by E. Beyza Guven
On June 17th, the Rutgers iJOBS program hosted a seminar exploring the complexities of drug development and the FDA approval process, led by pharmaceutical executive Dr. M. Daniel Gordin. The talk began with a compelling look at the historical roots of drug regulation (Figure 1) and progressed into a detailed overview of the FDA’s structure and the step-by-step path a drug takes from discovery to market approval. In this post, we’ll walk through the key insights and takeaways from Dr. Gordin’s presentation.
The Evolution of Drug Regulations
“The history of drug regulation is built on tombstones” – Michael Harris
Revisiting the tragic history of drug regulation underscores the importance of the FDA’s regulatory vigilance. The U.S food and drug marketplace was largely unregulated until the American journalist and political activist Upton Sinclair exposed unsanitary practices in the meatpacking industry in his 1905 novel The Jungle. This work provoked public outcry and led Congress to pass the Pure Food and Drug Act and the Meat Inspection Act granting government the authority to regulate food and drug products. This landmark legislative event encouraged the creation of the Bureau of Chemistry, later named the Food and Drug Administration (FDA) in 1930.
Congressional oversight of food and drugs continued into the 1960s. After the Sulfanilamide disaster in 1937, in which the antibiotic used to treat streptococcal infections caused the death of more than 100 people, many of which were children, Congress passed the Federal Food, Drug, and Cosmetic (FD&C) Act. This expanded FDA’s authority to regulate drugs. In the 1950s, Thalidomide, a drug prescribed in Europe to treat morning sickness, was denied FDA approval in the U.S. due to safety concerns raised by Dr. Frances Kelsey. It was later linked to congenital disabilities in over 10,000 European infants. In 1962, the Kefauver-Harris Amendment to the FD&C required manufacturers to provide substantial evidence of safety and efficacy. To this day manufacturers are required to file an Investigational New Drug (IND) application before clinical trials, conduct well-controlled studies, and submit a New Drug Application (NDA) for FDA review and market approval. These requirements have become essential aspects of the current drug development pipeline.
Drug Regulation by the FDA
The FDA’s core mission is to protect public health through the regulation of drugs, biologics, over-the-counter products, medical devices, food, cosmetics, tobacco, radiation-emitting devices, and veterinary products. The FD&C Act is the general legal framework that the FDA converts into actionable rules via the Code of Federal Regulations (CFR):
- 21 CFR 312: Requirements for IND applications
- 21 CFR 314: Procedures for NDAs
The FDA also issues guidance documents that reflect the agency’s current thinking. While not legally binding, these documents help industry stakeholders understand and comply with regulatory expectations.
The FDA’s organization is extensive, with nine centers and 13 headquarter offices. All drugs are monitored by the Center for Drug Evaluation and Research (CDER), including new drugs that are assessed in clinical trials by the Office of New Drugs (OND). OND includes eight review offices organized by therapeutic area. Review teams within the OND comprising medical reviewers, statisticians, pharmacologists, toxicologists, manufacturing inspectors, and specialists handling application reviews assess data quality and inspect manufacturing sites for compliance with Good Manufacturing Practices (GMP). The journey from drug discovery to submitting an FDA application is long and meticulous, requiring careful planning and execution at every stage of development.
Drug Development: Start to Finish
Dr. Gordin emphasized that developing a drug "takes a village." This requires a multidisciplinary team of scientists involved in drug discovery, scaling up production, and oversight of clinical trials.
- Preclinical Development Team: Handles drug discovery and early research while adhering to Good Laboratory Practices. They also prepare comprehensive study reports required for regulatory submissions.
- Pharmacologists (target identification)
- Chemists (compound synthesis)
- Toxicologists (in vitro/in vivo safety testing)
- Chemistry, Manufacturing, and Control (CMC) Team: Responsible for scaling up production and managing GMP compliance and the supply chain.
- Pharmaceutical scientists and formulation developers (drug product formulation and optimization)
- Chemical engineers (scaling up processes from lab to pilot or commercial manufacturing)
- Regulatory CMC experts (author and manage the CMC sections of regulatory submissions (INDs, NDAs, etc.)
- Clinical Development Team: Oversees all clinical trial phases and ensures good clinical practices.
- Clinicians, PharmDs, nurses (providing medical oversight of clinical trials)
- Statisticians (analyses and interpretation of trial data)
- Clinical Research Associates (CRAs) (ensuring data integrity and regulatory compliance at clinical sites and acting as the primary liaison between the sponsor and clinical site)
- Drug Development Project Team: Coordinates all activities for a specific drug with representatives from all prior teams.
- Regulatory affairs specialists (liaise with FDA, prepare Briefing Books)
- Project managers (timeline coordination)
- Clinical operations, toxicologists, MDs, etc.
The drug development process takes 14-17 years and includes five key stages (Figure 2). After completing the preclinical stages (4-7 years), four clinical trials phases (I-IV) are required to systematically assess a new drug’s safety, efficacy, and optimal dosage:
- Phase I: 20–100 healthy volunteers; assess PK and safety (70% advance)
- Phase II: 100s of patients; determine efficacy and optimal dosing (33% advance)
- Phase III: 300–3000 patients; confirm efficacy and monitor safety (25–30% advance)
- Phase IV: post-marketing surveillance for long-term safety and effectiveness
Following a successful Phase III clinical trial, an NDA is submitted in the Common Technical Document (CTD) format:
- Module 1: Region-specific (e.g., FDA forms)
- Module 2: Summary documents (clinical, preclinical, CMC)
- Module 3: Detailed CMC data
- Module 4: Nonclinical study reports
- Module 5: Clinical study reports
In an NDA, FDA reviews safety, efficacy, manufacturing consistency, and Critical Quality Attributes (CQAs):
- Strength (Active Pharmaceutical Ingredient (API) amount)
- Identity (confirmation of correct compound)
- Purity (absence of contaminants)
- Quality (batch consistency, stability)
If approved, the drug will be released to the market with a detailed Package Insert, which contains a summary of essential scientific information necessary for safe and effective use of the new drug for healthcare professionals.
The post-marketing surveillance phase tracks the long-term safety and rare side effects. During this stage, the sponsor assesses how well the drug works in more diverse patient populations than those in controlled clinical trials. Due to its long-term assessment, rare, delayed, or long-term adverse effects that were not detected in earlier trials can be identified. Risks and benefits are continuously evaluated as new data emerge to ensure that a drug remains safe and effective in the broader population over time.
Case Study: Risk-Benefit Analysis
Dr. Gordin used Thalidomide as a case study highlighting how the FDA assesses the benefit-risk profile of a drug. Thalidomide was initially rejected for treating morning sickness due to serious risks, such as fetal toxicity, neuropathy, and blood clots, but was later approved for patients with multiple myeloma (see Table 1).
Table 1.
When evaluating risks and benefits, four possible scenarios are identified (Table 2). Ideally most drugs are classified in the green category, where the efficacy and safety of a new drug is significantly higher than the controls and there is an increased probability of approval. However, approximately 50% of NDAs culminate in the red category and will not be approved. Drugs that fall into the yellow category have high efficacy but low safety. For these drugs, the probability of approval depends on whether the risks exceed the benefits coming from the use of a new drug like in the Thalidomide case study.
Table 2.
The drug development and approval journey are complex and highly regulated, with each stage designed to ensure that only safe and effective treatments reach the public. Dr. Gordin’s seminar provided valuable insights into the science, policy, and ethical considerations that shape the process.
This article was edited by Junior Editor Janaina Cruz Pereira and Senior Editor Antonia Kaz.