Author + information
- Norman Stockbridge, MD, PhD∗ (, )
- Kristen Miller, PharmD,
- Shashi Amur, PhD,
- Matthew Hillebrenner, MSE,
- Bram Zuckerman, MD,
- Mona Fiuzat, PharmD and
- Robert M. Califf, MD
- ↵∗Reprint requests and correspondence:
Dr. Norman Stockbridge, U.S. Food and Drug Administration, 10903 New Hampshire Avenue, Silver Spring, Maryland 20993.
This is our second contribution to the series “FDA in the 21st Century,” which highlights recent activity at the agency that may impact cardiovascular care. Our first commentary focused on policy changes potentially affecting heart failure device approvals and safety monitoring. This installment focuses on activities affecting cardiovascular drug development as overseen by the Center for Drug Evaluation and Research (CDER). Recent data have shown that investment in cardiovascular drug development has decreased over the past 2 decades (1) and that conducting clinical trials to answer key questions for U.S. Food and Drug Administration (FDA)-approved therapies is expensive and inefficient in the current environment. Here, we highlight a few programs to facilitate drug development and to use modern advances for monitoring safety.
Clinical Trial Quality and Oversight
The Clinical Trials Transformation Initiative (CTTI) is a public-private partnership organization composed of representatives from the FDA, academia, government agencies, industry, patient advocacy groups, professional societies, institutional review boards, investigators, and other interested parties. CTTI recognizes that clinical trials have become increasingly complex and costly and that trials need to be conducted more efficiently while reducing costs and maintaining quality. To achieve this mission, CTTI conducts projects to generate knowledge, recommendations, and tools. One such project, the Quality by Design and Quality Risk Management project, evaluated how quality could be built prospectively into the design of clinical trials to protect patients and ensure reliable results. CTTI determined that quality is the absence of important errors, that trials should be designed to prevent important errors rather than to use post-trial monitoring to try to resolve them, and that resources should be focused on supporting the quality of the collection and reporting of critical data directly related to study endpoints. The recommendations developed through this project highlight the importance of focusing on areas that are at the highest risk for generating important errors, tailoring monitoring approaches to trial design, and prospectively measuring error rates of important parameters.
Recognizing the need for guidance in this area, the FDA also published guidance for industry titled “Oversight of Clinical Investigations—A Risk-Based Approach to Monitoring.” This guidance assists sponsors of clinical investigations in the development of risk-based monitoring strategies and plans for investigational studies. The overarching goals are to enhance research participant protection and the quality of clinical trial data and efficient monitoring activities that reflect a modern, risk-based approach focused on critical study parameters. Taken together, the FDA’s guidance and CTTI’s recommendations highlight the point that quality is an overarching objective that must be built into the clinical trial enterprise, and both organizations recommend a quality risk management approach to clinical trials.
At CDER, review of applications for new drugs and new uses of approved drugs for cardiovascular disease are the responsibilities of the Division of Metabolic and Endocrine Products (antilipids) and the Division of Cardiovascular and Renal Products. These divisions hold meetings at the request of sponsors at various points in the development process. Optimized data collection and monitoring are routine topics for phase 3 and postmarket studies for which we recognize that the cost of traditional trial operations is not sustainable.
With regard to improvements in safety monitoring, the FDA launched the Sentinel Initiative, a national electronic safety surveillance system to strengthen the agency’s ability to conduct postmarket safety monitoring of medical products. Currently, the Sentinel database includes 200 million individuals and more than 350 million person-years of observation time. The database consists mostly of claims data supplemented with a growing amount of electronic health record data provided by hospitals, health systems, insurers, and universities. Sentinel provides a means of confirming and characterizing safety signals that have arisen from other sources, such as the spontaneous reporting system, and has been constructed to produce an environment with proper denominators for product use.
For example, the Sentinel Initiative was used to assess how well labeling was succeeding at influencing prescriber behavior with respect to use of prasugrel and clopidogrel in patients with a history of stroke or transient ischemic attack. Such use is contraindicated for prasugrel but not for clopidogrel. A Sentinel study confirmed that a much lower percentage of prescriptions for clopidrogel were ordered in such patients than for prasugrel. Numerous other safety studies have been completed, and all study reports are posted for the public to view.
Critical Path Innovation Meetings
To address issues in drug development, CDER initiated the Critical Path Initiative in 2004. An early step in exploring scientific issues of general interest in drug development is to seek a Critical Path Innovation Meeting. This program, established in 2013, allows members of regulated industry, academia, government agencies, and/or patient advocacy groups to request a meeting that includes representatives from the FDA. Topic areas include biomarkers, other drug development tools such as patient-reported outcome measurements, and innovative trial designs or analytic methodologies. However, these meetings do not substitute for formal, product-specific development meetings.
Letter of Support Initiative
To encourage development of promising biomarkers, CDER established the Letter of Support (LOS) Initiative in 2014. Letters of support are intended to enhance the visibility of promising biomarkers, to encourage data sharing, and to stimulate additional studies toward further development of biomarkers with the goal of qualification. This letter is issued after CDER determines that the scientific evidence may support the use of the biomarker to aid drug development. This determination is made based on evaluation of the submitted materials and does not constitute a regulatory decision. To date, six LOSs have been submitted for safety biomarkers for use in early drug development.
Biomarkers have been used in drug development programs for a variety of purposes, including enrichment of clinical trial populations and monitoring response to drug therapy. When used in the context of individual drug applications, the confidential information submitted to the FDA is made public after a drug is approved through drug labels and reviews and, in some instances, through guidance. Regulatory acceptance of biomarkers developed through scientific community consensus is yet another path to integrate the use of biomarkers in drug development. This is often a protracted process, one that includes challenges with respect to sample size, data reproducibility, and heterogeneity of the generated biomarker data (due to different assays/technologies used and heterogeneous populations). CDER has developed the Biomarker Qualification Program (2,3) to encourage systematic biomarker development guided by regulatory advice. Biomarker development can be conducted by individual scientists, collaborative groups, or consortia. When a biomarker is qualified through CDER’s Biomarker Qualification Program, guidance about the biomarker is published along with an executive summary and reviews that are made publicly available on the FDA website.
Biomarker qualification is defined as a conclusion, based on a formal regulatory process, that within the stated context of use (COU), a drug development tool can be relied upon to have a specific interpretation and application in drug development and regulatory review. The COU is a comprehensive statement that fully and clearly describes the manner and purpose of use for the biomarker in drug development. The COU drives the level of evidence needed to qualify the biomarker for the specific COU. Once qualified for a specific COU, a biomarker can be used in other drug development programs without undergoing re-review for the qualified COU.
CDER’s Biomarker Qualification Program process has the following 3 stages: 1) initiation; 2) consultation and advice; and 3) review. The process, documents, and pertinent FDA actions associated with each stage are shown in Figure 1. The biomarker guidance drafted in the review stage is published in the Federal Register, and the supporting information is added to the FDA Web page. Public comments submitted to the docket within 60 days are reviewed, and the biomarker guidance is finalized after comments are addressed. To date, 13 unique biomarkers have been qualified through the Biomarker Qualification Program; 10 of these are safety biomarkers for safety assessment in the nonclinical setting, and 2 are for cardiotoxicity assessment.
Biomarker qualification is reported to have demonstrated a significant impact on drug development and several companies have begun using the qualified nonclinical safety biomarkers for “candidate molecule prioritization, early safety reads on efficacy studies, candidate selection, and go/no go decisions at the pre-investigational new drug (IND) stage” (4). These biomarkers are also reported to “have decreased animal use and the number of interim time points to be assessed, with fewer necropsy and pathology endpoints.” Qualification of these safety biomarkers for use in clinical trials has yet to be established, but efforts are under way to generate the data to support a qualification determination.
Among the early drug development tools, CDER qualified cardiac troponins as early markers of cardiotoxicity in nonclinical studies (5). In addition, this year the FDA-National Institutes of Health Joint Leadership Council launched the BEST (Biomarkers, EndpointS, and other Tools) resource as a new textbook that includes a glossary of terms and definitions that will ensure the consistency and clarity needed to drive progress in biomedical research and clinical care.
We have described here some of the principal ways in which FDA/CDER is partnering with regulated industry, the healthcare community, academia, and other entities. These activities highlight CDER’s role in facilitating medical product development in addition to its role as an evaluator of safety and effectiveness. Consistent with our colleagues in the Center for Devices and Radiologic Health, CDER has developed strategic initiatives to improve the drug development process and advance drug safety monitoring. Going forward, CDER remains committed to finding innovative ways to accomplish these goals.
The authors have reported that they have no relationships relevant to the contents of this paper to disclose.
- Received October 5, 2016.
- Revision received October 11, 2016.
- Accepted October 12, 2016.
- Fordyce C.B.,
- Roe M.T.,
- Ahmad T.,
- et al.
- Amur S.,
- Sanyal S.,
- Chakravarty A.G.,
- et al.
- Dennis E.H.,
- Walker E.G.,
- Baker A.F.,
- Miller R.T.
- ↵Department of Health and Human Services. Qualification decision, review conclusions, and recommendations for use of circulating cardiac troponins T (cTnT) and I (cTnl) in nonclinical drug development studies in rats, dogs, and monkeys. February 23, 2012. Available at: http://www.fda.gov/downloads/Drugs/DevelopmentApprovalProcess/DrugDevelopmentToolsQualificationProgram/UCM294644.pdf. Accessed October 4, 2016.