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Drug approval hinges on positive results from well-designed trials
Common reasons for nonapproval include no application being filed, no clinical benefit or questionable product quality.
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WAILEA, Hawaii — The Food and Drug Administration approves a new drug when the benefits of the product outweigh the risks, as demonstrated in a well-controlled trial.
William M. Boyd, MD, a medical reviewer with the Center for Drug Evaluation and Research (CDER), described the FDA drug approval process here at Hawaii 2003: the Royal Hawaiian Eye Meeting.
“The mission of the CDER is to assure that safe and effective drugs are available to the American people,” he said.
Dr. Boyd is with the Division of Anti-inflammatory, Analgesic and Ophthalmology Drug Products.
The most common reason a drug is not approved is because an application was never submitted.
“If someone doesn’t submit an application to the FDA for us to review, that product is never going to be approved. It doesn’t matter how many articles have been written about it,” he said.
Other reasons for nonapproval include no demonstrated clinical benefit for the proposed indication, or risks that outweigh the benefit shown in clinical trials.
“If the quality of the product cannot be assured, or the product was not stable during its proposed shelf-life, then that product will not receive FDA approval,” Dr. Boyd said.
Beginning of the process
New drug approval begins with preclinical research, which can begin months or even years before clinical studies, Dr. Boyd explained. Preclinical research, which may include animal studies, is followed by phase 1, 2 and 3 clinical studies, and then the review of the new drug application (NDA).
By law, the CDER makes a distinction between ophthalmic antibiotics and anti-infectives, he said.
“The label reads that the product is indicated either for the treatment of bacterial conjunctivitis or corneal ulcers,” Dr. Boyd said.
Regarding to bacterial conjunctivitis, the panel looks for a clinical cure demonstrated in large phase 3 trials.
“We want to see resolution of ocular discharge and injection. We also need to see microbial eradication with no growth on subsequent cultures,” he said.
For a corneal ulcer indication, clinical success is defined as re-epithelialization with no infiltrate progression for two consecutive visits.
Terminology
“An investigational use for a drug is performed under an investigational new drug (IND) exemption. The IND allows a researcher to transport the drug across state lines,” Dr. Boyd said.
IND exemptions may be given to a manufacturer or an individual. Manufacturers are responsible for submitting a design, conduct and analysis of the proposed clinical study to the FDA. An investigator-sponsored IND has similar requirements, he said.
The investigator must submit a protocol or a clinical history for one or more patients.
“We need to know their qualifications, and they need to submit manufacturing information or have the authority to reference the information. If they’re using an approved product, they need to submit any planned modifications to the product,” Dr. Boyd said.
IND and NDA
An IND is required whenever human studies are conducted in the United States for off-label indications, unapproved drugs, changes in formulation or changes in route of administration. An IND is the first time paperwork is submitted to the FDA for a drug that someone wants to investigate, Dr. Boyd explained. An NDA is prepared after studies are completed. This is the information that is submitted to the FDA as the basis for the drug approval.
After an NDA is submitted, there is a medical review, he said.
“Within our division, all of the medical officers reviewing ophthalmic drug products are ophthalmologists. We also have a biopharmaceutical review, a statistical review, a microreview, a chemistry review and a pharmacology and toxicology review,” he said.
Labeling issues
The labeling review comes at the end of the review process, Dr. Boyd said.
“This is the description of the drug’s clinical pharmacology. Particular attention is paid to the indication, how the drug is supplied and the dosage,” he said.
“Specifically, if you look at ophthalmic anti-infective labeling in the microbiology section, there are two separate lists of organisms: an in vitro and clinical section and an in vitro-alone section,” he added. “The in vitro and clinical section describes pathogens that are actually identified and successfully treated in the clinical trials in vitro and clinically, and these pathogens are also described in the indications and usage section,” he said.
“The in vitro-alone section describes pathogens not actually identified and treated clinically in the well-controlled trials, but pathogens that have been shown to be susceptible in vitro to the drug product,” Dr. Boyd said.
At the end of the review process, three things can occur: the sponsor can receive a nonapprovable letter, an approvable letter or an approval letter.
“An approvable letter typically means there are items or deficiencies identified in the application that if the sponsor were to adequately address, could be the basis for approval,” he said.
The basis for drug approval is when the benefits of the drug outweigh the risks in adequate and well-controlled trials, Dr. Boyd said. After a product is approved, the sponsor is required to conduct postmarketing surveillance, such as MEDWatch and spontaneous reporting systems.
For Your Information:
- William M. Boyd, MD, medical reviewer with the Center for Drug Evaluation and Research, can be reached at HFD-550, 5600 Fishers Lane, Rockville, MD 20857; (301) 827-2119; fax: (301) 827-2531; e-mail: boydwecder@fda.gov.
- Contact the Food and Drug Administration at www.fda.gov/cder.