In an article published in June 2018 in JAMA Oncology, the FDA reviewed their accelerated approvals for malignant hematology and oncology drugs over the previous 25 years. In an earlier post, we reviewed the accelerated approval pathway. This expedited option is for drugs that provide a meaningful advantage over available therapies for serious conditions. The approval decision via this pathway is based on surrogate endpoints (as opposed to established clinical benefit). This pathway, although essential for speeding up the process of clinical drug development in serious conditions, requires extensive post-marketing studies and has met some criticism for its acceptance of certain surrogate endpoints. Surrogate endpoints (or surrogate markers) are measures of effect for specific treatments or drugs in clinical trials. A surrogate endpoint may correlate with a real clinical effect/endpoint but does not necessarily guarantee a relationship. The National Institutes of Health defines surrogate endpoint as “a biomarker intended to substitute for a clinical endpoint.” According to the FDA’s review, out of 93 accelerated approvals, 37 (40%) of the drugs had not completed post-marketing studies or confirmed clinical benefit, and 5 (5%) were pulled from the market due to an inability to verify clinical benefit. In this post, we’ll review the use of surrogate endpoints for accelerated approval and discuss some of their critiques.
Choosing the Right Endpoint and Proving its Value
For serious conditions, using surrogate endpoints to evaluate the efficacy of a drug instead of waiting to evaluate its effects on irreversible morbidity and mortality allows a drug with a meaningful advantage over available therapies to reach the market faster than waiting for a more standard efficacy endpoint. For example, it takes far less time to see whether a drug shrinks a single tumor than to determine whether the drug improves the survival of a cancer patient. Choosing the right surrogate endpoint and proving that it can predict the intended clinical benefit, however, is not always straightforward. When a disease has been sufficiently studied, surrogate endpoints can measure the underlying cause of a disease (such as low thyroxine levels and hypothyroidism) or an effect that predicts the ultimate outcome (such as measuring diuresis, which is expected to improve symptoms of heart failure). The FDA keeps a list of surrogate endpoints that have been the basis of drug approval or licensure on its website. Many diseases, however, manifest from an amalgam of physiological defects and defy our ability to identify an uncomplicated surrogate endpoint. Biomarkers, although an attractive option, may not always be the best surrogate endpoints. Even biomarkers that are well-established may not be able to predict clinical benefit, or their ability to predict benefit may vary depending on the disease or intervention. For example, increased levels of prostate-specific antigen (PSA) may be the result of advancing tumor burden, but the relationship between PSA and disease progression is not uniform, and therefore cannot be relied upon to predict a drug’s clinical benefit. In their 2014 guidance, Expedited Programs for Serious Conditions – Drugs and Biologics, the FDA stated that pharmacologic activity alone is insufficient to support a relationship between surrogate endpoint and clinical outcome. They did not address the specific clinical evidence needed to support such a relationship, since each case is necessarily specific and ungeneralizable. They did, however, suggest several factors to consider when identifying and assessing a surrogate endpoint:
- Is there reliable and consistent epidemiologic evidence supporting the link between the endpoint and clinical benefit (such as the large number of studies demonstrating the link between lowering blood pressure and reducing the risk of stroke)?
- How strong is the correlation between the endpoint and the clinical outcome?
- Has the endpoint been shown to predict a clinical benefit with a different drug?
Determining whether an endpoint can stand in for real clinical benefit will almost always be a matter of judgement. Making that judgement will depend on the depth and breadth of the epidemiological, pathophysiological, therapeutic, and pharmacologic evidence provided and the overall benefit:risk to patients with the disease of interest.
Confirmatory Trials
After a drug is granted accelerated approval, the Sponsor must conduct post-marketing confirmatory trials as soon as possible to determine conclusively whether or not the drug provides a clinical benefit. Ideally, these trials will already be underway at the time of approval, but at the very least, there should be agreement between the FDA and the Sponsor on the design and conduct of the trials at the time of approval. Generally, the confirmatory trials should evaluate clinical benefit in the same population used to support accelerated approval. In some instances, such as cancer, the confirmatory trials may enroll patients at an earlier stage of the disease. If the confirmatory trials fail to demonstrate a clinical benefit or show that the product is unsafe, the FDA can withdraw approval of the drug.
Criticism
The use of surrogate endpoints for the accelerated approval of oncology drugs has been criticized by many in the scientific community (for an example, see Kemp and Prasad, 2017). The argument against their use is that there is an uncomfortable lack of evidence of a correlation between most surrogate endpoints and overall survival. Some analyses of oncology drug approvals based on surrogate endpoints reveal that less than 6% of them use endpoints that are highly correlated with survival (R≥0.85) (Kim and Prasad 2017). Other important clinical drug development issues become apparent when a drug is approved based on a surrogate endpoint. The most important issue is that it may become less ethical to study the drug in a placebo-controlled setting (thus, making it difficult to assess whether adverse events are related to the drug or the disease). In addition, patients are less likely to enroll in a clinical trial when a drug is more readily accessible.
Conclusions
Balancing the FDA’s responsibility to ensure public safety with their desire to accelerate patient access to new treatments is a difficult task that relies on the availability of epidemiological, pathophysiological, therapeutic, and pharmacologic evidence that links a surrogate endpoint with clinically relevant efficacy endpoints (e.g., mortality). The success of this approach requires multidisciplinary cooperation across sectors (e.g., academia, industry, government) and will only occur when the benefit outweighs the risks to patients with serious diseases having a high unmet medical need. Are you considering attempting to get accelerated approval with surrogate endpoints for your own drug development program? Contact Allucent to learn how our consultants can help you ensure scientifically defensible and informative endpoints for your clinical studies.
References and Additional Resources
- Beaver JA, Howie LJ, Pelosof L, Kim T, Liu J, Goldberg KB, Sridhara R, Blumenthal GM, Farrell AT, Keegan P, Pazdur R, Luetz PG. A 25-Year Experience of US Food and Drug Administration Accelerated Approval of Malignant Hematology and Oncology Drugs and Biologics – A Review. JAMA Oncol. 2018;4(6):849-856. doi:10.1001/jamaoncol.2017.5618
- Kemp R, Prasad V. Surrogate endpoints in oncology: when are they acceptable for regulatory and clinical decisions, and are they currently overused? BMC Medicine201715:134 doi.org/10.1186/s12916-017-0902-9
- Kim C, Prasad V. Strength of Validation of Surrogate End Points Used in the US Food and Drug Administration’s Approval of Oncology Drugs. Mayo Clin Proc. 2016 May 10 : S0025-6196(16)00125-7. doi: 10.1016/j.mayocp.2016.02.012
- Surrogate Endpoint Resources for Drug and Biologic Development. U.S. Food and Drug Administration website
- Table of Surrogate Endpoints That Were the Basis of Drug Approval or Licensure. U.S. Food and Drug Administration website
- Considerations for Discussion of a New Surrogate Endpoint(s) at a Type C PDUFA Meeting Request
- Clinical Trial Endpoints for the Approval of Cancer Drugs and Biologics – Guidance for Industry. December 2018
- Expedited Programs for Serious Conditions – Drugs and Biologics – Guidance for Industry. May 2014