Regulatory approval

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Chapter: Pharmaceutical Drugs and Dosage: Drug development

Initiation of new clinical trials and clinical trials with new drug candidates by requiring the filing and approval of an IND.

Regulatory approval

Regulation and control of new drugs in the United States are the respon-sibilities of the federal FDA ( The FDA regulates the following:

·           Initiation of new clinical trials and clinical trials with new drug candidates by requiring the filing and approval of an IND.

·           Marketing of a new drug product or an existing drug product for a new application by requiring the filing and approval of an NDA or a BLA.

The agency, a frequently used synonym for the FDA, has various constit-uent centers, including the Center for Biologics Evaluation and Research (CBER), the Center for Drug Evaluation and Research (CDER), the Center for Devices and Radiological Health (CDRH), and the Center for Food Safety and Applied Nutrition (CFSAN). The CDER evaluates pre-scription, generic, and OTC drug products for safety and efficacy before they can be marketed. It also monitors all human drugs and biophar-maceuticals once they are in the market. The CBER regulates biologics not reviewed by the CDER, such as vaccines, blood and blood products, gene therapy products, and cellular and tissue transplants. Many bio-pharmaceuticals fall under the responsibilities of both the CBER and the CDER. The Office of Regulatory Affairs (ORA) is responsible for moni-toring sites and facilities in which pharmaceuticals are manufactured. The FDA has the authority to enforce withdrawal or recall of those drug products from the market that do not meet quality, safety, and efficacy requirements.

A typical process for the discovery and commercialization of new drug products in the United States generally follows the following pathway:

·           Preclinical laboratory tests and in vivo preclinical studies in animals.

·           Submission of an IND application to the FDA for clinical testing.

·           Clinical trials for establishing product safety and efficacy.

·           Submission of an NDA to the FDA for a BLA.

·           Approval of the NDA or BLA by the FDA before any commercial sale.

Investigational new drug application

After completing preclinical testing, the sponsor of a potential NDA/BLA makes the decision about whether or not the drug has enough potential to proceed to in vivo studies in humans. To initiate the clinical study, the sponsor needs to file an IND application with the agency. An IND appli-cation has several components, including chemistry, manufacturing, and control (CMC) of the test article or drug product, clinical study plan, and investigator’s brochure (IB). The IND application presents results of previ-ous experiments; how, where, and by whom the new studies will be con-ducted; the chemical structure of the compound; its mechanism of action in the body; any toxic effects found in animal studies; and how the compound is manufactured.

The IB is the document that the sponsor of the clinical study provides to the physician and healthcare professionals to successfully execute the clini-cal study. In addition to gaining the FDA’s approval for the IND, the IB must also be reviewed and approved by the institutional review board (IRB) of each clinical site (e.g., a hospital and medical center) where the proposed clinical trials will be conducted. Once an IND application is filed, the FDA has 30 days to respond to this initial admission. The IND application is considered approved if the FDA does not get back to the sponsor within that time.

New drug application

After successful completion of phase I through phase III clinical development, a drug’s sponsor submits the result of all the studies to the FDA in an NDA to obtain approval for marketing of the new drug. The NDA is a formal request to the FDA to approve a new drug product for sale and marketing in the United States. Technically, the FDA regulates inter-state transport of medicinal products, which is what it approves. Each state has its own regulatory body for new drug products that can be marketed within its territory. Usually, the regulations of each state reflect that of the U.S. FDA. Therefore, approval of the FDA is considered a benchmark for the ability to market a new drug in all states.

i. Basis of approval

The NDAs are usually comprehensive documents that detail all studies carried out and can run over 100,000 pages in print; however, recent electronic submissions have eliminated the need for printing. The average NDA review time for NMEs approved in 2016 was 10.1 months. The NDA must contain all of the scientific information that the company has gathered. The data gathered during the animal studies and human clinical trials of an IND become the part of the NDA. The goals of the NDA are to provide enough information to permit the FDA reviewers to reach the following key conclusions:

·           Whether the drug is safe and effective for its proposed use(s), and whether the benefits of the drug outweigh the risks.

·           Whether the drug’s proposed labeling is appropriate, and what it should contain.

·           Whether the methods used in manufacturing the drug and the con-trols used to ensure the drug’s quality are adequate to preserve the drug’s identity, strength, quality, and purity.

ii. Role of advisory committees

The FDA often constitutes advisory committees consisting of experts in respective areas in several disciplines, such as clinical practitioners in a spe-cific disease area, to assist in the review of an NDA. Committees are typically asked to comment on whether the approval, clearance, or licensing of a medi-cal product for marketing is supported by adequate data. The primary role of an advisory committee is to provide independent advice that will contribute to the quality of the agency’s regulatory decision-making and lend credibility to the drug product review process. In this way, the FDA can make sound decisions about new medical products and other public health issues.

Although advisory committees have a prominent role in the approval of new drug products, they may also be called in earlier in the product development cycle or asked to consider issues relating to products that are already in the market. Committees are typically asked to comment on whether the submitted data adequately support approval, clearance, or licensing of a medical product for marketing. Advisory committees may also recommend that the FDA request additional studies or suggest changes to a product’s labeling. Their recommendations are nonbinding advice to the agency. While committee discussions and final votes are very important to the FDA, the final regulatory decision rests with the agency.

Biologics license application

A BLA is an application for marketing authorization of a biologic drug product, such as proteins, antibodies, antibody–drug conjugates, vaccines, and gene and cell therapy products. These products are historically unique not only in their origin but also in the physicochemical characteristics and the extent of characterization contemporarily possible. For example, while the small-molecule drugs are well characterized to an atomic level, with crystal structures of crystalline drugs elucidated, the large-molecule compounds are generally not crystalline and are difficult to isolate in solid state as pure compounds. In their solution state, they are quite big (moluecular weight >10 kDa) and exact characterization of each atom and bond is currently not possible. Thus, while the impurities of small-molecule compounds are known and characterized to exact molecular structure, the structural variants of large-molecule compounds are generally character-ized only as size or charge variants.

Accordingly, the criteria for comparability of different drug substance and drug product batches, product scale-up and manufacturing control, scaling of dose across species, and analytical characterization of drug sub-stances and drug product differ significantly between the small- and large-molecule drug products. Although the process of drug development remains the same for both small- and large drug molecules, different experts within the FDA review BLA and NDA.

Abbreviated new drug application

An abbreviated NDA (ANDA) is used to gain approval for a generic equiva-lent of a drug product that is already approved and is being marketed by the pioneer or original sponsor of the drug. Generic drugs are defined as prod-ucts containing the same active ingredient as the branded drug, in the same dosage form, and intended for administration by the same route. Generic drug products may have different inactive ingredients and/or product-manufacturing process and controls.

Generic products offer low-cost alternatives to branded medicines once the patent life of the molecule expires. The underlying precept in the approval of generic drug products is that drug products with similar drug pharmacokinetics will have similar efficacy and toxicity profile. These pharmacokinetic parameters include area under the curve (AUC) and max-imum plasma concentration (Cmax). Therefore, clinical safety and efficacy testing for generic drug products are waived on the basis of their bioequiva-lence to the branded or innovator drug product. The CMC requirements for the generic drug products do not change.


Biosimilars are the generic equivalents of biologic drug products. Often called follow-on biologics, the equivalence requirements for generic bio-logics are still evolving. The clinical proof of equivalency for biosimilars currently involves abbreviated safety and efficacy studies. In addition, simi-larity criteria for biosimilar drug products to branded drugs are considered. These may include, for example, a combination of relatively proportion of size and charge variants in the molecule.

Approval and postmarketing surveillance

Once the FDA approves an NDA or a BLA, the drug’s sponsor can sell the new medicine to the public in the United States. Approval of the FDA for marketing of a new drug product does not end a sponsor’s responsibility toward clinical investigation of the drug. Continued clinical investigation, often called phase IV studies, may contribute to the understanding of the drug’s mechanism or scope of action, indicate possible new therapeutic uses, and/or investigate the need for additional dosage strengths, dosage forms, or routes of administration. Phase IV monitoring in commercial use may also reveal additional side effects, especially the rare events that may not be detected even in large-scale clinical trials.

The sponsor is required to submit periodic reports to the FDA, including any adverse event reports, internal quality investigations, and/or changes to manufacturing and controls since the NDA’s approval. If an adverse effect is identified with a marketed drug, the Office of Drug Safety (ODS) can take one or more of the following actions: labeling changes, boxed warn-ings, product withdrawals, and medical and safety alerts.

Accelerated development/review

Accelerated development/review is a specialized mechanism for speeding up the development of drugs that promise significant benefit over the exist-ing therapy for serious or life-threatening diseases for which no therapy exists. This process incorporates several elements, such as abbreviated clin-ical studies, aimed at accelerating drug development. Safeguards to protect the patients and the integrity of the regulatory process balance regulatory review. The fundamental element of this process is that the manufacturers must continue to test after approval to demonstrate that the drug indeed provides therapeutic benefit to the patient.

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