JAMA study likens using new prescription drugs to playing Russian Roulette

Subject: A study published in today's Journal of the American Medical Association looked at new drugs that were approved by the FDA from 1975 to 1999. Of the 548 drugs approved, 56 were later taken off the market or later given serious side effect warnings. If using drugs, stick with well established drugs and hold off on the new ones.

Here is this mornings Associate Press story reviewing the current study, followed by the study abstract and comments by the authors and a link to the full text of the study.

[from the Associated Press, May 1, 2002]

Study: New Drugs Have Side Effects
By LINDSEY TANNER
AP Medical Writer

CHICAGO (AP) - New research estimating that 20 percent of recently approved prescription drugs have serious and even life-threatening side effects suggests doctors should prescribe older medication whenever possible.

''It's like playing Russian roulette when a doctor prescribes a newly approved drug that doesn't have a big breakthrough,'' said Dr. Sidney Wolfe of Public Citizen Health Research Group, a co-author of the study.

The findings, published in Wednesday's Journal of the American Medical Association, should prompt the Food and Drug Administration to consider raising its threshold for approving new drugs when safe and effective alternatives exist, the researchers said. They said pressure from pharmaceutical companies and doctors' failure to closely read warning labels are partly to blame.

An accompanying editorial by two FDA experts said the analysis overstates the problem.

Safety studies that are conducted before a drug wins approval typically involve a few thousand patients and may not detect all side effects, especially relatively rare ones, Drs. Robert Temple and Martin Himmel said.

''Frequent post-marketing label changes are therefore inevitable and should be anticipated,'' they wrote.

Temple also noted that some medications cause side effects in only certain groups of patients, such as pregnant women, which does not mean a drug is dangerous for everyone.

The researchers, led by Dr. Karen Lasser of Cambridge Hospital and Harvard Medical School, analyzed 548 drugs approved from 1975 through 1999. Of these, 56, or more than 10 percent, were later given a serious-side-effect warning or taken off the market for safety reasons. The number climbed to about 20 percent when the researchers took into account drugs that were approved toward the end of the period studied.

''When a drug that comes on the market has a 1-in-5 chance that it's going to have to be banned or get a black-box warning is pretty worrisome,'' Wolfe said.

Most troublesome new drugs do not represent any advance in treatment and are at best no better than older, safer drugs already on the market, he said.

The study analyzed what are known as ``black-box'' warnings listed in the Physicians Desk Reference, a compendium of drugs and labeling information published annually. Black-box warnings highlight the most serious side effects.

Sixteen drugs studied were withdrawn from the market, about half of them within two years after winning FDA approval.

They include the diabetes drug Rezulin, which was approved in 1997 but has been linked to dozens of cases of fatal liver damage. Lasser said doctors continued to prescribe it in an unsafe manner even after it was given a black-box warning, and it was ultimately withdrawn from the market in 2000.

Two allergy drugs, Seldane and Hismanal, were linked with potentially fatal heart problems in certain patients but were not removed from the market until several years after receiving black-box warnings.

The FDA is correct in saying doctors don't pay enough attention to warning labels, but that is ``all the more reason to do the right thing on the front end,'' Wolfe said. ``The remedy should be don't put the drug on the market unless it's a breakthrough drug.''

The FDA has said that while its drug review process has gotten shorter in recent years, the procedure is still adequate. But the agency has expressed concern over doctors not reading drug warning labels closely.

Temple said that while doctors are getting better at reporting side effects to the FDA and drug companies, the agency is seeking further improvements, including a proposal to include a drug's approval date on packaging inserts.

''I don't think anybody believes that we're absolutely at the best we can do, but it's better,'' Temple said.

The study ''adds to the body of evidence that we really have to enhance our system of sk management and evaluation of drug safety and effectiveness,'' said Christopher Milne, assistant director of Tufts Center for the Study of Drug Development, who was not involved in the research.

But it also risks ''going overboard'' and making all patients on new drugs think they should stop taking them, which could be harmful, Milne said. ---

On the net:
The full test of the JAMA article is available at: http://jama.ama-assn.org/issues/v287n17/rfull/joc11497.html

Here is part of the text
JAMA May 1, 2002

Timing of New Black Box Warnings and Withdrawals for Prescription Medications

Karen E. Lasser, MD, MPH; Paul D. Allen, MD, MPH; Steffie J. Woolhandler, MD, MPH; David U. Himmelstein, MD; Sidney M. Wolfe, MD; David H. Bor, MD

Context Recently approved drugs may be more likely to have unrecognized adverse drug reactions (ADRs) than established drugs, but no recent studies have examined how frequently postmarketing surveillance identifies important ADRs.
Objective To determine the frequency and timing of discovery of new ADRs described in black box warnings or necessitating withdrawal of the drug from the market.
Design and Setting Examination of the Physicians' Desk Reference for all new chemical entities approved by the US Food and Drug Administration between 1975 and 1999, and all drugs withdrawn from the market between 1975 and 2000 (with or without a prior black box warning). Main Outcome Measures Frequency of and time to a new black box warning or drug withdrawal.
Results A total of 548 new chemical entities were approved in 1975-1999; 56 (10.2%) acquired a new black box warning or were withdrawn. Forty-five drugs (8.2%) acquired 1 or more black box warnings and 16 (2.9%) were withdrawn from the market. In Kaplan-Meier analyses, the estimated probability of acquiring a new black box warning or being withdrawn from the market over 25 years was 20%. Eighty-one major changes to drug labeling in the Physicians' Desk Reference occurred including the addition of 1 or more black box warnings per drug, or drug withdrawal. In Kaplan-Meier analyses, half of these changes occurred within 7 years of drug introduction; half of the withdrawals occurred within 2 years. Conclusions Serious ADRs commonly emerge after Food and Drug Administration approval. The safety of new agents cannot be known with certainty until a drug has been on the market for many years. JAMA. 2002;287:2215-2220

Adverse drug reactions (ADRs) are believed to be a leading cause of death in the United States.1 Prior to approval, drugs are studied in selected populations2, 3 for limited periods, possibly contributing to an increased risk of ADRs after approval. Pharmaceutical companies frequently market new drugs heavily to both patients and clinicians before the full range of ADRs is ascertained. Inadequate clinician reporting may delay detection of postmarketing ADRs; less than 10% of all ADRs are estimated to be reported to MEDWATCH,4 the Food and Drug Administration's (FDA's) voluntary postmarketing reporting system.
Patient exposure to new drugs with unknown toxic effects may be extensive. Nearly 20 million patients in the United States took at least 1 of the 5 drugs withdrawn from the market between September 1997 and September 1998.5 Three of these 5 drugs were new, having been on the market for less than 2 years. Seven drugs approved since 1993 and subsequently withdrawn from the market have been reported as possibly contributing to 1002 deaths.6 For example, cisapride was approved for the treatment of a benign condition, nocturnal gastroesophageal reflux in adults. After its introduction, many pediatricians prescribed the drug to infants with gastric reflux, 24 of whom were reported to have died.6
Should clinicians hesitate to prescribe newly approved drugs? Few data are available on how frequently serious ADRs are discovered after drug introduction. Previous studies examining drug labeling changes have found high rates of undetected postapproval risks7 with low rates of subsequent drug withdrawal.8, 9 However, no study has analyzed changes in the Physicians' Desk Reference,10-35 the most commonly used source of labeling information.36 We analyzed the incidence of new black box warnings in the Physicians' Desk Reference from 1975 to 2000, a marker of the most serious ADRs, and used survival analyses to determine the course of their discovery. We also calculated the frequency and timing of drug withdrawals over this period.

COMMENT
Many serious ADRs are discovered only after a drug has been on the market for years. Only half of newly discovered serious ADRs are detected and documented in the Physicians' Desk Reference within 7 years after drug approval. Our definition of a serious ADR was conservative, since it was limited to Physicians' Desk Reference black box warnings. We did not consider other labeling changes such as bolded warnings without boxes, "Dear Health Care Professional" letters, or case reports in the medical literature. Our finding that half of all drug withdrawals occurred within 2 years is consistent with previous research,9 as is our documentation of potentially dangerous inconsistencies in the Physicians' Desk Reference.48-50
Why are so many ADRs brought to light only after drug approval? Premarketing drug trials are often underpowered to detect ADRs,2, 51 and have limited follow-up. In some cases, drugs are approved despite identification of serious ADRs in premarketing trials.52 For instance, alosetron hydrochloride was reported to be associated with ischemic colitis prior to its approval, and grepafloxacin hydrochloride was approved despite reports of QT prolongation and 2 possible deaths.6 Both were subsequently withdrawn from the market because of these adverse events. Some drugs represent a significant advance over existing drugs in the reduction of morbidity and mortality and warrant use despite limited experience. However, the drugs that do not represent a significant advance should be considered second-line drugs until their safety profile is better known.
Despite limited knowledge about the safety of new drugs, their market uptake and sales volume may be explosive. The pharmaceutical industry promotes the early use of new drugs, and influences physicians' adoption of such drugs.53-55 Direct-to-consumer drug advertising also generates a high volume of new drug prescriptions.56 Drug firms may rush new drugs to market because of concerns about patent life, a desire to mold prescribing habits prior to the market entry of competitors, and hopes for a fast "ramp-up" in sales that will encourage investors and increase stock prices.57-59 New drug safety may be further compromised by the apparent failure by drug companies to conduct postmarketing (phase 4) studies, which are required by the FDA when a safety question arises during the preapproval period.6, 60 Given the frequent introduction of drugs for which new serious adverse events are discovered, the FDA should consider raising its threshold for approving new drugs when safe, effective therapies already exist, or when the new drug treats a benign condition. Postmarketing surveillance should be completed, analyzed, and disseminated to physicians. The date of drug approval should be prominently included in drug labeling, and changes in labeling should be highlighted and dated. Furthermore, when a serious ADR is discovered, labeling of all drugs in the same class should be reviewed if a class effect is suspected.
Based on our results and those of others,7 clinicians should avoid using new drugs when older, similarly efficacious agents are available. Patients who must use new drugs should be informed of the drug's limited experience and safety record, and be observed for possible hepatic, hematologic, or cardiac toxicity. Clinicians should report ADRs to MEDWATCH, the voluntary reporting system. Given the inadequacy of clinician reporting of ADRs, other reporting methods such as patient-initiated reporting should be explored. Innovative new therapies are important, but when safe and effective therapies already exist, any new drug should be considered a black box.