FDA HUMAN DRUG REVIEW AND APPROVAL BASICS MODULE

Introduction
The U.S. Food and Drug Administration (FDA) is composed of seven Centers responsible
for ensuring the safety, efficacy, oversight and security of the nation's human and
veterinary drugs, tobacco products, biological products, medical devices, food, cosmetics
and products that emit radiation.

FDA Drug Review and Approval Basics

FDA's Center for Drug Evaluation and Research (CDER) is the Center responsible for the
approval and safety monitoring of drugs, including certain therapeutic biologic products.
Through CDER, FDA works closely with the pharmaceutical industry, reducing their
regulatory burdens whenever possible, and helping to ensure that safe and effective
medicines get to the right people at the right time. To help accomplish this work, FDA
devotes a great deal of its resources towards advancing regulatory science and makes sure
its decisions are based on sound scientific evidence. CDER regulates drugs but does not
regulate the practice of medicine, which is the responsibility of state regulatory agencies.

FDA Regulatory Authority

Congress creates the laws that give FDA its regulatory authority. When a new law
involving FDA responsibilities is passed by Congress, FDA interprets the law and creates
regulations to implement the law. In the United States, Congress legislates (i.e., passes
laws) and agencies (such as FDA) regulate or carry out the intent of the law.

If further clarity is needed for a regulation, FDA may develop an industry guidance
document. FDA guidance is not legally binding but is intended to explain the agency's
current thinking behind the regulations.

The Federal Food, Drug and Cosmetic Act (FD&C) is the main law that controls all of FDA's
regulatory authorities. This law defines drugs, in part, by their intended use, as "articles
intended for use in the diagnosis, cure, mitigation, treatment or prevention of disease" and
"articles (other than food) intended to affect the structure or any function of the body of
man or other animals."

For more information, visit:

SEC. 201. [21 U.S.C. 321] Chapter II - Definitions 1.

Although the term "drug" is traditionally thought to refer to medicines, common household
products like fluoride toothpastes, antiperspirants, dandruff shampoos and sunscreens are
also considered drugs according to the FD&C Act, and are therefore also regulated by FDA.

The FD&C Act requires that some drugs only be available to patients via the authorization
of a licensed physician or other qualified health care professional. These professionals
authorize the delivery of such drugs by use of a prescription, which is a written or
electronically generated order for a drug for which authorization for use is required. These
drugs are therefore commonly called prescription drugs.

The FD&C Act allows other drugs to be available without a prescription. These drugs are
commonly called non-prescription or over-the-counter (OTC) drugs. CDER regulates both
prescription and non-prescription drugs. This regulation includes oversight of the review,
approval, manufacturing and continued monitoring for safety after approval of these
products. The review and approval process differs for prescription drugs and OTC drugs
and each of these different processes is explained in further detail later in this module.
Although FDA regulates dietary supplements, these products are not regulated as drugs by
CDER. Dietary supplements are compounds that do not make health claims regarding the
treatment of a specific disease or condition and are therefore regulated by FDA as foods.
FDA regulates both finished dietary supplement products and dietary ingredients under a
different set of regulations than those covering "conventional" foods and prescription and
OTC drug products. Under the Dietary Supplement Health and Education Act of 1994
(DSHEA), the dietary supplement or dietary ingredient manufacturer is responsible for
.ensuring that a dietary supplement or ingredient is safe before it is marketed

Many people sometimes find it difficult to distinguish between a drug and a dietary
supplement. The following helps make that distinction: If a product were approved by FDA
based on evidence that it was safe and effective for treating a disease, it would be
regulated as a drug; however, if a product does not make claims to treat, cure or mitigate
a disease and can only make claims to improve overall health - a broader statement - it
would be regulated as a dietary supplement. Regulation of dietary supplements falls under
.the responsibility of FDA's Center for Food Safety and Applied Nutrition (CFSAN)

Prescription Drug Development and Approval

Process
American consumers benefit from having access to the safest and most advanced
pharmaceutical system in the world.

The main consumer watchdog in this system is the U.S. Food and Drug Administration's
Center for Drug Evaluation and Research (CDER). The center's best-known job is to
evaluate new drugs before they can be sold. The center's evaluation not only prevents
quackery, but also provides doctors and patients the information they need to use
medicines wisely. CDER ensures that drugs, both brand-name and generic, work correctly
and that their health benefits outweigh their known risks.

The prescription drug development process actually begins outside FDA with preclinical
research in the laboratory. When various preclinical requirements are met, such as
establishing that the compound has limited toxicity, the company developing the drug,
which is known as the sponsor, then requests permission from FDA to conduct studies
involving human subjects.

Prior to using the drug on humans, the sponsor must submit to and receive approval from
FDA for an investigational new drug application (IND). An IND explains why a compound
may be a potential candidate to become a new drug.

FDA reviews the IND application for toxicity issues and determines a risk versus benefit
ratio. If FDA approves the IND application, the sponsor may then initiate a phase 1 clinical
trial. A phase 1 clinical trial involves between 20 and 100 healthy human subjects, and
takes place over several months. These studies evaluate safety, biological effects and
metabolism.
 Following a successful phase 1
clinical trial, testing then progresses to a phase 2 clinical trial. In phase 2 clinical trials,
several hundred selected human subjects may be involved. This phase can take several
months to years to evaluate the drug's therapeutic effect, dose range and metabolism.
During this phase, the goal is to minimize toxicity, maximize therapeutic effect and assess
populations of patients who may be beneficially or adversely affected when taking the
medication.

Phase 3 is the final clinical trials phase. This phase can include several hundred to
approximately 3,000 selected human subjects. Lasting between one to four years, clinical
studies during phase 3 evaluate safety, efficacy and dosing.

At various stages during the clinical trial process, FDA involvement is an important element
of success. In the past, drug sponsors seeking approval of their prescription drug would
have little communication between them and FDA. Today, however, ongoing dialogue
between the sponsor and FDA enables a more effective process and can save valuable time
and cost in the overall approval process. FDA recommends that sponsors meet with the
Agency at the conclusion of phase 2 trials and following phase 3 clinical trials. This
collaboration helps to ensure that the development effort stays on track, and that both
parties agree on the clinical trial design and that required safety and efficacy information
for the drug is appropriately developed.

After clinical studies of a drug are successfully completed, the sponsor may then submit a
new drug application (NDA) to CDER. The NDA is almost always electronically submitted to
FDA and assigned for review within 72 hours. For therapeutic biologics, a biologic license
application (BLA) is completed and submitted in the same manner.

Current law allows FDA to charge drug makers user fees to review NDAs and BLAs. These
user fees provide FDA with the necessary resources to review the application in a timely
and effective manner. The user fee is submitted by the sponsor with the application.

The NDA documentation is designed to tell the drug's entire story, including results of
animal studies, what happened during clinical tests, how the drug is constituted such as its
components and composition, how the drug behaves in the body and how it is
manufactured, processed and packaged, as well as all quality controls. Additionally, the
manufacturer is legally required to create comprehensive written information about the
drug. This information will be reviewed by CDER for approval. Approved written
.information about an FDA-approved drug is called the product label or labeling

Full reports of the drug's studies are submitted so FDA can evaluate the data. The
controlled clinical trials are especially important because they provide the only basis under
law to demonstrate safety and effectiveness.

Applications are reviewed by multiple scientific disciplines within CDER and are coordinated
by a project manager who serves as review coordinator and the liaison between the
sponsor and FDA. This review team is composed of chemists, pharmacologists, physicians,
pharmacokineticists, statisticians, microbiologists and others as needed.

When making decisions, FDA tries to inform the public as thoroughly as possible. This is
called transparency. One way CDER helps to ensure transparency is through public
meetings. Drugs that have new chemical structures never used before in the United States
are called new molecular entities (NMEs). Per the law, FDA conducts public meetings prior
to the approval of an NME. A public meeting may also be convened if safety concerns
develop after approval.

Following the application

review, FDA issues an official communication that informs the sponsor of the Agency's
decision as to whether or not to approve the drug. An Approval letter allows commercial
marketing of the product. A Complete Response letter describes important deficiencies that
preclude approval unless corrected.

Click the thumbnail on the right to open a pdf copy of a graphic that illustrates key steps in
the U.S. drug approval process.

Pre-approval use and expedited approval methods

Because the usual approval process for prescription drugs can take several years, FDA has
established special circumstances by which patients having various degrees of special
needs can have access to drugs faster than usual. These circumstances include one
method by which the drug is made available prior to approval, known as Single-Patient
Treatment IND or more commonly referred to as "Compassionate use" or "Treatment use"
and three methods by which the drug is approved faster than it would normally be
approved under standard procedures, known as Priority Review, Fast Track and
Accelerated Approval.

Compassionate use describes a way to make unapproved drug products available to

patients. The intent is to provide treatment of patients, not primarily to evaluate the safety
and effectiveness of the drug products. These unapproved drugs are called investigational
drugs.

Under compassionate use, a physician may request access to a drug that is under
development. The patient is informed that the drug is investigational and not FDA
approved. If the patient has exhausted all approved options for a severe and life-
threatening disease, they may choose to take a medicine during this investigational phase.
The patient is given the opportunity to understand the limitations in knowledge about the
risks and benefits of the drug at this stage of development.

The drug's sponsor decides whether to make the investigational drug available to an
individual or to many patients through what is called an open protocol. The data from
 compassionate use are included in the application for FDA review, but since the data are
not derived from a well-designed, adequately controlled clinical trial, they are not
considered to be pivotal.

Priority Review drugs are drugs that CDER determines to offer a major advance in
treatment, or provide a treatment where no adequate therapy exists. The Center seeks to
complete review of these drugs within six months of receipt of the drug's NDA, as opposed
to the standard target of ten months for review time.

Fast Track drugs are drugs that CDER considers to be able to treat serious diseases and
unmet medical needs. Fast Track speeds new drug reviews. For instance, this category of
review increases the level of communication CDER allocates to sponsors, is eligible for
Accelerated Approval and enables sponsors to use a "rolling review" process such that
CDER can review portions of an application before the submission of the full application.

Accelerated Approval applies to drugs or biologics that promise significant benefit over
existing therapy for severe or life-threatening illnesses and that fill an unmet medical
need. Under accelerated approval, early in the process (sometimes even before the phase
1 trials), a sponsor can inform FDA that it has a compound that is intended to treat or cure
a severe and life-threatening disease, and requests an expedited review. If FDA agrees
after meeting with the sponsor, the drug will be put on accelerated approval.

Under accelerated approval, FDA approves the product for marketing during or at the end
of phase 2 clinical trials. The initial approval is based on a surrogate endpoint. A surrogate
endpoint is a laboratory finding or physical sign that may not, in itself, be a direct
measurement of how a patient feels, functions or survives but nevertheless is considered
likely to predict therapeutic benefit. The sponsor still must show a clinical benefit. If the
company cannot complete future studies demonstrating such benefit, FDA can revoke the
product's approval and remove the product from the market.

Post-Market Surveillance and Epidemiology

Once a product is approved, the post-marketing phase of a product's lifetime begins.

During this phase, products are monitored for adverse events. These events are defined as
any unexpected or dangerous reaction to a drug.

Adverse events reports start once a product is on the market. By law, manufacturers are
required to report any adverse events that become known to them. Conversely, health
care professionals, such as doctors, nurses and pharmacists, as well as consumers are not
obligated to report but are encouraged to do so voluntarily. CDER staff involved with post-
market surveillance and epidemiology communicate on a regular basis with the CDER staff
that originally reviewed and approved the drug to discuss safety issues.

If post-marking surveillance reveals a safety issue, FDA must determine the appropriate
action, which can include:

 New information added to the product's labeling.

 A boxed warning, which is FDA's highest level of warning for a product. These
warnings are reserved for more serious adverse events. As the name implies, the warning
information is written inside a box to prominently highlight the product's information.
 Product withdrawals, which involve the sponsor's removal of a product from the
market. These actions may require taking the product off the market permanently.
 Medical and safety alerts, which contain important safety information about a
product are provided to health professionals, trade and media organizations.
 Restricted use, which limits prescribing ability to those in specific medical
specialties.
 Restricted distribution, which ensures that a product is not available from a local
pharmacy. Instead, the product must be obtained directly from the sponsor. Often training
and patient-informed consent forms must be submitted prior to being able to receive the
medication.
 Special safety programs which are known as Risk Evaluation and Mitigation
Strategy (REMS) to ensure that the benefits of a drug or biological product outweigh its
risks which may include establishing a process to confirm patient adherence to the safety
program, referred to as Elements to Assure Safe Use (ETASU).
 Medication guides, which are required by FDA to be issued with certain prescribed
drugs and biological products when the Agency determines that certain information is
necessary to prevent serious adverse effects. Patient decision-making should be formed by
information about a known serious side effect with a product, and patient adherence to
directions for the use of a product is essential to its effectiveness.
For more information, visit the FDA Drugs Web site at: Development & Approval Process
(Drugs).

Over-the-Counter Drug Development and

Approval Process
Over-the-counter (OTC) drugs are defined as being safe and effective for use by the
general public without seeking treatment by a health professional. Six out of every ten
medications bought by consumers in the United States are OTC.

Because there are more than 300,000 marketed OTC drug products, FDA reviews and
approves the active ingredients and about 80 therapeutic classes of OTC drugs instead of
individual products. Each category is defined by an OTC drug monograph which is a kind of
"recipe book" that covers acceptable ingredients, doses and formulations.

Using an FDA monograph, companies can manufacture and market an OTC product
without the need for FDA pre-approval. Monographs define the safety, effectiveness and
labeling of all marketed OTC active ingredients.

For more information, visit the OTC Web site at:

Drug Applications for Over-the-Counter Drugs.
Orphan Drug Product Act

The Orphan Drug Act, through the Orphan Drug Designation program, provides orphan
status to drugs and biologics. Orphan drugs are intended for the safe and effective
treatment, diagnosis or prevention of rare diseases or disorders that affect fewer than
200,000 people in the United States, or that affect more than 200,000 persons but
companies are not expected to recover the costs of developing and marketing a treatment
drug. The Orphan Drug Act was passed by the U.S. Congress to facilitate research and
development of such products.

For more information, visit: Developing Products for Rare Diseases & Condi

FAQs
1. European legislation makes a distinction between compassionate use and
off-label use. Are they the same in the United States?
1. No. Compassionate use is commonly used to describe some of the ways of making unapproved
products available to patients. Off-label use applies to a product that is marketed and approved for one treatment
but a prescriber chooses to use it to treat a different condition.
2. When FDA and a company seeking product approval meet, are the
application reviewers present?
1. FDA staff that review IND applications participate in the meetings with industry. The
reviewers are the same throughout the IND and NDA/BLA process. Since the process can take a long time before
the NDA and relevant data are sent to FDA, reviewers are familiar with the company, people in the company and
the compound.
3. Is FDA liable for medical product decisions?
1. While FDA is held to a high scientific standard by the courts, the Agency is not liable. The
company that sponsors the application is the liable party.

4. When a company has a treatment use protocol, does that information

support the approval of that product?
1. The answer is yes and no. Yes, because it gathers more data on the efficacy of the compound.
No, because it's not adequate and well-controlled. Although the data are good, they do not represent a controlled
set that FDA can use to render a decision.
5. How long does it take to establish whether an application will get a
priority or a standard review?
1. The decision about priority or standard review is made within 45 days of the NDA filing.

How are experts to the advisory committees appointed?

1. Nominations for scientific members, consumer, industry and patient

representatives originate from professional societies, industry, consumer and patient
advocacy groups, an individual or other interested persons. Members serve terms of up to
4 years.

Candidates are asked to provide detailed information regarding financial holdings,

employment, research grants and contracts and other potential conflicts of interest that
may preclude membership.

Persons nominated as scientific members must be technically qualified experts in their field
and have experience interpreting complex data. Candidates must be able to analyze
detailed scientific data and understand the public health significance of that data.

7. Does FDA have a fast-track application process for NDAs or is it a strict 6-

month to 10-month process?
1. There is a rolling review program for fast-track applications. If agreed upon in advance, the
company may submit completed sections of its NDA/BLA for review before they submit the entire application.
FDA will start on sections of the NDA before the 6-month time log starts. Some products that treat severe life-
threatening illnesses or unmet medical needs have been approved in less than 4 months.
8. With FDA's concept of Equal Voice, do all the reviewers have to reach a
consensus?

1. Equal Voice is an operational philosophy and set of practices to ensure that each professional
viewpoint has been fully expressed, understood and brought into the decision-making process. When there is
disagreement among members of a review team, each discipline must voice its concerns. This process engages the
entire team in scientific debate and brings each viewpoint into discussion so that a decision can be made at the
team level. The practice of Equal Voice does not mean that everyone necessarily agrees with the decision, but it
ensures that all scientific and regulatory experts have input before a decision is made.

Resources
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FDA CDER Contact Information

 Phone: (888) 463-6332
 Phone: (301) 796-3400
 Email: druginfo@fda.hhs.gov
 Address:
Division of Drug Information (CDER)
Office of Communications
 10001 New Hampshire Avenue
Hillandale Building, 4th Floor
Silver Spring, MD 20903
All links below will open in a new window.

Links
 SEC. 201. [21 U.S.C. 321] Chapter II - Definitions 1
 Development & Approval Process (Drugs)
 Drug Applications for Over-the-Counter Drugs
 Developing Products for Rare Diseases & Conditions
 Drug Approval Process Chart
FDA Centers
 Center for Drug Evaluation and Research
 Center for Devices and Radiological Health
 Center for Biologics Evaluation and Research
 Center for Food Safety and Applied Nutrition
 Center for Veterinary Medicine
 Center for Tobacco Products
 National Center for Toxicological Research

FDA HUMAN DRUG REVIEW AND APPROVAL BASICS MODULE