With the Food and Drug Administration’s Safety and Innovation Act (FDASIA), the Agency’s added a fourth expedited approval pathway – “Fast Track, Breakthrough Therapy, Accelerated Approval and Priority Review, Expediting Availability of New Drugs for Patients with Serious Conditions,” which expedites development and review for drugs intended to treat serious conditions, and provides significant improvement over existing therapies. As of April 2014, FDA received 165 requests for breakthrough status and has granted 42 such designations.
Most Breakthroughs are cancer drugs, although the latest designation (March 20) was earned by Pfizer for a meningococcal vaccine.
Breakthrough was in part a reaction to criticisms that FDA’s approval times were inordinately long, even though this notion was debunked in a June 14, 2012, New England Journal of Medicine article that compared FDA approval times with those of overseas regulators.
The experience of Catalyst Pharmaceutical Partners (Coral Gables, Fla.) is representative. Catalyst’s Firdapse therapy, for treating Lambert Eaton Myasthenic Syndrome (LEMS), received Breakthrough status in 2013. LEMS is a debilitating neuromuscular disease for which no safe treatment exists. Lack of competition, the seriousness of the disorder and encouraging efficacy signals played decidedly in favor of Firdapse.
BREAKTHROUGH STATUS CHALLENGES
While highly desirable, Breakthrough status challenges sponsors to keep product development on track, says Steve Miller, Ph.D., chief scientific officer at Catalyst. “Since the Agency is committing critical resources to expedited reviews, it expects companies to follow through with equal dedication, positioning these programs on the front burner.”
Nothing in FDA guidances or in FDASIA requires the Agency to investigate whether sponsors are capable of attaining development milestones expeditiously. One could imagine some level of due diligence based on a sponsor’s resources and previous compliance issues, but that is only conjecture.
Expedited review helps patients and the sponsor, which enjoys a longer exclusivity period for products. It also improves FDA’s image for facilitating timely approval of critical medicines. One thing it does not do is substantially help sponsors for follow-on indications. “There are no regulatory shortcuts,” Miller emphasizes. “Basic safety studies are of course indication-neutral. Other than that, submissions for second or third indications proceed normally.”
Orphan Drug status is another work-around that continues to be profitable. Sponsors receive a decent return on investment in the short term, says Susan Bain, DRSc, professor of practice, clinical, regulatory and quality at the Keck Graduate Institute of Applied Life Sciences (Claremont, Calif.). “Afterward, they can initiate clinical trials for a second indication and hope for off-label business as well. The idea is to get the drug out faster, with less data, and a lower clinical burden, all while benefiting from the drug’s market presence.”
Closely paralleling FDASIA’s supply chain directives are the EMA’s 2013 Falsified Medicines Act, which tightens requirements and control over drug product ingredients, including excipients, and similar laws in other jurisdictions, particularly in emerging markets. (Editor’s note: For a full account of FDASIA’s supply chain initiatives and additional commentary, see “Taming The Supply Chain Monster.”
Given the global nature of pharmaceutical industry sourcing, for both materials and services, FDASIA was long overdue. Luba Skibo, executive director at NSF International, an independent global standards-writing, training and education firm predicts rapid and significant growth of auditing activities and inspection readiness, including a rise in paper audits and site visits. “Five years ago, supply chain security was a vision, a plan, an initiative. Today it is a reality,” Skibo says. “It will still be here five years from now, hopefully with clear directions for implementation.”
FDASIA grants FDA the unprecedented authority to regulate foreign suppliers of raw ingredients and active pharmaceutical ingredients that make their way to U.S. markets, whether the eventual manufacturer domiciles stateside or overseas. While no geographic region of the supply chain is invulnerable, FDA will likely direct most of its oversight to countries with less-than-stellar reputations for following accepted business practices.
If the Agency believed, however, that its headaches would begin and end with supply chain regulation, last year’s scandal involving a GlaxoSmithKline (GSK) business unit in China dispelled that notion. The scandal, which involved bribery to promote off-label prescriptions, has deeper relevance in light of the company’s record-setting $3 billion fine in 2012 for engaging in similar behavior in the United States. And just this past April, GSK was found to be employing similar tactics in Iraq.
While FDA has no direct authority over foreign bribery cases, these incidents could alert the Agency to potential domestic wrongdoing. Eventually, FDA will discover that it cannot ignore malfeasance simply because it occurs beyond its territorial jurisdiction.
On the surface, GSK’s overseas troubles suggest that developing countries are beginning to take corruption seriously. Or, conversely, these incidents unveil even deeper malfeasance.