Examination of Clinical Trial Costs and Barriers for Drug Development. 4.5.6 Barriers Related to the Review Process


The expert consultants and drug company and CRO representatives interviewed acknowledged the difficulty of FDA’s position, as the Agency faces conflicting pressures from Congress and industry and must balance the need for scientific evidence with the need for timely access to the new drug. Most respondents commented that FDA is consistently understaffed and underfunded, and the resources it does have at its disposal are stretched too thin.

Nonetheless, there were some specific concerns shared by the interviewees regarding the regulatory review process at FDA. One issue that was frequently mentioned was the perceived concentration of too much responsibility and power in the hands of individual reviewers. When most of the burden of decision-making is borne by a single reviewer, that reviewer will bear full responsibility if something goes wrong; thus, he or she might be more risk averse than a group of individuals across whom responsibility is spread evenly. Anecdotal evidence suggests that junior reviewers might be particularly risk averse, while veteran reviewers might be inflexible. Additionally, turnover among reviewers becomes problematic, as it can take quite a long time to get a new reviewer up to speed. Such a system makes company representatives feel that their outcomes are subject to the whims of the individual reviewer and his or her personal feelings about a particular drug or company. Consequently, some respondents expressed a preference for the European regulatory review system, which involves multiple academic experts to reach a scientific consensus. While the FDA does use an advisory board, the interviewees felt that it is involved too late in the process, and its authority is too weak to overrule the reviewer’s decision.

Another common grievance among interview respondents was the difficulty of getting timely feedback from FDA. Though a recent New England Journal of Medicine article found that FDA reviewed applications involving novel therapeutics faster, on average, than the European Medicines Agency (EMA) or Health Canada (Downing, et al., 2012), many sponsors interviewed by ERG felt that there was still room for improvement in the efficiency and predictability of communication. There is a perception in the industry that FDA is becoming more bureaucratic and seeking to formalize all processes--making communication increasingly cumbersome. Rather than being able to contact the relevant FDA reviewers directly, companies say they must first go through project managers, fill out written requests, and complete other intermediate steps. While investigational new drug (IND) timelines are considered acceptable (feedback is received within 30 days), receiving feedback in the post-IND or review periods can take a long time.

A final oft-repeated refrain among industry representatives is the lack of consistency among reviewers and divisions within FDA’s Center for Drug Evaluation and Research (CDER). Respondents believed there to be appreciable variability across divisions at FDA in responsiveness, scientific expertise, flexibility, and openness to meetings. For example, it was mentioned that the Division of Cardio-Renal Drug Products has a reputation for being particularly innovative and flexible relative to other divisions, while Metabolism and Endocrinology Products and Pulmonary, Allergy, and Rheumatology Products are perceived as divisions where drugs are more likely to be delayed. Interviewees indicated that there are good scientists at FDA, but they are scattered across different departments, and the overall scientific caliber of reviewers could be improved to ensure better consistency.

A newly published study by Tufts CSDD explores the issue of consistency among the various FDA drug review divisions using data on new molecular entity (NME) New Drug Applications (NDAs) and “new” Biologic License Applications (BLAs) from the period between 2006 and 2010 (Milne & Kaitin, 2012). The authors outline the various factors that contribute to disparities in regulatory experiences on both the industry side (including therapeutic area, technology turnover, investment levels, and experience/expertise of the sponsor) and FDA side (including staffing levels, organizational changes, workload fluctuations, leadership, advisory committee dynamics, and political pressures). According to the study, there are substantial differences among divisions in terms of staff, workload, approval times, rates of clinical holds ordered on commercial INDs, the percentage of products for which an advisory committee meeting is held, NDA approval rates, and other measures. Confirming what was said in our interviews with industry representatives, the Metabolism & Endocrinology and Respiratory/Rheumatology divisions were indeed found to have exceptionally high rates of clinical holds relative to other divisions.


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