Successful companies are customer-focused, and in the research-based pharmaceutical industry, patients are the key customer. The biopharmaceutical industry is unique in many ways, however, with attributes that complicate the straightforward consumer-provider relationship enjoyed by many other businesses. To begin with, this industry is highly regulated. New biomedical innovations are not in and of themselves marketable products. National regulators must first agree that adequate clinical and preclinical data are in evidence to demonstrate a favorable benefit-to-risk profile. Absent regulatory approval, a company’s investigational compound is not a medicine. Once a drug is approved, product promotional messages—whether to patients or other stakeholders—must be consistent with the scope and content of the regulator-approved label.
Beyond this, pharmaceutical companies do not generally supply product directly to customers. The sophistication of most medicines and the narrow circumstance of use typically require prescribing and dispensing through healthcare intermediaries: physicians, nurses, and pharmacists. Direct patient access to medicine is limited to the relatively small group of over-the-counter therapies.
In addition to these complexities, the essential value of most medicines warrants that they are paid for—at least in part—by governments or third-party insurers. Patients are the prime customers, but the access, use, and purchase of innovative medicines involves other stakeholders— namely regulators, healthcare providers, and insurers.
Patient Participation in Industry Drug Development
Patient engagement is important to all healthcare system stakeholders, none more so than drug developers. At the most fundamental level, innovator drug companies generate 2 products: the intellectual property that defines the basic biochemical inventions and the approved product labeling that summarizes years of clinical and pre-clinical development.
Patients are involved in many aspects of company R&D with their most visible role being that of essential but generally anonymous clinical trial participants. The contribution of patients in industry drug development has always been more extensive than that, however. Even during the early stages of research, the project operating proposals that set company discovery priorities need patient data to characterize the unmet medical need for conceptual products and to define desired treatment attributes. During the discovery research stage, information may be gathered to characterize patient concerns regarding disease symptoms, aspects of care, function, and potential functional assessment methods.
Later in the R&D process at the pre-clinical phase, when investigational drug candidates have been identified, patient information may be collected from registries, from global patient communities, and from advocacy groups in order to assess patient willingness to participate in clinical trials or to partner in the development of functional measures and patient-reported outcome tools (PROs).
The clinical development phase, where the therapeutic characteristics of an investigational compound are explored and the data package to support product regulatory approval is assembled, by definition is focused on and depends on patients. However, beyond clinical trial design and operation, there are other patient-focused activities that take place during clinical development. For example, activities may include working with patients to conduct usability tests on devices intended for use in clinical trials such as diaries, seeking patient participation in advisory boards to inform aspirational product commercial profiles, using semi-structured qualitative interviews to understand disease symptoms and illness experience from the patient perspective, and partnering with patient groups to develop and qualify patient-reported outcome assessment tools.
Patient engagement during R&D has always been extensive and multifaceted. Before the recent launch of the U.S. Food and Drug Administration (FDA) Patient Focused Drug Development initiative,1 however, elements of company patient-centered drug development were often less visible, less coordinated, and, consequently, sometimes underdeveloped.
FDA Patient Focused Drug Development
The FDA Patient Focused Drug Development (PFDD) initiative includes several important components described in the 2012 Prescription Drug User Fee Act (PDUFA V).2 As an element of PDUFA, these FDA PFDD activities are supported in part by industry user fees. This new and successful FDA patient engagement program continues to integrate patient priorities further into FDA benefit-risk decision-making. A hallmark feature of the program is a series of FDA-hosted disease area stakeholder meetings. To date, FDA has held 11 of 20 meetings which are planned over the 5-year PDUFA interval. During these meetings, FDA listens to patients to receive their insights on disease conditions and the availability of acceptable treatment options. Gathering patient input to assess medical need is not in and of itself unique, having long been part of company discovery prioritization and development planning, but doing this through a common, inclusive, and public process is novel.
To assist in this process and to help to incorporate patient information into drug reviews, a second, PDUFA-supported regulatory tool, known as the Structured Benefit-Risk Framework,3 was developed and is being incorporated into product regulatory review procedures. The current version of the Benefit-Risk Framework is outlined in Figure 1.
Figure 1. Structured Benefit-Risk Framework.The Benefit-Risk Framework was created to organize and illuminate aspects of drug review benefit-risk decisions. Product approval (or non-approval) hinges on regulatory reviewer perceptions of the drug candidate benefit-to-risk profile. Product benefit-risk assessment is a fundamental responsibility of regulatory agencies and the touchstone decision from which most other drug regulatory tasks emanate.
A common framework to support the decision process is important, but the Benefit-Risk Framework is also a helpful tool to organize the flow of patient benefit-risk information derived from the FDA PFDD disease area meetings. Patient insights shared at these meetings are collated and consolidated to populate the first 2 sections of the Framework: the “Analysis of Condition” and “Current Treatment Options.”
While it is still early, the use of this framework as a review decision and organization aid may prove to be only part of the potential value. The FDA Benefit-Risk Framework may also become a useful tool in company product development processes. The availability of a single template containing common sets of patient disease characterization data can help to organize and align company-FDA benefit-risk discussions, and not just at the time of New Drug Application/Biologics License Application submission, but throughout the entire development process. While not in common practice yet, using this framework to guide the sponsor-regulator development dialogue, even at the IND stage, may prove to be a valuable efficiency enhancement. Employing a standard format to discuss disease attribute data developed from common patient data sets can help to ensure that sponsors and regulators are on the same page throughout the product development process.
Patient Reported Outcome Measures
Another key and an evolving aspect of patient engagement is the use of PRO measures both to inform the benefit-risk decision and to communicate product attributes to patients in product labels. PROs are defined by FDA to be “any report of the status of a patient’s health condition that comes directly from the patient, without interpretation of the patient’s response by a clinician or anyone else.”4 PROs record information concerning the impact of an intervention or therapy from the patient perspective. PRO instruments offer a means to capture how a patient feels or functions with respect to her or his health, condition, or disease and may include information about patient symptoms, function, adherence to medication, satisfaction with care, and perceived treatment value.5 PROs can be useful measures of benefit-risk and can play a significant role as study endpoints in drug clinical development programs. An analysis of the clinical trials registered in the ClinTrials.gov database showed that some 12% of interventional trials registered by the pharmaceutical industry incorporate some form of PRO assessment. Over 15% of non-industry trials include PROs.6
In drug development, regulator acceptance of the relevance and validity of a PRO measure is critical to its utility. PRO qualification for use in regulatory decision-making often occurs in the context of a particular drug development program when the sponsor seeks to include a novel PRO in the product submission package. However, cooperative development of PRO qualification data is also increasingly common.
To facilitate qualification of PROs and other clinical measuring tools, the FDA Center for Drug Evaluation and Research (CDER) provides a Drug Development Tool (DDT) Qualification Program. This voluntary program allows agency staff to guide sponsors as they develop or refine a DDT for a specific context of use. PROs are one of the DDTs included under this program. Through the Qualification Program, sponsors may submit a PRO or other DDT for evaluation by FDA to determine the suitability for use in regulatory processes. If successfully qualified, a sponsor can use the DDT in the qualified context of use, during drug development without requesting that CDER reconsider and reconfirm its suitability.7 Qualified DDTs are listed by FDA as being available for potential use in any drug development program for the qualified context of use.
The regulatory clarity provided through common understanding of agency views on acceptable use of specific PROs in development contexts is valuable. Regulatory predictability fosters innovation. Conversely, regulatory uncertainty regarding the potential use of development tools such as PROs can diminish R&D efficiency.
To build the data sets needed to support qualification submissions, industry and other stakeholders have worked both individually and cooperatively through organizations such as the PRO Consortium formed in 2008 as part of the Critical Path Institute.8 Significant progress has been achieved in building processes and collecting data; however, to date, very few PROs have been qualified through the FDA Program.9
FDA has made efforts to encourage the use of PROs in drug development and to support the CDER Qualification Program. A crossdivisional Study Endpoints and Labeling Development (SEALD) staff is available for reviewer training and consultation regarding PROs and other clinical measuring tools. The SEALD resource is a testament to agency recognition of the growing importance of PROs and other clinical outcome assessments in drug development. The effectiveness of this organizational construct, however, hinges on coordination of the efforts and advice provided by SEALD with that of the individual review divisions.
FDA has published guidance for industry on PRO development and use.10 The guidance outlines key considerations in PRO qualification, namely the intended use of the PRO in the product development program, the relevance of the PRO instrument to the patient population, the relationship between the PRO scale items or questions to the concept being measured, and the validity, sensitivity, and reliability of the instrument.
The current regulatory guidance, agency organizational structure, and qualification processes represent significant progress and provide necessary foundations to support efficient PRO qualification decisions. However, unlike drug product review submissions, FDA DDT qualification reviews are not bound by PDUFA review time goals. In addition, evidentiary standards to support qualification decisions are sometimes lacking. Ongoing attention is needed to ensure that DDT regulatory processes keep pace with advancing science.
Patient groups have recognized the opportunity and the need for novel PROs, and, consequently, an important evolution in the realm of PRO qualification has been the increasingly coordinated involvement of patient organizations. Access to patient data is a key qualification enabler and, spurred in part by the public Patient Focused Drug Development meeting dialogue, a growing number of patient-led data collection efforts have launched that will ultimately benefit PRO qualification. Patient organizations that have long been advocates in the policy arena are now also focusing efforts on activities such as the development of patient registries to facilitate data collection and construction of data standards and frameworks to ensure data quality. Optimizing PRO qualification is a nexus objective for patient-focused drug development, involving and benefiting patients, drug sponsors, and regulators. The continued coordinated efforts of each of these stakeholders will be needed to expand the catalogue of qualified PROs and other drug development tools.
Conclusion
Biopharmaceutical development is entering a new era of patient-centered drug development. The formerly disparate efforts of regulators, individual companies, and patient groups are coalescing around common goals and objectives. Patient empowerment, technological advances, astute regulatory policy, and remarkable drug development successes have provided some of the inspiration for this progress. Going forward, continuing to ensure that the patient voice is prominent both in the industry development activities and in regulatory benefit-risk decisions will remain key to the ongoing success of the innovative biopharmaceutical industry.
References
- US Food and Drug Administration. The Voice of the Patient: A Series of Reports from FDA's Patient-Focused Drug Development Initiative. Available at: http://www.fda.gov/ForIndustry/UserFees/PrescriptionDrugUserFee/ ucm368342.htm. Accessed January 12, 2015.
- US Food And Drug Administration. Prescription Drug User Fee Act (PDUFA). Available at: http://www.fda.gov/ForIndustry/UserFees/PrescriptionDrugUserFee/ UCM2005475.htm. Accessed January 12, 2015.
- US Food And Drug Administration. Enhancing Benefit-Risk Assessment in Regulatory Decision-Making. Available at: http://www.fda.gov/ForIndustry/UserFees/PrescriptionDrugUserFee/ucm326192.htm. Accessed January 11, 2015.
- US Food and Drug Administration. Clinical Outcome Assessment (COA): Glossary of Terms. Available at: http://www.fda.gov/Drugs/DevelopmentApprovalProcess/DrugDevelopmentToolsQualificationProgram/ucm370262.htm#pro. Accessed January 11, 2015.
- Calvert M, Blazeby J, Altman DG, Revicki DA, Moher D, Brundage MD. Reporting of Patient Reported Outcomes in Randomized Clinical Trials: The CONSORT PRO Extension. JAMA. 2013;309(8):814-833.
- Scoggins JF, Patrick DL. The Use of Patient Reported Outcome Instruments In Registered Clinical Trials; Evidence From ClinTrials.gov. Contemp Clin Trials. 2009;30(4): 289-292.
- US Food and Drug Administration. Drug Development Tools (DDT) Qualification Programs. Available at: http://www.fda.gov/Drugs/DevelopmentApprovalProcess/ DrugDevelopmentToolsQualificationProgram/. Accessed January 12, 2015.
- Critical Path Institute. Patient-Reported Outcome Consortium. Available at: http://c-path.org/programs/pro/. Accessed January 12, 2015.
- US Food and Drug Administration. Clinical Outcome Assessment Qualification Program. Available at: http://www.fda.gov/Drugs/DevelopmentApprovalProcess/DrugDevelopmentToolsQualificationProgram/ucm284077.htm. Accessed January 12, 2015.
- US Food and Drug Administration. Guidance for Industry Patient-Reported Outcome Measures: Use in Medical Product Development to Support Labeling Claims. December 2009. Available at: http://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/UCM193282.pdf. Accessed January 12, 2015.
J. Michael Maher, MS, MBA, is currently Executive Director, U.S. Regulatory Policy at Pfizer, Inc. In this role he works with internal and external partners to develop and implement policy solutions to support efficient drug development. With more than 30 years of experience in the pharmaceutical industry, Mr. Maher has managed large-scale pharmaceutical manufacturing, directed R&D planning, and led U.S. regulatory policy operations. Currently he provides strategic leadership to identify policy priorities, develop consensus positions, and represent Pfizer in regulatory policy forums.