Challenges of Clinical Trials in Rare Diseases – a perspective on Stevens Johnson Syndrome/Toxic Epidermal Necrolysis.

Omer Iqbal, MD, FACC, FESC

Rare diseases afflict as many as 350 million people around the world.  Given an estimated 7,000 rare diseases worldwide, the definition of “rare”, differs from country to country.  Rare diseases in the United States are defined as those that affect fewer than 200,000 people with a prevalence of < ~6.25 per 10,000 individuals.  Stevens Johnson Syndrome/Toxic Epidermal Necrolysis (SJS/TEN) is one such rare disease, often drug-induced, and immune-mediated Severe Cutaneous Adverse Reaction (SCAR), frequently involving the eyes leading to corneal blindness.  Since the pathophysiology is not completely understood, despite a multidisciplinary approach, the treatment is symptomatic and inadequate resulting in significant morbidity and mortality.  The survivors most often have long-term ocular sequelae.  Pediatric population affected by this condition may pose additional problems related to subject recruitment and retention, consenting, randomized clinical trial designing, operating, organizing and other issues related to determination of optimum power in order to obtain statistically valid outcome.  Approximately 80% of an estimated 7000 rare diseases involves genetics and a fraction of them are effectively treated by specific drugs.  However, SJS/TEN is itself mostly induced by drugs and it may not be ideal to treat by any other drug.  Based on the natural history of SJS/TEN and involvement of various Human Leucocyte Antigen (HLA) genes affecting different ethnic groups globally, conducting a multi-centric clinical trial with required optimum number of subjects could be quite a challenge.  Patient registries provide useful data but may be difficult or impossible to control for confounding variables and bias.  However, lack of adequate patient registries as in SJS/TEN may pose additional problems.  Given that this condition is drug-induced with more than 200 drugs known to be serious culprits, the existing and future drug pipelines are warranted to undergo cheminformatics-aided pharmacovigilance in order to control the incidence of SJS/TEN.  Although HLA genes are associated with this condition together with specific culprit drugs, but identification of how the HLA genes interact with the drug in the host system is of paramount importance in disease prevention, and earlier diagnosis in order to have a strategic multidisciplinary approach in its treatment.  With the advent of Precision Medicine, newer study designs pertaining to randomized clinical trials for rare diseases have to be established and technological advances such as exome sequencing used in order to achieve tangible clinical outcomes.  It is crucial to carefully map the genomic landscape of rare diseases like SJS/TEN in order to assess the response to combination immunomodulatory therapy with either Ipilumumab and Nivolumab or any other immunotherapy.  Precision medicine needs randomized clinical trials too.  The evolving nature of randomized clinical trials with immunotherapy will provide a pragmatic approach in the management of patients with SJS/TEN.  This presentation will provide a unique blend of discussions on the challenges of clinical trials on rare diseases in general and SJS/TEN in particular combined with the clinical manifestations of this rare condition.