Examination of Clinical Trial Costs and Barriers for Drug Development. 4.5.5 Lack of Clear Regulatory Pathways and Guidance for Some Therapeutic Areas


Sometimes, not having a clear idea of what FDA requires is the fault of companies, who might avoid meeting with FDA early in the process, perhaps out of fear of hearing bad news that must then be shared with their investors. However, industry representatives assert that, in many cases, much of the responsibility for failed communication and unclear expectations rests with FDA.

While the regulatory pathways for some therapeutic areas, such as oncology and cardiovascular disease, are well-established, the requirements remain much less clear for other, more “cutting edge” areas, like central nervous system disorders, metabolic diseases, and biosimilars, for which there is little in the way of precedent. In disease areas where guidelines are nonexistent, old, or otherwise lacking, sponsors find it difficult to understand what FDA expects of them before beginning their studies, and the process can result in lengthy back-and-forth discussions and negotiations with reviewers. Such a situation is both inefficient (as each individual company must take the time to seek out information or negotiate the requirements on its own) and unpredictable (as reviewers may change their minds over time).

According to one CRO representative, some drugs fall between the cracks of other regulatory pathways because they are intended to treat diseases that are exceptionally rare or sporadic. While the orphan drug pathway is appropriate for conditions affecting fewer than 200,000 patients, there are some conditions affecting only a few hundred patients that might be effectively treated with a new drug. The barriers to developing a drug for such conditions are substantial; from a regulatory perspective, it is similar to developing a drug for millions of patients, despite the fact that enrollment and other aspects of the process are much more difficult. The interviewee noted that, while there were cases in which FDA had been flexible and helped an important treatment to reach patients (e.g., Botulism Immune Globulin, or “BabyBIG”), there have been other instances where drugs have been dropped because the regulatory barriers were not adjusted. By existing rules, it seems infeasible to sponsors to test a treatment for Escherichia coli (E. coli), for example, as not enough patients can be found who become ill with hemolytic uremia to test the drug. While FDA’s Animal Rule allows sponsors to demonstrate effectiveness in animals, it has only been used a few times (e.g., anthrax).

For therapeutic areas where guidance is lacking, FDA often takes a long time to issue and update guidances. While FDA has undertaken some positive initiatives recently (e.g., starting to issue new guidances, including draft guidance for biosimilars; examining guidances for skin and pneumonia; considering guidances for unmet need pathogens; and considering new approval pathways for pathogens that would require more restrictive labeling and be for more limited populations), these processes can be very slow from industry’s perspective.

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