Cataract & Refractive Surgery Today asked Wiley Chambers, MD, Deputy Director for the Division of Anti-Inflammatory, Analgesic and Ophthalmic Drug Products at the FDA, to describe the agency's approval process for ophthalmic therapeutics in the US.

CRST: What is the estimated length of time for a chemical entity to gain FDA approval?

Dr. Chambers: The time it takes for a drug to receive FDA approval from its inception in the laboratory can be anywhere from 3 to 20 years and depends upon several factors. Some compounds are more familiar to researchers; they have an idea of its behavior and may even know from experience what animal tests to run and they are able to hypothesize the compound's effect on humans. Then there are other drug products that researchers sometime refer to jokingly as drug products in search of indication; they clearly have an effect on the body, but science has not yet determined their best indication.

FDA reviewers first become involved with a drug when human studies are proposed for it, sometimes many years into the development process. The FDA is generally not involved in the drug's preclinical development and research.

CRST: What type of information does the FDA require for a drug to achieve an Investigational New Drug (IND) Application?

Dr. Chambers: In order to present a drug to the FDA for consideration for use in humans, a company must satisfy a series of regulations. It must provide information to medical peers (FDA reviewers) about why it believes the product is safe for testing in humans and will lead to useful applications.

The information the company presents for the IND falls into three main categories. The first is chemistry/ manufacturing; companies are asked to show that the compound is what it claims and that it will remain stable for the duration of the trial. The second category is the results of any animal trials the company has so far conducted. The third is how the company proposes to use the compound in a clinical protocol.

Before the FDA receives an IND, the company usually conducts preclinical trials with the drug. This is often a critical stage for a drug. Generally, nonreversible adverse events (depending on the proposed dosage in humans) will halt a drug's IND application. If something causes a permanent defect in an animal at an equivalent dosage to that proposed for humans, then most investigators will not proceed. However, if the dosage required to cause a permanent defect is 10,000 times that of which will be given to humans, then the investigators will likely proceed with the trials but monitor the human patients for symptoms of the reaction. The purpose of preclinical testing is to discover what reactions to observe in humans.

CRST: Please describe the differences between the phases of the clinical trials.

Dr. Chambers: All clinical trials are conducted with humans, and phase 1 studies classically are an attempt to determine an initial safe dosage for healthy individuals (those who do not have the condition for which the drug is intended to treat). None of the phases of clinical trials has restrictions on patient enrollment in terms of minimums or caps. There are no magic numbers; it depends upon what the investigators are trying to learn about the drug. The idea is that the trials accomplish their objectives and build upon the information gathered from one trial to the next.

The phase 1 trials typically are conducted in normal healthy volunteers. They usually do not include patients who have the condition for which the drug is intended. Some products, however, have associated safety concerns, and may only be tested in patients that have a chance for potential benefit.

Classic phase 2 trials deal with dose ranging, determining the proper dosage of a drug for patients. Phase 2 trials generally include higher numbers of patients than phase 1, but they likewise have no minimum enrollment requirement or cap on the number of participants allowed.

The objective of phase 3 clinical trials is to demonstrate the safety and efficacy of a new drug for its intended population. After the phase 3 studies are completed and the company has credible data to present to the FDA about the drug's safety and efficacy for its proposed indication, the company may submit a New Drug Application (NDA). The decision to potentially approve a drug product is based on its benefit-to-risk ratio; do the demonstrated benefits of the drug outweigh the potential risks?

CRST: What is the timeline for approval after the FDA accepts the NDA? Does the company ever have to submit additional data?

Dr. Chambers: After the clinical trials have concluded, the time frame for the FDA to review the data can vary. If an NDA is a priority application, the FDA pledges to try to review the data within 6 months. A standard NDA has a time frame of 10 months. At the end of that time, the FDA issues a letter to the company citing the drug as either approved, in which case the company may begin marketing it as of the date of the letter; approvable, meaning the product will potentially be approved if the company provides additional information or conducts additional clinical studies; or nonapproval, meaning that sufficient information has not been submitted to show that the product is safe and efficacious.

Obviously, an approvable and a nonapproval letter are very similar, as they each ask for additional information before the drug product can be marketed. Both letters detail a list of requirements the company must meet before gaining approval. Because the requirements between an approvable and a nonapproval letter can be so similar, Congress has asked that the FDA look into changing the letters. Some have suggested something called a complete response, which would simply list the deficiencies of the drug in question that would need resolution in order to gain approval. This document would potentially replace the approvable and nonapprovable letters.

In some cases, the FDA may ask for phase 4 clinical trials, also known as postmarketing testing, to be conducted on the drug. These studies may lead to additional indications or uses that were not included in the original FDA-approved label. It may be based upon information that is useful but not critical for the use of the product. If there is information that the agency feels it needs prior to granting approval for a drug, it will ask the company to perform additional testing in the phase 3 trial rather than after the approval. Thus, not every approved drug will undergo phase 4 trials.

CRST: How are black-box warnings determined?

Dr. Chambers: Black-box warnings are a special category. They are similar to other warnings, except they actually have a black box around them and can be located anywhere on the drug's labeling instead of just in the warning section. They are usually placed close to the front for easy viewing, whereas normal warnings are typically located in the middle of the label. Black-box warnings generally are used for particularly severe potential side effects such as morbidity.

A few ophthalmic therapeutic drugs have black-box warnings, such as chloramphenicol, which at one time was the leading ophthalmic anti-infective product for bacterial infections. Chloramphenicol is still used today, although when the black-box warning was added, the drug product's indication was changed to say roughly, “use as a last resort.” The compound chloramphenicol, when given orally or intravenously, has been associated with aplastic anemia, the halting of blood production and subsequent death. In ophthalmology, the side effects related to chloramphenicol have all been associated with chronic usage at dose levels higher than recommended in the labeling.

Wiley Chambers, MD, is Deputy Director for the Division of Anti-Inflammatory, Analgesic and Ophthalmic Drug Products at the Food and Drug Administration in Washington, D.C. Dr. Chambers may be reached at (301) 827-2040; chambers@cder.fda.gov.