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David B. Ridley, Henry G. Grabowski, and Jeffrey L. Moe Developing Drugs For Developing Countries Health Affairs, March/April 2006; 25(2): 313-324. [Abstract] [Full Text] [Figures Only] [PDF] [Technical Appendix][Media/Policy Briefing][Interview with lead author] [Reprints & Permissions]

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Electronic letters published:

Benefits of Expedited Review Likely Overstated

Ian D. Spatz   ( 13 March 2006 )

Global Disease Burdens

Kevin Outterson   ( 15 March 2006 )

A Rights-Based Approach to Drug Development for Neglected Diseases

Sonal Singh   ( 30 March 2006 )

Response from the Authors

David B. Ridley, Henry G. Grabowski and Jeffrey L. Moe   ( 22 May 2006 )

Benefits of Expedited Review Likely Overstated 13 March 2006
Ian D. Spatz, Vice President, Public Policy Merck & Co., Inc. Send letter to journal: Re: Benefits of Expedited Review Likely Overstated spatzi{at}merck.com Ian D. Spatz	The authors deserve praise for seeking market-based mechanisms to encourage the development of medicines and vaccines for diseases that primarily affect the world's poorest nations. Those of us in the prescription drug industry understand that such mechanisms can stimulate the same incentives for research and development that have made such an enormous difference in creating new medicines and vaccines in the developed world. Unfortunately, their particular prescription — a transferable voucher for expedited review within the U.S. — is built on faulty assumptions that make the success of their plan questionable. The authors base their estimates of the value of expedited review on an estimate of standard FDA review of 18.4 months compared to 6.4 months for priority review. According to the FDA, in fiscal year 2003, the actual difference was 13.8 months compared to 6.4 months. Perhaps more importantly, under the Prescription Drug User Fee Act (PDUFA) program, the FDA has committed to delivering action on 90 percent of applications within a time frame of 10 months for standard reviews and 6 months for priority reviews. For companies like Merck, these are the review periods that we count on for planning purposes. Therefore, based on both the empirical data and the PDUFA deadlines, the article's assumption of a 12-month time saving in the review process is flawed. A more accurate estimate of time savings of four to seven months, while certainly valuable to an innovator company, would change substantially the article's estimate of the value of their proposed incentive. In addition, the authors' proposal depends on the FDA delivering priority review for drugs and vaccines that they otherwise would not deem to merit the resources required for such review. While the authors propose requiring the payment of additional user fees by the company seeking priority review, it is not obvious that this would be enough to ensure that the FDA would have the expert human resources necessary to speed the review of another product without taking away from the review of medicines and vaccines that they believe need priority review. Market mechanisms are the key to incenting firms to increase research and development commitments to developing world health needs. Proposals, now advancing rapidly, to create strong and certain Advance Market Commitments (AMCs) are, we believe, the most direct way to create these incentives.
Global Disease Burdens 15 March 2006
Kevin Outterson, Associate Professor of Law West Virginia University Send letter to journal: Re: Global Disease Burdens kevin.outterson{at}mail.wvu.edu Kevin Outterson	This article leaves the impression that the greatest disease burdens in developing countries are "neglected disease" conditions like leishmaniasis, Chagas disease, dengue fever and African trypanosomiasis. In particular, Exhibit 3 is labeled "Distribution of Global Disease Burden, 2004" but the list is almost exclusively infectious diseases. Surprisingly missing from Exhibit 3 are many of the conditions which the WHO considers to be among the top causes of global DALY burden, including CHD, stroke, depression, diabetes, arthritis, COPD, alcohol-related injuries, cataracts, hearing loss, traffic injuries and violence. The authors' neglected disease program overlooks the fact that chronic conditions in the high-income and low-income worlds are converging. It is the poor themselves who are neglected, rather than just their diseases. Global diseases are conditions which affect patients in both rich and poor countries. The global disease list includes many of the major chronic conditions associated with wealthy countries — including cardiovascular disease, stroke, mental illness, diabetes, and arthritis. These wealthy-country diseases are also among the leading causes of adult disease burdens throughout the world. A major characteristic of global diseases is that a robust level of research is assured by high-income markets alone. Anticipated R&D cost recovery from low- and middle-income countries carry little or no weight in the decision to commit resources to R&D concerning global diseases. The powerful lure of high-income markets — particularly the US and EU — draw R&D funds to global diseases, without much regard for the market potential in Brazil or Costa Rica. AIDS is a paradigmatic case of a global disease. Several thousand early AIDS cases in the United States and Europe were sufficient to trigger an avalanche of science. The global aspects of the epidemic were either unknown or relatively unimportant to the decision to allocate research resources. ARV drugs would probably have been invented on the same timetable even if no African or Asian had ever been infected. High-income markets alone were sufficient incentive for discovery. Cancer is another global disease. Development of HPV vaccines was prompted by the multi-billion-dollar market to prevent less than 17,000 cervical cancer deaths per year in high-income countries. Similar global disease profiles exist for other cancers: One recent study listed the 12 major types of cancer for which the global burden of disease largely falls in the low- and middle-income countries. In every category the majority of the global cancer disease burden fell in low- and middle-income countries. Only cancers of the lungs, pancreas, colon and rectum were disproportionately found in high-income countries, but nevertheless the majority of the burden remained in low- and middle-income countries. In short, the greatest effect on DALYs in low- and medium-income countries may well come from making existing global disease innovations available at generic prices. Research on tropical or neglected diseases, while valuable and important, is arguably less salient than ensuring that current global disease innovations are made available on an affordable basis. [These thoughts are developed in more detail in Outterson K., "Patent Buy-Outs For Global Disease Innovations For Low- and Middle-Income Countries." Am. J. Law and Med. 32 (2006) (pending)].
A Rights-Based Approach to Drug Development for Neglected Diseases 30 March 2006
Sonal Singh, Clinical Instructor Wake Forest University Send letter to journal: Re: A Rights-Based Approach to Drug Development for Neglected Diseases sosingh{at}wfubmc.edu Sonal Singh	Economic incentives in the form of vouchers should complement a rights-based approach to health to ensure drug development for neglected diseases. Several existing human rights instruments provide a normative framework to ensure research, development, and equitable access to drugs for neglected diseases. A rights-based approach to health implies safeguarding human dignity, paying attention to vulnerable groups, and ensuring equal access to health systems for all.[1] Article 25.1 of the Universal Declaration of human rights guarantees everyone “the right to a standard of living adequate for the health and well-being of himself and of his family.”[2] Similarly, article 12.1 of the International Covenant on Economic, Social, and Cultural Rights (ICESCR) states "the right of everyone to the enjoyment of the highest attainable standard of physical and mental health."[3] Article 12.2 of the ICESCR outlines “steps to be taken by the States parties ... to achieve the full realization of this right."[3] Similarly, article 15 of the ICESCR specifically guarantees “everyone the rights to benefits of scientific progress.”[3] The General Comment on the right to health highlights the principle of non-discrimination in the arena of health: “Health facilities, goods and services must be accessible to all, especially the most vulnerable or marginalized sections of the population, in law and in fact, without discrimination on any of the prohibited grounds."[4] Article 12.2 c and d of the general comment guarantees "the prevention, treatment and control of epidemic, endemic, and other diseases” 4 and emphasizes that “States’ individual and joint efforts to, inter alia, make available relevant technologies . . . the implementation or enhancement of immunization programmes and other strategies of infectious disease control."[4] In the same General Comment No. 14, the ESCR Committee specifically recognized access to “essential drugs, as defined by the WHO Action Programme on Essential Drugs,” as part of a state’s minimum core obligations under the ICESCR.[4] Thus, essential medications are part of each state party’s “core obligation to ensure the satisfaction of, at the very least, minimum essential levels of each of the rights enunciated in the Covenant.” A human rights framework implies that international treaties and international trade agreements (e.g. TRIPS, or Trade Related Intellectual Property Rights Agreements) cannot be arbitrarily implemented but have to be interpreted in manners that advance public health.[5] These rights are justiciable and have been successfully used in several instances to guarantee the availability of drugs. In the Mariela Viceconte v Ministry of Health and Social Welfare, Case No 31.777/96 (1998) from Argentina in 1998, [6] the courts ordered the Argentine government to make available a vaccine against a neglected disease, the Argentine Hemorrrhagic Fever, a disease that afflicted nearly three and a half million people. Similar cases in South Africa have successfully argued for the provision of nevirapine for HIV infected pregnant mothers. States and international agencies not only have moral and humanitarian obligations to ensure access to medicines for these neglected disease but also have legal obligations to respect the right to health by refraining from adopting measures that infringe on the right to health, protect the population from policies imposed upon by pharmaceutical companies and agencies such as the World Trade Organization, and fulfill the right to health by ensuring universal access to medicines for neglected diseases.[7] A human rights framework will allow policymakers, funding agencies, the research community, state parties, and international organizations to move from a profit-driven research and development agenda to one based on needs and develop safe, effective, and affordable medicines for all.[8] REFERENCES 1. WHO (2002) 25 Questions and Answers on Health and Human Rights. Health and Human Rights Publication Series Issue No. 1, July 2002. 2. UN (1948) Universal Declaration of Human Rights. 3. International Covenant on Economic, Social, and Cultural Rights. 4. UN Committee on Economic, Social, and Cultural Rights, General Comment 14 on Article 12 of the International Covenant on Economic, Social, and Cultural Rights. 5. UN Human Rights and Intellectual Property. UN Commission on Economic, Social, and Cultural Rights, 27th Session, 12 UN Doc E/C 12/2001/15. 6. Hunt P. Neglected Diseases, Social Justice and Human Rights -- Some Preliminary Observations. Health and Human Rights Working paper series no. 4. http://www.who.int/hhr/news/en/Series_4_neglected%20diseases_social_justice_human_rights%20Paul_Hunt.pdf Accessed on March 29, 2006. 7. Yamin AE. Not just a tragedy. Access to medications as rights under international law. Trustees of Boston University and Consumer Project of Technology. http://www.cptech.org/ip/health/cl/yamin03012004.pdf Accessed on March 29 2006. 8. Dentico N, Ford N (2005) The Courage to Change the Rules: A Proposal for an Essential Health R&D Treaty. PLoS Med 2(2): e14.
Response from the Authors 22 May 2006
David B. Ridley, Assistant Professor Duke University, Henry G. Grabowski and Jeffrey L. Moe Send letter to journal: Re: Response from the Authors david.ridley{at}duke.edu David B. Ridley, et al.	In “Developing Drugs for Developing Countries” we propose that the developer of a treatment for a neglected disease be awarded a priority review voucher for another drug. We appreciate the thoughtful responses to our paper and offer the following reply. In the first response, Ian D. Spatz raises several important questions. First, how much faster is the approval for priority drugs compared to standard drugs? Mr. Spatz reports that the difference was seven months in 2003 for new drug applications (NDAs). NDAs include new indications, delivery mechanisms, and combinations. We and Berndt et al. (2005) use data on new molecular entities (NMEs). In 2005, the difference in median total approval time between priority and standard NMEs was seventeen months (FDA 2006), which is longer than Mr. Spatz’s seven-month estimate and even longer than the twelve-month estimate in our paper. Even assuming seven months, the voucher value would be $180 million for a top-decile drug. Adding orphan drug tax credits would bring the incentive to about $430 million plus good will. Such an incentive would at least motivate salvaging of promising projects abandoned for lack of financial incentives. Second, will the voucher holder slow other drugs at FDA, despite the additional $1 million user fee paid by the voucher holder? Providing additional resources might create winners and losers but will shorten average approval times. Specialized FDA staff are not perfectly matched to submitted drugs under our proposal or under the status quo. If a $1 million user fee is too small, then it could be increased, since priority review is potentially worth hundreds of millions of dollars. Third, should advance market/purchase commitments (APCs) be used instead of priority-review vouchers? We agree with Mr. Spatz that APCs are promising, but to our knowledge no one is proposing a $3 billion APC for leishmaniasis, Chagas disease, dengue fever, and African trypanosomiasis. Hence, we wrote in our paper that “if the APC were directed at malaria, tuberculosis, and HIV/AIDS, then the voucher could be applied to other diseases.” In the second response, Kevin Outterson points out that we highlight neglected diseases in our paper (e.g., malaria, tuberculosis, leishmaniasis, Chagas disease, dengue fever, African trypanosomiasis) rather than global diseases (e.g., cardiovascular disease, stroke, mental illness, diabetes, arthritis). Neglected diseases are not prevalent in rich countries, so there is need for incentives for research and development (R&D) such as our proposed priority-review voucher. On the other hand, global diseases are those that are prevalent in rich and poor countries so there are incentives for developing treatments, but many people in poor countries cannot afford the treatments. While global diseases are not the focus of our paper, we cite Lanjouw (2003), who proposed a novel mechanism for increasing access to existing treatments for global diseases. We also refer interested readers to our own work in this area (e.g., Ridley 2005). In the third response, Sonal Singh argues that economic incentives should complement a rights-based approach to global health. Dr. Singh points to examples in which moral suasion and legal efforts have been successful in gaining access to existing treatments. We are pleased that our proposal for creating incentives for new treatments is viewed as a useful complement. We thank the respondents for highlighting other mechanisms for stimulating R&D (e.g., Advanced Market Commitment), other diseases of developing countries (e.g., cancer, heart disease), and other means for increasing access to existing treatments (e.g., rights-based initiatives). All of these are relevant for the health of people in developing countries. References E.R. Berndt et al., “Industry Funding of the FDA: Effects of PDUFA on Approval Times and Withdrawal Rates,” Nature Reviews: Drug Discovery 4, no. 7 (2005): 545–554. Food and Drug Administration. CDER Drug and Biologic Approval Reports. http://www.fda.gov/cder/rdmt (Accessed April 29, 2006) Ridley (2005). “Differential Pricing of Pharmaceuticals and the Role of International Organizations.” Pharmacoeconomics. 2005. Vol. 23, No. 7.