Yassine Kamal Lyauk, Daniël M. Jonker, Trine Meldgaard Lund
University of Copenhagen and Ferring Pharmaceuticals A/S
Introduction
The highest prevailing reason for non-approval of new molecular entity (NME) applications by the US Food and Drug Administration (FDA) between 2000 and 2012 was uncertainty regarding the adequacy of proposed marketing dose(s) [1]. Furthermore, post-marketing changes to the label dosage have occurred in 21% and 18.2% of FDA-approved drugs in the period of 1980 to 1999 [2] and 2000 to 2014 [3], respectively. These reports highlight the importance of dose finding and benefit-risk assessment for obtaining and maintaining regulatory drug approval.
We have characterized the dose finding process in the clinical development of drugs recently approved by the FDA and compared our findings to concepts rooted in Lewis B. Sheiner’s Learning versus Confirming paradigm [4]. Central in this paradigm are two learn-confirm cycles, with the first cycle confirming the efficacy of the highest tolerable dose of the drug in a small patient trial. In the second cycle, an adequately designed dose-ranging trial informs the dose for which benefit-risk is to be confirmed in a large study.
Objectives
- To investigate the clinical development paths, dose-ranging trial design, and dose-exposure response characterization, which formed the basis for label dose identification in drug development programs.
- To compare these to the concepts of Learning and Confirming.
Methods
60 drugs approved by the FDA between February 2015 and February 2017 were included for review following search of approval packages on the Drugs@FDA website [5]. All information available from the published FDA reviews was used to identify clinical trials relevant for dose finding. Clinical development programs were categorized based on initiation in healthy volunteers or in patients, and clinical trials were classified as exploratory or confirmatory. The number of doses studied in each of these stages was summarized, distinguishing between exploratory first-in-patient (FIP) trials and exploratory post-FIP trial(s). For exploratory dose-ranging trials, both the number of doses and dose range was summarized. Lastly, any information available regarding assessment of dose-exposure-response in FDA approval packages was retrieved.
Results
In terms of clinical development paths, 89% of development programs included several doses in the FIP trial, 43% proceeded directly from the FIP trial to confirmatory trials, and 52% included multiple doses in confirmatory development. The number of doses in exploratory development was found to be significantly higher for development programs with a single dose in confirmatory development compared to programs with multiple doses (median 6 vs. 4, p = 0.004). The median ratio of the number of doses in exploratory to confirmatory development was 2:1 for programs initiated in healthy volunteers and 5:1 for programs initiated in patients. Only 20% of dose-ranging trials included at least four investigational drug doses over an at least 10-fold dose range. Lastly, in a third of approval packages, no dose-response or exposure-response evaluation was identified, and model-based dose-exposure-response was alluded to in only two of 60 approval packages.
Conclusions
Results indicate that i) in many cases confirmatory development leans more towards learning than confirming as multiple doses are commonly included in this stage, questioning sponsors’ certainty of drug benefit/risk when initiating confirmatory development, ii) learning in dose-ranging trials may often be limited due to the low number of doses and dose range included, the latter presumably affecting the extent to which model-based analysis can be meaningfully applied and iii) dose-exposure-response appears to be robustly assessed in only a minority of clinical drug development programs, suggesting there may be room left for optimizing the benefit-risk profile of confirmatory/marketed dose(s).
References:
[1] Sacks, L. V., Shamsuddin, H. H., Yasinskaya, Y.I., Bouri, K., Lanthier, M. L. & Sherman, R.E. Scientific and regulatory reasons for delay and denial of FDA approval of initial applications for new drugs, 2000-2012. JAMA 311, 378–384 (2014).
[2] Cross, J., Lee, H., Westenlick, A., Nelson, J., Grudzinskas, C. & Peck, C. Postmarketing drug dosage changes of 499 FDA-approved new molecular entities, 1980-1999. Pharmacoepidemiol. Drug Saf. 11, 439–446 (2002).
[3] Duong, A. H. Abstract M-08 Postmarketing Drug Dosage Changes of 413 FDA-approved New Molecular Entities, 2000-2014. DIA 2017, Chicago, IL, United States; <https://www.diaglobal.org/en/flagship/dia-2017/program/posters/Poster-Presentations> (2017) Accessed June 11, 2018
[4] Sheiner, L. B. Learning versus confirming in clinical drug development. Clin. Pharmacol. Ther. 61, 275–291 (1997).
[5] US Food and Drug administration. Drugs@FDA: FDA Approved Drug Products. <https://www.accessdata.fda.gov/scripts/cder/daf/> (1997) Accessed June 8, 2018
Reference: PAGE 28 (2019) Abstr 9068 [www.page-meeting.org/?abstract=9068]
Poster: Methodology - Other topics