FDA Perspective

Keeping Abreast of New Drug Approvals and Labeling Changes



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Am Fam Physician. 1998 Sep 15;58(4):995-998.

The U.S. Food and Drug Administration (FDA) World Wide Web home page (http://www.fda.gov) has been greatly expanded since it was last described in this department.1 When a news story or a patient mentions a new medical product, a new drug indication or warning, a few keystrokes can provide the physician with access to the FDA's exact words on the topic. From the home page, the physician can simply click on “What's New,” and then choose between “Other Press Releases,” “Talk Papers” and “Other Publications.” Another strategy is to start at the FDA home page, click on “search” and enter the name of the product.

The MedWatch Web site (www.fda.gov/medwatch) is the FDA's centralized Internet location for new safety information that is of direct clinical importance. Regularly posted are such safety-related notifications as letters to health professionals, public health advisories and safety alerts, as well as press releases and talk papers, covering the range of medical products regulated by the FDA. For example, the site has included several postings of evolving information regarding a large and sudden drop in blood pressure that can occur when sildenafil citrate (Viagra) and organic nitrates are taken together.

In addition, MedWatch compiles and posts summaries of safety-related drug labeling changes that are approved by the FDA each month. Monthly summaries going back to July 1996, with annual indexes, allow a physician to quickly find updated safety information for any drug that he or she prescribes. There is information regarding adverse event reports on dietary supplements and medical devices, including a complete listing of all recalls classified by the FDA as safety-related. MedWatch also tells the physician how to report adverse events to the FDA.

The FDA's Center for Drug Evaluation and Research (CDER) maintains a listing of drug information (www.fda.gov/cder/drug.htm) that includes new and generic approvals. Newly approved labels often can be downloaded directly from the Internet. The CDER Freedom of Information Office Electronic Reading Room has meeting agendas and minutes from FDA advisory committees. The Reading Room even has a heading for Division of Drug Marketing, Advertising and Communications, with a posting of letters sent by the FDA to prescription drug manufacturers regarding possibly false or misleading claims.

New Devices Diagnose Osteoporosis Without X-Rays

The FDA recently approved two ultrasound devices that can help physicians diagnose osteoporosis and assess a person's risk of bone fracture. These are the first devices for diagnosing osteoporosis without the use of x-rays. They are intended to be used for patients at risk of bone fracture, not as a general screening tool. Their use is contraindicated in patients with abraded skin or those with an open lesion in the area that comes into contact with the system.

An estimated 23 million American women may have some degree of decreased bone strength. Most frequently, the first indication is a wrist or hip fracture, or compression fractures that cause the upper vertebrae to collapse, curving the spine into the dowager's hump that has come to symbolize osteoporosis. Early diagnosis and treatment of osteoporosis can help prevent these complications.

The Sahara Clinical Bone Sonometer (Hologic, Inc., Waltham, Mass.) was approved on March 12, 1998. The Achilles+ Bone Sonometer (Lunar, Madison, Wisc.) was approved on June 26, 1998. These portable devices transmit high-frequency sound waves through the patient's heel for a few seconds and automatically measure the speed and attenuation of sound through bone.

As with x-ray absorptiometry, the results are expressed as T-scores. The product labels recommend that the results obtained by the sonometer be used along with laboratory test results, radiographs and a family history to diagnose osteoporosis and estimate the patient's fracture risk. Clinical studies have shown sonometer results to be as good as x-ray bone density measurements currently in use to diagnose osteoporosis and predict bone fracture risk.

The FDA Web site can be used to find detailed information about the Hologic device. From the home page (www.fda.gov), click on search and enter “bone sonometer.” When the search is complete, click on “PMA March 1998,” and then on “P970017” (the application number appearing next to the name of the device). Within a few moments, these steps will produce a free download of Adobe Acrobat Reader and 46 pages of detailed information.

Effectiveness of Drugs in the Pediatric Population

For years, children have been erroneously considered small adults when the effect of prescription drugs on their overall health is estimated. Currently, in the United States, fewer than 20 percent of prescription medications are labeled for pediatric use. Nevertheless, drugs developed for adults may also be effective in and are sometimes the only options for treating children. Physicians using these drugs must estimate pediatric dosages from the dosages found to be safe and effective in adults. Such estimates are unreliable because children, particularly those younger than two years of age, often metabolize drugs differently than adults. Furthermore, some drugs have different side effects and toxicities in children than in adults, even when appropriate dosages are used. There is no systematic way of testing the safety and efficacy of drugs on the pediatric population.

Drug manufacturers may be hesitant to perform pediatric studies for medications intended primarily for adult use. Use in children may generate little additional revenue. Substantial product liability and medical malpractice issues, plus added difficulty in attracting patients, administering the drug and ensuring patient compliance, are additional deterrents to pediatric trials.

The FDA has attempted to alleviate this problem with a 1994 rule requiring drug manufacturers to survey existing data and determine if those data are sufficient to support the addition of pediatric use information to the product labels.2 The rule explicitly recognizes that controlled clinical studies to support pediatric use information need not have been carried out in pediatric patients if the course of the disease and the effects of the drug are sufficiently similar in children and adults to permit extrapolation from the adult effectiveness data to pediatric patients. In these cases, controlled clinical studies in adults, together with pharmacokinetic and adverse reaction data in pediatric patients, may be sufficient.

The FDA Modernization Act of 1997 (FDAMA),3 signed into law on November 27, 1997, created section 505A of the Federal Food, Drug, and Cosmetic Act (21 U.S.C. 355a) to provide a new incentive for pharmaceutical manufacturers to conduct studies in support of pediatric labeling. For new drug approvals, FDAMA provides an incentive of an additional six months of market exclusivity when a drug manufacturer, at the request of the FDA, conducts pediatric studies to support pediatric labeling for a drug. For drugs already approved, FDAMA can add six months to any existing period of exclusivity. For approved drugs with no exclusivity, the manufacturer can obtain six months of exclusivity for the new pediatric labeling. To qualify for exclusivity, the manufacturer must first solicit a written request for pediatric studies from the FDA. (Specifically excluded are antibiotics for which any application for marketing was received by the FDA before November 21, 1997.)

FDAMA also requires that the FDA, in consultation with experts in pediatric research, develop, prioritize and publish a list of currently approved drugs for which additional pediatric information may produce health benefits in the pediatric population.

The list, containing approximately 400 drugs, was issued on May 19, 1998, and is prioritized according to three criteria. First, the drug product has significant potential in the pediatric population in the treatment, diagnosis or prevention of a disease compared with marketed products. Second, the drug is widely used in the pediatric population, as measured by at least 50,000 prescriptions per year. Third, the drug is in a class or is intended for an indication for which additional therapeutic or diagnostic options in the pediatric population are needed. The list is available through fax-on-demand (telephone: 1-800-342-2722, document number 0504), and at this address: www.fda.gov/cder/pediatric/peddrugsfinal.htm.

FDA Approves Thalidomide for Hansen's Disease

On July 16, 1998, the FDA approved the use of thalidomide for treatment of erythema nodosum leprosum, a complication of Hansen's disease, which is commonly known as leprosy. Erythema nodosum leprosum causes debilitating and disfiguring lesions on patients with leprosy. In clinical trials, 70 to 80 percent of patients with erythema nodosum leprosum responded to thalidomide therapy with improvements in skin lesions compared with about 25 percent of patients receiving placebo. After reviewing data collected over 30 years, the FDA's Dermatologic and Dental Drugs Advisory Committee recommended approval of this use for thalidomide in September of 1997.

Because of its well-known potential for causing birth defects, thalidomide will be among the most tightly restricted drugs ever marketed in the United States. In the early 1960s, the drug was used as a sedative and even prescribed to combat morning sickness. Worldwide, thalidomide caused more than 10,000 birth defects and an unknown number of miscarriages before being withdrawn from the market in 1962. These birth defects were sometimes fatal and included shortened or missing limbs, deafness, blindness, paralyzed facial muscles, extra fingers and toes, digestive tract malformations, lesions on major organs and brain damage. Other side effects include peripheral neuropathy, weak limbs, lack of coordination, drowsiness and dizziness.

To ensure proper usage, the drug's manufacturer, Celgene Corp., has developed a program called the System for Thalidomide Education and Prescribing Safety (STEPS). Pharmacies are allowed to receive thalidomide only after passing Celgene's certification process. Only physicians who are registered in the STEPS program may prescribe thalidomide to patients, and those patients must comply with mandatory patient registration, contraceptive measures and a monthly patient survey as part of a registry administered by Boston University's Sloan Epidemiology Unit. No more than a 28-day supply of the drug can be dispensed at one time.

Prescriptions for female patients will not be filled without a physician's written report of a negative pregnancy test conducted within the previous 24 hours. Weekly pregnancy testing will be required during the first month of use and at monthly intervals thereafter in women with regular cycles, or every two weeks in women with irregular cycles. While taking the drug, women are required to use two reliable forms of contraception simultaneously.

Male patients will receive written and oral warnings about the risk of possible contraceptive failure and the need to use condoms when having intercourse with women of childbearing age. It is unknown if thalidomide is present in sperm or semen, or whether its presence in sperm or semen would affect fetal development.

Thalidomide is sold by Celgene Corp., of Warren, N.J., under the trade name Thalomid.

Consistent Claims for Dietary Supplements

The Dietary Supplement Health and Education Act of 1994 (DSHEA) allows dietary supplements to carry structure/function claims, but not claims that they can treat, diagnose, cure or prevent a disease. Structure and function claims pertain only to the product's ability to affect the structure or function of the body. However, because most disease treatments can be described in terms of their effects on a structure or function of the body, it is sometimes difficult to distinguish between allowable structure and function claims and prohibited disease claims.

On April 29, 1998, the FDA proposed a rule4 that would define criteria for the structure and function claims permitted by DSHEA and the disease claims prohibited by DSHEA. The rule provides examples for both categories. DSHEA allows truthful and non-misleading claims about the effects of a dietary supplement on the structure or function of the body for maintenance of good health and nutrition. FDA approval is not required for these claims. Under the proposal, such permissible structure and function claims can state, for example, that the product “promotes regularity,” “helps maintain cardiovascular health” or “supports the immune system.”

The proposal also identifies many types of so-called “disease claims” that are prohibited under DSHEA. Relying on standard medical and legal usage, the FDA's proposal defines “disease” as “any deviation from, impairment of, or interruption of the normal structure or function of any part, organ, or system (or combination thereof) of the body that is manifested by a characteristic set of one of more signs or symptoms, including laboratory or clinical measurements, that are characteristic of a disease.”

Under the proposal, dietary supplements that expressly or implicitly claim to diagnose, treat, prevent or cure a disease are regarded as drugs and must meet the safety and effectiveness standards for drugs under the Food, Drug, and Cosmetic Act (FDCA). Examples of such prohibited disease claims for a dietary supplement include “protects against cancer,” “antiseptic,” “lowers cholesterol” and “reduces nausea associated with chemotherapy.”

Adverse events associated with dietary supplements should be reported to MedWatch, regardless of the claims made for the supplement. The final version of the rule will be announced after consideration of public comments.

Dr. Rheinstein, a family physician, is director of medicine staff at the U.S. Food and Drug Administration. Veling W. Tsai is a third-year M.D./J.D. student at Southern Illinois University.

REFERENCES

1. Rheinstein PH, McGinnis TJ. Ways to access FDA information. Am Fam Physician. 1996;54:353–8.

2. Specific requirements on content and format of labeling for human prescription drugs. Revision of ‘pediatric use’ subsection in the labeling. Fed Regist. 1994;59(258):64240.

3. Guidance for industry on qualifying for pediatric exclusivity. Fed Regist. 1998;63(129):36707.

4. Dietary supplements. Comments on report of the commission on dietary supplement labels. Fed Regist. 1998;63(82):23633.

Coordinator of this quarterly series from the U.S. Food and Drug Administration is Stuart L. Nightingale, M.D., Associate Commissioner for Health Affairs.



Copyright © 1998 by the American Academy of Family Physicians.
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