Even if a CVD therapeutic is developed relatively rapidly, large and/or lengthy clinical trials are required. Consider the development of Praluent (alirocumab), a CVD therapeutic developed by Sanofi and Regeneron Therapeutics. Phase I trials began in 2011, and FDA approval occurred in 2015.

Each oval represents a completed clinical trial. The left and right edges approximate the years the trial started and ended. The number of participants in each trial are shown in white. The dark green ovals are for hypercholesterolemia trials; the light green oval is for the ODYSSEY OUTCOMES study.

The approach of focusing on a narrow indication (in this case, hypercholesterolemia) has been advocated by many as a way to speed up market entry.7 In the ODYSSEY OUTCOMES study, 18,924 subjects were enrolled, which helped the developers garner FDA approval for Praluent’s use in atherosclerotic cardiovascular disease in 2019. Not to be outdone, Amgen enrolled 27,564 participants in its FOURIER study for Repatha (evolocumab), Praluent’s competitor product, so that Repatha could gain FDA approval for dyslipidemia (abnormal levels of blood lipids). The quest for Praluent’s approval in major international markets (United States, Europe, Japan) has so far required 29,702 participants.

A clinical trial snapshot for the CVD therapeutic diagram
A clinical trial snapshot for the CVD therapeutic known as Praluent (alirocumab). Praluent was developed by Sanofi and Regeneron Therapeutics to target PCSK9 and reduce “bad” cholesterol.

I propose that each regulatory agency should be required to factor in the size and/or length of the clinical trials they relied on for approval in a particular indication and “compensate” by adding to the period of exclusivity for that indication after patent expiration in that jurisdiction.

Phase I trials (blue) are designated according to location, to highlight the multinational nature of even a simple safety study. Phase II trials (purple) are designated by their NCT number in ClinicalTrials.gov with the “NCT” removed for brevity. Phase III trials (green) are designated by the nomenclature used by Sanofi. The term “ODYSSEY” that was applied to all of these clinical trials was removed for brevity (that is, “ODYSSEY JAPAN” is simply “JAPAN”). (Data obtained from ClinicalTrials.gov accessed on February 26–28, 2021.)

See the main article accompanying this one at It’s Time to Give the World’s Deadliest Disease Orphan Status.



1. Fordyce, C.B. et al. Cardiovascular drug development: is it dead or just hibernating? J. Am. Coll. Cardiol 65, 1567-1582 (2015).

2. Thomas, D. & Wessel, C. The state of innovation in highly prevalent chronic diseases; Volume V: Systemic hypertension and congestive heart failure. in Highly Prevalent Chronic Disease Series 1-23 (BIO Industry Analysis, 2020).

3. Downing, N.S., Aminawung, J.A., Shah, N.D., Krumholz, H.M. & Ross, J.S. Clinical trial evidence supporting FDA approval of novel therapeutic agents, 2005-2012. JAMA 311, 368-377 (2014).

4. Wood, S. Glory—Is cancer beating cardiovascular disease? Medscape (2011)

5. European Medicines Agency. Rare diseases, orphan medicines: Getting the facts straight. Report No.: EMA/551338/2017 (London; 2018).

6. Fidler, B. A record number of biotechs are going public. Here’s how they’re performing. Accessed on June 26, 2021. 

7. Jackson, N. et al. Improving clinical trials for cardiovascular diseases: a position paper from the Cardiovascular Round Table of the European Society of Cardiology. Eur. Heart J 37, 747-754 (2016).

8. Eder, J., Sedrani, R. & Wiesmann, C. The discovery of first-in-class drugs: origins and evolution. Nat. Rev Drug Discov 13, 577-587 (2014).

9. Aitken, M. & Kleinrock, M. Orphan drugs in the United States (IQVIA Institute for Human Data Science) 1-25 (2018).


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