Bristol-Myers Squibb's Pravachol/aspirin combination should not be viewed as a precedent for approval of other combination products, FDA's Cardiovascular & Renal Drugs Advisory Committee members suggested July 18.

"If we do recommend approval to the FDA, this could be seen as precedent-setting in some ways," Committee Chair Jeffrey Borer, MD, Cornell University, said.

However, "the fact that we may recommend to you to approve this combination doesn't mean that every time two different things that are aimed at the same disease process are put together in the same pill somehow that we would necessarily suggest approval of that combination," he said.

FDA Office of Medical Policy Director Robert Temple said that the committee will likely see many proposals for combination products. "You can very easily think of a very large combination of drugs for various ills of the elderly."

The committee voted eight to one that the co-package of the lipid-lowering agent and aspirin be approved for "long-term management to reduce the risk of cardiovascular events in patients with clinically evident coronary disease."

The advisory committee rejected the original NDA because of concerns of excessive aspirin use and the inability to titrate the pravastatin dose in the combination. At the time, Bristol offered only 40 mg pravastatin with 81 mg or 325 mg of aspirin (¹ Also see "Pravachol/Aspirin Fixed-Dose Inflexibility May Lead To Undertreatment" - Pink Sheet, 21 January, 2002., p. 7).

To address the concerns, Bristol resubmitted its NDA using multiple doses of pravastatin. Six combination packages will be available: 20 mg, 40 mg or 80 mg pravastatin with either 81 mg or 325 mg aspirin.

The labeling of pravastatin from the combination was changed to recommend a 40 mg starting dose based on clinical event data supporting the application. The revised application does not include analysis of the 20 mg or 80 mg doses.

The committee continued to express concern that patients may not be aware they are receiving aspirin and could take supplemental doses of aspirin, leading to excessive bleeding especially in patients undergoing surgery.

The co-package should be approved "in the context of very distinctive packaging," committee member Beverly Lorell, MD, Beth Israel Deaconess Medical Center, said.

"If the common tablet or capsule were packaged somewhat uniquely to both enhance recognition that aspirin was in the pill and that there were safety issues regarding surgery, as well as recognition of major side effects of statins, then I would support approval," Lorrell said.

"I'm not talking about it being hidden on a small-print package insert that many patients never read," she added.

However, committee member Thomas Fleming, PhD, University of Washington, said that, while concerned about the theoretical risk of bleeding, he was "persuaded [that] with appropriate packaging that clearly identified aspirin content," the product could be approved.

Bristol Executive Director-Metabolics Clinical Design & Evaluation Rene Belder, MD, said that packaging for the product will list aspirin four times and include a Patient Information Leaflet. Initially pravastatin and aspirin will be available as separate tablets in blister packs.

One of the other concerns of the committee was that, while Bristol presumed that compliance in patients who require both drugs would increase with a combination product, the company has not conducted studies to show that.

Bristol's NDA is based on a meta-analysis of five clinical trials conducted to support previously approved Pravachol indications. The analysis found that the combo product was superior to either agent alone in reducing cardiac events and death.

Committee member Paul Armstrong, MD, University of Alberta, suggested that Bristol conduct a prospective trial to test its hypothesis of compliance.

"They have provided hypothesis-generating information that such a combination will enhance the way doctors prescribe drugs and patients take drugs....If this is precedent-setting, then why not do the research that is necessary to determine that indeed the idea is verified," he said.

During the committee's original review of the NDA in January, members suggested that patient compliance data would be useful in determining the actual benefit of combination products (² Also see "Bristol Pravachol/Aspirin Patient Compliance Study Suggested By Cmte." - Pink Sheet, 28 January, 2002., p. 14).

One of FDA's questions for the committee was whether the re-filed for NDA addresses their concern regarding "the inappropriate use of the co-packaged product in a non-indicated population."

"I don't think it is totally relevant to the approval issue we are facing here today," Borer said. "Anyone who wanted to use pravastatin for something other than secondary prevention can still do it."

Bristol says it will not replace the presently marketed pravastatin 20 mg, 40 mg and 80 mg tablets with the combination product.

The committee also raised questions about cost of the combination versus the single products. Aspirin is OTC and pravastatin will go off patent on October 20, 2005, possibly earlier if a patent challenge is successful.

"If patients in the next two years are switched from brand Pravachol to brand combination, and then subsequently the brand becomes generically available, then the pharmacist will be precluded from substituting generic pravastatin and it is essentially an evergreening of the patent on the drug," committee member Steven Nissen, MD, Ohio State University, maintained.

Belder responded that "the approval of this product would perhaps lead to some additional exclusivity but it falls within the current patent life of pravastatin."

Noting that he was uncomfortable with the discussion of cost by the advisory committee, FDA's Temple concurred that exclusivity for the combination product would end after "three years, barring some patent thing I don't understand."

"This setting could be considered somewhat coercive as to the response; after all, they are seeking approval," he noted.

Bristol plans to offer the pravastatin/aspirin combo "at no additional cost over pravastatin as it is currently available," Bristol VP-Clinical Design and Evaluation & Exploratory Development Fred Fiedorek, MD, said.

The company is planning to offer a single tablet containing pravastatin and aspirin at the various doses once stability testing is complete. The single tablet version could be patented, thereby excluding generics of a single pill; however, generic packaging of separate pravastatin and aspirin tablets could still occur.

Bristol Pravachol/Aspirin Co-Package Not Precedent For Combo Submissions

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