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Assaulting Drug Patents

In recent years, generic drug companies located in India and other developing markets have launched an all-out assault on the drug patent system that locks them out of the most lucrative first-world markets. What they have not achieved in their science labs and their manufacturing floors they hope to make up in the courtrooms, in the press, and inside the halls of the World Health Organization (WHO).

These efforts are waged aggressively in Africa, where Indian generic drug companies are selling a small amount of knock-off AIDS drugs at predatory prices. Their aim isn't to turn profits or slow the spread of disease, but to slowly erode the laws and practices that govern modern drug patents. They have shrewdly chosen to press their case in places where widespread suffering and disease compels strong action, rightly betting that world health leaders will discard broader considerations for quick solutions.

Before the World Health Organization places its next order for these knock-off drugs, they should understand the business interests of their corporate partners and the drug development model they are embracing. There are long-term implications for this effort. There is a human cost to Africans suffering from AIDS today, and those Africans who may need access to the lifesaving benefits of new drugs in the future. While the knock-off AIDS drugs are cheap, they are also not certified safe, creating a dangerous double standard that may make the continent a permanent marketplace for second-rate drugs. Moreover, by opening their borders to these medicines, Africa has become a no-profit zone when it comes to new drug development. This all but ensures that drug development aimed at purely African maladies will remain the province of charity — driven by a few large drug makers and foundations, rather than the concerted effort of thousands of drug makers bringing to bear their best scientific resources in search of profits.

At issue right now are so-called "generic" drugs for HIV, the infection that causes AIDS. These knock-off pills are made by Indian generic drug companies, including Cipla Ltd. and Ranbaxy, and contain fixed dose combinations (FDCs) of a typical AIDS cocktail consisting of three drugs. The most popular of these medicines is a Cipla drug called Triomune, which contains a fixed dose of nevirapine, stavudine and lamivudine. The branded drug makers that own patent rights to the chemicals that the Indian drug makers are using have agreed not to work their patents in Africa, essentially clearing the way for their drugs to be copied into the combination products. These FDCs have simplified greatly the arduous medical regimen that most patients are obligated to into one cheap, daily pill. But are they safe and effective drugs?

The fixed dose combinations have been approved as safe and equivalent to their branded parts by the World Health Organization but, so far, not by the US Food and Drug Administration (FDA). So, the United States has been reluctant to use money from the Bush administration's $15 billion President's Emergency Plan for AIDS Relief (PEPFAR) program, largely for countries in Africa and the Caribbean, on the drugs — until they can be sure that the medicines have gone through some of the same basic testing and review processes that make a drug a suitable for sale to Americans. To satisfy critics who wanted the President's fund to stretch the benefits of its money by buying the cheap FDCs, and therefore opening up therapy to more infected patients, the FDA announced a policy last spring to fast-track the review of these knock-off medicines. The goal was to make sure they are safe, effective and suitable for purchase by the President's fund.

The FDA policy had four elements that, together, effectively give the Indian generic drug makers what they most prized: American sanction to sell knock-off versions of patented drugs. The first element of the policy is an expedited process for reviewing the FDCs produced by Indian generic drug makers. Under the FDA policy, the Indian generic drug makers — as well as drug makers from other countries (including at least one interested generic drug producer from South Africa) — can file for formal approval with the FDA for the fixed combination drugs, under a legal mechanism inside the agency known as 505B2. Once they have completed this expedited FDA evaluation, the drugs could get tentative approval. They could not get full approval, because patents here would block their sale in the US, but the American government has said that tentative approval would clear the way for the drugs to be procured by PEPFAR.

The second element of the policy was the FDA's proactive listing of the three-drug antiretroviral drug combinations with sufficient clinical data about their combination, to allow this expedited process to go forward. To prove these products are safe and effective, two data components are required. First, the FDA needs clinical proof that the combinations, used together, are actually effective for the treatment of HIV. That requires clinical evidence. The second requirement is chemical testing data to demonstrate that the products maintain their integrity when combined into a single pill, and that they are absorbed into a patient's blood at the levels needed to have its intended effect. The first element usually requires many years of clinical data, where the drug is given to patients, and their progress monitored. In this case, the FDA made a list of the about 30 different triple combinations of HIV medications that the agency believed had sufficient clinical data in the public domain to prove they would be effective if used in combination. No additional clinical testing would be required.

The practical result of these policy efforts is clear: If a generic sponsor wanted to apply for approval for a new fixed dose combination drug that incorporated one of these three-drug regimens into a single pill, all they would need to do is provide bioequivalence and chemical stability data on the copied drugs for those combinations highlighted in the FDA guidance. That kind of data can be generated in a very short timeframe. There is only one other instance in the FDA's history where the agency took proactive steps to delineate when they felt sufficient clinical data existed, allowing a sponsor to come in with an application for a drug without first going through clinical trials.

The third element is a precise articulation of the data on the chemical composition of the FDCs. The FDA needs this information, known as bioequivalence data, to prove that the new drugs are chemically identical to the original medicines that they are designed off of. Finally, the fourth element was a pledge by the agency to complete all of these reviews on speedy timeframes — as short as three-to-six weeks.

Shortly after the FDA announced these guidelines, six drug companies expressed interest in developing new fixed dose combination products. Yet the Indian generic drug companies haven't taken the agency up on its offer, despite the fact that FDA approval — in this case — would enable them to quickly market their products in the most lucrative Western markets, once patents on the constituent drugs expired. This is a considerable incentive, and it would enable the slow erosion of the world patent system that they have set out to achieve. The fact that the Indian firms demurred on this opportunity led many to speculate that these companies did not take their drugs through all the rigorous testing that they alleged to, and didn't even have clean bioequivalence data to show the FDA.

Recent events have only added to that speculation. On Nov. 9th, the Indian firm Ranbaxy, considered one of the best of the Indian generic drug makers, withdrew all its AIDS drugs from the WHO list. The World Health Organization said the company took the step voluntarily, after discovering "discrepancies" in tests done to show the antiretrovirals were equivalent to brand-name drugs. That action followed WHO de-listings in spring and summer of five drugs made by Ranbaxy and Cipla. This seems to have mattered little to the World Health Organization, which is still anxious to certify the Indian drugs safe and effective, and to keep using many of them.

Editor's Note: Since this story was written, two generic drug products by Cipla for treating HIV/AIDS have been reinstated on the World Health Organization's recommended list.

Few people doubt that a low-cost fixed dose combination pill, like the kind Cipla and Ranbaxy produce, is a valuable addition to the drug arsenal in Africa and other markets with high needs and limited medical infrastructure. Plagued with drug delivery problems that Western markets don't share, the prospect of a once-daily pill is particularly attractive in these regions. Yet the FDC option is not the panacea that the Indian generic drug makers have painted it to be. The pills are surely not for everyone. Moreover, the route by which the World Health Organization has gone about trying to procure these drugs does not serve the continent's long-term interests well.

For the World Health Organization, however, progress is measured by how many people are started on any therapy at all, rather than on how many people are started on durable therapy. Under the World Health Organization's program, known as "3 by 5," the goal is to supply antiviral drugs to three million AIDS patients by the end of 2005 — hence their favor for FDCs, which provide an easy way to distribute lots of low cost pills, with less medical infrastructure than would be required for more complicated drug regimens. The 3 by 5 yardstick is a notable political objective, sure to capture headlines and maybe even international acclaim for the WHO leadership. But is it an appropriate healthcare goal? The FDCs themselves are not a cure-all. For many patients, the fixed dose regimens are going to be too toxic. Many people will need a more tailored regimen. For patients who fail these fixed regimens, however, the WHO contemplates few additional options.

But optimizing medical outcomes was never the only goal when it comes to the 3 by 5 program; achieving political aims was also driving the dash to the Indian knock-offs. Satisfying the needs of politicians inside the World Health Organization, however, is not going to fight AIDS infection, and neither will fulfilling the business interests of the Indian generic drug firms.

For more information, visit http://www.aei.org

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