While nations and athletes compete briefly on a world stage for Olympic gold, three recent articles in the BMJ remind us that pharmaceutical companies compete across the world for real gold. For instance, the worldwide market for insulin is huge and the papers question the ethics of global pharmaceutical companies. Sanofi-Aventis, Novo-Nordisk, and Eli Lilly have all aggressively marketed a switch to newer forms of insulin that have not proven to achieve better health outcomes than cheaper insulins.
The newest forms of insulin are called “insulin analogues.” They are genetically engineered forms of insulin that alter the absorption, distribution, and metabolism of insulin. Some insulin analogues are short acting, thereby permit more rapid availability; others are long acting, slowing down release, giving people coverage over an extended period.
Together, these pharmaceutical companies have enrolled more than 400,000 people with diabetes worldwide into postmarketing studies on insulin analogues, according to one paper. Insulin is an essential health medicine for people with type 1 diabetes: people without it will die. As type 2 diabetes progresses, many people eventually require it.
In absolute terms, the insulin analogues are 2 to 4 times more costly than human insulin, and in resource-poor countries with low per capita incomes, the relative costs are astronomical. The costs are also prohibitive to the uninsured in the USA.
Technology assessments by the International Cochrane Collaboration, Germany’s Institute for Quality and Cost Effectiveness in the Healthcare Sector, and the Canadian Agency for Drugs and Technologies in Health all concluded that there is not compelling evidence to back insulin analogues over human insulins. “There is no clear therapeutic advantage [to the insulin analogues],” Lisa A. Bero, PhD, professor of clinical pharmacy and health policy, University of California San Francisco, said in an email. She added: “Some people still feel that convenience or ease of use is a benefit – but how much is it worth in terms of cost? And who’s paying?”
The drug companies have already seen gold in marketing the insulin analogues. According to 2010 company reports discussed in the BMJ, the most successful analogue, glargine, helped to give Sanofi-Aventis sales of around $5.1 billion, while Novo-Nordisk insulin analogues brought in sales of $4.7 billion, and $3.1 billion for Eli Lilly.
Marketing, Not Science
Postmarketing drug studies are often referred to as seeding trials because they are undertaken to generate a switch to a new drug, i.e. to seed widespread adoption of the newer insulin analogues, supplanting human insulin.
In one of the three BMJ papers, Edwin A. Gale, MD, emeritus professor of diabetic medicine at the University of Bristol, Bristol, UK, writes: “Many of the postmarketing studies considered here did not ask a clear or novel research question, addressed the same issues, lacked any comparator group, and seem larger than needed to answer the questions proposed… Poor quality studies merely impede progress.” Gale challenges the drug companies to rise to a high level of scientific rigor, even though the countries where they conduct the research may not have the infrastructure to demand it.
An anonymous author, employed by a major drug company’s medical department for more than seven years, questions the transparency of postmarketing observational studies in the second paper, which is not specifically about diabetes studies: “Some of the studies I worked on were not designed to determine the overall risk:benefit balance of the drug in the general population. They were designed to support and disseminate a marketing message.” Especially disconcerting was this claim: “We occasionally resorted to ‘playing’ with the data that had originally failed to show the expected result. This was done by altering the statistical method until any statistical significance was found…it was always worth giving it a go to see what results you could produce. And it was possible because the protocols of postmarketing studies were lax, and it was not a requirement to specify any statistical methodology at all.”
These ways of working are rarely shared, except from ex-employees, often anonymous, or in cases where access to confidential company documents are subpoenaed under court order.
Asked what he thought of the conduct of postmarketing drug research, Rodney Hayward, MD, professor of medicine and health policy, and director of the Michigan Diabetes and Research Training Program, University of Michigan, Ann Arbor, MI, and not an author of any of the studies, stated in an email: “All research on commercial products needs to be available by direct inspection, in some regulated way, by the research community. There is no reliable way to stop people lying with data unless the data can be inspected. It seems reasonable to me that to sell commercial products to the public that you must not be able to withhold or distort evidence on their safety and efficacy from the public.”
A third paper by John S. Yudkin, MD, emeritus professor of medicine, University College London, addresses the impact of postmarketing observational trials on catastrophic health expenditures. Yudkin describes Novo Nordisk’s PREDICTIVE study, noting: “The company paid doctors in 26 countries to start 47,565 people on its long-acting insulin analogue, detemir. The sponsor did not provide the study insulin; instead its cost fell to the health system, insurance company, or patient.”
Catastrophic Health Expenditures
Yudkin writes that in India, one of the low-income countries in the study, GDP per capita was $1410, and the retail price for insulin detemir is equivalent to $17.77 for a 3 mL insulin pen. “For a patient using 30 U insulin daily, the annual cost of insulin would be $648.60, compared with $74.32 for a generic human insulin (among the lowest prices in the world, thanks to India’s thriving generic drugs industry),” Yudkin writes, adding: “What might justify an eightfold price difference? Paying for essential health expenses is catastrophic."
K.M. Venkat Narayan, MD, professor of global health, Emory’s Rollins School of Public Health, Emory University, in Atlanta, GA, who was not involved in the BMJ papers, noted: “It’s not uncommon for a poor family in rural India to face a terrible choice: should they send one child off to school or make sure that the other child has insulin. The way to look at it is in low and middle income countries, people spend half their monthly income on a vial of insulin.”
Narayan says: “On a broad level, there is not compelling evidence that the insulin analogues are necessarily better,” but he does think the improved side effect profile and ease of administration are worth considering in care. Like others working in Noncommunicable Disease Initiatives worldwide, he thinks it is foolhardy to take the position that we don’t need better drugs. Down the road, he envisions a time when the insulin analogues may be in so much greater demand that prices may well go down.
Narayan believes that the collaborative models similar to those that are ratcheting up HIV care in the developing world could serve as a model. Bulk purchasing and use of local brands (for example, in India and Brazil) could enhance affordability. As with headway in HIV care, he sees partnerships between groups, such as the Clinton Foundation, Doctors Without Borders, might prove sustainable. Narayan also believes building a solid public health infrastructure is imperative in low-resource nations.
Part and parcel of this approach, according to Narayan, low resource countries will need to learn how to build investigator capacity, understanding of human subjects protection, good science, and Institutional Review Boards. “Large populations in these countries need to become aware of their own rights.”
Narayan is not alone in putting forth these proposals. Many people and organizations working in diabetes care and Noncommunicable Diseases in impoverished nations, including Yudkin, Gale, and Partners in Health, share this view and are working hard to bolster the public’s health.
Gale, EAM. Post-marketing studies of new insulins: sales or science? BMJ. 2012;344:e3974.
Yudkin, JS. Post-marketing observational trials and catastrophic health expenditure. BMJ 2012; 344: e3987.
Post-marketing observational studies: my experience in the drug industry. BMJ 2012; 344:e 3990.
Horvath K, Jeitler K, Berghold A, Ebrahim Sh, Gratzer T, Plank J, Kaiser T, Pieber T, Siebenhofer A (2007). Horvath, Karl. ed. Long-acting insulin analogues versus NPH insulin (human isophane insulin) for type 2 diabetes mellitus. Cochrane database of systematic reviews (online) (2): CD005613.doi:10.1002/14651858.CD005613.pub3. PMID 17443605.
Institut fur Qualitat and Wirtschaftlichkeit im Gesundheitswesen. Rapid-acting insulin analogues for the treatment of diabetes mellitus type 2: Final report.
Banerjee S, Tran K, Li H, Cimon K, Daneman D, Simpson S, Campbell K. Short-acting insulin analogues for diabetes mellitus: meta-analysis of clinical outcomes and assessment of cost-effectiveness. Technology Report No 87. Ottawa: Canadian Agency for Drugs and Technologies in Health; 2007.