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Molecular Genetics and Metabolism 105 (2012) 367 Contents lists available at SciVerse ScienceDirect Molecular Genetics and Metabolism journal homepage: www.elsevier.com/locate/ymgme Editorial SIMD statement on investigational new drugs for rare disease therapies Members of the SIMD (Society for Inherited Metabolic Disorders) care for patients with inborn errors of metabolism. These rare diseases frequently require unique therapeutic interventions arising from the specific biology underlying any given disorder. Examples include approved drugs used for non-indicated conditions, investigational new drugs, or unapproved compounds with variable levels of previous experience in humans. The rarity of the target diseases makes such interventions difficult to implement. Specifically, substantial development costs are difficult to recoup and statistically significant evidence is difficult to obtain from a small number of treated individuals. Furthermore, the gold standard for testing new drugs has evolved into a set of highly expensive procedures. These facts suggest that the methods used to develop therapies for rare diseases should be different from those used for common diseases. In other words, adherence to the dictum “rare disease patients deserve the same protections that other individuals enjoy” may actually do more harm than good when a new treatment promises some therapeutic benefit. Currently, investigational new drug (IND) applications to attempt therapy for rare disease patients are dealt with according to uniform policies. Specifically, drugs for rare and ultra-rare diseases must meet the same standards for clinical and pre-clinical testing as drugs for common symptoms such as hypertension or diabetes. Exemptions are available, but only if they do not compromise the protections given to subjects or the scientific integrity of product development and marketing approval processes. This appears to be true even in the case of single patient treatment INDs, designed to provide eligible subjects with investigational drugs to treat serious and life-threatening illnesses for which there are no satisfactory alternative treatments [21 CRF 312.34 and 312.35]. Such INDs require enough data to show the drug may be effective for its intended use in its intended patient population and does not expose the patients to an unreasonable risk or significant additional risk of illness or injury. The assessments of effectiveness and associated risk are discretionary, but treatments for rare diseases are consistently subjected to the same preclinical requirements as for any other treatments, with no measure of discretion applied. 1096-7192/$ – see front matter © 2012 Elsevier Inc. All rights reserved. doi:10.1016/j.ymgme.2012.01.002 As advocates for patients with rare diseases, we disagree with this position, and we know that affected patients, their families, medical institutions, principal investigators, disease experts, institutional review boards, and data safety and monitoring boards also disagree. Instead, we strongly believe that the ethical principle of comparing risks with benefits for any proposed therapy should prevail. For scores of rare diseases, the benefit constitutes the possible avoidance of death, neurological damage or permanent disability; these outcomes, which are often a certainty without intervention, raise the threshold for risks deemed acceptable by affected parties. Evidence of the magnitude of that threshold lies in the alternative treatments pursued by patients denied investigational drugs by reputable physicians, i.e., expensive and life-threatening “cures” promoted by charlatans. We propose that the emphasis for evaluation of new drugs needs to be shifted from unattainable and possibly harmful adherence to current standards to a model of best available evidence plus adequate patient informed consent. The SIMD emphatically believes that expert opinion must be weighed heavily when evaluating applications for the investigational use of drugs to treat patients with rare diseases. A rare disease expert is an internationally recognized authority in the field whose knowledge of the natural history of the disease allows her/him to predict the likely outcome if no therapy is attempted. Experts can also gauge the likelihood that standard preclinical testing, which requires a huge investment not available to rare disease patients, can be practically performed. The SIMD is able and willing to provide rare disease experts for the evaluation of these considerations, which should be balanced against the risks of the proposed intervention, rather than uniformly imposing rigid requirements for assurance of safety. Society for Inherited Metabolic Disorders Board of Directors