A new drug application (NDA) is submitted by the Sponsor company when the Sponsor intends to market the drug in the United States. An NDA should include crucial information such as drug manufacturing process, drug pharmacokinetics and pharmacodynamics, as well as all relevant human and animal research data.1 In addition, the application should have details such as labeling, directions for use, patent application information, safety updates, data from trials conducted outside USA, and compliance to IRB/IEC. The FDA will refuse to accept any NDAs that do not furnish complete and accurate data.2
Role of FDA in drug approval
The primary role and priority of FDA is to ensure that new drugs or devices are safe and effective for public use. With the increasing burden of chronic diseases, FDA understands the urgency to expedite the time taken from pre-clinical trials to approval for new drugs and devices.3
Steps involved in NDA review
Pre-NDA meet: The Sponsor company representative team and the FDA meet before submission of a NDA for what is called the pre-NDA meeting. The Sponsor submits a briefing document containing the discussion points well in advance to the FDA. This document contains manufacturing data, drug indication along with data from previous studies. In case the FDA has additional or specific questions, these questions are sent to the Sponsor 24 to 48 hours before the scheduled pre-NDA meeting.1,4
NDA application and review: The Sponsor submits the NDA within 30 calendar days after the pre-NDA meeting for approval by FDA. FDA, in turn, has 60 days to file the NDA for review. Once the NDA is filed, the FDA review team begins to evaluate all steps taken by the Sponsor to prove the safety and effectiveness of the drug, taking anywhere between 6 to 10 months to decide on whether the drug should be approved or not. Some of the processes involved are expert review of data from animal studies and at least two Phase III clinical trials demonstrating drug safety and efficacy, site inspection of manufacturing facilities, inspection of clinical trial sites, as well as monitoring to check if any data has been fabricated or withheld.3,4,5,6 The review team records all observations and submits details of the inspection to a senior FDA official for approval.7
Approval of NDA: Once the drug has been approved by the FDA, the relevant FDA expert will contact the Sponsor team to inspect the labeling information of the drug before marketing. In addition, all queries raised by the FDA on existing data have to be answered before marketing of the drug.7
Denying approval of NDA: FDA is authorized to deny an NDA due to safety and quality control issues such as lack of efficacy of drug contrary to submitted data, or due to defects in the manufacturing process that can potentially lead to drug instability. FDA can also deny approval of NDA citing the need for additional studies to cover aspects such as the effect of the drug on a broader population or to understand the effect of the new drug when administered for a prolonged period.7
Accelerated Approval processes for NDA
For life-threatening diseases that have no effective treatments options, FDA can accelerate approval of drugs by evaluating effectiveness during the early phases of a trial. In addition, the Prescription Drug User Fee Act (PDUFA) allows the USFDA to collect fees for expedited approval of drug through priority review. However, FDA will continue to monitor the drug through post marketing surveillance programs for serious adverse events.7 FDA may withdraw approval if the sponsor does not conduct post approval studies to demonstrate the new drugs continued benefits on irreversible morbidity or mortality or if the applicant uses misleading promotional materials to increase sale of the new drug.8
The accelerated approval mechanisms benefit a Sponsor by facilitating shorter clinical trials. There are four types of FDA approval processes for new drugs, i.e. priority review, fast track approval, breakthrough therapy, and accelerated approval.8
Priority review is provided to those new drugs that demonstrate significant therapeutic efficacy for the treatment of serious or life-threatening conditions. In such circumstances, FDA can approve a trial that shows drug safety and effectiveness using a historical control in a sub population. The benefit of priority review is the reduction in FDA review time by approximately four months.
Fast track approval is possible for drugs that are intended for use in combination with other drugs or as a standalone for any serious or life-threatening condition and if the trial shows promising preliminary non-clinical and clinical data.
Breakthrough therapy is accorded to a new drug that shows substantial therapeutic benefits if used alone or in combination with other drugs when compared to existing therapeutic interventions, placebos or another new compound. For such a therapy, FDA would need sufficient evidence from animal studies, invitro studies, as well as from Phase I or Phase II trials that have enrolled enough patients to provide data that is statistically significant. This approval process also requires constant and consistent communication between the Sponsor and senior FDA experts to ensure quick approval of the new drug.
Accelerated approval of a drug involves review of surrogate endpoints such as laboratory parameters, vital parameters, radiographic images that indicate clinical benefits on irreversible morbidity and mortality. The efficacy can also be established using biomarkers or other scientific tools.
FDA also mandates completion of post-marketing surveillance to ensure continued safety and efficacy of a new drug for rare or severe disease conditions.8
Modernization of new drug regulatory projects and programs
While it is necessary to maintain strict regulations, most applicants view the FDA drug approval process as a lengthy and costly process. The estimated average cost to get a drug to the market is more than USD 1 billion.3 With growing requests to speed up the approval of drugs especially for diseases with limited treatment options, FDA faces constant pressure to hasten review and approval of drugs and devices while upholding public safety and preventing unauthorized and harmful advertising of new therapies.
The Center for Drug Evaluation and Research (CDER) initiated the modernization of existing regulatory processes for new drugs in 2017 to improve patient safety and increase access to quality drugs. This modernization initiative focuses on six important pillars, i.e. benefit-risk monitoring, integrated assessment using a multi-disciplinary model, robust scientific expertise to lead at the forefront, talent management, management of knowledge, and operational efficiency. This modernization by the FDA is aimed at implementing past success approaches to tackle and decode evolving challenges in new drug review and approval.9
- USFDA. The FDA’s Drug Review Process: Ensuring Drugs Are Safe and Effective. https://www.fda.gov/drugs/drug-information-consumers/fdas-drug-review-process-ensuring-drugs-are-safe-and-effective. Accessed on May 22, 2020.
- USFDA. Step 4: FDA Drug Review. https://www.fda.gov/patients/drug-development-process/step-4-fda-drug-review. Accessed on May 22, 2020.
- Norman GAV. Drugs, Devices, and the FDA: Part 1: An Overview of Approval Processes for Drugs. JACC: Back to Translational Science. 2016;1(3):170-79.
- Milstein J. Meetings with CDER. https://www.fda.gov/media/89217/download. Accessed on May 22, 2020
- USFDA. FDA Drug approval process. https://www.fda.gov/media/82381/download. Accessed on May 22, 2020.
- Hoang H. An NDA at the FDA Understanding the Drug Approval Process. https://www.fda.gov/media/97229/download. Accessed on May 22, 2020.
- USFDA. FDA’s Drug Review Process: Continued. https://www.fda.gov/drugs/drug-information-consumers/fdas-drug-review-process-continued. Accessed on May 22, 2020.
- Kepplinger EE. FDA’s Expedited Approval Mechanisms for New Drug Products. Biotechnology Law Report. 2015;34(1):15-37.
- USFDA. Modernizing FDA’s New Drugs Regulatory Program. https://www.fda.gov/drugs/regulatory-science-research-and-education/modernizing-fdas-new-drugs-regulatory-program. Accessed on May 22, 2020.