Celine Halioua
Celine Halioua

Basics of Regulatory Affairs

The federal definition of a drug is defined as a product used in diagnosing, curing, mitigating, treating or preventing a disease or affecting a structure or function of the body. A “biologic” is defined as a substance derived from or made with the aid of living organisms.

The purpose of drug development is to determine the efficacy (benefit) and safety (risk) as tied to the body’s exposure to the drug (pharmacokinetic profile).

Preclinical → IND → Clinical → FDA Review/NDA/BLA → Post-market monitoring


Clinical Trials

Phase 1 - first in human. Evaluate drug metabolism, pharmacologic action, dosing, side effect, and potentially early efficacy

Exploratory IND/early Phase 1 studies are efficacy doses to get bio-distrubution etc data

Phase 2 - 100-300 subjects generally speaking, further evaluate safety and efficacy at the determined dose

Phase 2a refers to dosing assessment, 2b to study efficacy

Phase 3 - 500 - multiple thousands of patients. Pivotal efficacy, monitor side effects, compare to SOC. Randomized, multi-center studies often of longer duration. Usually include a follow up period.

Phase 3b studies continue while undergoing marketing approval to ensure patients have access to medicines. 

Phase 4 - post-marketing studies to gather info on drugs effect on various populations, long-term safety/efficacy


FDA - The Food and Drug Administration, led by the commissioner

EMA - European Medicines Agency

CDER - Center for Drug Evaluation and Research (FDA)

CBER - Center for Biologics Evaluation and Research (FDA)

ICH - International Conference on Harmonization

  • EU, US, and Japan

  • Release guidelines on quality, safety, efficacy, and misc.

IND - Investigative New Drug Application, the FDA submission necessary to begin testing your drug in humans

NDA - New Drug Application, the FDA market approval process for drugs regulated under CDER

BLA - Biologics License Application, the FDA market approval process for biologics regulated under CBER


An inevitable part of building a biotechnology company is interfacing with regulatory agencies. Complying with regulatory standards can be a long, laborious, and confusing process and it is important to understand as best you can the regulatory pathway before you begin so you may traverse it effectively and efficiently. 

In the United States, you will be interfacing with The Food and Drug Administration (FDA). The FDA is a federal agency. Its responsibilities include: human and veterinary drugs, biologics, medical devices, food, cosmetics, radiation, and tobacco. 

Drugs and biologics are regulated under the Center for Biologics (CBER) and the Center for Drug Evaluation and Research (CDER). 


CBER regulates:

  • Blood

  • Blood products

  • Drugs derived from biological organisms

  • Allergenic extracts

  • Vaccines

  • Cell & gene therapies

  • Transplanted tissues

CDER regulates:

  • mAbs

  • Cytokines

  • Enzymes

  • Therapeutic proteins

  • Classic drugs 

  • Generics


FDA regulations as relevant to drugs are documented with the Code of Federal Regulations (CFR). Within the CFR, Title 21 (of 50 total titles) is the most relevant to drug development. Within Title 21, Part 200-99 covers cGMP and labeling, 300-99 covers human drugs, and 600-99 covers biologics.

Outside of the CFR, the most current requirements of the FDA are released as “guidance documents”. Thes

Meeting with the FDA

You can request a meeting with the FDA at any time, although it is up to their discretion if they’ll approve it. Regulatory incentive programs often explicitly include opportunities and promises of increased FDA interaction. 

Kefauver-Harris Amendments (Drug Amendments) - 1962

  • Required drug manufactures to demonstrate safety and efficacy (previously just safety)

  • Gave FDA control over advertisements

  • Established GMP

  • Created the IND

  • Requirement for informed consent 

Hatch-Waxman Act 

  • Facilitated generics by creating abbreviated applications

  • Must demonstrate bioequivalence to the reference listed drug (RLD) e.g. by crossover studies

Important Regulatory Documents

The Investigative New Drug Application (IND) [XXXX]

The New Drug Application (NDA) - filed after pivotal efficacy studies to apply for marketing authorization in the United States. It is formally known as the 505(b)(1) NDA, with the numbers referring to studies were conducted by the sponsor to support the NDA filing. A 505(b)(2) filing is supported using data referenced from the FDA’s previous finding of the safety and efficacy in another market approved product. An Abbreviated New Drug Application (ANDA) is the approval process for generics. You can find marketing authorization approvals online! (INDs are generally kept confidential)

The document includes:

  • Preclinical data

  • Clinical data demonstrating the safety and efficacy

  • Draft labeling for the product

  • CMC information including highlight of important processes and assays

  • Manufacturer information

  • Case reports on clinical experiences

  • Case reports on serious AEs

Important here is the package label - this is the end goal of the NDA and marketing authorization. Labels must contain (Physician Labeling Rule, PLR)

  • Highlights 

  • Contents

  • Full prescribing information 

In addition to the clinical and preclinical data, the FDA will likely complete a Good Manufacturing Practice (GMP) Preapproval Inspection (PAI) of the drug product manufacturing site, and your NDA will include significant information on the manufacturer and the processes conducted in the manufacturing of your drug. The specific objective of the FDA here is to ensure that the manufacturing and storage is sufficient to have consistent and high drug identity, strength, quality, stability, and purity. 

You should also consider asking for patent restoration at point of NDA filing.

In addition to facilitating generics of market approved drugs, the 505(b)(2) route is also used for:

  • Change in dosage

  • Change in active ingredient (different salt/acid/base)

  • New combination products where both active ingredients have been previously approved

  • Change from prescription to OTC

  • Indication not previously approved for the active ingredient

  • NCE that is a pro-dug or active metabolite of a previously approved drug

The Biologics License Application - equivalent to the NDA but for biologics. Preclinical and clinical studies required for a successful application will differ from the NDA, due to the varying safety profile and risks introduced with biologics. 

Regulatory incentives

There are a number of incentive programs to encourage development for rare and severe diseases with unmet need.

Orphan drug designation

Orphan drug designation is designed to incentivize the development of drugs for rare but serious diseases. This is generally considered < 200,000 persons in the US affected, and no reasonable expectation of recovering development costs through US sales. It provides a seven year exclusive marketing right once the drug receives marketing approval, a tax credit for up to 50% of qualified clinical research expenses, and the eligibility to apply for orphan drug grants.

Fast Track designation

For drugs indicated to treat serious or life-threatening conditions that are unmet medical needs. If given this designation, the program receives more interaction with the FDA, a “greater probability” of priority review of their marketing application (6 mo vs 10 mo), and the ability to submit the NDA/BLA in a rolling manner. 

Breakthrough Therapy designation

A benefit above Fast Track. Aims to expedite the review of drugs for serious diseases where the developer’s candidate drug shows substantial improvement over the current available therap(ies) on clinically significant endpoint(s). Drugs that quality for Breakthrough therapy designation receive Fast Track designation benefits, additional guidance from the FDA on drug development, and “organizational commitment involving senior managers”.

Rare Pediatric Disease Priority Review Voucher Program

A sponsor who receives a market approval for a ‘rare pediatric disease’ can receive a voucher that is redeemed for priority review of a subsequent marketing application. After receiving AA, the drug developer must still conduct Phase 4 confirmatory studies demonstrating the relevant clinical benefit. If these studies do not read out, the drug can be removed from the market. 

Regenerative Medicine Advanced Therapy (RMAT) designation

This was recently enacted by the 21st Century Cures Act. A drug is eligible for RMAT designation if it is a “regenerative medicine therapy” defined by the FDA as a cell therapy, tissue engineering product, human cell or tissue product, or combination thereof (some gene therapies also qualify); if it is intended for a serious disease, and the preliminary clinical evidence demonstrates its potential to address unmet need. This is filed with the IND. RMAT designated products may be able to circumvent late stage efficacy trials and also qualify for Priority Review. Most interestingly, RMAT designation includes language re: “real world evidence” (RWE) as an effcacy standpoint, derived from health records or patient registries, to be used to confirm efficacy in Phase 4 confirmatory trials instead of a formal clinical trial. 

Accelerated Approval

Accelerated approval allows for earlier and quicker approval of drugs indicated for serious conditions with unmet need based on a surrogate endpoint readout. 

Patent Restoration

In some cases, the FDA and the US PTO may grant up to 5 years of patent exclusivity to market approved products, to make up for the time lost due to regulatory review. This is discussed with the FDA at the point of NDA/BLA.

GMP, GLP, and GCP - Good Manufacturing and Good Laboratory Practices

Once you start considering testing or using a compound in humans, generally speaking GLP and GMP regualtions apply. 

Good Laboratory Practice is a set of quality management controls for research laboratories. It is a data quality system. Its purpose is to ensure the highest quality and replicability of all preclinical studies. The following are not covered under GLP:

  • Human CTs

  • Basic exploratory trials

Good Manufacturing Practice is a system for ensuring consistency in quality for manufacturing. It covers from starting materials to staff training.

Good Clinical Practice (GCP) is a quality management system for design, conduct, performance, aduttig, and recordkeeping of clinical trials. GCPs were developed in response to a number of events where clinical testing on humans was performed with ignorance of the individuals’ safety, agency, and rights. 

The Nuremberg Code was established in response to the valid defense of Nazi doctors that there was no international law that differentiated between legal and illegal human experimentation. The Nuremberg code states that: Voluntary consent is essential; research must benefit the good of ssociety and not be procurable by other means; research must be based on preclinical animal studies; must avoid unnecessary physical and mental suffering; should not be conducted if reasonable expectation of disability or death; risk must be minimized and in ratio to the anticipated research benefit; proper facilities must be used and maintained to protect the patient; should only be conducted by scientifically qualified; subjects have the right to end their participation at any time; and that hte research should be terminated at any time if continuation will lead to harm or death. The Declaration of Helsinki is another internation standard for research. 

Generally speaking, any work conducted under GMP/GLP conditions will be more expensive and complicated.