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 (NIH) Joint 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!
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.”
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!
Here 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
- 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.