ROLE OF FDA IN DRUG DEVELOPMENT PROCESS (MODULE 4)

• The FDA represents the American regulatory authority.

• Mission statement  ‘protect public health’.
• It regulates many products/consumer items, the total annual value of which is estimated to be US$1 trillion.
• The FDA was founded in 1930.

S.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
Table 1.1: Detailed outline of the substances regulated by the FDA

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 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.

Center for veterinary

Center for biologics medicine (CVM)
evaluation & research
(CBER)

Center for devices &

Center for drug
radiological health
evaluation & research Center for food safety & (CDRH)
(CDER) applied nutrition

Figure 1.1: Partial organizational structure of the FDA, displaying the various centres primarily responsible for regulating drugs, devices and food

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 Allenergic extracts
Table 1.2: Major biotechnology/biological-based drug types regulated by CDER and CBER

• 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.

1. THE INVESTIGATIONAL NEW DRUG APPLICATION (IND)

An investigational new drug (IND) is a:

• new chemical-based, biologic 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

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

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 being 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 2.1: 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.

2.1 TYPES OF IND

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 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.
Table 2.1.1: Types of INDs

2. 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 upon 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 upon the chemical type of the drug and its therapeutic potential.
• After 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: 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 which 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 3.1: The CDER review process for a typical NDA

 ICH GUIDELINES

The International Council for Harmonisation of Technical Requirements for Pharmaceuticals for Human Use (ICH) is a project that brings
together the regulatory authorities of Europe, Japan and the United States and experts from
the pharmaceutical industry in the three regions to discuss scientific and technical aspects of
pharmaceutical product registration.
PURPOSE:
• Reduce or eliminate the need to duplicate the testing carried out during the
research and development of new medicines by recommending ways to achieve
greater harmonisation in the interpretation and application of technical guidelines and requirements for product registration.
• Harmonisation would lead to a more economical use of human, non-human animal and material resources, and the elimination of
unnecessary delay in the global development and availability of new medicines while maintaining safeguards on quality, safety, and
efficacy, and regulatory obligations to protect public health.
ICH guidelines have been adopted as law in several countries, but are only used as guidance for the U.S. Food and Drug Administration.

ICH GUIDELINES:

ICH guidelines are provided for:

1. Quality
2. Safety
3. Efficacy
4. Multidisciplinary
5. Consideration

THE GUIDELINES

ICH guidelines include:

1. Text and methodology for analytical methods

for stability.
2. Information of impurities in pharmaceutical
finished products.
3. Determination of residual solvents in drug
products.
4. Information about impurities in active pharmaceutical ingredients.
5. Test for extractable volume of parenteral preparations.
6. Test for particulate contamination.
7. Microbiological examination of non-sterile products.
8. Pharmaceutical development.
9. Lifecycle management of pharmaceutical products.
10. Recommendations to maintain quality of products.
11. Development and manufacture of drug substances.
12. Good manufacturing practice guide for API.
13. Recommendations for evaluation of risk involved in manufacturing
processes.
14. Test procedures and acceptance criteria for biological products.
15. Viral safety evaluations and analysis of quality of biological products.
 CURRENT GOOD MANUFACTURING PRACTICE (CGMP) REGULATIONS

The Food and Drug Administration (FDA) regulates the quality of pharmaceuticals very carefully. The main regulatory standard for ensuring
pharmaceutical quality is the Current Good Manufacturing Practice (CGMPs) regulation for human pharmaceuticals.

What are CGMPs?

• CGMP refers to the Current Good Manufacturing Practice regulations enforced by the FDA.
• CGMPs provide for systems that assure proper design, monitoring, and control of manufacturing processes and facilities.
• Adherence to the CGMP regulations assures the identity, strength, quality, and purity of drug products by requiring that manufacturers
of medications adequately control manufacturing operations.

This includes:

• establishing strong quality management systems

• obtaining appropriate quality raw materials
• establishing robust operating procedures
• detecting and investigating product quality deviations
• maintaining reliable testing laboratories

This formal system of controls at a pharmaceutical company helps to prevent instances of contamination, mix-ups, deviations, failures, and
errors. This assures that drug products meet their quality standards.

Why are CGMPs so important?

• A consumer usually cannot detect that a drug product is safe or if it will work.
• While CGMPs require testing, testing alone is not adequate to ensure quality.
• It is important that drugs are manufactured under conditions and practices required by the CGMP regulations to assure that quality is
built into the design and manufacturing process at every step.
• Facilities that are in good condition, equipment that is properly maintained and calibrated, employees who are qualified and fully
trained, and processes that are reliable and reproducible, are a few examples of how CGMP requirements help to assure the safety and
efficacy of drug products.

How does FDA determine if a company is complying with CGMP regulations?

FDA inspects pharmaceutical manufacturing facilities worldwide, including facilities that manufacture active ingredients and the finished product.
Inspections follow a standard approach and are conducted by highly trained FDA staff.

If a manufacturer is not following CGMPs, are drug products safe for use?

If a company is not complying with CGMP regulations, any drug it makes is considered “adulterated” under the law.

• For consumers currently taking medicines from a company that was not following CGMPs, FDA usually advises these consumers not to
interrupt their drug therapy, which could have serious implications for their health.
• Consumers should seek advice from their health care professionals before stopping or changing medications.
• Regulatory actions against companies with poor CGMPs are often intended to prevent the possibility of unsafe and/or ineffective
drugs. The impact of CGMP violations depends on the nature of those violations and on the specific drugs involved.

What can FDA do to protect the public when there are CGMP violations?

If the failure to meet CGMPs results in the distribution of a drug that does not offer the benefit as labeled because, for example, it has too little
active ingredient, the company may subsequently recall that product. This protects the public from further harm by removing these drugs from
the market. While FDA cannot force a company to recall a drug, companies usually will recall voluntarily or at FDA’s request. If a company refuses
to recall a drug, FDA can warn the public and can seize the drug.

Good manufacturing practice guidelines provide guidance for manufacturing, testing, and quality assurance in order to ensure that a
manufactured product is safe for human consumption or use. Many countries have legislated that manufacturers follow GMP procedures and
create their own GMP guidelines that correspond with their legislation.
GUIDELINES OF cGMP

All guideline follows a few basic principles:

• Manufacturing facilities must maintain a clean and hygienic manufacturing area.

• Manufacturing facilities must maintain controlled environmental conditions in order to prevent cross-contamination from adulterants
and allergens that may render the product unsafe for human consumption or use.
• Manufacturing processes must be clearly defined and controlled. All critical processes are validated to ensure consistency and
compliance with specifications.
• Manufacturing processes must be controlled, and any changes to the process must be evaluated. Changes that affect the quality of the
drug are validated as necessary.
• Instructions and procedures must be written in clear and unambiguous language using good documentation practices.
• Operators must be trained to carry out and document procedures.
• Records must be made, manually or electronically, during manufacture that demonstrate that all the steps required by the defined
procedures and instructions were in fact taken and that the quantity and quality of the food or drug was as expected. Deviations must
be investigated and documented.
• Records of manufacture (including distribution) that enable the complete history of a batch to be traced must be retained in a
comprehensible and accessible form.
• Any distribution of products must minimize any risk to their quality.
• A system must be in place for recalling any batch from sale or supply.
• Complaints about marketed products must be examined, the causes of quality defects must be investigated, and appropriate measures
must be taken with respect to the defective products and to prevent recurrence.