Long Story Short – How have expedited drug approval programs shaped the biotech market?
Impact of FDA’s Expedited Drug Approval Programs on Biotech Industry
Food and Drug Administration (FDA) approval is mandatory for marketing drugs in the United States. Drug development is a scrutinizing and costly process for biopharmaceutical companies. It starts with the drug discovery/preclinical phase, which consists of screening compound libraries for a drug with positive activity. It could take up to 6 years to identify a lead drug. To start human clinical trials, the sponsor or the drug development company is required to file an “Investigational New Drug (IND)” application with the FDA. Only after the green light is given by regulators, human clinical trials with the drug can start. The clinical programs consist of three phases: Phase I, II and III human clinical trials. This extensive and costly process can last up to 7 years to complete, depending upon chosen indication (targeted disease) and other factors. Once the trials are finished, a “New Drug Application (NDA)” for drug commercialization is submitted for FDA review. It could take up to 2 years until a verdict is delivered. Hence, introducing a promising treatment into the marketplace is a laborious, expensive and time-consuming process (Exhibit 1).
Exhibit 1. Drug Discovery and Development Timeline
FDA introduced the Priority Review (PR) and Accelerated Approval (AA) programs in 1992 to expedite the availability of drugs for the treatment of serious conditions. In 1997 (in the wake of the AIDS crisis), the Fast Track (FT) program was introduced to quicken NDA filing for drugs targeting a life-threatening illness. In 2012, the FDA launched the Breakthrough Therapy (BT) program for investigational drugs targeting life-threatening illness and showing an improvement over available treatments. This improvement is measured using a clinically significant endpoint or endpoints, which are indicators of patients’ morbidity, mortality or severe symptoms of the targeted disease.
1. Priority Review (PR)
Following submission of an NDA application for approval of a drug as a treatment for neglected or rare pediatric diseases, the company or sponsor could apply for Priority Review (PR). The novel drug therapy must demonstrate a significant improvement in the effectiveness of the treatment, showing superior safety and efficacy. There has to be a significant improvement in the prevention, treatment, and/or diagnosis of the targeted disease.
For a sponsor to secure PR, the readout from early clinical trials must demonstrate significant improvement in safety and efficacy compared to standard available treatment. Once the PR voucher is obtained, the sponsor has the right to use it for the targeted disease, or alternatively, it could use it for another drug filing. The company could also monetize the PR voucher by selling it to another sponsor. The FDA aims to render a decision in 6 months instead of 10 months of standard review process with PR designation. In 2018, FDA has granted 60 PR designation, which represents 35% of total number of drugs approved in that year.
2. Accelerated Approval (AA)
Accelerated Approval (AA) allows the use of surrogate endpoints for a faster drug approval process for serious conditions that fill an unmet medical need. Clinical trial endpoints measure the outcomes (improvement in symptoms) in the trial, while surrogate endpoints measure the effect of a specific treatment that may correlate with real clinical endpoints. Surrogate endpoints do not represent direct clinical benefit, instead predict clinical benefit (e.g. tumor shrinkage can be used as a surrogate endpoint, where the endpoint is longer survival in clinical trials). Surrogate endpoints can be laboratory results, radiographic images, or physical signs to predict clinical benefit. AA does not necessarily shorten the standard 10-month review process, however, it allows FDA to start deliberating NDA much earlier within the drug’s development cycle, as early as Phase 2 stage (Exhibit 2). As displayed in Exhibit 2 (below), within the past 5 years the FDA has steadily increased AA designations to bring new drugs faster into the market. In 2018, 18 drugs (11% of total drug approvals compared to 5% in 2013) with AA designation were approved.
3. Fast Track (FT)
Fast Track (FT) designation works only for drugs that treat serious conditions filling the unmet medical need. FT can be granted if the drug shows significant advantage (efficacy or safety) over available options or if there is no available treatment for the target condition. To expedite development, companies with FT designated drug meet more frequently with FDA to discuss and coordinate clinical trial design, use of appropriate biomarkers (biological marker refers to a broad subcategory of medical signs – that is, objective indications of medical state observed from outside the patient). Drugs with FT designations can be eligible for AA or PR if relevant criteria are met (Exhibit 2). In 2018, the FDA has granted 33 FT which represented 19% of total drug approvals compared to 4% in 2013 (Exhibit 2).
4. Breakthrough Therapy (BT)
Breakthrough Therapy (BT) designations allow expedition of drug development to treat serious illnesses. BT is granted based on preliminary evidence of target drug demonstrating substantial improvement over available treatment. Advantages can be established from safety profile, surrogate endpoint, intermediate clinical endpoint, or changes in critical biomarkers. Drugs with BT designation are eligible for FT features and FDA guidance on efficient clinical development beginning as early as Phase 1 stage (Exhibit 2). FDA has dramatically increased drug approvals with BT designation from 3 in 2013 to 38 in 2018, which represents 3% and 22% of total drug approvals, respectively.
Exhibit 2. Summary of FDA’s Expedited Drug Approval Programs
Expedited programs rely on surrogate endpoints and limited clinical data compared to standard processes to bring treatment in the market faster for serious conditions with unmet needs. In 2019, a study published by JAMA Internal Medicine by Gyawali et. al. showed only 20% of 93 cancer drugs provided improvement in overall survival in post-approval trials, however other responses were improved (such as diseases control rate and quality of life). FDA emphasizes a robust safety profile to minimize introducing ineffective/harmful compounds in the market. Despite efforts, few drugs failed to demonstrate clinical benefit and/or safety in patients in post-approval mandatory confirmation trials. A key example of expedited failure is Lilly’s Lartruvo for soft tissue sarcoma, which received BT, FT, PR designations. Lartruvo received approval in 2016 based on preliminary readout from Phase 2 clinical study. Unfortunately, Lartruvo was retracted from the market due to a lack of improvement in overall survival compared to the standard of care in its post-approval Phase 3 trial. The regulatory agencies tightly control these expedited programs to minimize the risk of failure in the confirmatory studies.
To date, FDA’s expedited programs have been successful at speeding up the drug approval process. In a study that considered oncology approvals from 1992 to 2017, FDA reported that 55% of 93 drugs were validated for clinical benefit in post-approval trials, while 40% were still under post-approval evaluation and 5% were withdrawn. In light of these statistics, it can be concluded that the low failure rate in post-approval studies demonstrates the effectiveness of their expedited pathways. Based on statistics, these designations have helped patients with serious illnesses to receive effective treatment earlier than the regular path. Favorable success rates show that these programs have been valuable in the biotechnology sector. However, stringent assessments and selection of criteria (surrogate endpoints, biomarkers, etc.) are required to minimize failure in confirmatory studies. The advancements in research and genetic tools, as well as lessons learned from past failures, will provide a more defined path and improve the drug development and approval process.
Beaver et al. “A 25-Year Experience of US Food and Drug Administration Accelerated Approval of Malignant Hematology and Oncology Drugs and Biologics: A Review”. JAMA Oncology. 2018;4(6):849-856.
Gyawali et al. “Assessment of the Clinical Benefit of Cancer Drugs Receiving Accelerated Approval”. JAMA Internal Medicine. 2019;179(7):906-913.