Compulsory Licensing of Kaletra

Abbott's patent for Kaletra (ritonavir/lopinavir) has been annulled by a Brazilian federal Judge Daniela Pereira on constitutional grounds, meaning that the Brazilian government will now be able to purchase and dispense generic versions of the drug for its HIV-infected population. The nullification arises from anger at the cost of Kaletra, expressed by international advocacy groups last year in a call for compulsory licensing in several countries, including the US. For details I recommend Ed Silverman's post, Activists Challenge Abbott Over Its AIDS Drug.

The importance of Kaletra for HIV-treatment lies in the fact that a small percent of infected individuals do not respond to the first anti-retroviral with which they are treated, e.g., efavirenz. The ritonavir/lopinavir combination has literally proven lifesaving to these people. Another approach to assuring access to essential medications is that of Indian patent law, under which Abbott's patent application for Kaletra was denied because it sets a higher standard for what constitutes a new invention. This has the same result as the ruling in Brazil - the government has the opportunity to purchase significantly less expensive generic versions. As of the publication of the PLoS article, Trends in Compulsory Licensing of Pharmaceuticals Since the Doha Declaration: A Database Analysis, seventeen countries have taken the compulsory license route to providing health care access.

As the table indicates, Thailand granted several compulsory licenses early on after international negotiations led to the TRIPS agreement and the DOHA declaration. In Abbott's case, retaliation took the form of refusal to sell any of its drugs in Thailand and the withdrawal of applications for Thai patents. International public pressure caused the company to relent in one instance. A later, pediatric version of Kaletra was eventually sold in Thailand

The Benefits of Proprietary Drug Patents

Since July 28, 2011, when Natco Pharma applied for a compulsory license to market Bayer's Nexavar (sorafenib) in India, patent and civil litigation has resulted in the grant of this license March 12, 2012. Indian law requires Natco to provide the drug free to 600 patients per year who cannot afford their $176/month price. For comparison, the price of Bayer's product is $5,600/month. Based on clinical trial data, people with renal cell carcinoma (kidney cancer) can expect to live 4-5 years with the drug; those with hepatocellular carcinoma (liver cancer), 6-8 months.

Even at $176 monthly, this drug is only affordable to India's upper middle class. The GLOBOCAN Project of the World Health Organization estimates an annual total of 30,000 new cases for all liver and kidney cancers in India, leaving untreated many more than the 600 annually who will receive free treatment for renal cell and hepatocellular carcinoma. What has so far been accomplished under Indian law is the possibility that the Indian government will be able to afford to fund treatment of its poorer population. A balance has been struck between the benefits of an Indian patent monopoly granted to Bayer in 2008, and the benefits of affordable sorafenib treatment for a larger portion of India's population.

The conflicts involved in balancing public and private interests continue, with one venue being the Trans-Pacific Free Trade Agreement presently being negotiated among Australia, Brunei, Chile, Japan, Malaysia, New Zealand, Peru, Singapore, The United States, and Vietnam. These negotiations are typically secretive, but with leaks that have made clear that protections demanded by the US pharmaceutical industry against events such as have occurred in India have contributed to a breakdown in negotiations. (See this live news feed from Brunei for many relevant links.) The TRIPS trade agreement (aka The Doha Declaration) contributed to the present reality of Indian compulsory licensing, and multinational pharmaceutical companies do not wish to see an extension of this reality to other countries.

My favorite US representative from Texas, Lloyd Doggett, has cosponsored HR 2293 with Representative Chris Van Hollen. US Senator Debbie Stabenow has sponsored matching Senate bill S. 1644. In a letter to their Congressional colleagues asking for more cosponsors, they write:

"Global trade agreements increasingly affect the public's health, from the price of medicines to regulations that protect the safety of food and water supplies. The Government Accountability Office and the Center for Policy Analysis on Trade and Health (CPATH) have documented the absence of public health representation on U.S. trade advisory committees. Advisors from health-related industries including pharmaceuticals, tobacco, processed foods, alcohol beverages and health insurance have had exclusive access to government trade negotiators."

This legislation is part of a larger campaign by CPATH to give public health interests a voice where only the pharmaceutical industry has thus far been heard. In summary, it is also time in the US to rebalance the interests of the pharmaceutical industry against the interests of the US population which grants them patent monopolies.

Relevant prior posts:
Proprietary Drug Patents

Compulsory Licensing of Proprietary Drugs

Indian Compulsory Licensing Case May Reveal Research Costs 

Indian Compulsory Licensing Case May Reveal Research Costs

During the Superbowl, Amy O'Connor published a post on the Eli Lilly official company blog which has stimulated discussion of the research and development costs of a new drug. Her dollar amount was $1.3 billion, based on the methodology of the Tufts Center for Drug Development. In response Matthew Herper of Forbes published an estimate ranging from $3.7-11.8 billion. Merrill Goozner critiques the methodology that produced both these estimates in a blog post on GoozNews. At the other extreme of the range of estimates is the $43 million estimate from Light and Warburton in BioSocieties, rebutted by Derek Lowe in this post and a follow-up post on his blog, In the Pipeline.

Herper's estimated range has the advantage of being based on public information, but his approach is far too simplistic. Since Light and Warburton's article is behind a paywall, Timothy Noah's article in Slate is worth reading as long as you take account of Derek Lowe's criticisms. These high and low estimates revolve around the work done on the subject at Tufts. Their research is funded by various drug companies with the proviso that the dollar amounts of the costs they submit to the researchers remain confidential. Besides the required public information such as used in the Forbes' article, all drug companies are extremely protective of this information

So we arrive at an interesting situation which is developing in India. In my previous post, Compulsory Licensing of Proprietary Drugs, I referred to the public record of Natco's application for compulsory licensing of Bayer's proprietary drug Nexavar (sorafenib). LiveMint gives some history and the recent developments, which include the scheduled disclosure by Bayer of the research and development costs on which they base their price for the drug. Ed Silverman has an excellent post on what is required of drug companies who import brand name drugs to India. He links to articles in the Indian press that are also very worth reading. Compulsory licensing in India and elsewhere is based on the World Trade Organization's Declaration in the TRIPS [Trade-Related Aspects of Intellectual Property] Agreement and Public Health, commonly known as the Doha Declaration since it arose at the 4th Ministerial Conference in Doha, India. The Public Library of Science has published more background in a research article, Trends in Compulsory Licensing of Pharmaceuticals Since the Doha Declaration: A Database Analysis. Table 1 below is a summary from this article.

Shortage of guar gum

Rx360 reports a shortage of guar gum. The legume, Cyamopsis tetragonoloba, is the source of guar seed and gum, a major cash crop in India and Pakistan, but it has also been grown in the southern US for some time. The shortage has been attributed to a weak crop in Brazil, and also to increased use in the fluid used for fracking wells. The US food industry is the major user, but its use in drug formulations as a binder and stabilizer is also significant. India is the major world supplier, and there the Forward Markets Commission launched an investigation into price fixing, has banned some Indian commodities traders, and is considering banning more. The FMC has also increased the margins (PDF) required for guar gum and seed trades. TopNews.in reports that prices continue to increase.

Compulsory Licensing of Proprietary Drugs

Compulsory licensing is the process by which a country such as India grants a license to produce a patented proprietary drug without the consent of the patent holder. A provision of Indian patent law is that a compulsory license may be granted three years after a patent has been granted. The first case involves Natco Pharma, an Indian generic drug manufacturer, and Pfizer, the patent holder for maraviroc. As far as I can tell from searching the Internet, this case is still at the stage in which Natco requests a voluntary license from Pfizer. There was supposed to be a response from Pfizer by May 2011, and a negative response is expected. If someone has factual information on the status of this case, please share it.

Since this first case, it is now a matter of public record that Natco has applied for a compulsory license for Bayer's sorafenib. If you like you can skip to PDF p. 16, item 7 of the application.

Today's post is a continuation of my post Proprietary Drug Patents.

Proprietary Drug Patents

Drug life cycle management involves the US patent system, since sales of brand name drugs are mostly increased by patent extension strategies. These strategies work because the number of items related to a proprietary medicine that are considered novel and therefore eligible for patent monopoly protection increased from five in the 1980s to 18 in the 1990s. After the initial patent grant, the patent holder immediately starts work on these items, resulting in a series of overlapping 20 year intellectual property monopolies that delay the market entry of lower-priced generic versions of the brand name drug. People who see this as an abuse of the patent system's intent view it as one of the legal and business strategies that are included under the title evergreening. The pharmaceutical industry has strong objections to even the use of this term, and you can read them in the PDF version of GlaxoSmithKline's policy position paper of August 2011. Judge for yourself, I will only add a link to a couple of case studies that present more common scenarios than the case study presented by GSK.

Patent law is an international affair of numerous agreements, but the patent systems of other countries nevertheless illustrate alternatives to the US system. India is a country with a strong generic drug industry noted for sale of inexpensive medications to poorer nations because their patent law is designed to prevent patenting minor changes in medications or patent extensions. Novartis has been battling the Indian system and is about to go to trial again in the Indian Supreme Court because a patent for a new salt form of its cancer drug Gleevec has been denied because of patent office and court rulings that the new form of the drug is not any more effective than the old form. This is an entirely different standard than those applied in the US. The Indian court system has already ruled that this standard does not conflict with The Agreement on Trade Related Aspects of Intellectual Property Rights.

The Life Cycle of a Drug: Pediatric Exclusivity

The Life Cycle of a Drug: Pediatric Exclusivity - Update

The Life Cycle of a Drug: New Indication

Off-Label Drug Use: The Good, The Bad, and the Inexcusably Ugly

The Life Cycle of a Drug: New Formulation