Process Concepts

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Understanding the FDA Approval Process

By Desiree Crawford, BS; Kay Mary Harrell, BS, JD; Lawton Seal, PhD; and Vicki Worthington

Increased regulation for approval of articles intended for use in diagnosis, cure mitigation treatment, or prevention of disease in man or other animals "has advanced in quantum leaps because of abuses, catastrophes, and political change."1 For millennia, people expressed concern about the quality and safety of food and medicines, and historical events contributed to the current FDA statutes and guidelines that form the basis for the drug and device approval process.

Food and drug law dates back as early as 1202 when King John proclaimed the first English food law that prohibited the adulteration of bread with such ingredients as ground peas or beans. In 1862, President Lincoln appointed a chemist to head the Bureau of Chemistry, the predecessor of the FDA. In 1902, Congress enacted the Biologics Control Act. This led to the 1906 Food and Drug Act that prohibited interstate shipping of misbranded and adulterated foods, drinks, and drugs. In 1933, a bill introduced into the Senate to revise the 1906 drug law--widely recognized then as being obsolete--was approved in 1938 as the Federal Food, Drug, and Cosmetic (FDC) Act. Disclosures of unsanitary conditions in meatpacking plants, the use of poisonous preservatives and dyes in food, and cure-all claims for worthless and dangerous medicines, exposed major problems and led to the enactment of these laws. In 1962, Congress passed the Kefauver-Harris Amendment to the Act. Before marketing a drug, firms now have to prove the product both safe and effective for its intended use.

While the Food, Drug, and Cosmetic Act provides the foundation for implementing the approval process, FDA regulations and guidlines provide the means for approval, marketing, and distribution of drugs, drug products, and medical devices proven safe and effective for their intended use by the consumer.

Process Concepts

Before distribution of drugs, medical devices, or biologics into interstate commerce, the FDA generally requires pre-approval by one of the following FDA Centers:

  • Center for Drug Evaluation and Research (CDER), for drugs.
  • Center for Devices and Radiological Health (CDRH), for medical devices.
  • Center for Biologics Evaluation and Research (CBER), for biologics.

One exception: marketing a drug under an FDA OTC monograph, which lists certain product requirements but does not require FDA approval. For example, the Tentative Final Monographs (TFMs) for Healthcare Antiseptic Drug Products, provides requirements for skin asepsis products containing anti-microbial ingredients as active ingredients in formulations for healthcare personnel handwashes, patient preoperative skin preparations, and surgical hand scrubs. A product marketed in these categories must meet the TFM requirements for active ingredients, labeling, and testing. If an OTC product does not meet the requirements of the appropriate monograph, FDA may consider it misbranded and not legally marketed under the monograph. A New Drug Application (NDA) is the vehicle through which drug companies formally propose FDA approval of a new pharmaceutical for sale and marketing in the US. A new drug (as defined in the FDC Act) must have an approved NDA before it can be introduced into interstate commerce. Regulatory actions may be taken against manufacturers, distributors, and/or individuals who market or distribute drug products without such approval.

The concept of product approval for new drugs, before marketing, involves establishing product safety and effectiveness with scientific data thoroughly reviewed and accepted by the FDA (Figure 1). The development process of the product includes a discovery or basic-research phase followed by pre-clinical scientific work for the gathering of the safety data.

The development phase in humans begins with an Investigational New Drug Application (IND) submitted to the FDA, for approval to perform human clinical studies for new drugs, usually filed after successful pre-clinical (animal) studies of a drug product. If identified as a viable candidate for further development, the company then collects data to prove the product safe and effective in humans.

Clinical trials, performed in three phases, with the intent of demonstrating safety and effectiveness of the product in (or on) humans, can take several years. The FDA reviews the study design and conduct of clinical trials to ensure that people in the trials are not exposed to unnecessary risk. An Institutional Review board (IRB) reviews and monitors biomedical research involving human subjects. After obtaining satisfactory results from the clinical trials, a sponsor files a New Drug Application for approval by the FDA.

The approval process for new drugs can involve a significant amount of time. However, in 2000, NDA approval time by the FDA decreased to a median of 11.2 months. The FDA also implemented further regulations to expedite the approval process for drugs in certain categories, to reduce review time required by the agency.

Manufacturing facilities must comply with current Good Manufacturing Practices (cGMPs) for drug products, and with Quality Systems Regulations (QSRs) for medical devices, to safeguard public health and achieve goals for consistent, reproducible and acceptable products.

The FDA requires an Abbreviated New Drug Application (ANDA) for drugs equivalent to currently approved, marketed "reference" drugs, or to others allowed by FDA-approved petition for other reasons. These drugs are commonly referred to as "generics." This type of application relies on existing information about the safety and effectiveness of the reference drug. The applicant must show the reference drug and the application drug to be bioequivalent and pharmaceutically equivalent.

Even after approval, the FDA monitors drug products and devices through reporting programs (annual reports, adverse-reaction reports), sampling and testing of products on the market, and regular inspections of manufacturers.

Similar to the NDA, sponsors file a Pre-Market Approval (PMA) for medical devices demonstrated safe and effective and for which there are no substantially equivalent devices already on the market. The PMA outlines specific controls for devices and bases requirements upon the type of device and its intended use. An Investigational Device Exemption (IDE), similar to an IND, is the document filed before testing a new device prior to submission. A 510K application to the FDA is required when the device to be marketed is substantially equivalent to an already marketed predicate medical device.

As with nonbiological drug products, sponsors of new biologic drugs submit a Biologics License Application (BLA) to the FDA. Biologic drugs for use in humans must be shown to be safe, pure, and potent. The FDA adopted regulations to minimize the differences in the review process for products requiring an approved BLA and for those requiring approved NDAs.

The FDA does not generally pre-approve cosmetic products or ingredients, with the important exception of color additives. The FDA stipulates that cosmetic manufacturers market safe, properly labeled products, use no prohibited ingredients, and adhere to limits on restricted ingredients.

Opportunities to Participate

FDA regulations cover some of the most commonly used items of infection prevention, such as products of skin asepsis (TFM for surgical handscrubs and site preps, or healthcare personnel handwashes) and liquid chemical germicides/sterilants used to reprocess medical devices sensitive to steam sterilization temperatures (510Ks). As these products affect the ability of infection control professionals (ICPs) to successfully perform their healthcare functions, as well as affect the well-being of the ICPs using the products, it proves beneficial for ICPs to participate in the process of product design, development, evaluation, and application. However, many ICPs feel that any appreciable level of involvement exceeds the scope of their job description or available time.

The authors would like to offer some suggestions for allowing participation in the process and, in many cases, without onerous expenditures of time or energy. For example, an ICP may volunteer to be a co-investigator or participant in local clinical trials of products undergoing the evaluation/application process, or become a member of an IRB that reviews these studies. In addition, attend meetings or seminars sponsored by the FDA. The FDA web site ( lists upcoming meetings to discuss regulatory and related issues, identifies committees for which one may apply for membership, posts draft guidance documents, and solicits comments by interested individuals. Apply for membership in FDA Advisory Committee meetings, open for membership to those with proper credentials and letters of support and nomination. FDA also holds meetings/seminars, science forums, and focus groups on specific topics with industry and academia.

Additionally, the FDA solicits comments from healthcare professionals and the public for guidances and regulations. Usually published on the FDA Web site and in the Federal Register, these documents note the deadlines for comments. These meetings and publications offer an opportunity to communicate an understanding of the framework, content, process, and issues involved in review activity, including labeling for use of the product.

Healthcare providers should familiarize themselves with FDA's means of ensuring safe and effective drugs for American people. In addition, healthcare providers can play a vital role in assisting FDA to achieve this mission.

Desiree Crawford received a BS in Biomedical Science from Texas A& M University. She is a Regulatory Affairs professional for Healthpoint,® Ltd. and DPT Laboratories affiliated with DFB Pharmaceuticals, Inc.

Kay Mary Harrell earned her BS in Pharmacy from The University of Texas College of Pharmacy, Austin, Texas; and a JD from St. Mary's University School of Law, San Antonio, Texas. She is Director of Regulatory Affairs at DFB Pharmaceuticals, Inc., which is involved in contract manufacturing (DPT Laboratories, Ltd.) and distribution of branded pharmaceuticals (Healthpoint(r), Ltd.).

Lawton A. Seal received his BS in Microbiology from Louisiana State University; an MS and PhD in Microbiology and Immunology, respectively, from LSU Medical Center; and currently holds a Specialist rating in Public Health and Medical Laboratory Microbiology from the American Academy of Microbiology. Dr. Seal joined Healthpoint,® Ltd., as Program Manager, Infection Prevention, after serving as Chief, Infectious Disease Laboratories, Department of Pathology, Walter Reed Army Medical Center.

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