May Man of the Month – Thomas Maeder
May 3rd, 2010
Thomas Maeder, our May 2010 Man of the Month, is the author or co-author of twelve books and numerous articles in national publications, and has long experience in the biomedical field as a writer, educator, and consultant. Below, he shares his thoughts on rare disorders and their place in the drug market.
Orphan Diseases – Bellwether of Health Care
“The only people interested in rare diseases are those who have them, and that’s not a lot,” an editor once told me when rejecting my proposal for a book on orphan diseases.
In reality, nearly thirty million Americans – one in ten – suffer from some 7,000 rare diseases, making them collectively very common indeed. Though they differ wildly in their causes and manifestations, they share many characteristics in terms of the uncertainty, isolation, and costs imposed upon sufferers and their families, the challenges they pose for our health care system and sense of social responsibility, and their potential value to medical research.
In the United States, orphan diseases were defined by the Orphan Drug Act of 1983 as those that affect fewer than 200,000 people domestically. This landmark legislation offered incentives – tax credits, a period of market exclusivity independent of patent protection, research grants – for manufacturers to develop clinically valuable treatments that would not be economically viable in the normal pharmaceutical market. Previously there had been tragic instances of known, potentially useful therapeutics never taken to market, or others of already proven effectiveness that were withdrawn, because they did not meet a drug company’s threshold of profitability. The definition encompasses some familiar disorders, such as cystic fibrosis, muscular dystrophy, hemophilia, Huntingdon’s Disease, and Crohn’s disease, along with thousands of much rarer conditions, including fibrodysplasia ossificans progressive (FOP), Jumping Frenchmen of Maine, and Sakati Syndrome, or acrocephalopolysyndactyly type III, which for many years was represented by a single patient in Saudi Arabia.
In less than thirty years since passage of the Act, more than 300 orphan drugs have been approved for market. Some are produced by large pharmaceutical companies. The biotechnology industry also benefited tremendously from the orphan drug market and its incentives. In addition, as one pharmaceutical executive told me, big drug companies may need billion dollar drugs to support not only R&D but also massive corporate infrastructures and the sales and marketing machinery, but a small company aiming at a well-defined population, with a small number of specialized physicians and facilities, patient advocacy organizations, and unusually motivated patients, can get by quite nicely on mere tens of millions of dollars in revenues.
Research on orphan diseases is often unusually productive. William Harvey, who discovered the circulation of blood, wrote in 1657 that nowhere does nature more openly “display her secret mysteries than in cases where she shows traces of her workings apart from the beaten path; nor is there any better way to advance the proper practice of medicine than to give our minds to the discovery of the usual law of Nature by careful investigation of cases of rare forms of disease.” Sigmund Freud more generally stated in the New Introductory Lectures on Psychoanalysis that studying abnormal behavior was valuable because the broken structures of mental patients’ minds were as revealing as the fracture planes of a shattered crystal, which yielded clues to otherwise invisible molecular structures. Rare diseases, often resulting from a single gene mutation or flaw in one step of a metabolic pathway or developmental process, may reveal stark outlines of underlying mechanisms difficult to tease out of complex, multifactorial diseases like hypertension, diabetes, obesity, or cancer.
Clues provided by rare diseases like Fragile X syndrome, Gaucher’s disease, and tuberous sclerosis complex provide insights into the mechanisms of more complex neurological disorders; WAGR and Chanarin-Dorfman syndromes give clues on obesity and fat metabolism; Schnyder crystalline corneal dystrophy helps elucidate cholesterol metabolism defects that may be implicated in heart attack and stroke; alpha-1-antitrypsin deficiency causes emphysema at an early age, allowing the lung condition to be studied separately from the effects of smoking and other factors in later life; and the study of progeria, a tragic premature aging disease with only a few dozen patients living truncated lives worldwide, sheds light on the normal process of aging.
Research on other rare disorders has already yielded important clinical and pharmaceutical discoveries. The study of kuru, a rare neurodegenerative disorder found among members of a New Guinea tribe that engaged in ritualistic cannibalism, led Stanley Prusiner to his Nobel Prize-winning identification of prions. Studies of the rare condition homozygous familiar hypercholesterolemia led to another Nobel Prize-winning discovery and the development of the important statin family of drugs. A few hundred people suffer from the adenosine deaminase deficiency form of severe combined immunodeficiency disease – a variant of “bubble boy disease” – but the treatment strategy developed for it, of decorating therapeutic enzymes with protective polyethylene glycol (PEG) polymer chains, inaugurated a whole family of PEGylated drugs now used for the effective treatment of many more common diseases.
One unfortunate omission in the Orphan Drug Act was the field of medical devices, which were not given the same incentives as pharmaceuticals. FDA’s device regulations do provide for what are called “custom devices” – variants of a commercially marketed device that are prescribed for an individual patient, like prosthetics or dental implants. In the early 1980s, Cook Medical, an Indiana device company that manufactured a bladder stent for ureteral obstructions, custom produced a diminutive version for use in fetuses. Cook sold this device at cost, as it was an effective way to treat an otherwise fatal condition affecting 200 fetuses each year. When the number reached 680, FDA decided that the stents were no longer custom devices, but manufactured products, whether sold at a profit or not. Cook successfully lobbied for new legislation, and the Safe Medical Devices Act of 1990 included provisions for a Humanitarian Device Exemption. Alas, Cook won the battle but lost the war, because the exemption applies only for conditions affecting fewer than 4,000 Americans per year, explicitly bars manufacturers from making any profit, and provides incentives too paltry to encourage and facilitate the sort of robust R&D projects seen in the orphan drug world.
In addition to the research and product development benefits, orphan diseases present models of health care collaboration and service delivery that, though perhaps not fully scalable to more common diseases, inspire one to think of more efficient and effective approaches, particularly in an era of increasing specialization and of finer diagnostic differentiation among subtypes of medical conditions. My own first exposure to an orphan disease, more than twenty years ago, came through a chance meeting with Dr. Frederick Kaplan of the University of Pennsylvania, an expert on FOP, a rare genetic bone disease in which muscles, tendons, and ligaments are progressively transformed into bone. What struck me most – after the tragic oddity of the disease – was the extraordinarily close and productive collaboration between FOP clinicians, basic researchers (including Drosophila geneticists studying homologous gene defects in a boneless creature), and the patient population, all working together with a sense of respect and combined purpose that I had never seen before. These three distinct populations directly informed and powerfully inspired one another with their respective understanding of the disease, and all of them benefited from the experience.
Because of the level of communication within rare disease communities, and with companies developing diagnostics or therapeutics for diseases where such candidates exist – there was tremendous efficiency and economy in the sharing and evaluation of knowledge. And if, in the end, a treatment was developed, the companies’ ability to market products directly to a well-defined physician and patient population enabled everyone to benefit, eliminating the massive waste of buckshot marketing.
Perhaps nowhere are some of the most critical issues in health care and its costs thrown into harsher relief than with orphan diseases. One might justifiably say that our approach to rare diseases is a bellwether of how our society will meet health challenges and deal with vulnerable populations generally. A utilitarian or egalitarian approach recommends policies that yield the greatest good to the greatest number, not the disproportionate allocation of more money to patients whose conditions are rare or severe. At some point benevolence towards heart-rendingly tragic cases may compromise the well-being of many. On the other hand, a belief in equal rights suggests that we should, to the extent possible, help all people to become whole, even the blameless victims of random genetic mutations, and provide medical care adequate and appropriate to their conditions whether they are commonplace or not.
In a time of health care reform, we all are conscious that medical care is expensive, that we need to control costs, reduce errors and inefficiencies, and foster a system based on evidence rather than on marketing. But “expensive” has meaning only in the context of what we are trying to do. Inevitably we will develop better methods of screening for potential problems, targeting drugs at those who respond best to them, customizing therapies, and monitoring responses. This costs. But if greater up-front costs in approaches to smaller and smaller, more orphan-like populations lead to longer term savings or improved patient outcomes, the equation shifts. What are we trying to do? How important is health? And what is our moral responsibility as a society, as humans, to care for the orphans or for others with more common serious ailments and infirmities who are also, ultimately, alone and distressed in their suffering?
For further information on orphan diseases and drugs, see:
- Thomas Maeder “A Few Hundred People Turned to Bone,” The Atlantic Monthly
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