Statistical Challenges with the Advances in Cancer Therapies
Statistical challenges in designing, analyzing and interpreting the data are being encountered with the recent development of new classes of drugs to treat cancer. The existing paradigm of drug development from Phase I to Phase III clinical trials is not
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Abstract Statistical challenges in designing, analyzing and interpreting the data are being encountered with the recent development of new classes of drugs to treat cancer. The existing paradigm of drug development from Phase I to Phase III clinical trials is not optimal. New and innovative trial designs and statistical methods are needed to evaluate the new classes of drugs. In this chapter we present the regulatory considerations in the evaluation of drug products, the drug development paradigm in the last century and the current time, and the statistical challenges that need to be addressed. keywords Regulations
Cancer drug development paradigm Immunotherapies
1 Regulatory Considerations With the signing into law of the Kefauver-Harris Drug Amendments to the Food and Drug Cosmetic Act in 1962, drug manufacturers were for the first time required to prove to the US FDA the effectiveness of their products before marketing them [1]. This amendment was intended to ensure both drug efficacy and safety, and gave a statistical framework for conducting clinical trials to prove the effectiveness of drug products. Section 505(d) of the Food and Drug Cosmetic Act [2, 3] as amended states that “…evidence consisting of adequate and well-controlled investigations, including clinical investigations, by qualified scientific experts, that proves the drug will have the effect claimed by its labeling …”. This statement has been used as the regulatory standard for establishing evidence and interpreted to mean the following: the evidence should be reproduced in at least two independent studies, the probability of one-sided type I error should be controlled at a threshold of 0.025, a clinically meaningful treatment effect should in general be established R. Sridhara (&) Office of Biostatistics, Center of Drug Evaluation and Research, US Food and Drug Administration, Silver Spring, MD 20993, USA e-mail: [email protected] © Springer Nature Singapore Pte Ltd. 2017 S. Matsui and J. Crowley (eds.), Frontiers of Biostatistical Methods and Applications in Clinical Oncology, DOI 10.1007/978-981-10-0126-0_2
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even if the results are statistically significant, and the product should have an acceptable risk-benefit profile. Two decades later, in 1981, the FDA and the Department of Health and Human Services revised the regulations for the protection of human subjects, detailing the contents of informed consent and widening the representation in institutional review boards. Another landmark in the history of the FDA was the publication of regulations in 1991 establishing a new path to accelerate the review of drugs for life-threatening diseases. Today we have two regulatory pathways for marketing approval of drug products: regular or traditional approval and accelerated approval. The regular approval decision is based on demonstrated clinical benefit of the drug product, for example, improved overall survival in cancer patients compared to placebo, or on an outcome that clearly benefits a patient, such as an improvem
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