Process Concepts

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 usein diagnosis, cure mitigation treatment, or prevention of disease in man orother animals "has advanced in quantum leaps because of abuses,catastrophes, and political change."1 For millennia, peopleexpressed concern about the quality and safety of food and medicines, andhistorical events contributed to the current FDA statutes and guidelines thatform the basis for the drug and device approval process.

Food and drug law dates back as early as 1202 when King John proclaimed thefirst English food law that prohibited the adulteration of bread withsuch ingredients as ground peas or beans. In 1862, President Lincoln appointed achemist 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 DrugAct that prohibited interstate shipping of misbranded and adulterated foods,drinks, and drugs. In 1933, a bill introduced into the Senate to revise the 1906drug law--widely recognized then as being obsolete--was approved in 1938 as theFederal Food, Drug, and Cosmetic (FDC) Act. Disclosures of unsanitary conditionsin meatpacking plants, the use of poisonous preservatives and dyes in food, andcure-all claims for worthless and dangerous medicines, exposed major problemsand led to the enactment of these laws. In 1962, Congress passed the Kefauver-HarrisAmendment to the Act. Before marketing a drug, firms now have to prove theproduct both safe and effective for its intended use.

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

Process Concepts

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

  • 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 listscertain product requirements but does not require FDA approval. For example, theTentative Final Monographs (TFMs) for Healthcare Antiseptic Drug Products,provides requirements for skin asepsis products containing anti-microbialingredients as active ingredients in formulations for healthcare personnelhandwashes, patient preoperative skin preparations, and surgical hand scrubs. Aproduct marketed in these categories must meet the TFM requirements for activeingredients, labeling, and testing. If an OTC product does not meet therequirements of the appropriate monograph, FDA may consider it misbranded andnot legally marketed under the monograph. A New Drug Application (NDA) is thevehicle through which drug companies formally propose FDA approval of a newpharmaceutical for sale and marketing in the US. A new drug (as defined in theFDC Act) must have an approved NDA before it can be introduced into interstatecommerce. 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, involvesestablishing product safety and effectiveness with scientific data thoroughlyreviewed and accepted by the FDA (Figure 1). The development process ofthe product includes a discovery or basic-research phase followed bypre-clinical scientific work for the gathering of the safety data.

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

Clinical trials, performed in three phases, with the intent of demonstratingsafety and effectiveness of the product in (or on) humans, can take severalyears. The FDA reviews the study design and conduct of clinical trials to ensurethat people in the trials are not exposed to unnecessary risk. An InstitutionalReview board (IRB) reviews and monitors biomedical research involving humansubjects. After obtaining satisfactory results from the clinical trials, asponsor 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 11.2months. The FDA also implemented further regulations to expedite the approvalprocess for drugs in certain categories, to reduce review time required by theagency.

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

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

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

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

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

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

Opportunities to Participate

FDA regulations cover some of the most commonly used items of infectionprevention, such as products of skin asepsis (TFM for surgical handscrubs andsite preps, or healthcare personnel handwashes) and liquid chemical germicides/sterilantsused 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 thewell-being of the ICPs using the products, it proves beneficial for ICPs toparticipate in the process of product design, development, evaluation, andapplication. However, many ICPs feel that any appreciable level of involvementexceeds the scope of their job description or available time.

The authors would like to offer some suggestions for allowing participationin the process and, in many cases, without onerous expenditures of time orenergy. For example, an ICP may volunteer to be a co-investigator or participantin local clinical trials of products undergoing the evaluation/applicationprocess, 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 ( upcoming meetings to discuss regulatory and related issues, identifiescommittees for which one may apply for membership, posts draft guidancedocuments, and solicits comments by interested individuals. Apply for membershipin FDA Advisory Committee meetings, open for membership to those with propercredentials and letters of support and nomination. FDA also holdsmeetings/seminars, science forums, and focus groups on specific topics withindustry and academia.

Additionally, the FDA solicits comments from healthcare professionals and thepublic for guidances and regulations. Usually published on the FDA Web site andin the Federal Register, these documents note the deadlines for comments. Thesemeetings and publications offer an opportunity to communicate an understandingof 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 ofensuring safe and effective drugs for American people. In addition, healthcareproviders can play a vital role in assisting FDA to achieve this mission.

Desiree Crawford received a BS in Biomedical Science from Texas A& MUniversity. 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 TexasCollege of Pharmacy, Austin, Texas; and a JD from St. Mary's University Schoolof Law, San Antonio, Texas. She is Director of Regulatory Affairs at DFBPharmaceuticals, Inc., which is involved in contract manufacturing (DPTLaboratories, Ltd.) and distribution of branded pharmaceuticals (Healthpoint(r),Ltd.).

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

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