By James E. Valentine* & Sara A. Khan**
On July 11, 2014, the House Energy and Commerce’s Subcommittee on Health sought input regarding the incorporation of patient perspectives in drug development and review. (See our coverage of two previous 21st Century Cures hearings here and here.) The Subcommittee leadership set the tone early that the most important aspect of the 21st Century Cures Initiative is what medical innovation and faster cures mean for patients. They also emphasized that there is a need to understand the patient perspective in order to focus on results for patients who lack adequate medical treatment options.
The witnesses (representatives from patient groups, healthcare professional organizations, industry, and FDA) described the current state of patient input in drug development and review and highlighted models and frameworks to further integrate the patient perspective. Recommendations for elevating the patient voice emerged as two distinct categories of “input:” (a) increasing the use of patient-reported outcomes (“PROs”) in clinical research and (b) incorporating the patient perspective, either directly or indirectly, in the drug development enterprise and throughout FDA review.
Patients as Participants in Clinical Research. Historically, the role of patients in drug development has been limited to their role as research subjects, and measures of patient symptoms, overall mental state, or the effects of a disease on how a patient functions were captured by clinician observations or tests. Recently, however, the medical community has begun to recognize that there is value in measuring the status of a patient’s health directly from the patient, rather than through the lens of a clinician. As such, various parties in the drug development process have begun to show an interest in incorporating PROs into clinical trials.
As the FDA panelist at the hearing, Janet Woodcock, Director of FDA’s Center for Drug Evaluation and Research (“CDER”), discussed how CDER is working to advance development and improve the use of PROs under the Prescription Drug User Fee Act V (“PDUFA V”). Previously, FDA did not have a rigorous process for qualifying PROs, but, now relying on the science of measurement, consortia can come to FDA to propose a PRO endpoint, if qualified. Qualified PROs, which are published on FDA’s website, are considered by FDA to be valid outcome measures that could be used to support drug labeling claims. (We previously reported on FDA’s 2009 Guidance on review and evaluation of PROs here). Dr. Woodcock noted that FDA is currently engaged in 79 PRO qualification projects.
Noting that in cancer drug development, certain self-reported symptoms that are measured qualitatively, such as nausea and pain, are often reported differently by physicians than by their patients, Dr. Leonard Lichtenfeld, the Deputy Chief Medical Officer of the American Cancer Society, advocated the use of PROs in all clinical trials.
Many panelists cited the lack of established and consistent methods to assess PROs as a barrier to their widespread acceptance and use. Richard Pops, the Chairman and CEO of Alkermes, a pharmaceutical company that specializes in therapies for chronic central nervous system diseases, called for standardized methods for industry to follow when using patient-reported data. Both Dr. Woodcock and Dr. Robert Beall, President and CEO of the Cystic Fibrosis Foundation, recommended that Congress provide federal agencies with increased resources for regulatory science, which could support efforts in this area.
The Patient Perspective in Drug Development & Review. Of much greater interest to Subcommittee members and witnesses alike were models for incorporating the patient perspective in both industry and FDA decision-making throughout the drug development lifecycle. As patients ultimately experience the risks and benefits of approved medical treatments, witnesses offered suggestions for increasing the patient voice in various aspects of drug development and review.
Prior to the enactment of the Food and Drug Safety and Innovation Act (“FDASIA”), patient input in drug approval decisions was generally limited to patient representatives serving on FDA Advisory Committee meetings, which are mainly focused on approval decisions upon submission of a marketing application. The FDA Office of Health and Constituent Affairs, in concert with the Agency’s medical product centers, recruits and trains patients to serve as Special Government Employees. Recognizing the need to include patient input earlier in the FDA review process, Section 1137, which calls for FDA to develop and implement strategies to include the patient representatives earlier in drug review, at appropriate FDA-sponsor meetings, was included in FDASIA. Dr. Lichtenfeld, from ACS, advocated that the FDA Patient Representative Program be expanded to include patient representatives in the review process, so that patients can provide input on risk tolerance and contribute to discussions of clinical trial design. As Dr. Lichtenfeld pointed out, FDA Patient Representative Program would need additional resources in order to realize this goal. The time burden for FDA to conduct conflict-of-interest screening of patient representatives is a barrier to their inclusion in FDA-sponsor meetings (i.e., pre-IND, end of Phase 2), which are scheduled under tight PDUFA-directed timeframes. Although this barrier was not discussed at the hearing, it is important for the Subcommittee to recognize it when considering approaches to implement Dr. Lichtenfeld’s recommendation.
Dr. Woodcock described a more recent program for incorporating the patient perspective in FDA’s regulatory decision-making. FDA committed under PDUFA V to hold at least twenty patient meetings over five years, each focused on a particular disease area, in an effort to obtain and utilize patient input in clinical trial design. This Patient-Focused Drug Development (“PFDD”) program provides an opportunity to more systematically obtain patient perspectives on how their disease impacts their daily lives, gauge the types of treatment benefits that matter most to patients, and assess the adequacy of available therapies for the disease with respect to the treatment benefits that patients desire. Dr. Woodcock highlighted that the first meeting, which was held for patients with chronic fatigue syndrome (“CFS”) and myalgic encephalomyelitis (“ME”), resulted in a draft guidance for industry on CFS/ME drug development.
Pat Furlong, Founder and CEO of Parent Project Muscular Dystrophy (“PPMD”), described her recent experience conducting a survey of on risk and benefit preferences in the Duchenne Muscular Dystrophy (“DMD”) community and suggested that other patient groups consider conducting similar surveys. With FDA’s encouragement, PPMD developed and conducted the survey with the help of researchers at Johns Hopkins University. PPMD shared the results of this study with FDA, showing that this population (parents of children with Duchenne Muscular Dystrophy, a condition that is 100% fatal at a young age) had a particularly high risk tolerance for treatment options.
Dr. Marshall Summar, Director and Chair of the Scientific Advisory Committee for the National Organization for Rare Diseases (NORD), suggested that FDA develop guidance for patient groups to hold independent drug development meetings and present their findings to the Agency. In the absence of such guidance, Ms. Furlong discussed PPMD’s six month effort, in collaboration with medical experts, industry, and their patient community to draft a document to FDA on DMD clinical trial design and other drug development issues. She described that their model was successful because of the structure the put in place with a multi-stakeholder Steering Committee, seven Working Groups to focus on various sections of the guidance, and an overarching Community Advisory Board, made up of DMD patient groups and patient advocates. There was consensus among the witnesses that PPMD’s guidance development could serve as a model for other patient groups to effectively engage with FDA and industry and ultimately influence key issues in drug development.
A final, and probably most dramatic, model for incorporating the patient perspective in drug development is for patients to provide resources that situate them as partners in drug development programs. Dr. Robert Beall, President and CEO of the Cystic Fybrosis Foundation (“CFF”), discussed a series of investments his group made that led to the first approval of a drug for CF, as well as a second promising therapy in Phase 3 that targets a larger segment of the CF patient population. First, in 1965, CFF created the first patient registry in the U.S., which enabled the group to collect the data that was needed to understand the natural history of the disease. CFF also accredits health care centers, which treat 90% of all CF patients. The CFF accreditation program improves access to potential clinical research participants. To further this goal, CFF created a CF clinical trial network, the first clinical trial network developed by a patient group, in 1998. Finally, CFF raised funds and provided the initial investment in the biotech company developing the two drugs mentioned previously. All of CFF’s efforts allowed for advancement in the research and development of product candidates for CF and ultimately de-risked the transition into clinical research. CFF continues to engage with FDA on substantive regulatory and scientific issues, seen as an active partner in ongoing drug development programs.
Piecing Together a Patient Engagement Framework. Overall, there was consensus that patient engagement is not new, but the wide range of emerging models that further incorporate the patient perspective are advantageous to the drug development and review process. There was also agreement that, to better incorporate patient perspectives, it is necessary to do so in a data-driven, systematic, and efficient manner. Mr. Pops added, from the industry perspective, that the framework for patient input should not add new steps to the already complex drug development program. Additionally, Dr. Woodcock stated that CDER believes it has the statutory authority it needs to meet the needs of expanded patient input into regulatory decision-making (although there are concerns regarding conflict-of-interest rules that are barriers to including FDA Patient Representatives in appropriate FDA-sponsor meetings).
For more information on FDA’s framework for patient engagement, Hyman, Phelps & McNamara, P.C.’s James E. Valentine presented an overview of FDA’s framework for patient engagement at the 2014 Drug Information Association Annual Meeting. Best practices for effective engagement by industry and academia with patient groups around clinical trials will be emerging from the Clinical Trials Transformation Initiative, an FDA public-private partnership (see here).
* Not admitted in the District of Columbia
** Summer Associate
