Since the Mid-2010s FDA Drug and Biologic Guidelines have been Growing at a Faster Clip than Prior Years: Is it Time to Analyze Their Effectiveness?

An Food and Drug Administration (FDA; Agency) guideline (which may include Guidance Document, Compliance Policy Guide (CPG), Small Entity Compliance Guide, Information Sheet, Good Review Practices, Special Controls Document, Industry Letter, Concept Paper, Manual or Memorandum)1 was instituted to present the Agency’s ‘current thinking around a certain topic (see 21 CFR 10.115,2^,3).’ From an industry perspective, these guidelines have been an important set of documents that may decrease the regulatory uncertainty (risk) around specific aspects of the drug discovery, development and delivery (DDDD) process. The content of these guidelines has varied, including recommendations on specific conditions/diseases, modalities, and compliance matters.

Since the first recorded drug or biologic FDA guideline (based the FDA data-repository that houses guidelines) was issued in September 1977, there has been an uptick in the number of issued guidelines (see Fig. 1 and Appendix for supportive data and analysis [2–10]). The increase in the number of guidelines may be due to several factors including the concomitant rise in the sophistication of science and technology supporting the DDDD process or the COVID-19 crisis, among others. On a per annum basis, time will tell if the total number of drug and biologic guidelines in 2021 will exceed the values in 2018 (132) or 2019 (145).

Figure 1.

The chronological number of US FDA (drugs/biologics) guidelines (actuals in gray; model in red) [All data presented in Electronic supplementary materials].

The number of COVID-19-related guidelines has also contributed to the recent upswing.4 From a guideline perspective, starting on March 18, 2020 and until Aug 06, there were 21 COVID-19-related FDA drug and biologics guidelines. Interestingly, this number may seem comparable with the 20 and 22 drug and biologic guidelines in the prior months (Jan and Feb, respectively), though the pre-COVID-19 guidelines covered an assortment of disease, platform and/or conduct of certain DDDD activities.

Albeit efforts have been underway to empirically test if guidelines facilitate approval of medicines, it is challenging to use statistical tests to ascertain true causality between the two (see [1]). Anecdotal evidence appearing in the literature suggest the importance of guidelines to the DDDD process. While there are reports critical of these guidelines (see, e.g., [12, 13]), and those advocating an opportunity for collaboration between developers and the FDA (see, e.g., [14]), there are examples of general successes in clarifying forward pathways (see, e.g., [15–17]). In some cases, there are explicit calls for guidelines; e.g., on endpoint selection for cancer cachexia [18, 19], or performing studies in cancer in the geriatric population [20].

Given the general interest and importance to the DDDD process, it is surprising that—to the author’s knowledge—there has not been a robust investigation detailing the effectiveness of the guidelines. For example, from a data economization perspective wherein a multipronged approach would be to think about a given guideline in terms of its ability for abstraction (how general is the concept?), for codification (how explicit can the text be (see, e.g., [21]), and for diffusion (is the guideline sufficient to convey all the important aspects of a topic) (see, e.g., [22]). Any effectiveness analysis should seek to also elucidate objective optimization parameters to optimize readability and understandability.

Beyond a general scientometric approach, there are several other avenues of research inquiry, such as:

• Assessing the impact of specific legislation related (and unrelated) to Prescription Drug User Fee Act constructs on the number of guidelines (and their effectiveness),

• Investigating trends in specific ‘types’ of guidelines (Guidance Document, Compliance Policy Guide (CPG), Small Entity Compliance Guide, Information Sheet, Good Review Practices, Special Controls Document, Industry Letter, Concept Paper, Manual or Memorandum),

• Investigating trends in ‘classes’ of guidelines: chemistry, manufacturing and controls (CMC), biomarkers, e-submissions, and so on,

• Comparing US with non-US guidelines (particularly, those of ICH countries) both in terms of specific content and trends (general, by class, by type).

The increase in the number of FDA guidelines has been most welcome as they provide an avenue to clarify Agency thinking on a given topic (specifically, the COVID-19 crisis). Additional work needs to be done to identify variables that may attest to its effectiveness and increase their utility for readers. It is only through mutual understanding that sponsors and global health authorities may expedite the DDDD process for the sake of patients everywhere; optimal drafting of guidelines is a critical component of the process.

Electronic Supplementary Material

Below is the link to the electronic supplementary material.

Compliance with Ethical Standards

Disclosures

The author is an employee of Takeda Pharmaceuticals; however, this work was completed independently of his employment. The views expressed in this article may not represent those of Takeda Pharmaceuticals. As an Associate Editor for Therapeutic Innovation and Regulatory Science, the author was not involved in the review or decision process for this article. For data and methods to reproduce Fig. 1, see Electronic supplementary material.