Drug Approval Process Infographic
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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
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."
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.
- Frequently Asked Questions about the FDA Drug Approval Process
- Protecting America's Health Through Human Drugs
- FDA Drug Approval Process Infographic (Horizontal)
- FDA Drug Approval Process Infographic (Vertical)
How long does FDA approval review take? ›
Once FDA receives an NDA, the review team decides if it is complete. If it is not complete, the review team can refuse to file the NDA. If it is complete, the review team has 6 to 10 months to make a decision on whether to approve the drug.
The name-brand approval process consists of five steps — discovery/concept, preclinical research, clinical research, FDA review, and FDA post-market safety monitoring. The company must test the product on animals before humans to ensure safety. After the product is tested, the company submits a New Drug Application.How long does the FDA drug approval process typically take? ›
The clinical trial phase can take years to complete. However, once research has shown that the drug is safe and useful, the FDA typically reviews and either approves or denies an application for a new drug within 6 months.What are the 4 phases of FDA approval? ›
- Step 1: Discovery and Development.
- Step 2: Preclinical Research.
- Step 3: Clinical Research.
- Step 4: FDA Drug Review.
- Step 5: FDA Post-Market Drug Safety Monitoring.
The FDA approval process can take between one week and eight months, depending on whether you self-register, submit a 510(k) application or submit a Premarket Approval (PMA) application.Why does the drug approval process take so long? ›
Establishing a safety profile of a drug is a key reason why the process of drug development takes time. There are numerous studies that regulators require in determining if a drug is safe enough to be dosed in humans—and these safety studies continue throughout clinical trials and the drug's lifecycle.What does FDA drug review mean? ›
FDA Approval: What it means. FDA approval of a drug means that data on the drug's effects have been reviewed by CDER, and the drug is determined to provide benefits that outweigh its known and potential risks for the intended population.How many stages are there in FDA process validation? ›
The Three Stages of Process Validation are: Stage 1 – Process Design. Stage 2 – Process Validation or Process Qualification. Stage 3 – Continued Process Validation.What is the FDA process for approving a drug? ›
FDA Drug-Approval Process. A pharmaceutical company seeking FDA approval to sell a new prescription drug must complete a five-step process: discovery/concept, preclinical research, clinical research, FDA review and FDA post-market safety monitoring.How can the FDA speed up the drug approval process? ›
More frequent meetings with FDA to discuss the drug's development plan and ensure collection of appropriate data needed to support drug approval. More frequent written communication from FDA about such things as the design of the proposed clinical trials and use of biomarkers.
How long should it take for the FDA to process the application? ›
The 2002 amendments to PDUFA set a 10 month goal for a standard review. Priority Review designation is given to drugs that offer major advances in treatment, or provide a treatment where none existed. The goal for completing a Priority Review is six months.How often does the FDA deny approval? ›
So in reality, the FDA approval rate is more like 96%. Eliminating BioMedTracker's counting of multiple uses for the same drug means FDA approved 23 drugs and rejected 1, Merck 's anesthesia antidote, Bridion. Again, that means 19 of 20 new drug applications were approved.How many days does FDA have to decide whether to accept the file to review for new drug application? ›
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.What percent of drugs pass FDA approval? ›
Overall success rates from Phase I to FDA approval is nearly 9%. This number is comprised of lead and secondary indications. When separated, lead indications have close to a one in seven rate of approval and secondary indications have a rate of one in 30.What is the probability of FDA approval? ›
The probability of FDA approval after submitting a New Drug Application (NDA) or Biologic License Application (BLA), taking into account re-submissions, was 85.3% (n=1,050).What are the reasons for drug failure during FDA review? ›
Around 30% were due to unmanageable toxicity or side effects, and 10%-15% were due to poor pharmacokinetic properties, or how well a drug is absorbed by and excreted from the body. Lastly, 10% of failures were attributed to lack of commercial interest and poor strategic planning.What are the 4 types of medication review? ›
This process required four main tasks: selection of relevant studies; assessment of study quality; synthesis of the results; and grading of the evidence.What are the types of FDA review? ›
In 1992, under the Prescription Drug User Act (PDUFA), FDA agreed to specific goals for improving the drug review time and created a two-tiered system of review times – Standard Review and Priority Review.What is continuous process verification? ›
In pharmaceutical process and product development, design and qualification stages are succeeded by Continuous Process Verification (CPV). This provides ongoing assurance that the product attributes remain within compliance for regulatory bodies.What are the 5 major phases in validation process? ›
- Stage 1 – Process Design.
- Stage 2 – Qualification. Part 1 – Facility Design. Part 2 – Qualification of Utilities & Equipment. Subsection 1 – Installation Qualification. Subsection 2 – Operational Qualification. Subsection 3 – Performance Qualification. ...
- Stage 3 – Continued Process Verification.
What is the difference between process validation and verification? ›
In the simplest terms, verification determines whether the product was built right, while validation determines whether the right product was built.How long does FDA Pdufa review take? ›
Inspections: FDA's goal is to complete all GCP, GLP, and GMP inspections for applications in the Program within 6 months of the date of original receipt for priority applications and within 10 months of the date of original receipt for standard applications.How long does it take for FDA to review breakthrough designation? ›
What are the timelines for FDA to respond to a breakthrough therapy designation request? FDA will respond to breakthrough therapy designation requests within 60 days of receipt of the request.How many days is an FDA audit? ›
The duration of an inspection (abbreviated or comprehensive) in the draft is usually 3-6 consecutive days. Depending on the scope of the inspection (e.g. following recalls), this period may also be extended, but this should be communicated to the company by the FDA.How do I know if my FDA is approved? ›
Look up the drug in Drugs @ FDA.
Most FDA-approved human drugs and therapeutic biologic products are listed in Drugs @ FDA, a searchable database. The database allows you to search by drug name, active ingredient, or application (NDA, ANDA, or BLA) number.