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Adverse Drug Reactions

Posted by medconsumers on July 19, 2005

Remarks of Maryann Napoli at a Meeting of the Institute of Medicine ‘s (IOM’s) Committee on the Assessment of the US Drug Safety System, July 19, 2005.

I have been a consumer advocate for nearly 30 years, writing about medical research and critically appraising clinical trials. I’m still surprised that I could have been at it so long without fully understanding-until about two years ago-that it is not unusual for drug company-sponsored trials to withhold data about adverse drug reactions. I am referring to trials published in high-profile medical journals.

I learned this while writing about the cholesterol-lowering drugs, statins, when I was putting together a poster for the Cochrane Collaboration’s 2003 conference. My work has long focused on the selling of drugs to healthy people-drugs to reduce a risk factor, drugs that healthy people will take for the rest of their lives. I have always been interested in the way we Americans have come to accept the idea that a risk factor should be treated as if it were a disease. Bisphosphonate drugs for bone loss, postmenopausal estrogen to improve lipid profiles-that sort of thing. The emphasis-when selling healthy people the idea of lifelong preventive drug therapy-is on the benefits. We don’t hear much about the drugs’ risks.

For my Cochrane Poster, I summarized the proven benefits of statins for people who do not have heart disease-just a few risk factors like high cholesterol. I found only one review of the five major mostly primary prevention trials that had compared a statin drug with a placebo. All five were drug company-sponsored and published in leading medical journals. Here’s what jumped out at me. The authors of that review, who are based at the University of British Columbia , wrote in their on-line publication, Therapeutics Initiative, that only two of the five trials had reported their serious adverse events (SAE). The UBC authors reported that they had asked the investigators from other three trials for their SAE data and were refused. Working with what they had (data from only two of the trials), the UBC authors found that the benefit of statins was far more modest than doctors and the general public have been led to believe. There was approximately a 1.8% lower rate of non-fatal heart attacks in the male study participants, but this was offset by the 1.4% increase in SAE among the statin users. SAE were defined as “any untoward occurrence that results in death, is life-threatening, requires hospitalization or results in prolonged hospitalization, or significant disability.” [1]

It troubled me to see that statins aren’t anywhere near the lifesaving medications they’re purported to be. In fact, this review showed that for primary prevention, only middle-aged men under 70 benefited from these drugs. Not only was the benefit small, it was canceled by the risks. But it was far more alarming to learn that we do not have the full story on the safety of statins because three of the trials had refused to release all their SAE data [2] .so it is quite possible that the risks could considerably outweigh the benefits. But we simply do not know. Keep that in mind the next time you see a doctor quoted in the media, telling us that statins are safer than aspirin. I would learn later that this withholding of data is not unusual. In fact, sometimes the lead investigator has received only incomplete data on the drug.

I have since relayed my “revelation” to other experienced consumer advocates and every one of them said that they never heard that published drug trials often provide incomplete data about safety. I have also reported this to physicians and researchers who also say that they never heard of this withholding of SAE data. In fact, most deny that it is so.

How can healthy people who are on lifelong drug therapy make an informed decision about their medications when drug companies are allowed to withhold such important information? To go beyond statins for a moment, I’ve found that it is not unusual for anti-hypertensive drug trials to show that the cardiovascular death rate is reduced by the drug. But the overall death rate is no different from that of placebo group. Often this finding goes unexplored.

How prevalent is the non-reporting of SAE? A study by Ioannidis and Lau surveyed the safety reporting of new medications in 192 randomized drug trials, which altogether included over 130,000 participants. Only 46% of these trials reported or specified the drugs’ SAE. Overall, the researchers found the space allocated to safety results was equal to the amount of space devoted to contributor names and affiliations. The conclusion: “The quality and quantity of safety reporting vary across medical areas, study designs, and settings, but they are largely inadequate.” 3 I hope that the IOM report will shine a light on this issue and related questions like:

Why do medical journal editors let the trial sponsors get away this these glaring omissions of important data? Why aren’t these omissions “redflagged” in the abstract of every published trial that fails to provide complete safety data? Why do these editors allow drug company-sponsored trials to express their results in relative risk reduction terms and omit the more-understandable-to-consumers absolute risk reduction? Is it any wonder that many consumers overestimate the effectiveness of their prescription drugs?

We must find a better way to quickly detect SAE once drugs are on the market.

I urge the IOM to encourage more government-funding of epidemiological studies like the one announced last year by Kaiser Permanente. It found a greater incidence of heart attacks and sudden deaths among the enrollees who had been taking higher than normal doses of Vioxx. Everything should be done to encourage Center for Medicare and Medicaid Services to continue using its database to determine the safety and effectiveness of drugs prescribed to people on Medicare and Medicaid. And registries should be established for all clinical trials from their onset to prevent drug companies from hiding the existence of clinical trials that show negative results and from withholding SAE data from their trials [see related article].

I thank this committee for taking on this important issue and giving me the opportunity to present my perspective.

[1] Therapeutics Initiative Evidence Based Drug Therapy. Do statins have a role in primary prevention? University of British Columbia . Vancouver , April-May-June 2003. The reviewers attempted to answer the question: What is the overall health impact when statins are prescribed for primary prevention? ” In the 2 trials where serious adverse events are reported, the 1.8% absolute reduction in myocardial infarction and stroke should be reflected by a similar absolute reduction in total serious adverse events; myocardial infarction and stroke are, by definition, serious adverse events. However, this is not the case; serious adverse events are similar in the statin group, 44.2%, and the control group, 43.9% . This is consistent with the possibility that unrecognized serious adverse events are increased by statin therapy and that the magnitude of the increase is similar to the magnitude of the reduction in cardiovascular serious adverse events in these populations.”

[2] Walsh J and Pignone M. Drug treatment of hyperlipidemia in women. JAMA, May 12, 2004. “For women without cardiovascular disease, lipid lowering does not affect total or CHD mortality. Lipid lowering may reduce CHD events, but current evidence is insufficient to determine this conclusively.”.. The risk for total mortality was not lower in women treated with lipid-lowering drugs, regardless of whether they had prior cardiovascular disease or not. In the primary prevention studies, there was no reduction in either CHD or total mortality. This may be because lipid lowering does not affect total mortality in women or because there were few deaths in the small, relatively healthy cohorts of women studied, even after summarizing study findings. In most of the studies, the length of follow-up was only 2.8 to 6 years. It is possible that a reduction in total mortality might have been observed with a longer duration of follow-up. For secondary prevention, CHD mortality is reduced, but total mortality is not. Possible explanations include chance, the limitation that not all studies reported both CHD and total mortality, or not all studies could be included in each summary estimate. Another potential explanation might be an increase in a competing cause of mortality, for example, an increase in hemorrhagic stroke with lipid-lowering therapy. However, information on the causes of non-CHD mortality is not available for all the trials, so this possibility cannot be proven. Publication of cause-specific mortality for many of the larger trials could help to clarify the association between lipid-lowering therapy and total mortality.”

[3] Loannidis JME, Lau J. Completeness of safety reporting in randomized trials of seven medical areas. JAMA 2001, Jan 24-31.

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