Incentives, Opportunities Abound as Orphan Drug Demand Grows

By Dr. Lisa Pitt, VP, Global Regulatory Affairs, Premier Research & Angi Robinson, Executive Director, Pediatrics & Rare Disease, Premier Research

If ever a drug development effort called out for priority review and approval, this was it. A U.S. pharmaceutical company was developing a treatment for hypophosphatasia, a progressive, ultra-rare metabolic disease for which only supportive therapy was available. Asfotase alfa, an innovative enzyme replacement drug, was the first real hope for those diagnosed with HPP, a disease that attacks bones and multiple systems of the body with devastating consequences.

The Food and Drug Administration granted the compound Breakthrough Therapy designation and issued the developer a Rare Pediatric Disease Priority Review Voucher, which confers priority review to a subsequent drug application that would not otherwise qualify for priority status. The voucher program encourages development of new drugs and biologics to prevent or treat rare pediatric diseases. Meanwhile, the European Medicines Agency conferred orphan status and provided scientific advice through its Committee for Medicinal Protocols for Human Use.

The expedited development and subsequent approval of the drug — on the market today in the U.S., European Union, Japan, and Canada — reflects a large and promising trend in the battle against rare diseases. Concerted effort by governments, regulators, and industry is rapidly expanding development of new therapies, opening doors and giving fresh hope to the hundreds of millions who suffer from the more than 7,000 known rare diseases.

To understand the rising urgency in developing and approving treatments for these conditions, it’s helpful to recognize that “rare disease” is largely a misnomer. While no single condition claims many victims, there are a lot of them. An estimated 30 million Americans (that’s almost one in 10) live with a rare condition, according to rare disease advocacy group Global Genes. The number is about the same in Europe, and worldwide, it’s around 350 million. Even more tragic, half of the known rare diseases afflict children.

Considering the time and expense involved in developing new treatments, it’s hardly surprising that there are only about 400 approved therapies, and that 95 percent of diseases today go untreated. While 2015 was a landmark year for these so-called “orphan” drugs, with 21 approved in the U.S. and 18 in the European Union, the industry is still just scratching the surface.

Since the U.S. Orphan Drug Act passed more than 30 years ago, U.S. regulators have provided extensive guidance and resources to support rare disease research. Orphan designation qualifies drug companies for development incentives that include:

  • Financial grants
  • Increased access to regulatory agencies for scientific support and interaction
  • Protocol assistance
  • Extended periods of market exclusivity
  • Fee reductions and waivers

The FDA and EMA are showing unprecedented support in addressing this vast unmet need, aiming these efforts largely at the biotech and specialty pharma companies that are at the forefront of orphan drug development. Because many of these companies are very small — some pursuing a single compound — they often lack the resources to research and make best use of what’s available. Premier Research frequently counsels these companies, and here’s some of what we’re telling them.

Grant programs

Last fall, the FDA awarded 18 research grants for product development in rare diseases. Averaging just over $1 million each, they include $1.1 million to continue developing a drug that makes tumor cells in HPV patients more susceptible to immunologic attack and $1.6 million for a vascular-targeted prodrug to treat recurrent glioblastoma. Other FDA initiatives include the Orphan Products Natural History Grants Program, which in fiscal 2017 will fund $2 million in rare disease-related natural history studies.

The EMA, meanwhile, is two years into Horizon 2020, the largest research and innovation program in its history and one of the biggest worldwide. The program has budgeted nearly 80 billion euros through 2020 to promote scientific excellence and strengthen industrial leadership.

Early regulatory engagement

Let’s face it: This is a business of longshots. More than 90 percent of the drugs that reach clinical testing fail, and when you further consider the treatments that don’t make it that far, it’s clear how much is at stake. Recognizing this reality, U.S. and European regulators increasingly push for earlier involvement with sponsors, who — to their credit — are mostly embracing the opportunity.

At a recent industry conference in Europe, a speaker from EMA was vocal in calling on sponsors to engage early to ensure efficient and scientifically rigorous processes. The agency’s Innovation Task Force, offering an information platform for early dialogue on scientific, technical, and regulatory issues, is one of multiple avenues for early involvement. The FDA is always willing to talk with sponsors prior to study start-up. Sponsors can request formal Type B (pre-IND, end of Phase 2a) meetings or Type C (general guidance) meetings throughout product development.

Precompetitive collaboration

More sponsors also are turning to a process called precompetitive collaboration, working with government organizations, academic research centers, and even competitors. The extreme complexity and paucity of data inherent in rare drug research make these efforts time-consuming and expensive and produce a terrible success rate. Precompetitive collaboration played a major role in HIV/AIDS research as competing pharma and biotech companies joined with academic researchers and government research institutes to answer a challenge that demanded the best of their collective ingenuity.

Some level of precompetitive discourse is almost a necessity today, prompting the 2014 launch of the Accelerating Medicines Partnership. AMP is a public-private partnership among the NIH, FDA, 10 biopharmaceutical companies, and multiple nonprofit organizations intended to transform the current model for developing new diagnostics and treatments by identifying and validating promising biological targets for therapeutics.

Collaboration between U.S. and EU regulators is also on the rise. The FDA and EMA have greatly increased their level of cooperation and information-sharing in recent years. There are frequent interactions, and they maintain structured scientific and regulatory working groups, or “clusters.” In 2015 they established a cluster on patient engagement to share experience and best practices around patient involvement in drug development, evaluation, and post-authorization activities.

Better access to government data

Another boon to researchers is rapidly expanding access to the results of scientific research funded by government agencies, information that resides in hundreds of data-sharing repositories. The U.S. Department of Health and Human Services in 2015 issued a public access policy covering its largest operating divisions: the FDA, the NIH, the Centers for Disease Control and Prevention, and the Agency for Healthcare Quality and Research.

The agency has two goals: to make publications resulting from the research it funds freely available to the public, and to make the information available in digital formats (the effort is young, so the digital infrastructure is still emerging). HHS Secretary Sylvia Burwell declared this “an inflection point in history” in describing plans to give the public maximum value from federally funded health research data.

Recognizing the urgency

Any discussion of government support for orphan drug development needs to acknowledge legislative action to promote new treatments. Most notable on the legislative front is the 21st Century Cures Act, an effort to accelerate approval of medicines for conditions currently lacking cures. The act and a long list of companion proposals have long been pending in the U.S. Congress.

Legislation can prompt regulatory change, but doesn’t necessarily need to precede it. It’s clear that the U.S. and European governments recognize the urgency in promoting development of orphan drugs and are committed to giving the subject continued high priority.