FDA Drug Approval Process

The History, Pre-Market Stages, and Post-Market Regulation

Hunter Larson
PLS 130
Professor Roark
5 July 2015
FDA Drug Approval Process

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The History, Pre-Market Stages, and Post-Market Regulation
I. Introduction
The Food and Drug Administration is a regulation agency within the
Department of Health and Human Services. Its role in our nation is to be
responsible for protecting the public health by assuring the safety, efficacy and
security of human and veterinary drugs, biological products, medical devices, our
nations food supply, cosmetics, and products that emit radiation ("What We
Do."). One of the most important responsibilities and the topic I will be discussing
throughout this paper is drug regulation. The Food and Drug Administration
approves drugs that are intended for use in diagnosis, cure, relief, treatment, or
prevention of disease, and is intended to affect the function of the body. In order
to do so, The Food and Drug Administration reviews drug manufacturers via
application to put drugs on the market; therefore, a drug may not be sold or
marketed unless it has and remains approved by the FDA. Even though a drug
has been approved does not mean it will remain on the market, drugs have the
likelihood to be recalled. For example, when you see those late night personal
injury lawyer commercials saying, If you have been prescribed and taken said
drug, and experienced any of these side effects such as blood clots, seizures,
etc., you may be entitled to compensation. those drugs have usually been
recalled due to adverse effects outside of the initial research and studies prior to
the drugs approval.
II. History of Drug Regulation

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The Food and Drug Administration is one of the oldest consumer
protection agencies in the U.S federal government. It all began in the late-19 th
century from one chemist from the U.S Department of Agriculture branching off to
the Division of Chemistry. This chemist was Harvey Washington Wiley. When he
arrived as chief chemist in 1883, the government's handling of the adulteration
and misbranding of food and drugs took a decidedly different course, which
eventually helped spur public indignation at the problem (Swann, "FDA's
Origin."). Wiley broadened the divisions research to foods and food adulterants,
and in 1902 composed a group of twelve men gathered for dinner in a
government buildings basement, and served them food spiked with food
additives to determine their impact on the volunteers health. After this
experiment, similar tests were conducted on salicylic acid, copper sulfate, and
even formaldehyde. This later led to the passage of the Pure Food and Drug Act
of 1906, which in turn prevents the manufacture, sale, or transportation of
adulterated, misbranded, poisonous foods, drugs, medicines, and liquors, and for
regulating traffic therein, and, for other purposes. Throughout the next 60 years,
Congress passed two more preeminent pieces of legislation expanding FDA
power, The Federal Food, Drug, and Cosmetic Act in 1938 which prohibited the
movement in interstate commerce of adulterated and misbranded food, drugs,
devices, cosmetics, and in 1962 an amendment was made to the Federal Food,
Drug, and Cosmetic Act called the Kefauver-Harris Drug Amendment in response
to the Thalidomide tragedy in the 1960s which caused birth defects in children

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from mothers who took thalidomide for morning sickness. The birth defect in the
children was phocomelia, which is a congenital disorder involving malformation,
and absence of limbs. Within the few years of the widespread use of thalidomide
in Europe, Australia, and Japan, approximately 10,000 children were born with
phocomelia, leading to the ban (Kim, Scialli 1). Therefore, The Kefauver Harris
Amendment of 1962 requires the manufacturers of drugs to provide proof of the
effectiveness and safety of their drugs as well as the effectiveness before
approval of the drug. US Legal also states, that the amendment requires that an
advertisement of a drug should disclose accurate information about its side
effects (US Legal). This now leads us to what we know as the modern day Food
and Drug Administration.
III. Pre-Clinical Stage: Drug Sponsors Discovery and Screening
My report will be describing the process for a new drug to be released on
the market. However, the approval process begins before the Food and Drug
Administrations involvement, therefore, before the drug manufacturers can
submit an Investigational New Drug Application, do clinical trials, submit a New
Drug Application, and be FDA reviewed; they must develop a drug first. This is
generally called the pre-clinical stage. By pre-clinical it means that it has not yet
been through the Investigational New Drug Application (IND), which allows the
drug manufacturers sponsor to develop a plan for testing the drug on humans.
Therefore, the absolute first step of the process is for development of the new
drug compound by a drug sponsor. Once the drug manufacturers have noticed a

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significant relevance in the synthesized chemicals structure to similar chemicals
that have a physiological effect in humans, they are required to begin testing the
new drug on animals for the possibility of toxic effects. When people think of
animal testing they generally think that it consists of testing rats and mice. Which
is mostly true. The American Physiological Society states, being that rats and
mice have so many biological similarities to humans, they make up 90 to 95% of
the mammals in biomedical research ("What Types of Animals Are Needed for
Medical Research?"), and some strains of rats and mice are susceptible to
diseases such as cancer or high blood pressure. However, depending on what
condition is being tested other species of animals suit better. Most animals used
in research are in fact bred for research purposes, and therefore researchers
choose the most fitting species that suit the biology of what they want to test on.
Pigs suit a great capability to research skin issues, and what may happen if
toxins and drugs are absorbed through the integument. Where as primates,
dogs, and cats, though are not widely used, they make a good model for the
study of heart disease, neurological disorders, and HIV/AIDS. They may not be
widely used for human based research, but for veterinary research, dogs, and
cats are a necessity. Researchers even use worms, zebra fish, and fruit flies for
genealogical studies. The results of this stage of testing are used to support the
last step of the pre-clinical stage, the Investigational New Drug Application (IND).
The Investigational New Drug Application consists of chemical and
manufacturing data, pharmacology and safety data, the reasoning for testing a

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new compound in humans, strategies for protection of human volunteers, and a
plan for clinical testing. At this point, the Food and Drug Administration has
become involved in the process and if the FDA believes the documentation of the
Investigational New Drug Application is satisfactory, the course is ready for phase
one of clinical trials.
IV. Clinical Stage
Now that the drugs have been studied in laboratory animals and have not
posed any significant threat of toxicity, and the FDA was satisfied with the
Investigation New Drug Application, we may move onto the clinical stage. The
clinical stage of the FDA approval process is focused on conducting clinical trials,
or also referred to as clinical studies, to test treatment in human volunteers to
determine if the drugs should be approved for a larger spectrum of use in the
general population. In the clinical stage there are general three phases of clinical
trials. Phase one typically involves a range from 20-80 subjects. This phase is
focused on safety and the pharmacology of the drug by attempting to determine
the dosage, bioavailability of the compound, and how it is metabolized and
excreted from the body. By doing so, researchers are able to discover smallscale side effects of the drug. If the drug sponsor is satisfied with the results of
phase one, the drug continues to phase two. Phase two studies the effectiveness
of the drug. However, during this phase a larger sample of the general population
is used. Phase two generally involves 100-300 subjects who actually suffer from
the condition the drug is designed to treat. Phase two is used to determine the

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effective dose, route of administration, and safety. The phase two trials are
usually done in controlled experiments where the scientific method comes into
play. A group of selected volunteers are given the true drugs, and are compared
to a group of volunteers who are given a placebo to observe the beneficial effects
as well as the short-run side effects. A significant number of drugs do not
advance passed this step due to the ineffectiveness of drugs and side effects that
outweigh the benefits. The final phase of clinical trials is phase three. Phase
three is large-scale clinical testing of thousands of subjects at a time. This series
of studies consists of multiple trials of different demographics of groups in
thousands being tested on different dosages, and drug interactions between
other substances and medications. Phase three can take two years all the way to
ten years to complete. After a drug has completed all clinical trials, the drug
sponsor can now submit a New Drug Application (NDA) leading to the FDAs New
Drug Application (NDA) Review Stage.
V. New Drug Application (NDA) Review Stage
Once phase three of the clinical trials has been completed, the drug
manufacturer can now file and submit a New Drug Application (NDA). The New
Drug Application requests all date from animal and human clinical studies, and
the information analyzed on how the drug is metabolized and how it acts in the
body gathered from the clinical trials in the clinical stage. FDA Review states
during the NDA stage The FDA also gathers safety information as the drug is
used and adverse events are reported, and it will occasionally request changes

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in a labeling or will submit press releases as new contraindications arise
("FDAReview.org, a Project of The Independent Institute."). After the New Drug
Application (NDA) has been submitted, it is sent for NDA Review. The FDA has
three main categories it goes over before approving the New Drug Application
Review; safety and effectiveness of the drug, appropriate information displayed
on the drugs container labeling, and satisfactory means of manufacturing the
drug in the manufacturers facilities. The safety and effectiveness of the drug is
portrayed from the clinical trials from the three phases in the clinical stage. The
FDA reviews that the drugs label meets the Code of Federal Regulations Title 21
general requirements for drug labeling. The Code of Federal Regulations Title 21
is published in Cornell Universitys law school page and states the drug labeling
must meet the following general requirements:
1.The labeling must contain a summary of the essential scientific
information needed for the safe and effective use of the drug. 2.The labeling
must be informative and accurate and neither promotional in tone nor false or
misleading in any particular. 3.The labeling must be based whenever possible on
data derived from human experience. No implied claims or suggestions of drug
use may be made if there is inadequate evidence of safety or a lack of
substantial evidence of effectiveness. Conclusions based on animal data but
necessary for safe and effective use of the drug in humans must be identified as
such and included with human data in the appropriate section of the labeling

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("21 CFR 201.56 - Requirements on Content and Format of Labeling for Human
Prescription Drug and Biological Products.").
Manufacturing processes are reviewed during the New Drug Application
process, and the FDA wants to be assured that the controllers and instruments
used in the manufacturing facilities are satisfactory to maintain the drugs
consistent identity, purity, and quality. Therefore, if all of the requirements are
met, the FDA reviewers will approve the New Drug Application and issue a letter
of response granting FDA Drug Approval within the 6 months the FDA has to
review and accept the New Drug Application, however, the FDA has the
Accelerated Approval program, which allows for quicker and earlier approvals for
drugs that treat life-threating illnesses and for drugs that meet an unmet need in
the field of medicine. If the drug is not approved the manufacturer will be sent a
response letter with an approval recommendations to have a certain flaw in the
application corrected for further approval. Once the New Drug Application has
been approved the drug can be marketed in the United States.
VI. Post-Marketing: FDAs Post Approval Risk Assessment Systems
The FDAs role of assuring the safety, efficacy and security of human and
veterinary drugs, and biological products extends beyond the approval process,
but continues when the drug hits the market. Since it is not possible to assess all
the side effects during the clinical stage the FDA has a post-market regulatory
policy after the drug has been considered satisfactory in safety and effectiveness
to be FDA approved. The role of the post-market regulation is to determine

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seriously unexpected side effects to determine the risk of the drug. Once the
post-market regulation begins, the drug manufacturer is to report serious adverse
effects and safety updates periodically to the FDA. Generally when adverse
effects are reported by consumers, the drug manufacturer is required to put the
possibility of the adverse effect on the labeling, and send the possibility of the
adverse effect in letters to inform the public using that drug. If the complication
becomes reported more frequent the drug will be restricted to limited use, and
even stripped from the market.
VII. Conclusion
The Food and Drug Administration plays an indispensable role in our nation by
protecting the public health by assuring the safety, efficacy and security of
human and veterinary drugs, biological products, medical devices, our nations
food supply, cosmetics, and products that emit radiation ("What We Do.").
Without the Food and Drug Administration we would not be provided with the
safe feeling and assurance of what we are putting in our bodies to provide
ourselves with nourishment or to treat our ailments. It may take up to nearly 15
years to have a drug become FDA Approved, but as William Shakespeare once
wrote Out of this nettle, danger, we pluck this flower, safety.

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Works Cited

"21 CFR 201.56 - Requirements on Content and Format of Labeling for Human `
Prescription Drug and Biological Products." 21 CFR 201.56. Cornell
University, 24 Jan. 2006. Web. 4 July 2015.
"FDAReview.org, a Project of The Independent Institute." FDAReview.org, a
Project of The Independent Institute. FDAReview. Web. 4 July 2015.
Kim, James, and Anthony Scialli. "Toxicological Sciences." Thalidomide: The
Tragedy of Birth Defects and the Effective Treatment of Disease. 2 Apr.
2011. Web. 1 July 2015.
Swann, John. "FDA's Origin." FDA's Origin. Web. 1 July 2015.
US Legal. "Kefauver Harris Amendment Law & Legal Definition." Kefauver Harris
Amendment Law & Legal Definition. USLegal. Web. 1 July 2015.
"What Types of Animals Are Needed for Medical Research?" What Types of
Animals Are Needed for Medical Research? The American Physiological
Society, 2013. Web. 3 July 2015
"What We Do." What We Do. U.S. Food and Drug Administration, 2014. Web. 1
July 2015.

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