ANALYTICAL
Figure 1. Structured Benefit-Risk Framework.
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.
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
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
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 cross- divisional 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
Pharmaceutical Outsourcing | 24 | March/April 2015
Significant progress
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