#HEORInsights

Drug development is a challenging and time-consuming procedure. An unmet medical need is a condition, the cure or diagnosis of which is not being addressed effectively by currently available therapies. To meet such an unmet medical need and treat severe diseases, Fast Track approval process has been introduced by Food and Drug Administration (FDA), which is intended to ease the development and quicken the review of drugs.

The expedited review processes are fast-track approval processes, in which a new chemical moiety (drug) can be approved based on its efficacy, proven from single phase 2 clinical trial. The review process is usually completed within 180 working days, (1) There are four expedited or conditional pathways for novel products for serious diseases or unmet medical needs. Twenty-eight of the 2017 novel drug approvals (61%) were selected in one or more of the following expedited categories (3).

1. Fast Track (FT) Designation – Designed to expedite the review of drugs, to be used to treat serious conditions
2. Breakthrough Therapy Designation (BTD) – Designed to accelerate the development and review of drugs, that may demonstrate substantial improvement over available therapy
3. Priority Review (PR) Designation – Designed to take action on any application within 6 months by FDA
4. Accelerated Approval (AA) Pathway – Allows drugs to be approved based on a surrogate endpoint (2)

Drug approval is a process that involves risks, firstly for the people who participate in the trials and secondly for them, who will be taking the drugs once they are granted approval. Although fast-track processing of drugs expedites earlier access of drugs that are urgently needed for the society, it also may undermine safety aspect of them as well. Expedited approval has several critics who feel that it challenges the safety and approving a drug solely on the basis of trivial information is non-scientific and unethical (3). From 1988 to 2010, some of the fast-track products have gone unpredicted and withdrawn. The historical disasters involving drugs such as Elixir Sulfanilamide and modern COX-2 inhibitors are well known. Both were approved following fast-track designation and the latter caused an increase in cardiovascular events. (4)

US-FDA approved 7 molecules of dipeptidylpeptidase IV inhibitors and SGLT inhibitors for diabetes between 2011 and 2014, which are now proven to cause serious adverse reactions like severe mouth ulcers, renal impairment and angioedema. In this case, there was no question of justifying an unmet need, and FDA has not explained why these molecules did not undergo regular scrutiny and were, instead, given accelerated approval. Strict analysis should be required in the pre-marketing phase itself, for the drugs for non-communicable diseases, instead of giving them accelerated approval (5, 6).

Most countries in Asia grant ‘preferential review’ to drugs approved by regulators in US and Europe, so expedited approval in these regions potentially interprets into world-wide approval of a given drug. Said that, expedited review should be considered, when the new molecule is really expected to treat a disease with no cure, or when there is sufficient data of post-marketing surveillance supporting the efficacy and safety of the other molecule of the same drug class. The manner in which these drugs are proven as “non-inferior” to the standard treatment, also needs to reconsidered, as even such a non-inferior molecules may have adverse effects and high cost implication. (7, 8) In malignancies with very poor prognosis, the statistical significance of an increase in survival from a fast-track process must be matched with clinical benefits.Approval based only on surrogate markers should be reconsidered as well. Also, regulatory authorities should be more vigilant about undue or fallacious evidence-based information by pharmaceuticals. (9-12)

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References:

1. Fast Track, Breakthrough Therapy, Accelerated Approval, Priority Review [Internet]. US Food and Drug Administration 
2. Liberti L, et al. FDA facilitated regulatory pathways: Visualizing their characteristics, development, and authorization timelines.  Front Pharmacol. 2017; 8:1-6.
3. Center for drug evaluation and research advancing health through innovation 2017 new drug therapy approvals
4. Recalls, Market Withdrawals & Safety Alerts. U.S. Food and Drug Administration.
5. Longo DL, et al. PART 7: Oncology and Hematology. In: Harrison’s Principles of Internal Medicine. 18th ed. New York, USA: McGraw Hill Education; 2011; pp.646-1003.
6. Chary KV. Expedited drug review process: Fast, but flawed. J Pharmacol Pharmacother. 2016; 7:57-61.
7. Schumi J, et al. Through the looking glass: Understanding non‑inferiority. Trials 2011; 12:106.
8. Hahn S. Understanding noninferiority trials. Korean J Pediatr 2012; 55:403‑7.
9. Johnson EP. Pros and cons of the new drug application fast track review process. Clin Res Educ 2009.
10. Leonard CE, et al. Utilization and cost of anticancer biologic products among Medicare beneficiaries, 2006-2009: Data Points #6. 2011.
11. In: Data Points Publication Series [Internet]. Rockville (MD): Agency for Healthcare Research and Quality (US); 2011‑. Available from: http://www.ncbi.nlm.nih.gov/books/ NBK65148 26. Osoba D. Health‑related quality of life and cancer clinical trials. Ther Adv Med Oncol 2011; 3:57‑71.
12. Marx RE. The deception and fallacies of sponsored randomized prospective double‑blinded clinical trials: The bisphosphonate research example. Int J Oral Maxillofac Implants 2014, 29:37‑44.