Funding Grants for Rare Diseases at the Food and Drug Administration

Abstract

With the availability of various funding sources for studying therapies in rare diseases, choosing the right funding source is often challenging. Assessing the unique aspects of each individual funding source may benefit the applicant as the correct funding source will help ensure that their study receives an appropriate level of support. One such funding source for rare diseases is offered through the Food and Drug Administration (FDA). This paper will discuss the mission, specific program details and achievements of the FDA's Orphan Products Grants Program in an effort to help future grant applicants determine if the program is suited to their needs.

Keywords::

• food and drug administration
• funding sources
• grants
• humanitarian device exemption
• humanitarian use device designation
• investigational new drug
• Office of Orphan Products Development
• Orphan Products Grants Program
• Prescription Drug User Fee Act
• rare disease
• request for applications
• Review Division

1. Introduction

Finding safe and effective therapies for the estimated 5,000 – 8,000 rare diseases affecting approximately 25 to 30 million Americans [1] remains an important goal of the Food and Drug Administration (FDA) or the Agency. Under the Federal Food, Drug, and Cosmetic Act (FFDCA), a rare disease or condition is one that affects fewer than 200,000 persons in the US or is one that affects more than 200,000 persons in the US and for which there is no reasonable expectation that the cost of developing and making available a drug for such disease or condition will be recovered from its sales in the US [2]. Due to the rarity of these disorders, making a profit may be difficult. However, incentives that are available once a product is designated as an orphan drug under §526 of the FFDCA (e.g., tax credits, possible 7 years of marketing exclusivity, possible waiver of the Prescription Drug User Fee Act [PDUFA] fee of $1,958,800 for 2013) [2,3], and the availability of a variety of funding sources for studies for rare diseases, ensure that research for these conditions continues. In a country where multiple funding sources exist, identifying an appropriate funding program for a study can help ensure that the study receives the proper level of support so that neither time nor money go wasted in an attempt to find potentially helpful therapies to battle these rare conditions. Aside from identifying the available funding avenues, unique aspects of a program may help assist applicants in determining which funding program is best suited to their needs. One federal funding source for rare disease research is available through the FDA's Orphan Products Grants Program located within the Office of Orphan Products Development (OOPD). This editorial will discuss the mission, specific program details and achievements of the Orphan Products Grants Program and will provide some examples of successful grants that have led to marketing approvals of products, in an effort to help future grant applicants determine if the program is suited to their needs.

2. Orphan Products Grants Program

Since its inception in 1983, the mission of the Orphan Products Grants Program has been to support the clinical development of drugs, biologics, devices or medical foods for use in rare diseases or conditions where no current therapy exists or where the proposed product will lead to a new rare disease indication. The program provides funding for clinical studies (Phases I, II or III) to evaluate the safety and/or efficacy of drugs, biologics, medical devices and medical foods in rare diseases or conditions that will either result in, or substantially contribute to, the marketing approval of these products. Depending on the phase of the study, funding may vary between $200,000 and $400,000 total costs per year. Funding is available to public or private, for profit or nonprofit entities as well as to Federal Agencies that are not part of the Department of Health and Human Services. Although many of the grants funded by the Orphan Products Grants Program are awarded to US institutions, several of these grants have contributed to the inclusion of foreign study sites within the funded study. Foreign institutions are eligible and encouraged to apply.

3. Unique aspects of the Orphan Products Grants Program

A Project Officer is assigned to each grant funded through the Orphan Products Grants Program to oversee the grant for its entire duration. Project Officers come from a variety of backgrounds and can generally provide a regulatory science as well as a medical perspective. Project Officers help ensure that the grant is monitored effectively and serve as a liaison between OOPD and the Review Divisions who oversee the marketing approval of a product. In certain situations, Project Officers may suggest ways to augment patient accrual or help locate commercial sponsorship. All these methods help to ensure that federal funds are used appropriately and that study results can be useful should a marketing application be submitted for the product.

Because the Orphan Products Grants Program is administered by the same Agency that also houses the Review Divisions that oversee the approval process of a product, the Review Divisions are involved throughout the entire grant. This involvement begins at the time a grant application is initially reviewed by an ad hoc review panel comprising experts in either the clinical specialty area of the application and/or in clinical trials in general. During the review of a grant application, Review Division representatives are invited to provide their perspective on any potential regulatory issues with respect to the study and answer any questions ad hoc reviewers may have. The Review Division and the Project Officers continue to work closely throughout the lifetime of the grant. For instance, if issues arise with the study conducted under the Investigational New Drug (IND) Application that would affect continued funding of a grant (e.g., if the IND was placed on clinical hold, the study encountered enrollment problems and so on), the Project Officers will communicate with the appropriate Review Division to discuss potential solutions. Similarly, if changes are made to the protocol, the appropriate Review Division and the Orphan Products Grants Program must be informed and both parties must approve the changes prior to implementation.

4. Examples of successful grants funded by the Orphan Products Grants Program

The program began in 1983 with $500,000. The authorizations and appropriations have increased over the next 20 years. However, since 2005 the amount of appropriated funds has remained constant at approximately $14 million. As a result, the Orphan Products Grants Program has been able to fund 12 – 22 new foreign or US-based grants per fiscal year, and continues to fund 60 – 90 ongoing grants. Since its inception, the Orphan Products Grants Program has been able to fund over 500 grant applications submitted by both foreign and US sponsors and has contributed in bringing more than 40 products to the market. Below are three examples of several product types (biologic, drug and device) that have received grant funding through the Orphan Products Grants Program and subsequently received marketing approval for a rare disease.

In 1996, OOPD funded a Phase II/III, 12-week study of an antitumor necrosis factor agent known at that time as cA2 (now referred to as infliximab [REMICADE]), in adults with moderate-to-severe Crohn's disease resistant to treatment [4]. Patients were randomly assigned to receive a single 2 h intravenous infusion of either placebo or cA2 [4]. Clinical response was defined as a reduction of ≥ 70 points in the score on the Crohn's Disease Activity Index at 4 weeks that was not accompanied by a change in any concomitant medications [4]. At 4 weeks, 81% of patients given a cA2 dose of 5 mg/kg, 50% of patients given a dose of 10 mg/kg and 64% of patients given a dose of 20 mg/kg had a clinical response compared with 17% of placebo-treated patients [4]. Remission was noted in 33 versus 4% of cA2 and placebo-treated patients, respectively [4]. At 12 weeks, clinical response was noted in 48, 29 and 46% of patients treated with cA2 doses of 5, 10 and 20 mg/kg, respectively, resulting in an overall response rate of 41%. The rate of response in placebo-treated patients was 12% [4]. cA2 was granted orphan designation in November 1995, because at that time, the prevalence of Crohn's disease was below 200,000. The product was granted marketing approval on August 24, 1998 for the treatment of moderately to severely active Crohn's disease in patients who have an inadequate response to conventional therapy and for the treatment of patients with fistulizing Crohn's disease [5]. Seven years of exclusivity was granted upon marketing approval because REMICADE was designated an orphan drug and its sponsor was the first to receive marketing approval for this product for this indication.

A more recent example of a study funded by OOPD is of a Phase II study of ivacaftor (KALYDECO) in 39 adults with cystic fibrosis with at least one copy of the G551D mutation in the Cystic Fibrosis Transmembrane Regulator (CFTR) gene [6]. This study was carried out in two parts. The first part involved 20 patients who were randomly assigned to receive either ivacaftor (25, 75 or 150 mg) every 12 h or placebo for 14 days (total 28 days separated by washout period) [6]. The second part involved 19 patients who were randomly assigned to receive either ivacaftor (150 or 250 mg) every 12 h or placebo for 28 consecutive days [6]. Although the primary objective was to evaluate the safety and adverse event profile of ivacaftor, secondary endpoints included measurements of the nasal potential difference and sweat chloride concentration, which were both used as measures of CFTR function [6]. Clinical efficacy was evaluated based on a change in the forced expiratory volume in 1 s (FEV₁) from baseline and a disease-specific health-related quality-of-life questionnaire [6]. The results demonstrated that ivacaftor was associated with within-subject improvements in CFTR and lung function [6]. The Phase III clinical program design, including dosage selection, was based upon this OOPD-supported study. This Phase III clinical program formed the basis for the approval of ivacaftor. After undergoing priority review, ivacaftor received marketing approval on January 31, 2012 for the treatment of cystic fibrosis in patients aged 6 years and older who have a G551D mutation in the CFTR gene [7]. Ivacaftor became the first treatment that targets the CFTR gene that is the underlying cause of cystic fibrosis [8]. The product received orphan designation in December 2006, and was granted 7 years of marketing exclusivity upon approval because KALYDECO's sponsor was also the first to receive marketing approval for this product for this indication.

One last example is of a pivotal, multicenter study that evaluated the safety and probable benefit of the Berlin Heart Pediatric Ventricular Assist Device (EXCOR Pediatric System) as a bridge to heart transplant or successful weaning in 48 children with severe heart failure [9]. Although heart transplantation offers relief from symptoms of severe heart failure, there are fewer pediatric-sized donor hearts available for transplantation than for adults, thereby prolonging the waiting period in children until transplantation can occur [10]. This study compared children with severe end-stage heart failure requiring mechanical support as a bridge to transplant who underwent implantation of EXCOR, with a similar group of historical controls who received circulatory support with extracorporeal membrane oxygenation (ECMO) [9]. Survival in each of the two cohorts (cohorts based on size: < 0.7 m², and ≥ 0.7 m² < 1.5 m²) receiving EXCOR mechanical support exceeded 88% [9]. This was a significant improvement compared to survival in the two size-and-propensity-score-matched historical control groups undergoing ECMO (75 and 67% successfully transplanted or weaned) [9]. EXCOR support afforded substantially longer support times in each of the two study cohorts (median 28 – 43 days) when compared to their ECMO controls (median 5 days each) with a lower overall rate of adverse events [9]. Stroke was a major concern, occurring in 29% of patients supported with EXCOR [9]. In January 2001, this device was granted a Humanitarian Use Device (HUD) designation. On December 16, 2011, a Humanitarian Device Exemption (HDE) marketing application was approved for EXCOR to provide mechanical circulatory support as a bridge to cardiac transplantation for pediatric patients. Pediatric candidates with severe isolated left ventricular or biventricular dysfunction who are candidates for cardiac transplant and require circulatory support may be treated using EXCOR [11].

5. Conclusion

The above examples demonstrate how the Orphan Products Grants Program has helped facilitate the availability of needed therapies for rare diseases by providing funding for clinical studies that evaluate the safety and effectiveness of potential therapies. These examples also show that OOPD provides funding for product development at many stages. Had OOPD not funded an earlier phase study, development of that product for that rare disease may have been stalled. Continuing the efforts to promote research for rare diseases is important to the FDA. Through the Orphan Products Grants Program the FDA has been able to maintain its commitment to orphan drugs and to the development of potential treatments for rare diseases.

To learn more about the Orphan Products Grants Program, please refer to the below link.

http://www.fda.gov/ForIndustry/DevelopingProductsforRare DiseasesConditions/WhomtoContactaboutOrphanProduct Development/default.htm

To learn more about the Request for Applications (RFA) for Orphan Grants for receipt dates 2013 and 2014, please refer to the below link.

https://www.federalregister.gov/articles/2012/08/06/2012- 19086/clinical-studies-of-safety-and-effectiveness-of-orphan-products-research-project-grant-r01

Declaration of interest

The authors state no conflict of interest and have received no payment in preparation of this manuscript.