Date of Award

January 2020

Document Type


Degree Name

Medical Doctor (MD)



First Advisor

Joseph S. Ross


The US Food and Drug Administration (FDA) is responsible for protecting public health by ensuring the safety and efficacy of drugs and biologics. One challenge for the FDA is establishing a balance between timely new drug access and patient safety through rigorous trial evidence. In response to its evolving needs, the FDA has created several programs to promote earlier availability of certain drugs and biologics, such as those for serious or life-threatening conditions. Notably, the FDA’s expanded access program was developed to allow patients with life-threatening conditions to access investigational medicines outside clinical trials, and the Breakthrough Therapy Designation was developed to expedite the approval of drugs that may offer significant advantages over existing therapies. Our purpose was to quantitatively examine how these programs have affected the timing of drug access, and in the case of the Breakthrough Therapy designation, how it has affected the FDA’s approval standards. First, to study expanded access programs, we performed a cross-sectional analysis of expanded access programs registered through August 1, 2017 on and identified key regulatory dates from publicly available FDA documents. Through, 92 FDA-approved drugs and biologics with associated expanded access programs initiated prior to FDA approval were identified. The median (interquartile range [IQR]) premarket expanded access availability was 10.0 (6.0-19.5) months, constituting a median (IQR) of 14% (7%-25%) of the premarket clinical development period (investigational new drug application activation to FDA approval). Of 92 expanded access programs, 64 (69.6%) were initiated just before or after new drug application submission: 24 (26.1%) were initiated during the 6-month period before, and 40 (43.5%) in the 6 months after. Next, to study the Breakthrough Therapy Designation, we identified all FDA approvals granted the Breakthrough Therapy Designation from January 2012 through December 2017. For each new therapeutic, we abstracted key regulatory dates as well as pivotal trial data supporting its approval. From 2012 through 2017, the FDA approved 46 therapeutics with Breakthrough Therapy designation on the basis of 89 pivotal trials. The median number of pivotal trials per indication approval was 1 (IQR, 1-2), and the median number of patients enrolled among all pivotal trials supporting an indication approval was 222 (IQR, 124-796). Among these approvals, 27 were made on the basis of pivotal trials using randomization (58.7%), 21 using double-blind allocation (45.7%), 25 using an active or placebo comparator group (54.3%), and 10 using a clinical primary end point (21.7%). Our findings suggest that the FDA’s expanded access program generally provides access to investigational medicines late in clinical development when evidence of safety and effectiveness has been established. In addition, our findings show that drugs approved through Breakthrough Therapy Designation are often based on weak clinical trial evidence, informing patients and providers about the safety and efficacy of these drugs as well as the need for rigorous postmarketing studies.


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