Using Personalized Information to Shape Rare Disease Public Policy


Unorthodox clinical study design, innovative FDA public policy, and increased levels of patient involvement may be necessary to develop suitable treatments for rare diseases.

Unorthodox clinical study design, innovative FDA public policy, and increased levels of patient involvement may be necessary to develop suitable treatments for rare diseases.

The development of orphan products to treat rare diseases is the most “open” area in drug development, stated Mark Trusheim, visiting scientist, MIT School of Management, on June 24, 2013, during a panel presentation on personalized therapy innovation in rare disease at the Drug Information Association’s 2013 49th Annual Conference. But, he added, mounting pressures to keep drugs affordable may force drug developers to become more creative as they labor to bring rare disease products to market.

Historically, Trusheim noted, diseases have been fragmented by molecular type, and drug development for a given disease is generally prioritized for diseases with high incidence. But in developing drugs to treat rare diseases, he pointed out, it is often not enough to just look at a drug’s mechanism of action and hope that it will be effective to treat other diseases that are molecularly similar. In addition, economic prospects can seem very grim if manufacturers take a traditional approach to rare disease drug development, Trusheim asserted. The key to delivering effective drug therapies more quickly and affordably to patients, then, is coordinating rare disease patients through biobanks, small trial population cohorts, and longitudinal patient health records; creating innovative trial designs based on Breakthrough Regulatory status public policy tools; and diagnosing patients rapidly through the use of big data screening and crowdfunding.

Examining molecular phenotype may also be a fruitful tactic when designing trials to test rare disease therapies, pointed out Frederico Goodsaid, PhD, vice president, strategic regulatory intelligence, Vertex Pharmaceuticals. Dr. Goodsaid used Gaucher’s Disease, Duchenne muscular dystrophy (DMD), and cystic fibrosis (CF) as examples to illustrate how subtle mutations in DNA coding can change individual patient genotypes and the way a disease manifests itself within certain patient subgroups. For example, the molecular phenotype for Gaucher’s Disease is found in other diseases for which enzyme therapies have been developed. In addition, exon-skipping drug therapies (which are not as dependent on the actual DNA defect location) such as eteplirsen (AVI-4658), made from mRNA, were found to more effectively treat a subgroup of patients with DMD. Lastly, Dr. Goodsaid mentioned that analysis of in vitro data, sweat chloride levels, and disease severity helped identify 3 different groups of CFTR gene mutations in CF that have a range of impacts on chloride channel gating and opening probability.

Dr. Goodsaid concluded in his slides that clinical study designs “can be adequately powered if these subpopulations are considered as a single population and are collectively defined by the molecular function affected by the individual genotypes.” Additionally, he pointed out that there is an “urgent” need for regulatory guidance in the application of alternative clinical study design strategies. Dr. Goodsaid believes that bringing therapies to market more quickly through the use of accelerated pathways and “advanced market commitments” by payers, wherein health plans pay up front for drug development costs, must be explored.

"Novel approaches are being demonstrated in the developing world which we might want to import back to the developing world," Trusheim told Specialty Pharmacy Times. "One example is the advanced market commitment approach in which governments or other payers guarantee that they will buy a volume of doses at a pre-specified price for a novel treatment that meets specific performance levels. This approach has helped deliver vaccines to the developing world and could just as readily be applied to rare diseases."

To improve alternative trial funding, the last panel speaker, J. Russell Teagarden, BSPharm, PhD, senior vice president of medical and scientific affairs for the National Organization for Rare Disorders (NORD), said that rare disease groups are increasingly using public policy to enable development efforts. Because of structural challenges in policy, payment for rare disease treatments through the use of specialty tiers is being put into place before effective treatments have even been discovered. Medications for rare diseases are tough to finance, and many new molecules that are found to be effective (albeit only for a small subset of patients) fall into the “Valley of Death” because they don’t help all patients within an orphan condition group.

When rare disease groups get involved in development of public policy regarding personalized therapies, they help to “improve the regulatory science of pharmacogenomics and biomarker validation,” Dr. Teagarden said. Evidence used to support an endpoint that is “reasonably likely” to predict clinical trial benefit may even include evidence developed through the use of biomarkers.

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