FDA Drug Approval Process

The FDA drug approval process involves several steps that take years to complete. FDA approvals are based on animal studies and then clinical trials. The FDA approval process is explained here in detail.

All new drugs need proof that they are safe and effective before marketing. Of course, no drug is 100 percent safe. There is always some risk of an adverse reaction. The FDA uses a cost benefit analysis to determine when the benefits outweigh the risks.

Pre-clinical Research

The first step is the synthesis and purification of the new drug. Bioassay is one of the starting points. A bioassay measures the effects of some substance on a living organism. That living organism could be a group of cells. It is necessary to determine the degree of drug toxicity. Quantitative bioassays are analyzed using the methods of biostatistics.

The synthesis and purification of a drug will occur in a research laboratory at a hospital, or university, or biotechnology company. Quality control measures will be in place to check on the manufacture of the drug. “Currently, the research and development cost of each new molecular entity is approximately $1.8 billion.” (Nature Reviews Drug Discovery)

Animal Testing

The purpose of the animal testing is to move from cell cultures to a total organism. There are usually two or more species chosen for testing. One is frequently a rodent (mice or rats) and the other is non-rodent (rabbit or monkey). This takes months of study and involves dedication and money to run the animal testing laboratories. This is the home of pharmaceutical research.

Long-term animal studies are needed to continue testing for efficacy. These long-term studies continue long after the clinical trials begin. At this point the FDA‘s Investigational New Drug (IND) application occurs.

The Investigational New Drug Application

The IND program means that a pharmaceutical company obtains permission to ship an experimental drug across state lines to clinical investigators. The FDA reviews the IND application for safety to assure that research subjects will not be subject to unreasonable risk.

There are basically three parts to the IND application.

1. Animal Pharmacology and Toxicology Studies This is pre-clinical data based on cell growth results and animal testing.

2. Chemistry and Manufacturing Information This includes chemical composition of the drug and chemical stability and activity of the product.

3. Clinical Protocols and Investigator Information These are detailed reports to assess whether the subjects will be exposed to unnecessary risks. Qualifications of the clinical investigators must be included.

The IND application must also include an Investigator’s Brochure to educate the trial doctors of the significant facts about the drug they need to know before their clinical trials.

Institutional Review Boards

An Institutional Review Board (IRB) is a committee that is formally designated to approve, monitor and review biomedical research involving humans. The aim is to protect the rights and welfare of the research subjects. The FDA empowers the IRBs to approve, require modifications to planned research prior to approval or disapprove the research.

All IRBs are subject to the FDA’s IRB regulations when studies involve FDA regulated products, such as new drugs. Originally, IRBs were committees at academic institutions and medical facilities to monitor research studies involving human participants. Today, some IRBs are for-profit organizations known as commercial IRBs. The responsibilities are the same and the regulations are the same.

There are specific guidelines for the IRB. Some of them are:

• The IRB must have at least five members.
• The IRB should include both men and women.
• The members of the IRB must not be all of the same profession.
• If testing vulnerable populations, such as prisoners, an advocate for prisoners should be on the IRB.
• The IRB must include at least one person who is not affiliated with the institution.
• The IRB may include consultants in their discussions to meet requirements for expertise and diversity. The consultants cannot vote.

Clinical Trials

After IND application approval and the establishment of an IRB, clinical trials with human beings may begin. The FDA drug approval process continues. There are three phases to the clinical trials.

1.    Phase 1 involves 20 to 80 participants. They may be healthy volunteers or sometimes they are patients. The purpose of these studies is to evaluate the

a.    Metabolism

b.    Structure-reactivity relationships

c.     Mechanism of action and

d.    Side effects of the drug.

2.    Phase 2 involves several hundred patients. It is to determine the efficacy of a certain drug to treat patients with a specific disease or condition. Various doses at this stage of the trials are used. It is designed to test the short-term side effects at a given dose.

3.    Phase 3 involves several hundred to thousands of people even in different countries. It is typically a double-blind, placebo controlled investigation. There are some far-reaching effects that are studied. The larger the population, the more valid are the statistics governing the trials. This phase of study provides more information about the effects and safety of the drug. Scientists can then extrapolate the results of the clinical trial to the general population.

4.    In phase 4 trials, they are post-approval trials that are sometimes a condition attached by the FDA to the approval.

The clinical trials lie at the heart of the regulatory program fro drugs. Data for the application must come from rigorous trials

The New Drug Application

The New Drug Application (NDA) in the United States is how drug sponsors formally propose that the FDA approve a new pharmaceutical for sale and marketing. The goals of NDA are to provide sufficient information so that the FDA reviewers can determine the following:

• Is the drug safe and effective in its proposed use when used as directed and do benefits outweigh the risks?
• Is the drug’s proposed labeling (package insert) appropriate and what should it contain?
• Are the methods used in manufacturing the drug and the controls used to maintain the quality adequate to preserve the drug’s identity, strength, quality and purity?

The results of the testing program are in a public document called the product label or the package insert. The documentation required in an NDA is supposed to tell the drug’s whole story including:

• What happened during the clinical trials?
• What are the ingredients in the drug formulation?
• What are the results of the animal studies?
• How does the drug behave in the body?
• How is it manufactured, processed and packaged?

Conclusion to the FDA Approval Process

Once the thousands of pages of an application has been submitted, the FDA has 60 days to conduct a preliminary review which will assess the NDA for completeness. If the NDA is insufficiently complete, then the FDA rejects the application and issues a Refuse to File letter.

If the NDA is acceptable, the FDA will decide if the NDA gets a standard or accelerated review. Acceptance of the application and their review choice is sent in a communication known as the 74-day letter. A standard review implies an FDA decision in about 10 months while a priority review is complete in 6 months.

The FDA drug approval process takes years to complete. The purpose of the regulations is to insure the safety of new drugs. Rgulatory Affairs Associates (RAA) can help youi with this approval process.

Written by: Margret Stenerson

10 5 2010