The
FDA's Drug Review Process: Ensuring Drugs Are Safe and Effective
The path a drug travels from a lab
to your medicine cabinet is usually long, and every drug takes a unique route.
Often, a drug is developed to treat a specific disease. An important use of a
drug may also be discovered by accident.
For example, Retrovir (zidovudine,
also known as AZT) was first studied as an anti-cancer drug in the 1960s with
disappointing results. Twenty years later, researchers discovered the drug
could treat AIDS, and Food and Drug Administration approved the drug,
manufactured by GlaxoSmithKline, for that purpose in 1987.
Most drugs that undergo preclinical
(animal) testing never even make it to human testing and review by the FDA. The
drugs that do must undergo the agency's rigorous evaluation process, which
scrutinizes everything about the drug--from the design of clinical trials to
the severity of side effects to the conditions under which the drug is
manufactured.
Stages
of Drug Development and Review
Investigational
New Drug Application (IND)--The pharmaceutical industry sometimes seeks advice
from the FDA prior to submission of an IND.
Sponsors--companies, research institutions, and other organizations that take
responsibility for developing a drug. They must show the FDA results of
preclinical testing in laboratory animals and what they propose to do for
human testing. At this stage, the FDA decides whether it is reasonably safe for
the company to move forward with testing the drug in humans.
Clinical
Trials--Drug studies in humans can begin only after an IND is reviewed by the
FDA and a local institutional review board (IRB). The board is a panel of
scientists and non-scientists in hospitals and research institutions that
oversees clinical research.
IRBs approve the clinical trial protocols, which describe the type of people
who may participate in the clinical trial, the schedule of tests and
procedures, the medications and dosages to be studied, the length of the study,
the study's objectives, and other details. IRBs make sure the study is
acceptable, that participants have given consent and are fully informed of
their risks, and that researchers take appropriate steps to protect patients
from harm.
Phase
1 studies are usually conducted in healthy volunteers. The goal here is to
determine what the drug's most frequent side effects are and, often, how the
drug is metabolized and excreted. The number of subjects typically ranges from
20 to 80.
Phase
2 studies begin if Phase 1 studies don't reveal unacceptable toxicity. While
the emphasis in Phase 1 is on safety, the emphasis in Phase 2 is on
effectiveness. This phase aims to obtain preliminary data on whether the drug
works in people who have a certain disease or condition. For controlled trials,
patients receiving the drug are compared with similar patients receiving a different
treatment--usually an inactive substance (placebo), or a different drug. Safety
continues to be evaluated, and short-term side effects are studied. Typically,
the number of subjects in Phase 2 studies ranges from a few dozen to about 300.
At
the end of Phase 2, the FDA and sponsors try to come to an agreement on how
large-scale studies in Phase 3 should be done. How often the FDA meets with a
sponsor varies, but this is one of two most common meeting points prior to
submission of a new drug application. The other most common time is
pre-NDA--right before a new drug application is submitted.
Phase
3 studies begin if evidence of effectiveness is shown in Phase 2. These studies
gather more information about safety and effectiveness, studying different populations
and different dosages and using the drug in combination with other drugs. The
number of subjects usually ranges from several hundred to about 3,000 people.
Postmarket
requirement and commitment studies are required of or agreed to by a sponsor,
and are conducted after the FDA has approved a product for marketing. The FDA
uses postmarket requirement and commitment studies to gather additional
information about a product's safety, efficacy, or optimal use.
New
Drug Application (NDA)--This is the formal step a drug sponsor takes to ask
that the FDA consider approving a new drug for marketing in the United States.
An NDA includes all animal and human data and analyses of the data, as well as
information about how the drug behaves in the body and how it is manufactured.
When an NDA comes in, the FDA has 60 days to decide whether to file it so that
it can be reviewed. The FDA can refuse to file an application that is
incomplete. For example, some required studies may be missing. In accordance
with the Prescription Drug User Fee Act (PDUFA), the FDA's Center for Drug
Evaluation and Research (CDER) expects to review and act on at least 90 percent
of NDAs for standard drugs no later than 10 months after the applications are
received. The review goal is six months for priority drugs. (See "The
Role of User Fees.")
"It's
the clinical trials that take so long--usually several years," says Sandra
Kweder, M.D., deputy director of the Office of New Drugs in the CDER. "The emphasis on
speed for FDA mostly relates to review time and timelines of being able to meet
with sponsors during a drug's development," she says.
Drug Review Steps Simplified
- Preclinical (animal) testing.
- An investigational new drug application (IND) outlines
what the sponsor of a new drug proposes for human testing in clinical
trials.
- Phase 1 studies (typically involve 20 to 80 people).
- Phase 2 studies (typically involve a few dozen to about
300 people).
- Phase 3 studies (typically involve several hundred to
about 3,000 people).
- The pre-NDA period, just before a new drug application
(NDA) is submitted. A common time for the FDA and drug sponsors to meet.
- Submission of an NDA is the formal step asking the FDA
to consider a drug for marketing approval.
- After an NDA is received, the FDA has 60 days to decide
whether to file it so it can be reviewed.
- If the FDA files the NDA, an FDA review team is
assigned to evaluate the sponsor's research on the drug's safety and
effectiveness.
- The FDA reviews information that goes on a drug's
professional labeling (information on how to use the drug).
- The FDA inspects the facilities where the drug will be
manufactured as part of the approval process.
- FDA reviewers will approve the application or issue a
complete response letter.
Supplemental Information About the
Drug Approval Process
Reviewing Applications
Though
FDA reviewers are involved with a drug's development throughout the IND stage,
the official review time is the length of time it takes to review a new drug
application and issue an action letter, an official statement informing a drug
sponsor of the agency's decision.
Once
a new drug application is filed, an FDA review team--medical doctors, chemists,
statisticians, microbiologists, pharmacologists, and other experts--evaluates
whether the studies the sponsor submitted show that the drug is safe and
effective for its proposed use. No drug is absolutely safe; all drugs have side
effects. "Safe" in this sense means that the benefits of the drug
appear to outweigh the known risks.
The
review team analyzes study results and looks for possible issues with the
application, such as weaknesses of the study design or analyses. Reviewers
determine whether they agree with the sponsor's results and conclusions, or
whether they need any additional information to make a decision.
Each
reviewer prepares a written evaluation containing conclusions and
recommendations about the application. These evaluations are then considered by
team leaders, division directors, and office directors, depending on the type
of application.
Reviewers
receive training that fosters consistency in drug reviews, and good review
practices remain a high priority for the agency.
Sometimes,
the FDA calls on advisory committees, who provide FDA with independent opinions
and recommendations from outside experts on applications to market new drugs,
and on FDA policies. Whether an advisory committee is needed depends on
many things.
"Some
considerations would be if it's a drug that has significant questions, if it's
the first in its class, or the first for a given indication," says Mark
Goldberger, M.D., a former director of one of CDER's drug review offices.
"Generally, FDA takes the advice of advisory committees, but not
always," he says. "Their role is just that--to advise."
Accelerated Approval
Traditional
approval requires that clinical benefit be shown before approval can be
granted. Accelerated approval is given to some new drugs for serious and
life-threatening illnesses that lack satisfactory treatments. This allows an
NDA to be approved before measures of effectiveness that would usually be
required for approval are available.
Instead,
less traditional measures called surrogate endpoints are used to evaluate
effectiveness. These are laboratory findings or signs that may not be a direct
measurement of how a patient feels, functions, or survives, but are considered
likely to predict benefit. For example, a surrogate endpoint could be the
lowering of HIV blood levels for short periods of time with anti-retroviral
drugs.
Gleevec
(imatinib mesylate), an oral treatment for patients with a life-threatening
form of cancer called chronic myeloid leukemia (CML), received accelerated
approval.
The drug was also approved under the FDA's orphan drug program, which gives
financial incentives to sponsors for manufacturing drugs that treat rare
diseases. Gleevec blocks enzymes that play a role in cancer growth. The
approval was based on results of three large Phase 2 studies, which showed the
drug could substantially reduce the level of cancerous cells in the bone marrow
and blood.
Most
drugs to treat HIV have been approved under accelerated approval provisions,
with the company required to continue its studies after the drug is on the
market to confirm that its effects on virus levels are maintained and that it
ultimately benefits the patient. Under accelerated approval rules, if studies
don't
confirm
the initial results, the FDA can withdraw the approval.
Because
premarket review can't catch all potential problems with a drug, the FDA
continues to track approved drugs for adverse events through a postmarketing
surveillance program.
Bumps in the Road
If
the FDA decides that the benefits of a drug outweigh the known risks, the drug
will receive approval and can be marketed in the United States. But if there
are problems with an NDA or if more information is necessary to make that
determination, the FDA may issue a complete response letter.
Common
problems include unexpected safety issues that crop up or failure to
demonstrate a drug's effectiveness. A sponsor may need to conduct additional
studies--perhaps studies of more people, different types of people, or for a
longer period of time.
Manufacturing
issues are also among the reasons that approval may be delayed or denied. Drugs
must be manufactured in accordance with standards called good manufacturing
practices, and the FDA inspects manufacturing facilities before a drug can be
approved. If a facility isn't ready for inspection, approval can be delayed.
Any manufacturing deficiencies found need to be corrected before approval.
"Sometimes
a company may make a certain amount of a drug for clinical trials. Then when
they go to scale up, they may lose a supplier or end up with quality control
issues that result in a product of different chemistry," says Kweder.
"Sponsors have to show us that the product that's going to be marketed is
the same product that they tested."
John
Jenkins, M.D., director of CDER's Office of New Drugs, says, "It's often a
combination of problems that prevent approval." Close communication with
the FDA early on in a drug's development reduces the chance that an application
will have to go through more than one cycle of review, he says. "But it's
no guarantee."
The
FDA outlines the justification for its decision in a complete response letter
to the drug sponsor and CDER gives the sponsor a chance to meet with agency
officials to discuss the deficiencies. At that point, the sponsor can ask for a
hearing, correct any deficiencies and submit new information, or withdraw the
application.
The
Role of User Fees
Since
PDUFA was passed in 1992, more than 1,000 drugs and biologics have come to the
market, including new medicines to treat cancer, AIDS, cardiovascular disease,
and life-threatening infections. PDUFA has allowed the Food and Drug
Administration to bring access to new drugs as fast or faster than anywhere in
the world, while maintaining the same thorough review process.
Under
PDUFA, drug companies agree to pay fees that boost FDA resources, and the FDA
agrees to time goals for its review of new drug applications. Along with
supporting increased staff, drug user fees help the FDA upgrade resources in
information technology. The agency has moved toward an electronic submission
and review environment, now accepting more electronic applications and archiving
review documents electronically.
The
goals set by PDUFA apply to the review of original new human drug and
biological applications, resubmissions of original applications, and
supplements to approved applications. The second phase of PDUFA, known as PDUFA
II, was reauthorized in 1997 and extended the user fee program through
September 2002. PDUFA III, which extended to Sept. 30, 2007, was reauthorized
in June 2002.
PDUFA
III allowed the FDA to spend some user fees to increase surveillance of the
safety of medicines during their first two years on the market, or three years
for potentially dangerous medications. It is during this initial period, when
new medicines enter into wide use, that the agency is best able to identify and
counter adverse side effects that did not appear during the clinical trials.
On
September 27, 2007, President Bush signed into law the Food and Drug
Administration Amendments Act of 2007 which includes the reauthorization and
expansion of the Prescription Drug User Fee Act. The reauthorization of PDUFA
will significantly broaden and upgrade the agency's drug safety program, and
facilitate more efficient development of safe and effective new medications for
the American public.
In
addition to setting time frames for review of applications, PDUFA sets goals to
improve communication and sets goals for specific kinds of meetings between the
FDA and drug sponsors. It also outlines how fast the FDA must respond to
requests from sponsors. Throughout a drug's development, the FDA advises sponsors
on how to study certain classes of drugs, how to submit data, what kind of data
are needed, and how clinical trials should be designed.
The Quality of Clinical Data
The
Food and Drug Administration relies on data that sponsors submit to decide whether
a drug should be approved. To protect the rights and welfare of people in
clinical trials, and to verify the quality and integrity of data submitted, the
FDA's Division of Scientific Investigations (DSI) conducts inspections of
clinical investigators' study sites. DSI also reviews the records of
institutional review boards to be sure they are fulfilling their role in
patient protection.
"FDA
investigators compare information that clinical investigators provided to
sponsors on case report forms with information in source documents such as
medical records and lab results," says Carolyn Hommel, a consumer safety
officer in DSI.
DSI
seeks to determine such things as whether the study was conducted according to
the investigational plan, whether all adverse events were recorded, and whether
the subjects met the inclusion/exclusion criteria outlined in the study
protocol.
At
the conclusion of each inspection, FDA investigators prepare a report
summarizing any deficiencies. In cases where they observe numerous or serious
deviations, such as falsification of data, DSI classifies the inspection as
"official action indicated" and sends a warning letter or Notice of
Initiation of Disqualification Proceedings and Opportunity to Explain (NIDPOE)
to the clinical investigator, specifying the deviations that were found.
The
NIDPOE begins an administrative process to determine whether the clinical
investigator should remain eligible to receive investigational products and
conduct clinical studies.
CDER
conducts about 300-400 clinical investigator inspections annually. About 3
percent are classified in this "official action indicated" category.
The
FDA has established an independent Drug
Safety Oversight Board (DSOB)
to oversee the management of drug safety issues. The Board meets monthly and
has representatives from three FDA Centers and five other federal government
agencies. The board's responsibilities include conducting timely and
comprehensive evaluations of emerging drug safety issues, and ensuring that
experts--both inside and outside of the FDA--give their perspectives to the
agency. The first meeting of the DSOB was held in June 2005.
