Category Archives: drug safety
See my previous post on the need for data sharing. For the past three years, a group of researchers has been trying to gather all of the clinical trial data for the anti-influenza drug Tamiflu (oseltamivir), without success. As a result there is continuing uncertainty about the benefits — and harms — of the drug. They tell their story in a New York Times op-ed and an article in PLoS Medicine. Here is the summary from the PLoS Medicine article:
- Systematic reviews of published randomized clinical trials (RCTs) are considered the gold standard source of synthesized evidence for interventions, but their conclusions are vulnerable to distortion when trial sponsors have strong interests that might benefit from suppressing or promoting selected data.
- More reliable evidence synthesis would result from systematic reviewing of clinical study reports—standardized documents representing the most complete record of the planning, execution, and results of clinical trials, which are submitted by industry to government drug regulators.
- Unfortunately, industry and regulators have historically treated clinical study reports as confidential documents, impeding additional scrutiny by independent researchers.
- We propose clinical study reports become available to such scrutiny, and describe one manufacturer’s unconvincing reasons for refusing to provide us access to full clinical study reports. We challenge industry to either provide open access to clinical study reports or publically defend their current position of RCT data secrecy.
Also in PLoS Medicine, a response by a group of European drug regulators. The regulators agree that that data secrecy is no longer acceptable but list some reasons for caution.
Peter Doshi and Tom Jefferson, “Drug Data Shouldn’t Be Secret,” New York Times, April 10, 2012.
Doshi P, Jefferson T, Del Mar C (2012) The Imperative to Share Clinical Study Reports: Recommendations from the Tamiflu Experience. PLoS Med 9(4): e1001201. doi:10.1371/journal.pmed.1001201
Eichler H-G, Abadie E, Breckenridge A, Leufkens H, Rasi G (2012) Open Clinical Trial Data for All? A View from Regulators. PLoS Med 9(4): e1001202. doi:10.1371/journal.pmed.1001202
Here is a summary from Pharmalot.
Because I was on vacation when the latest Chantix (varenicline) news broke, I’m a week late in posting on it. Last Monday, a meta-analysis was published online in the Canadian Medical Association Journal. The meta-analysis, which combined 14 Chantix clinical trials involving 8216 partcipants, showed a 72% increased risk of ischemic or arrhythmic adverse cardiovascular events. Moreover, all except one trial involving approximately 700 participants excluded patients with a history of cardiovascular disease, indicating that Chantix may have heart risks even for people without a history of heart trouble. The meta-analysis follows last month’s FDA warning that Chantix may raise the risk of cardiovascular events in persons with a history of cardiovascular disease.
A number of people have raised safety concerns with Chantix since it was approved in 2006, including John Spangler and Curt Furberg of Wake Forest University School of Medicine (see background here, here and here), both of whom were co-authors on the meta-analysis. In 2008, researchers at the Institute for Safe Medication Practices issued a report showing a high rate of serious adverse events associated with the drug. In response to the ISMP report, the Federal Aviation Administration said it would no longer permit pilots or air traffic controllers to use Chantix, and the Federal Motor Carrier Safety Administration advised medical examiners to not qualify anyone currently using Chantix for a commercial motor vehicle license. The Chantix label includes a warning that Chantix may impair driving ability. The label also contains a boxed warning relating to Chantix’s psychiatric risks. Last year, a study published in The Annals of Pharmacotherapy found that Chantix was associated with violent or aggressive thoughts and acts. A study in PLoS One found that Chantix was associated with acts of violence toward others.
In my opinion, smokers should rely on other methods to stop smoking, such as nicotine replacement therapy, bupropion or counseling, rather than using Chantix.
In a recent post, I discussed a panel discussion on May 14, 2011, at the American Heart Association Quality of Care and Outcomes Research in Cardiovascular Disease and Stroke conference. The discussion addressed lessons from experiences with three drugs that were withdrawn or greatly restricted because they caused cardiovascular (CV) harm — rofecoxib (Vioxx), rosiglitzone (Avandia) and sibutramine (Meridia). I summarized the introduction by Sanjay Kaul and the presentations by Steve Nissen and Milton Packer. In this post I will discuss the presentations by statistician Dean Follmann of National Institute of Allergy and Infectious Diseases, NIH, and Ellis Unger of the Center for Drug Evaluation and Research, FDA.
Follmann’s presentation was similar to one he gave at the July 2010 joint meeting of the Endocrinologic and Metabolic Drugs Advisory Committee and Drug Safety and Risk Management Advisory Committee that was held to discuss Avandia. Follmann discussed the hierarchy of study designs, with randomized controlled trials (RCTs) that are double blind superiority trials being at the top. In such a design, randomization ensures that the groups are similar and double blinding ensures that the investigators can’t favor one arm over another. In addition, in a superiority trial the incentives encourage good study conduct because sloppiness (e.g. missing data, loose inclusion criteria, lack of adherence) makes it more difficult to show that the drug is effective. At the next level of reliability, according to Follman, are RCT noninferiority trials and meta-analyses. In a noninferiority trial, the goal is to conclude that a drug is not “unacceptably worse” than a comparator. In Follmann view, the incentives in a noninferiority trial “encourage sloppiness,” since sloppiness will tend to make the two arms more similar and thus meet the goal of noninferiority. (The RECORD trial was a noninferiority trial and was used to assess the safety of Avandia.) A meta-analysis is a quantitative synthesis of RCTs. In Follmann’s view, the quality of evidence of a meta-analysis is a bit less than a RCT, because (1) there may be unpublished trials that are not available for inclusion in the meta-analysis, (2) studies may be heterogeneous in population, endpoints, and comparators, and (3) the decisions on how to conduct the meta-analysis (e.g., what to include, how to analyze, endpoint definition) are made with knowledge of the potential safety signal. For example, to counter the Nissen-Wolski and FDA Avandia meta-analyses, which used myocardial infarction (MI) as the endpoint, GlaxoSmithKline chose a wider endpoint of serious and nonserious ischemia, resulting in a smaller hazard ratio. In addition, GSK used a “very unconventional and some would say illegitimate method of analyzing the data,” according to Follmann. Follmann also stated that it was a “revelation” to him to learn from Nissen’s presentation that GSK had done previous meta-analyses that had similar results as the Nissen-Wolski meta-analysis.
Follmann stated that the next study type in the hierarchy is observational studies. Because, observational studies are not randomized, drug choice may be based on patient characteristics, doctor preference, and unquantifiable factors. Statistical adjustment is done, but the result is less reliable than a RCT. Below observational studies are the FDA’s Adverse Event Reporting System (AERS) and data collected for other purposes, such as data collected by HMOs or the Centers for Medicare & Medicaid Services (CMS). In summary, Follmann stated that assessing a post marketing safety signal is difficult. RCTs are the best data source but are not always available.
Ellis Unger’s first remark was that Nissen had a “retrospectoscope in his back pocket” and was being a “Monday morning quarterback” with respect to the FDA’s actions concerning Vioxx and Avandia. He pointed out that the FDA has to make decisions in real time, which is not so easy, and he is not convinced that the FDA did the wrong thing, based on what it knew at the time. He does agree with the ultimate outcome for Vioxx, Avandia and Meridia.
With respect to Vioxx, Unger stated that at the time of approval it was known that there were associations between Vioxx and hypertension and edema, but in the preapproval trials there were no differences with respect to MI and stroke. The VIGOR trial showed a hazard ratio of 1.94 for the composite endpoint of death, MI and stroke. For non-fatal MI, the hazard ratio was 4.51 (p < 0.05). He does not believe the VIGOR data were enough that Vioxx should have been removed from that market at that point (2000). Unger next discussed the APPROVe trial, which was stopped two months early due to an excess in serious thrombotic events in the Vioxx group (RR 1.92), and resulted in the voluntary removal of Vioxx from the market. In the wake of Vioxx’s withdrawal, the FDA held a joint meeting of the Arthritis and Drug Safety and Risk Management Advisory C0mmittees on February 16-18, 2005 to discuss Cox-2 inhibitors. Unger summarized the data presented at the meeting as follows: (1) “all Cox-2-selective agents seem to increase CV risk (no ranking)” and (2) “available data do not support greater CV risk for selective agents as compared to non-selective agents.” After the meeting, the FDA added labeling warning of the potential for increased risk of CV thrombotic events to all NSAIDs.
With respect to rosiglitazone, Unger stated that the evidence of cardiovascular risk is “neither robust nor conclusive” and “remains an open question,” while acknowledging that there were “multiple signals of concern from various sources of data, without reliable evidence to refute risk.” He stressed the limitations of the Nissen/Wolski meta-analysis, including that the results were based on a relatively small number of events. Interestingly, Unger said that the FDA was more worried about the finding for cardiovascular death (odds ratio 1.64, p = 0.06) than the finding for MI (odds ratio 1.43, p = 0.03), even though the result for CV death was not statistically significant. Unger views the ADOPT and DREAM trials as being neutral on cardiovascular death, with both showing trends for increased MI.
With respect to the RECORD trial, Unger criticized the open-label design and possibility of ascertainment bias but also stated that the results for all-cause death are “unlikely to be influenced by bias,” and showed a favorable trend for rosiglitazone. With respect to MI, the results were “inconclusive,” as neither the GSK nor the FDA analysis showed a statistically significant increase in MIs. Unger stated that viewed as a means to test the two hypotheses generated by the Nissen/Wolski meta-analysis — rosiglitazone causes MI and increases the risk of CV death — RECORD “does not substantiate the findings of the Nissen/Wolski meta-analysis.” (For more on Unger’s views on RECORD, see his slides from the 2010 advisory committee meeting on rosiglitazone here). Finally, Unger noted that the David Graham epidemiological study of Medicare patients did not find a statistically significant higher risk of MI with rosiglitazone as compared to pioglitazone. Why didn’t the FDA take rosiglitazone off the market instead of leaving it on the market with restricted access? Unger cited conflicting data on the existence and magnitude of risk, the need for detailed re-adjudication and analysis of RECORD, the fact that some patients are currently taking rosiglitazone and want to stay on it even with knowledge of the risk.
With respect to sibutramine (Meridia), a weight loss drug that is an inhibitor of norepinephrine, serotonin and dopamine reuptake, Unger noted that at approval in 1997 the drug was known to increase blood pressure and heart rate and result in miscellaneous ECG changes, but the adverse effects were deemed “monitorable.” The European regulators, however, required a post-marketing cardiovascular outcomes study. This was the SCOUT trial, a large randomized, double-blind, placebo-controlled trial in obese patients over age 55 with a history of coronary artery disease, peripheral vascular disease, or stroke and/or Type 2 diabetes with at least one other risk factor. The primary endpoint was a composite of CV death, resuscitation after cardiac arrest, non-fatal MI and non-fatal stroke, which occurred in 11.4% of the patients on sibutramine and 10.0% of the patients on placebo (HR 1.16, p = 0.02). Following this trial, sibutramine was removed from the market in the U.S. and Europe.
Unger noted that post-marketing safety used to focus on rare, severe events that were detectable from spontaneous reporting. In recent years, there has been greater interest in small increases in common but serious events, such as MI, stroke, and CV death. Quantification of common risks is challenging with longer, larger studies required. If the drug is for a symptomatic condition such as depression or pain, it is difficult to keep patients from dropping out of the trial. It is difficult to interpret the results of a trial when there have been a lot of dropouts.
Unger stated that when the FDA reviews clinical trial data they are interested in imbalances in virtually any safety issue so we “always see safety signals because we look at 150 adverse events.” They have to consider a number of issues in assessing causality: whether there is a plausible mechanism of action, whether it has been observed in other related drugs, whether there is a dose-response relationship, etc.
Comment: I think the problem of post approval safety is not entirely solvable, because there will always be safety signals that crop up after drugs are approved. However, I am in sympathy with Dr. Nissen’s view that safety signals should be investigated and acted on as early as possible, and preferably before approval.
Also, on the topic of Vioxx specifically, I suggest the following for further reading:
Joseph S. Ross, MD, MHS; Kevin P. Hill, MD, MHS; David S. Egilman, MD, MPH; Harlan M. Krumholz, MD, SM. Guest Authorship and Ghostwriting in Publications Related to Rofecoxib: A Case Study of Industry Documents From Rofecoxib Litigation. JAMA. 2008;299(15):1800-1812.
Keven P. Hill, MD, MHS; Joseph S. Ross, MD, MHS; David S. Egilman, MD, MPH; Harlan M. Krumholz, MD, SM. The ADVANTAGE Seeding Trial: A Review of Internal Documents. Annals of Internal Medicine. 2008;149(4):251-258.
Joseph S. Ross, MD, MHS; David Madigan, PhD; Kevin P. Hill, MD, MHS; David S. Egilman, MD, MPH; Yongfei Wang, MS; Harlan M. Krumholz, MD, SM. Pooled Analysis of Rofecoxib Placebo-Controlled Clinical Trial Data: Lessons for Postmarket Pharmaceutical Safety Surveillance. Archives of Internal Medicine. 2009;169(21): 1976-1985.
Joseph S. Ross, MD, MHS; David Madigan, PhD; Marvin A. Konstam, MD; David S. Egilman, MD, MPH; Harlan M. Krumholz, MD, SM. Persistence of Cardiovascular Risk After Rofecoxib Discontinuation. Archives of Internal Medicine. 2010;170(22):2035-2036.
Snigdha Prakash, All the Justice Money Can Buy: Corporate Greed on Trial (2011) (book by former NPR reporter Snigdha Prakash on the Vioxx saga — focuses on a particular Vioxx trial).