By Amy McKee, Vice President Regulatory Consulting Services, Parexel
Among biotech companies, a primary concern is how to establish a clinical strategy for scientific and commercial success at the earliest stage. In that respect, regulatory considerations figure prominently. In my work at Parexel, and in 11 years in oncology development at the U.S. Food & Drug Administration (FDA), I learned that there are many common misconceptions about working with the FDA. By debunking these myths, I hope to help set up more companies for success in bringing new oncology therapies to patients in need.
Myth #1: The FDA gives all new products accelerated approval based on a Phase 1/2 trial.
In fact, regular approvals far exceed accelerated approvals: from 2016 to 2019, there were 115 regular approvals versus 39 accelerated approvals for new molecular entities.
Myth #2: The FDA requires two randomized trials with overall survival as the endpoint, allows enrollment only of U.S. patients, and does not permit crossover within the pivotal trial.
This represents a lot of related myths rolled into one. Let’s break them down:
- While the two-trial requirement is generally the rule at FDA, oncology is one exception; one pivotal trial is usually adequate for an approval due to the serious nature of the disease and unmet medical need.
- There is no requirement to conduct a trial in the U.S. population. However, the trial population must be relevant to the U.S. population, especially in terms of previous and subsequent available therapy.
- The FDA does not agree or disagree with crossover in a clinical trial; the question is whether the sponsor wants to take the risk. Thus, there are key questions to ask before writing crossover into a protocol.
Myth #3: The FDA and the industry agree that more is always better for dosing in an oncology setting.
This concept dates to the chemotherapy era when cell kill was the goal. But monoclonal antibodies and cellular therapies often do not reach a maximum tolerated dose (MTD) level. The FDA emphasizes that MTD designs are not optimal and encourages adaptive designs with better biomarkers for dose-finding.
Myth #4: FDA advisory committees such as the Oncologic Drugs Advisory Committee (ODAC) are the final decision-makers in drug approval.
The ODAC is an advisory body whose role is to give unbiased advice and to publicly discuss certain thorny applications for the Agency. The way the ODAC votes does not always align with the FDA decision.
Myth #5: The FDA determines the cost of anticancer agents.
The FDA has no regulatory decision-making over the cost of a drug. The FDA only reviews scientific data to determine whether a drug should be approved based on the risk/benefit ratio.
Myth #6: The FDA will reject oncology clinical trials where there is discordance between the investigator’s and the blinded independent review committee’s (IRC) assessment of radiology scans.
Actually, discordance between the investigator and IRC assessments is expected and frequently occurs in up to 30% of subjects in an individual trial., We recommend discussing the IRC methodology to be used in the pivotal trial with the FDA at the beginning of the study.
Myth #7: The FDA has never granted a marketing approval using real-world data (RWD) as evidence of efficacy for the investigational product.
While the FDA remains hesitant to explicitly describe real-world evidence (RWE) in labeling, and guidance is not yet published, multiple examples exist where RWD/RWE has influenced regulatory decision-making, including providing the primary evidence to support safety and effectiveness for a new indication.
Myth #8: The FDA chooses to withhold its reasons for a negative review and non-approval of a drug.
Reviews and approval letters are public information and are posted on the FDA website . Note, however, that the FDA is not legally permitted to post reviews or letters to the applicant for products that do not receive approval.
Myth #9: The FDA does not use the expedited programs available to speed drug development for promising therapies.
The FDA offers several expedited programs, each with different criteria and features. The general objective is to provide pathways for drugs used to treat serious illnesses that show promise in early trials.
Myth #10: Regulatory agencies act independently of one another.
Not true! Under a confidentiality agreement, the FDA holds a monthly teleconference with peers including the EMA, Health Canada, Japan's PMDA, Australia's TGA and Swiss Medic.
For much more on the FDA, along with additional insights from my colleagues on the Parexel team, please listen to the webinar, “Roadmap for Oncology Drug Development,” available here.
Teaming Up with Parexel Biotech
Parexel Biotech is a division of Parexel that offers the essential services biotech companies require to advance through their drug development journey. Our lean operational structure, flexible processes, and focus on the patient all work together to bring our biotech customers the comprehensive regulatory, commercialization and operational expertise necessary to succeed. Your goal is to save lives. Our goal is to make that easier.
 Food & Drug Administration (FDA). Hematology/Oncology (Cancer) Approvals & Safety Notifications. Available at: https://www.fda.gov/drugs/resources-information-approved-drugs/hematologyoncology-cancer-approvals-safety-notifications Accessed August 2020.
 Dodd LE, et al. “Blinded independent central review of progression-free survival in phase III clinical trials: important design element or unnecessary expense?” J Clin Oncol. 2008 Aug 1;26(22):3791-6. doi: 10.1200/JCO.2008.16.1711
 Zhang JJ, et al. “Evaluation of blinded independent central review of tumor progression in oncology clinical trials: a meta-analysis.” Drug Inf J 2013. 47.167-74. doi: 10.1177/0092861512459733