FDA: Food and Drug Administration Safety and Innovation Act (FDASIA) and Patient Focused Drug Development

Last week, President Obama signed into law the Food and Drug Administration Safety and Innovation Act (FDASIA). Among the numerous provisions contained in this Act are several provisions that will enhance and increase patient participation in medical product regulation.  Specifically, Sec. 1137 of the new law will allow the agency to develop and implement strategies to solicit the views of patients during the medical product development process and consider the perspectives of patients during regulatory discussions.  This will include: 

• Fostering participation of FDA Patient Representatives as Special Government Employees in appropriate agency meetings with medical product sponsors and investigators; and,
• Exploring means to provide for identification of FDA Patient Representatives who do not have any, or have minimal, financial interest in the medical products industry. 

Consequently, Theresa Mullin, Ph.D. Associate Director for Planning and Informatics FDA Center for Drug Evaluation and Research (CDER) recently gave a presentation on “Patient-Focused Drug Development.” 

Presentation 

Mullin first outlined FDA’s benefit-risk (B-R) framework, which looks at five (5) key considerations: 

1. Severity of Condition
2. Unmet Medical Need
3. Benefit
4. Risk
5. Risk Management 

Severity of Condition and Unmet Medical Need provide regulators with the clinical context for weighing benefits and risks and the associated uncertainties. 

Benefit and Risk incorporate expert judgments based on evaluation of the efficacy and safety data. 

Risk Management incorporates expert judgments on the expected impact of efforts to reduce and further characterize risks. 

Assessment of a drug’s benefits and risks involves analysis of severity of condition and current state of the treatment armamentarium.  Patients who live with a disease have a direct stake in drug review process and are in a unique position to contribute to drug development.  As a result, FDA noted that its review process could benefit from systematic approach to obtaining patient perspective on disease severity or unmet medical need. 

Mullins noted how FDASIA – the provisions reauthorizing the Prescription Drug User Fee Act (PDUFA) – provides resources to support additional program staff to expand activities dedicated to providing review divisions with patient input.  FDA will convene meetings with participation from review divisions, the relevant patient advocacy community, and other interested parties. 

FDA will hold four public workshops per year—a total of 20 meetings over 5 years.  Each meeting will focus on a different disease area, reviewing the armamentarium for that indication, and identifying areas of unmet need. 

Benefit‐Risk Assessment Framework: Analysis of Condition 

Assessing Evidence and Uncertainties– for a given drug for a given indication‐questions FDA considers include: 

• What is the treated (or prevented) condition?
• What are its clinical manifestations (i.e., symptoms that are either reported or observed)?
• What is known about the natural history and progression of the condition, including in specific subpopulations?
• How severe is the condition for those who have it?
• How does severity vary across the sub‐populations we have defined? (Note specific subpopulations and nature of differences.)
• What is the basis for our assessment of the condition and its severity? (Note any relevant literature, clinical experience, expert opinion, etc.)
• What are the major uncertainties in the available information? What are their implications? 

Benefit‐Risk Assessment Framework: Unmet Medical Need 

Assessing Evidence and Uncertainties –for a given drug for a given indication‐FDA considers: 

• What other pharmacological therapies are approved for this condition?
• How effective are these alternative therapies?
• How does their effectiveness vary by sub‐population?
• How well tolerated are these alternative therapies?
• How does tolerance vary by sub‐population?
• What off‐label pharmacological therapies might be considered?
• How effective and how well tolerated are they reported or believed to be?
• What non‐pharmacological therapies might be considered?
• How effective and how well tolerated are they reported or believed to be?
• What kinds of evidence are available about the use of alternative treatments for this condition?
• What is the strength of evidence in each case?
• What are the major uncertainties in the evidence? What are their implications? 

The presentation then discussed Patient‐Reported Outcome (PRO) Measures, which FDA defined as “any report of the status of a patient’s health condition coming directly from the patient, without interpretation by physicians or anyone, about how the patient functions or feels in relation to a health condition and its treatment.”  FDA reviews PRO instruments and looks at whether the instrument measures the concept it is supposed to measure.  FDA looks at whether the instrument is: 

• Well‐specified and reliable
• Specific for target population
• Specific for target indication
• Adequate measurement properties (e.g., content validity) 

The presentation then noted that qualitative research can be used to establish PRO content validity.  This might include: 

• Focus groups to generate a pool of patient outcome‐related domains and their components (e.g., What symptoms and functions or activities impacted by disease that are most important to patients)
• Surveys including a larger and more diverse sample patients with a given condition (e.g., examine the importance and relevance of domains identified by literature review, expert opinion or among a smaller set of patients, to validate these items and perhaps explore other measurement characteristics) 

Mullins then used the example of people with chronic pain.  Focus groups conducted with patients who experience chronic pain identified 19 aspects of their lives (outcome domains) that are significantly impacted by the presence of their symptoms and for which improvements were important criteria that they use in evaluating the effectiveness of any treatment. 

Next Steps Patient‐Focused Drug Development 

Throughout the rest of this summer, FDA will develop preliminary list of 20 disease areas for public comment to inform planning for the set of 20 PDUFA V meetings.  FDA will also develop a basic roadmap that could be used by patient groups interested in pursuing need for and development of PRO measures in a specific disease area.  This roadmap will identify important but currently unaddressed aspects of their disease experience to potentially be considered in evaluating new therapies. 

In September 2012, FDA will publish an FR notice with the preliminary list of 20 disease areas for public comment.  In October 2012, FDA will plan to hold public meeting to: 

• Discuss the proposed list of disease areas for the PDUFA meetings and get public input;
• Discuss strategies for getting broader public input and basic roadmap for identification of important patient outcomes and strategies for collaborative development PRO measures 

FDA Patient Representative Program 

The Patient‐Focused Drug Development initiative will also add to the existing FDA programs designed to integrate patients’ perspectives.  FDA’s patient advocacy programs are run by FDA’s Office of Special Health Issues.  One of their main programs is the FDA Patient Representative Program. 

Patient Representatives provide FDA with the unique perspective of patients and family members directly affected by serious or life‐threatening disease.  Patient Representatives serve in the several ways, including: 

• On Advisory Committees, where they offer the patient perspective, ask questions, and give comments to assist the committee in making recommendations.
• As consultants for review divisions –the clinicians and scientists who review data submitted to determine whether the product’s benefits outweigh the potential risks
• As presenters at FDA meetings and workshops on disease‐specific or regulatory and health policy issues 

The Programs activities include:

 

• Recruitment of New Patient Representatives
• Selection of Patient Representatives for:
  • Advisory Committees
  • Consultation with Review Division
  • Conducts Training For Patient Representatives
    • Individual FDA 101 Training
    • Monthly Webinars
    • Annual Workshop for Newly Recruited Patient Representatives 

In choosing Patient Representatives, FDA looks for someone who brings a personal viewpoint to the process and communicates a collective patient perspective.  A patient perspective is created when a person goes through personal experience with the disease.  A collective patient perspective is created when the person has knowledge of others’ disease experiences and conveys this collective patient perspective.

 Patient Representatives provide Advisory Committee and FDA insight on issues, problems, and/or questions pertinent to the viewpoint of patients and family members living with a specific serious or life‐threatening disease. 

• Personal experience with/knowledgeable about the specific illness
• Ability to articulate the perspective of patients
• Experience as a patient advocate
• Formal affiliation with a patient advocacy organization
• The ability to identify issues through communication with patient constituencies 

Patient Representatives serve on an Advisory Committee when a product or therapy related to specific illness is under review, as either voting or non‐voting member 

• Voting: must be appointed as special government employees (SGEs); requires disclosure of personal financial information to the FDA in order to determine whether their financial interests pose a possible conflict of interest on an advisory committee
• Non‐voting: may only vote on procedural matters concerning the conduct of the meeting
• In both cases: expected to provide the patient perspective, ask questions, and offer comments to assist the committee in making recommendations 

Drug Development Patient Consultant Program 

FDA also uses patients in its Drug Development Patient Consultant program.  This program incorporates the perspective of patient advocates into the drug development process; allows opportunity to participate in the FDA drug review regulatory process. 

Patients are selected to participate in meetings by matching a specific illness and proposed indication for the new therapeutic drug being developed.  Patients may participate in meetings (via telephone ) between the FDA and drug companies. 

The newly selected patient consultant receives training and participates in monthly telephone lecture series in preparation for these meetings.  To provide consultation to both FDA and the drug company, it is important that the patient consultant have background information on the drug under review.  About three weeks before each meeting, the patient consultant is mailed the meeting package containing the meeting issues and questions. The patient consultant reviews the meeting package in preparation for the meeting.