Boston, MA -More concern about Pfizer's plans to market its new cholesterol drug, torcetrapib, in combination with atorvastatin (Lipitor) has been raised by a leading pharmacoepidemiologist.

Writing in a Perspective in the June 23, 2005 issue of the New England Journal of Medicine [1], Dr Jerry Avorn (Harvard Medical School, Boston, MA) claims Pfizer's development strategy for torcetrapib is just a way of protecting sales of Lipitor once its patent expires and is not in the best interest of anyone apart from the company. He suggests that the US Food and Drug Administration (FDA) should have done more to prevent this and that the industry has become too powerful in the field of medical research. But the doctor heading up the major trial with torcetrapib says Avorn is being unrealistic.

Torcetrapib is one of a new class of drugs that brings about an increase in HDL by inhibiting cholesteryl ester transfer protein. But the major outcome study that Pfizer is conducting with this new drug involves its combination with the company's best-selling statin, atorvastatin, the patent of which is due to expire in 2010. The combination will be compared with atorvastatin alone.

Avorn explains that because of the design of this study, the FDA is likely to approve torcetrapib for use in a combination product that includes atorvastatin. He points out that Pfizer will market this new product as a combination, preventing physicians from using torcetrapib with any other statin or with generic atorvastatin when it becomes available.

Noting that antitrust laws normally prohibit a manufacturer from offering a drug only when it is "bundled" with another of its products, Avorn says that because the FDA has accepted the proposed trial design "it appears that Pfizer will avoid such antitrust prohibitions by having the FDA do its bundling for it."

"These studies will enroll thousands of patients who are at risk for cardiovascular disease, cost Pfizer millions of dollars, and go on for years. But when they are completed, clinicians, patients, payers, and regulators will still not know how well this new treatment for atherosclerosis performs in combination with any risk-modifying therapy other than Lipitor," Avorn states.

He adds that while high costs may be the most obvious downside to this "FDA-sanctioned yoking of the two brand-name drugs," there will also be clinical problems. "Patients who cannot tolerate (or afford) Lipitor will have no way of obtaining torcetrapib for use with another statin that may be better for them," he points out.

Avorn says the FDA should have tried to convince Pfizer to implement a study design that would better protect the interests of science, patients, and even payers. He suggests that such studies could have set a target level of LDL cholesterol and randomized participants to one of several statins or could have left the choice of statin to the individual investigator and then randomized patients to torcetrapib or placebo; both designs would have produced more generalizable findings.

Avorn goes on to say that this controversy "brings several long-standing questions about clinical drug research into sharp focus." He notes that because of their great profits, the annual research expenditures of the pharmaceutical companies exceeds the entire budget of the National Institutes of Health (NIH), which has "helped entrench the dominance of pharmaceutical companies over the research agenda for therapeutics," a situation that has been made worse by the increasing scarcity of public funds for medical research.

He comments that the studies of bundled torcetrapib/atorvastatin illustrate where this trend can lead. "The current trial design may not meet the scientific needs of prescribers, the clinical needs of patients, the economic needs of payers, or the regulatory needs of policy makers. But they superbly meet the business needs of the sponsor—to gather information in a way that will protect the market share of the largest drug company's most important product."

Avorn suggests that more federally funded trials should be done, and he believes that these could pay for themselves. He uses rofecoxib (Vioxx, Merck) as an example. "If a moderate-sized NIH-funded clinical trial of the cardiovascular risks of coxibs had been performed in 2000 and 2001, most of the $2.5 billion per year—about $1 billion annually from public coffers—that was spent on rofecoxib might have been saved."

Avorn adds that with pharmaceutical costs increasing faster than most other healthcare expenditures, the nation requires studies that will meet the needs of evidence-based prescribing and not just the needs of the pharmaceutical industry. "It is not a question of whether we can afford to pay for our own drug trials; it is increasingly evident that we cannot afford not to do so," he concludes.

Responding to these views for heartwire, Dr Philip Barter (The Heart Research Institute, Sydney, Australia), who is chair of the steering committee of the torcetrapib major-outcome trial, said that Avorn's ideas were idealistic. "Avorn's points are appealing and supportable in an ideal world, but the world is not ideal, and his points are quite unrealistic," he commented.

Barter, who also consults for several other statin companies, says that torcetrapib will have a role only if it is shown to have benefits over and above current best practice, which includes statins. He maintains, "Because studies to test such incremental benefits are extremely expensive, it is not feasible for any one provider to fund studies of torcetrapib in combination with all currently available statins."

He added: "Given that the primary scientific and clinical question being asked relates to the efficacy (or otherwise) of adding torcetrapib to a statin, the question will be answered as well with atorvastatin as it would with any other statin capable of achieving recommended LDL targets. However, the efficacy of such a combination must be balanced against possible risks. The fact that risks associated with the combination may vary with different statins makes it imperative that a given study be conducted with a single statin."