with, rather than just supporting, researchers and started Patient Advocates In Research (PAIR) to continue these efforts globally.

Overall, the consultation document contains useful information that should help produce research summaries for patients, their families, and the public. This is a critical step to ensure clear, quality information that provides much needed transparency, and I commend your efforts and leadership in this area. One can only hope that other countries’ governmental agencies will soon follow your lead by creating compatible requirements of their own. Below, I list suggestions for additional clarity, important word changes that address unintended barriers, and a few errors.

First, the extensive use of the terms “lay,” “laypersons,” “lay summaries,” “lay language,” “lay title,” and “lay audience” run counter to the goal of producing clear, understandable summaries for trial participants and the public at large. “Lay” is often used to reinforce the superiority of an elitist group (i.e. “professionals”) to separate themselves from an audience they prefer to avoid. The constant use of these terms in the consultant document (and corresponding EMA No 536/2104) sets up an artificial barrier and mindset that creates separate classes where none should exist. Please use more accurate terms, such as “general summary,” “simple language,” “patients,” “people,” “persons,” and “the public.” Specific lines that need to be changed include: 7, 47, 49, 50, 51, 57, 58, 60, 66, 143, 148, 157, 241, 272, 273, 288, 289, and many throughout Annex 1 and the rest of the document.

Another term that should be eliminated (for similar reasons listed above) is “subject,” which is also referred to in Annex V requirement 4 of the EMA No 536/2014. Human beings should not be called “subjects” simply because professionals cannot think of a better term than they use for lab rats. The term “subject” is a verb to patients, not a noun. Please replace it with “participant” or “patient” instead, especially since these words are used throughout the rest of the consultation document.

There is confusion, and possibly conflicting information, between statements made within the consultation document that need to be clarified:

Lines 73/74 say “Develop the layout and content for each section in terms of style, language and literacy level to meet the needs of the general public.” Lines 95/96 say “Communications written for the public should use simple everyday language to ensure ease of reading and understanding.” These statements are incredibly important, and I wholeheartedly support them.

Unfortunately, the statement in Annex 1, page 13 states “It should be noted that the wording of the ten elements cannot be changed but that sponsors can, if they wish, combine categories where this makes sense,” and that the order can be changed. The words used as headings from Annex V’s 10 requirements do not meet health literacy standards and would be very confusing for patients and the public. It is imperative that sponsors are able to change the words of the requirements if they are used as headings on plain language research result summaries. This applies especially to pp. 13-25 that list Annex V requirements 1, 3, 4, 5, 6, 7, 8, 9, and 10. The MRCT template offers good alterative words, and I would be happy to help as you resolve this situation.

There were references to language levels 2-3 in Europe (lines 148-155) and 6th grade level in the US through Microsoft Word (lines 165-175) that do not seem compatible. It was mentioned that Level 2 is approximately high school level, which matches grades 9-12 in the US. There may be additional discrepancies listed in other languages as well (lines 176-231). Please clarify the language levels so they consistently address the same target between various language tools.

All references to the MRCT Guidance Document and Toolkit should include the latest revisions. This includes lines 246-247, 284-287, p. 11, pp. 24-25, and p. 28. The latest versions are posted at http://mrctcenter.org/projects/return-of-results-to-participants/.

It was mentioned in Annex 1 p. 18 that the term “side effects” could be used instead of “adverse reactions,” but the Annex V heading requirement 6 uses “adverse reactions.” Please clarify that it is acceptable to change the heading names to fit clear, plain language health literacy standards.

Pp. 18 -19 also states that side effects for each group/arm should be listed separately, but if the side effects are the same for each group/arm, this can become confusing and lengthy. For these cases, please allow sponsors to list side effects once and then show the amount of side effects for each group/arm.

There is potential confusion with the way endpoints are described on p.19, Annex 1. Please clarify the kind of endpoints that would fit the statement, “Patient relevant secondary endpoints and results by study arm.” For instance, sponsors should list primary endpoints, and secondary endpoints that are clearly measured regarding safety and clinically actionable results.

The template in Annex 1 has inconsistent grammar and health literacy principles in the suggested wording. Please use action verbs consistently with bullets. Simpler words can also be used throughout the template.

On p. 19, the heading should not have an “s” on “Overall Results of the Clinical Trials.”

Finally, demands that force conformity to the literal interpretation of the law (rather than its intent) are counterproductive when creating useful information for patients, their families, and the public. Please be prepared to quickly address the issues that will surface from this regulation. In addition, regulations and corresponding documents need to change often and openly, and encourage innovations that will develop over time. For instance, while the current instructions are firmly focused on print formats, it is clear that other issues will surface when more innovative web applications are produced. Thank you again for seeking public comments to your documents.

I consent to the publication of all information in my contribution in whole or in part including my name/the name of my organisation, and I declare that nothing within my response is unlawful or would infringe the rights of any third party in a manner that would prevent publication.

How to Work with Patient Advocacy Groups & Patients

It’s been awhile since I posted anything – sorry about that. Between excessive travel, new projects with new partners, and unexpected foot surgery, time marched on without me! I actually wrote 2 guest posts that I haven’t mentioned, though. Here is the first one:

Get Real with Patients and Their Advocacy Groups at Clinical Trials Arena. It summarizes a talk I gave at their April 2016 Clinical Operations in Oncology Conference.

People ask me how to work with patients and patient advocacy groups all the time.

Short answer: it depends on the disease, and what type of input is desired at different times. The post listed above offers some ideas.

Two more opportunities are also coming up quickly with eyeforpharma:

  1. Join Jamie Roberts from CTTI, Victoria Dibiaso from Genzyme and I on August 4th at 11a EST as we discuss how to Drive Value and make the Patient-Centric Trial a Reality. It’s free!
  2. I’ll also be speaking with many other patient advocates and companies at the Patient-Centered Clinical Trials conference October 10-11th. Be sure to say hi if you see me there.

There are more happenings in this area – look for future posts here on this topic!

Happy Summer…

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.