Download investigational new drugs for rare disease therapies

Molecular Genetics and Metabolism 105 (2012) 367
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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