Role of FDA in Drug Development Process

The Food and Drug Administration (FDA) is an organization that serves as the regulatory authority in the United States. Its mission statement is to "protect public health." Established in 1930, the FDA plays a crucial role in ensuring the safety and efficacy of various products and consumer items available in the market.

The FDA's jurisdiction extends to a wide range of products, and it is responsible for regulating and overseeing their production, distribution, and marketing. These products include but are not limited to food and beverages, drugs, medical devices, cosmetics, dietary supplements, and tobacco products. The FDA's primary focus is on safeguarding public health by enforcing regulations that promote the safety, efficacy, and accurate labeling of these products.

The sheer scale of the FDA's regulatory reach is substantial. It oversees products with an estimated annual value of approximately US$1 trillion. This staggering figure highlights the significance of the FDA's role in protecting public health and ensuring the safety of the American consumer.

Through rigorous research, testing, and regulatory oversight, the FDA aims to prevent and address potential risks associated with the consumption or use of various products. The organization collaborates with scientific experts, healthcare professionals, industry stakeholders, and the general public to make informed decisions that positively impact public health.

Overall, the FDA is a pivotal institution in the United States, charged with the responsibility of protecting the well-being of the American population. With its extensive reach and commitment to its mission statement of "protecting public health," the FDA continues to play a vital role in ensuring the safety and efficacy of a wide array of products consumed and utilized by the American public.

Role of the FDA in the Drug Development Process

Sr. No.	Substances Regulated by the FDA
1	Foods, nutritional supplements
2	Drugs: chemical-based, biologics, and biopharmaceuticals
3	Blood supply and blood products
4	Cosmetics/toiletries
5	Medical devices
6	All radioactivity-emitting substances
7	Microwave ovens
8	Advertising and promotional claims relating to the above product types

The major FDA responsibilities with regard to drugs include:

1. Assessing pre-clinical data to decide whether a potential drug is safe enough to allow the commencement of clinical trials.
2. Protecting the interests and rights of patients participating in clinical trials.
3. Assessing preclinical and clinical trial data generated by a drug and deciding whether that drug should be made available for general medical use (i.e. if it should be granted a marketing licence).
4. Overseeing the manufacture of safe effective drugs (inspecting and approving drug manufacturing facilities on the basis of compliance to the principles of good manufacturing practice as applied to pharmaceuticals).
5. Ensuring the safety of the US blood supply.

In relation to the drug development process:

CDER: regulated the development and marketing approval of mainly chemical-based drugs. 

CBER: is more concerned with biologics.

CDER: assigned regulatory responsibility for the majority of products of pharmaceutical biotechnology.

CDER regulated	CBER regulated
Monoclonal antibodies for in vivo use	Blood
Cytokines (e.g. interferons and interleukins)	Blood proteins (e.g. albumin)
Therapeutic enzymes	Vaccines
Thrombolytic agents	Cell- and tissue-based products
Hormones	Gene therapy products
Growth factors	Antitoxins, venoms, and antivenins
Additional miscellaneous proteins	Allergic extracts

• The FDA then assesses the application; if it does not object within a specific time frame (usually 30 days), then clinical trials can begin.
• The  FDA  usually meets with the drug developers at various stages to be updated, and often to give informal guidance/advice.
• Once clinical trials have been completed, all the data generated during the entire development process are compiled in a multi-volume dossier.
• The dossier submitted to the CDER is known as a new drug application (NDA), which, if approved, allows the drug to be marketed

THE INVESTIGATIONAL NEW DRUG APPLICATION (IND)

An investigational new drug (IND) is a:

• New chemical-based, biologic,al or biopharmaceutical substance
• For which the FDA has given approval to undergo clinical trials.

An IND application should contain information:

• Detailing preclinical findings
• Method of product manufacture
• Proposed protocol for initial clinical trials

1. The FDA and drug sponsor (company submitting the IND) will agree to hold a pre-IND meeting.
2. An IND application can consist of up to 15 volumes of approximately 400 pages each.

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Once received by the FDA, it is studied to ensure that:

1. It contains sufficient/complete information required.
2. The information supplied supports the conclusion that clinical trial subjects would not be exposed to an unreasonable risk of illness/injury (the primary FDA role is to protect public health).
3. The clinical investigator named is qualified to conduct the clinical trials.
4. The sponsor’s product brochures are not misleading/incomplete.

Figure: Outline of the IND application process

• Based on their findings, the FDA may grant the application immediately or may require additional information which the sponsor then submits as IND amendments.
• Once clinical trials begin,  the sponsor must provide the FDA with periodic updates, usually in the form of annual reports. Unscheduled reports must also be submitted under a variety of circumstances, including:

1. If any amendments to the trial protocol are being considered.
2. If any new scientific information regarding the product is obtained.
3. If any unexpected safety observations are made.

TYPES OF INVESTIGATIONAL NEW DRUG APPLICATION (IND)

IND Type	Description
Commercial INDs	Filed by companies to obtain marketing approval for a new drug.
Research or Investigator INDs	Filed by researchers to study an unapproved drug.
Emergency Use INDs	Filed for emergency use of an unapproved drug when the clinical situation does not allow sufficient time to submit an IND.
Treatment INDs	Filed to make a drug available for the treatment of serious or immediately life-threatening conditions prior to FDA approval.
Screening INDs	Filed for multiple, closely related compounds in order to screen for the preferred compounds or formulations.

THE NEW DRUG APPLICATION (NDA)

• Upon completion of clinical trials, the sponsor will collate all the preclinical, clinical, and other pertinent data and submit this to FDA in support of an application to allow the new drug to be placed on the market. For CDER-related drugs, this submission document is termed an NDA.
• The NDA must be an integrated document.
• It often consists of 200–300 volumes, which can represent over 120,000 pages.
• Several copies of the entire document and sections are provided to the CDER.
• The FDA then classifies the NDA based on the chemical type of the drug and its therapeutic potential.
• After the initial submission of the NDA, the FDA has 45 days in which to undertake a preliminary inspection of the document, to ensure that everything is in order.
• They then ‘file’ the NDA; or, if more information/better information management is needed, they refuse to file until such changes are implemented by the sponsor.
• Once filed, an NDA undergoes several layers of review.

Primary Review:

The panel generally consists of a chemist, microbiologist, pharmacologist, biostatistician, medical officer, and bio-pharmaceutics scientist. The team is organized by a project manager or consumer safety officer (CSO). The CSO initially forwards relevant portions of the NDA to the primary review panel member with the appropriate expertise. Each reviewer then prepares a review report.

Secondary Review:

The review report is forwarded to their supervisory officers, who undertake a second review. All of the reports are then sent to the division director who,  in turn,  recommends rejection or approval, or asks the sponsor to provide more information. On average, this entire process takes some 12 months.

Even when the NDA is approved and the product goes on sale, the sponsor must provide the FDA with further occasional reports.

The CBER licensing process for a new drug consists of three phases:

1. The IND phase
2. The pre-marketing approval phase (licensure phase)
3. The post-marketing surveillance phase

The pre-marketing approval phase is a clinical trial phase that aims to generate data that prove the potency, purity, and safety of the product. Upon completion of clinical trials, the sponsor collates the data generated and submits it to the FDA.

Figure: The CDER review process for a typical NDA

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