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Originally Published February 1999

REGULATORY FOCUS

Extra Labeling for Certain Drugs

Two final rules issued by FDA in early December will require extra labeling for certain pharmaceutical products. The more prominent ruling, published December 2 in the Federal Register (63 FR:66631– 66672), requires pediatric studies of many new drugs and biologics. It takes effect April 1. The second ruling requires distribution of patient medication guides for drugs that pose significant health concerns and takes effect June 1.

The agency says that pediatric studies are necessary because "most drugs and biologics have not been adequately tested in the pediatric subpopulation. As a result, product labeling frequently fails to provide directions for safe and effective use in pediatric populations."

Currently, many drugs used by both adults and children either give no specific directions and indications for children or call for a reduced dosage for children without citing any clinical-trial evidence to back up the specific dose.

"The absence of pediatric labeling information poses significant risks for children," the agency states. "Inadequate dosing information exposes pediatric patients to the risk of adverse reactions that could be avoided with an appropriate pediatric dose."

In December 1994, FDA issued a regulation requiring manufacturers of existing drugs to survey available data and determine whether the data supported the inclusion of additional pediatric use information on the product label. If so, they were required to file an application for a label change with FDA. If there was insufficient information, the agency required manufacturers to include the following phrase on the label: "Safety and effectiveness in pediatric patients have not been established."

Manufacturers found very little existing data. FDA received label-change applications for only 430 drugs or biologics, many of which showed insufficient data or simply requested the addition of the phrase.

The problem also existed for new drugs. In 1996 there were 40 new molecular entities with potential usefulness for children reported, but only 15 had some sort of pediatric labeling.

The new rule requires the evaluation of pediatric safety and effectiveness in new drugs and biologics if the product is intended to be used in a significant number of children or would provide a meaningful therapeutic benefit to children over existing treatments. The manufacturer must prove that an exemption from the requirement is justified.

In the December 1 Federal Register (63 FR:66377–66400), the agency published a rule that will be much less widely enforced than the one for pediatric use, but it will also require extra labeling for certain products.

The agency has encouraged the distribution of medication guides to patients in order to promote compliance and to reduce complications caused by improper or missed doses. In August 1995, it proposed a rule supporting private sector efforts to make and disseminate such guides. Part of that proposal was a provision allowing FDA to require distribution of guides, with agency-approved wording, for prescription drugs and biologics posing a "serious and significant public health concern."

Then, in 1997, Congress enacted legislation establishing a voluntary private sector process to achieve the patient labeling goals from FDA's 1995 proposal. The final rule published in December, designed to supplement the voluntary program, will require the guides for products of "serious and significant concern."

FDA says the extra labeling will be required for products that meet one or more of the following criteria:

• Patient labeling could help prevent serious adverse effects.

• There are serious risks, relative to benefits, that patients should know about when deciding to use or to continue to use the product.

• The product is important to health, and regimen compliance is critical to effectiveness.

The patient medication guides will outline why a medication poses a serious and significant public health concern, and then list indications, contraindications, directions for use, precautions, and possible side effects. Storage information and specific instructions for using products that are not orally administered will also be included.

For more information on the pediatric issue, contact Khyati N. Roberts, Center for Drug Evaluation and Research, FDA, 5600 Fishers Ln., Rockville, MD 20857, 301/594-6779; or Karen D. Weiss, Center for Biologics Evaluation and Research, FDA, 1401 Rockville Pike, Rockville, MD 20852, 301/827-5093.

For more information on the medication guides, contact Nancy M. Ostrove, CDER, FDA, 5600 Fishers Ln., Rockville, MD 20857, 301/827-2828; or Toni M. Stifano, CBER, FDA, 1401 Rockville Pike, Rockville, MD 20852, 301/827-3028.