FDA Issues Report to Congress on Findings and Recommendations of Rare and Neglected Tropical Disease Groups; Groups Report Strengths and Opportunities to Improve Regulatory Paradigms and Science

September 1, 2011

By Kurt R. Karst –      

In a Report to Congress issued earlier this year and recently made public, FDA’s Rare Disease Group (“RDG”) and Neglected Tropical Disease Group (“NTDG”) report on their findings and recommendations to improve the current regulatory/scientific  armamentarium to facilitate the development of products for rare and neglected diseases.  As we previously reported, the report was required by Section 740 of the Agriculture, Rural Development, Food and Drug Administration, and Related Agencies Appropriations Act of 2010 (Public Law No. 111-80), which also required FDA to establish the RDG and NTDG.  An attempt to build on Section 740 in appropriations legislation for Fiscal Year 2011 – see our previous posts here and here – was unsuccessful given all of the wrangling over the budget.  The findings and recommendations for both the RDG and NTDG are reported below.

RDG Report

Based on its review of FDA practices for regulating products for rare diseases, and comments and recommendations from a June 2010 public hearing (Docket No. FDA–2010–N–0218) (see our previous post here) and an October 2010 report from the Institute of Medicine, titled “Rare Diseases and Orphan Products: Accelerating Research and Development,” the RDG “identified both strengths and constraints in the current paradigm for drug and device regulation.”  According to FDA,

An evaluation of current agency practices revealed that extant regulations provide the flexibility needed for the review of medical products for the diagnosis, treatment, and prevention of rare diseases.  FDA recognizes that, for all serious and life-threatening diseases, greater drug safety risks may be justified when the potential benefits of the drug are seen in the essential aspects of the disease and outweigh these risks.  The approval standard for drugs and biologic medical products of “substantial evidence of effectiveness” and safety remains an appropriate one for rare diseases.  In devices, the approval standard for a humanitarian device exemption (HDE) of reasonable assurance of safety and probable benefit is also appropriate.  Current regulations allow for flexibility and scientific judgment9 when applying the standard in assessing the totality of the evidence. FDA has successfully applied this flexibility to approve therapeutics for rare genetic diseases (e.g., Huntington’s disease) and rare cancers, among others. . . .

In addition, FDA says that the Agency “makes best use of existing regulatory provisions to facilitate efficient drug development and availability of drugs to patients during the investigational period,” including use of the Fast Track and Accelerated Approval processes, Priority Review, and Expanded Access of patients to investigational products. 

Notwithstanding the various FDA strengths identified in the report, FDA says that there are “clear areas for potential improvement,” which the Agency is trying to address through various ongoing activities, including “[e]xamining and evaluating policy and procedures for the regulation of medical products for rare diseases,” “[d]eveloping education and training programs for FDA rare disease reviewers and external stakeholders,” and “[i]ncreasing communication efforts involving rare diseases to stakeholders within the Federal government and outside FDA, as well as academia and the research community, industry, professional associations, and advocacy organizations.”  Given the significant increase in recent years to develop products for rare diseases (which is expected to continue for years to come), it is important that certain “impediments to progress” be addressed, including, according to FDA, “the often inadequate scientific foundation and core knowledge vital to support medical product development for rare diseases, limited regulatory precedents for most of the individual diseases and some of the most technologically innovative products in development, and suboptimal collaboration among relevant stakeholders.”  Some of the items listed under "Advancing Development of Drugs for Rare Diseases" in the proposed PDUFA V Reauthorization Performance Goals and Procedures (Fiscal Years 2013 through 2017) issued on August 31, 2011 appear to be directed to addressing some of these issues.

The RDG’s recommendations identify three key areas in need of additional efforts: (1) “increase the foundation of biomedical and regulatory science required to support development and regulatory assessment of medical products for rare diseases,” including conducting disease-specific natural history studies, identifying, developing, and qualifying novel biomarkers, and exploring the use of novel clinical trial designs and statistical methods; (2) “[i]ncrease collaboration among rare disease stakeholders both within and outside FDA;” and (3) “[g]ain a thorough understanding of the regulatory history of orphan drug products to help identify effective development approaches, particularly for addressing the uncertainties of biomedical knowledge along the product development pathway, so that patterns can be adapted to future development programs.”  This last key area includes performing “a detailed analysis of FDA’s 27-year history of Orphan drug approvals to identify factors and methods that have led to successful drug development and approval or have impeded development and identify areas for improvement,” and, in the case of medical devices, analyzing “the reasoning presented in device applications for requesting a [HDE] as well as why an application was successful or not with the goal of identifying areas for improvement” and undertaking an assessment of the barriers to and incentives for the development of medical devices for rare diseases.

NTDG Report

The NTDG report is less detailed than the RDG report, presumably given the more recent focus on tropical diseases product development, which the Tufts Center for the Study of Drug Development has tracked (see our previous report here).  (According to a World Health Organization report, neglected tropical diseases blight the lives of 1 billion people worldwide!)  The NTDG report is based on the group’s assessment of ongoing and planned activities and input and recommendations FDA received from a September 2010 public hearing (Docket No. FDA-2010-N-0364) on issues and concerns related to the development of neglected tropical disease products.  According to the NTDG,

appropriate regulatory paradigms are in place through FDA’s existing programs and activities related to FDA review of marketing applications for products for NTDs.  FDA has approved, licensed, or cleared a number of products for NTDs. . . .  FDA’s Office of International Programs has existing outreach activities related to NTD product development.  Nevertheless, the NTD group found that enhancing efforts, including those in Federal, academic, and other collaborative programs, could help strengthen certain basic and applied research areas (e.g., regulatory science), that form the foundation for medical product development and the basis of regulatory review and assessment.  The NTD group also found that enhancing the clinical trials infrastructure, through clinical trials consortia or other organizations, could facilitate the conduct of trials in countries of the developing world where NTDs mostly occur.

The NTDG makes four recommendations for improving the development of neglected  tropical disease products, including issuing guidance documents on neglected tropical disease drug product development (like the draft guidance FDA issued last week, titled “Neglected Tropical Diseases of the Developing World: Developing Drugs for Treatment or Prevention"), revising CBER’s “General Principles for the Development of Vaccines to Protect Against Global Infectious Diseases,” holding a CDRH Expert Panel meeting to discuss FDA’s regulation of diagnostic tests for pulmonary tuberculosis, and issuing guidance on the regulation of diagnostic tests for pulmonary tuberculosis.  The NTDG also notes that “[o]ne other consideration is to explore extending FDA’s Orphan Drug Grants Program to include grants for studies of diagnostic tests or other devices for NTDs.”

The NTDG report also says that “strengthening the scientific foundation that forms the basis of drug development and FDA’s regulatory process would greatly improve overall development process for NTD products.”  This includes basic and applied neglected tropical disease research by other Federal agencies (e.g., the National Institutes of Health), academia, or other consortia. 

We also note that FDC Act § 524, added to the statute by the 2007 FDA Amendments Act, created a new Priority review Voucher (“PRV”) program.  Under the PRV program, sponsors of certain new drugs and biologics for “tropical diseases” that have received priority review may receive a PRV entitling the holder to a 6-month priority FDA review of another application that would otherwise be reviewed under FDA’s standard 10-month review clock.  That program, as we recently reported, has not yet panned out, perhaps due, in part, to the high PRV redemption user fee FDA has set.  In Fiscal Year 2011 the PRV redemption fee was set at $4,582,000.  The Fiscal Year 2012 PRV redemption fee was just set by FDA at $5,280,000 – and that figure is in addition to the Fiscal Year 2012 full application fee of $1,841,500.  As we previously reported, legislation has been introduced to amend FDC Act § 524.