Two federal agencies play pivotal roles in CBI’s activities the National Institutes of Health (NIH), and the US Food and Drug Administration (FDA).
As the steward of medical and behavioral research for the nation, NIH directs, coordinates and funds fundamental research in the biomedical sciences. Through NIH’s numerous disease- and organ-focused research programs, CBI and its affiliated investigators are advancing our collective knowledge of the use of imaging biomarkers to understand and monitor disease progression.
NIH has a long history of supporting image-based understanding of diseases. Examples of recent disease programs with a strong imaging component include the Osteoarthritis Initiative and Alzheimer’s Disease neuroimaging. Indeed, the formation of the National Institute for Biomedical Imaging and Bioengineering (NIBIB) underscores the importance of imaging to the mission of NIH and the healthcare of our nation.
The Food and Drug Administration (FDA) is the nation’s foremost consumer protection agency, dedicated to ensuring that medical products are safe and effective for their approved indications. Key to achieving these goals are the efficient, accurate evaluation of medical products.
Imaging biomarkers, appropriately applied and validated, hold the promise of swifter and less subjective product evaluation in both the pre-clinical and clinical setting. Congress and the FDA have recognized this potential in statutes and regulations promoting the use of surrogate endpoints in the evaluation of therapies intended to treat serious or life threatening conditions, as found in Section 112 of the Food and Drug Administration Modernization Act of 1997, and in the Act’s "least burdensome provisions" applicable to medical devices.
Crucial to realizing this potential is recognizing that good science is the foundation of biomarkers in imaging. Without adequate validation and appropriate application, biomarkers in imaging will ultimately fail to achieve the fidelity required to make timely, accurate regulatory decisions.
The Center for Biomarkers in Imaging (CBI), built on the science developed at the Massachusetts General Hospital Department of Radiology and beyond, is committed to respecting the role of sound research in supporting our biomarkers mission. Composed of imaging professionals who have made significant contributions to the biomarkers field, CBI has the research capacity to validate imaging biomarkers ranging from the most basic imaging finding to the most complex molecular probe, and the experience to appropriately apply this knowledge to specific clinical and pre-clinical questions. Importantly, the physicians, scientists and staff of CBI realize that the ultimate success of biomarkers in imaging depends on the academic integrity of their work.
The Center for Biomarkers in Imaging stands ready to assist government regulators, regulated industry and the academic community to realize the full potential for imaging biomarkers by conducting, promoting, and applying sound science to pre-clinical and clinical endpoints.
STATUTORY AND REGULATORY PROVISIONS SUPPORTING THE USE OF BIOMARKERS
Formal FDA Acceptance of Biomarkers
Present Treatment of Biomarkers Under the Food and Drug Administration Modernization Act of 1997 (FDAMA)
New pharmaceuticals, biologics, and medical devices must gain approval from the U.S. Food and Drug Administration (FDA) prior to their marketing for clinical use. Genuinely new products generally undergo human clinical testing to demonstrate their safety and effectiveness for a specific clinical application to gain this approval. Historically, the endpoints of these trials were "traditional" ones tied to the actual disease being evaluated, such as a decrease in mortality or an objective/semi-objective decrease in clinical symptoms associated with the condition. In the last 10 to 15 years, there has been a move by FDA to incorporate "surrogate endpoints," including biomarkers, non-traditional findings that are related to the presence or absence of disease. Often, biomarkers may be measured though various imaging techniques.
Formal FDA Acceptance of Biomarkers
FDA’s initial formal acceptance of biomarkers in its new product evaluation process came in a series of initiatives enacted from 1987 to 1993, designed to expand access and expedite approval for drugs employed in the treatment of serious and life-threatening conditions. Intended primarily to combat HIV/AIDS, these initiatives explicitly embraced "surrogate endpoints," implicitly including biomarkers as well.
Specific regulations included:
- Accelerated Approval of New Drugs for Serious or Life-Threatening Illnesses, 21 C.F.R. § 314.500. Enacted in 1993, this provision permitted the approval of a drug on the basis of adequate and well-controlled studies establishing its effect on a surrogate endpoint that is reasonably likely to provide clinical benefit, or on the basis of an effect on a clinical endpoint other than survival or irreversible morbidity. Approval under this pathway was subject to the requirement that the sponsor further study the drug to verify its clinical benefit, where there was uncertainty as to the relationship of the surrogate endpoint to clinical benefit, or of the observed clinical benefit to ultimate outcome.
- Accelerated Approval of Biological Products for Serious or Life-Threatening Illnesses, 21 C.F.R. § 601.41. This is the biological product equivalent of the drug provisions found above in 21 C.F.R. § 314.500, and features similar requirements and language.
- Notably, there were no similar provisions for devices, likely because such products were not employed in treating HIV/AIDS.
Present Treatment of Biomarkers Under the Food and Drug Administration Modernization Act of 1997 (FDAMA):
FDAMA, enacted in 1997, codifies and expands the surrogate endpoints/biomarkers provisions, in many instances employing similar language.
Provisions applicable to drugs are found in Section 112, Expediting Study and Approval of Fast Track Drugs. These provisions include:
- Expanded coverage compared to prior regulations. Drugs, which are intended to treat any serious or life-threatening condition, are covered by this provision, expanding pre-FDAMA regulations that many believed applied only to HIV/AIDS and cancer. A condition that qualifies is one that affects day-to-day functioning, or the likelihood, if left untreated, that the disease would progress from a less serious one. Commentators believe that this encompasses HIV/AIDs and cancer, but also Alzheimer’s Disease, coronary artery disease, and many others. Practically speaking, this definition could conceivably be applied to almost any medical condition of consequence.
- Securing marketing approval when FDA makes the determination that the product has an effect on a clinical or surrogate endpoint that is "reasonably likely" to predict clinical benefit.
- Provisions for post-market surveillance to confirm the validity of the surrogate endpoint/biomarker.
- Specific provisions requiring that FDA establish a program to encourage the development of surrogate endpoints that are reasonably likely to predict clinical benefit for serious or life-threatening conditions for which there exists significant unmet medical need. This provision clearly extends beyond previously promulgated FDA regulation.
- Surrogate endpoints or biomarkers are not explicitly discussed in FDAMA device provisions. However, Section 205 of the legislation imposes on FDA the requirement that it employ the "least burdensome means" necessary when approving or clearing a medical device for market. This requirement can easily be seen to encompass surrogate endpoints and biomarkers.
The MGH-HST Center for Biomarkers in Imaging (CBI) offers the following services:
- Understanding the role of imaging biomarkers in drug approvals
- Understanding the validation process and the role of new biostatistical tools
- Imaging biomarker consultation and education
- Assessing the development of new imaging agents
- Characterization of imaging techniques in terms of sensitivity, specificity, and reliability
Please feel free to contact us for additional information or to arrange an initial consultation (firstname.lastname@example.org).