Industry-Funded Trials Often Use Improper Comparators, JAMA Editorial Says

Industry-sponsored comparative trials are often ineffective at answering clinically relevant questions due to the use of substandard comparators, according to a commentary in the April 12 issue of the Journal of the American Medical Association.

"Industry-funded trials that compare their products as first-line drug therapy with inferior agents do not provide useful evidence about either first-line or second-line drug treatment," the article states.

The commentary by Bruce Psaty (University of Washington), Noel Weiss (University of Washington) and Curt Furberg (Wake Forest University) evaluates the clinical trial designs of large, long-term comparative hypertension trials.

The JAMA commentary is the second critique of industry-sponsored trials in recent months; an analysis of antipsychotic trials published in the American Journal of Psychiatry found comparative trials were biased toward the sponsor's product (¹ (Also see "Antipsychotic Trials Biased Towards Sponsor’s Drug, Study Suggests" - Pink Sheet, 6 Feb, 2006.), p. 9).

Psaty, Weiss and Furberg note that "industry sponsors have no obligation to serve the health of the public," and "as a result, the design of large, long-term comparative trials may, in some instances, function as commercial speech rather than compelling science."

The authors assert that recent hypertension outcomes trials were not designed to support a first-line indication. "If an industry sponsor really wanted its antihypertensive to compete for first-line treatment status, the comparison drug would have to be a low-dose thiazide diuretic," they state.

The article points to the National Institutes of Health Antihypertensive & Lipid-Lowering treatment to prevent Heart Attack Trial (ALLHAT) as establishing low-dose diuretics as the first-line therapy for hypertension. Furberg chaired the ALLHAT steering committee.

The study found the generic diuretic clorthalidone was superior to Pfizer's calcium channel blocker Norvasc (amlodipine) and angiotensin converting enzyme inhibitors in preventing cardiovascular events (² (Also see "NIH Hypertension Guidelines Suggest Newer Agents For Certain Risk Factors" - Pink Sheet, 19 May, 2003.), p. 26).

The authors use Pfizer's Anglo-Scandinavian Cardiac Outcomes Trial (ASCOT) as an example of how a study comparing an antihypertensive agent against a therapy that is not established as the standard of care fails to yield clinically useful information.

The ASCOT-BPLA trial - which compared calcium channel blocker amlodipine to a beta blocker atenolol for prevention of cardiovascular events - was stopped early based on an observed mortality benefit for amlodipine (³ , p. 17).

Based on the ASCOT trial and a post hoc analysis of ALLHAT data, Pfizer has suggested that Norvasc labeling should include non-inferiority language relative to diuretics (⁴ , p. 5).

The commentary, however, contends that ASCOT data is useless to support a first-line claim for Norvasc.

"The existence of a published amlodipine-based vs. atenolol-based comparison trial may make it appear as if the answer to this question is valuable or important science," the article says.

However, "from the point of view of public health and clinical practice, this trial indeed addresses an uncommon clinical question and provides no information about whether amlodipine or atenolol might be the preferred second-line therapy among patients already receiving low-dose diuretics."

In fact, the article suggests randomizing patients to atenolol may have been unethical because it provided them with substandard therapy. "The direct comparison of amlodipine with atenolol required, in effect, withholding optimal therapy, low-dose diuretics, from about 45% of the participants randomized to the atenolol-based regimen."

The authors find similar design faults in three other major comparative hypertensive trials, all failing to use diuretics as the comparator to support first-line use.

The Losartan Intervention For Endpoint reduction in hypertension (LIFE) study of Merck's angiotensin II receptor blocker Cozaar (losartan) and the International Verapamil-Trandolapril (INVEST) study of calcium channel blocker verapamil both use the beta blocker atenolol as the comparator.

Novartis' Valsartan Antihypertensive Long-term Use Evaluation (VALUE) study compared angiotensin II receptor blocker Diovan (valsartan) to Norvasc.

With diuretics established as first-line therapy for hypertension, comparative trials should focus on identifying the best second-line treatment, Psaty, Weiss and Furberg maintain.

"When the optimal first-line therapy is clearly defined, the key clinical and public health question becomes the optimal second-line drug therapy in patients whose blood pressure is not adequately controlled. This question...would best be answered by a direct comparison among several drug therapies in patients who were all receiving a low-dose diuretic."

The commentary suggests that ACE inhibitors, angiotensin receptor blockers, beta blockers, calcium channel blockers and aldosterone antagonists could be evaluated for second-line use.

The three authors have long been outspoken critics of industry and FDA. They were co-authors of a JAMA article highlighting issues with Bayer's withdrawn statin Baycol to assert that there is an inherent conflict of interest in FDA's postmarket safety system (⁵ , p. 12).

Psaty and Furberg also published an article in the New England Journal of Medicine in 2005 advocating limits on the use of COX-2 inhibitors.

Most recently, as a consultant to FDA's Drug Safety & Risk Management advisory committee, Furberg was a central figure in the panel's recent decision to include a black box warning in labeling for attention defecit/hyperactivity disorder drugs (⁶ , p. 14).

In an interview with "The Pink Sheet," Furberg suggested that clinical trial designs need additional safeguards and review by an independent, external group such as NIH.

In addition, FDA should have the authority to deem a trial design unacceptable, Furberg said. However, the agency's ability to review trial protocols would likely be limited due to resource and regulatory constraints. The AJP article concerning antipsychotic trials made a similar recommendation.

Design shortcomings identified in the survey of hypertensive trials are common among comparative studies, but they are more prevalent in lucrative therapeutic areas where there are several therapeutic options, Furberg said.