When zebras run with horses – inherited metabolic diseases come mainstream
1 When you hear hoofbeats, think of horses, not zebras – Dr. Theodore Woodward
Training in the specialty of endocrinology and metabolism is dominated by the “endocrinology”. “Metabolism” training occurs primarily a “by-product” of the study of common diseases such as the interplay of carbohydrate and fat metabolism that influences outcomes in patients with diabetes. However, the study of “metabolism” also includes inherited metabolic disorders (IMDs). IMDs were previously considered the “zebras” of medicine, disorders that were extremely rare and usually resulted in death in childhood, so physicians who practiced adult medicine could spend their entire career without ever seeing an affected patient. However, this situation is changing rapidly due to major advances in both treatment (such that patients identified with IMDs are living longer) and diagnosis (with high throughput genetic testing methods leading to an increased number of patients being diagnosed with IMDs at all ages).
2 Why endocrinology?
Endocrinologists are uniquely suited to become the primary subspecialists involved in the care of patients with IMDs. Endocrinologists are arguably the medical subspecialists with the most experience in multi-system diseases. Endocrinologists are comfortable dealing with patients whose conditions like diabetes and adrenal insufficiency that fluctuate with day-to-day events like exercise, altered diet, pregnancy, intercurrent illness and surgery. They are used to situations where individualized treatment plans are needed (e.g. managing diabetes in patients with cognitive impairment) and protocol based therapies will not suffice. Most endocrinologists already work within multidisciplinary teams and are comfortable being involved in treatment plans (e.g. diabetes, lipid disorders) where nutrition therapy is at least as important, or even more important, than any drug therapy. Endocrinologists are increasingly experienced in the use of genetic testing modalities to guide diagnosis (e.g. genetic forms of diabetes) and treatment (e.g. using genetic testing results to guide interpretation of indeterminate thyroid biopsy results) and this experience is critical for physicians who will care for patients with IMDs.
Endocrinologists routinely deal with rare conditions like Cushing syndrome and carcinoid tumours, conditions where large scale randomized placebo controlled trials are not available to guide treatment decisions and are experienced in making treatment decisions possible based on the evidence available. At the same time, endocrinologists do have skills of critical appraisal honed by their work in common diseases which allow them to identify limitations in the evidence and clinical trial design. In this respect, endocrinologists have quite different expertise from other groups of physicians more traditionally associated with IMD patients (for example, medical geneticists) in that these other groups don’t have the same background in treatable common diseases with high quality evidence standards to allow them to demand better quality evidence for less common conditions. As the impact of rare diseases on health care resources is increasing at an exponential rate, physicians who have these critical appraisal skills are desperately needed in order to use resources in a way that is responsible both to the patient with the IMD and to the health care system as a whole.
3 The scope of the rare disease challenge
Rare diseases are the “next big thing” in medicine and drugs developed for these indications are referred to as “orphan” drugs. It has been estimated that the potential return on investment for an orphan drug is 1.7X greater than that for a common drug . Thus, the paradigm of drug development is shifting from block-buster to ‘niche products’. Not only are new biotech companies focusing solely on orphan drugs, but big pharma companies are creating entire ‘niche product’ markets in order to exploit this market opportunity, and rightly so, given their fiduciary responsibility to provide return on investment to their investors.
However, many drugs for rare diseases are priced in excess of $500 k per year per patient, and treatment is most often lifelong. Thus, no patient can pay out of pocket. Treatment is only provided if the drug is covered as an insured benefit by either a public or private insurer. Therefore, pharmaceutical companies are earning profits on the backs of tax payers and employers, and continue to exploit the expectation that, because the disease is rare and is often “just one patient”, these diseases are often life-threatening diseases of childhood with no other treatment option, there is a responsibility to provide the drug to the patient. However, although a rare disease is rare, having a rare disease is not rare, with over 7000 rare diseases currently having been identified.
The number of orphan drug designations has been rising steadily since 2003, increasing from 96 in 2003 to a peak of 354 in 2015 in the US. However, this is likely to continue increase as the number of orphan drugs in the pipeline continues to rise, in part due to almost double return on investment for an orphan drug relative to a drug for a common disease. More drugs in the pipeline will inevitably lead to more orphan drugs designations and more approvals, ultimately leading to greater pressure on payers, if they choose to pay. According to a recent report, in 2016, the average annual per patient cost for an orphan drug was $140,000 versus $27,700 for a non-orphan drug. Worldwide orphan drug sales are forecast to be $209billion in 2022, an 11.1% growth from 2017, double that of the overall prescription drug market . This is a result of the orphan drugs anticipated to account for 21.4% of overall worldwide prescription drug sales by 2022. The median cost per patient is approximately 5.5 times higher for an orphan drug relative to a non-orphan drug. Orphan drugs are forecast to account for 55% of the cumulative value of the European drug pipeline by 2022.
4 Rare diseases still need good data
Unfortunately, data supporting the use of expensive drugs for rare diseases remains of very low quality. Although guidelines exist to try and assist manufacturers with clinical trial design with the limitations of dealing with a rare disease in mind [3, 4], the quality of the data remains poor. The huge financial incentive to develop drugs for rare diseases has led to a plethora of low quality studies looking at biochemical outcomes simply because these can be measured, even when these biochemical outcomes have no proven relationship to disease progression or patient outcomes. Clinicians, rather than laboratory scientists, are needed to help define outcomes that are relevant to the patient rather than the biochemistry. Indeed, involvement of clinicians and patients to define outcomes was a recommendation from a recent report which sought to outline solutions to the problem of low data quality in rare diseases . Endocrinologists, who deal with common and rare diseases together every day, are uniquely suited to fill this void and to help advance the quality of the data available on the treatment of rare diseases.
The authors would like to thank Dr. Marshall Dahl who provided the photograph which accompanies this article.
Compliance with ethical standards
Conflict of interest
Sandra Sirrs has received travel support, speaking fees, and/or participated in advisory boards or clinical trials funded by Sanofi-Genzyme, Shire Human Genetics Therapies, Actelion, and Alexion.
Larry Lynd has no conflicts of interest relevant to this manuscript.
This editorial does not contain any studies involving human participants or animals performed by any of the authors and, as such, informed consent is not required.
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