Glossary of Orphan Drug Regulatory Terms

Orphan Drug Designation (ODD)

As described in the code of federal regulations (CFR part 316) this is the means by which a sponsor with a drug for a rare disease is awarded the economic benefits of the Orphan Drug Act (ODA). The award usually rests upon satisfaction of two criteria; the prevalence criteria and the medical rationale criterion. 

Prevalence Criterion 

The prevalence criterion is satisfied either when the number of people diagnosed in the US with an acceptable rare disease is fewer than 200,000 OR when a valid orphan subset of a common disease (>200,000) that has a subset is less than 200,000.

Valid Orphan Subset

A valid Orphan Subset may exist if within a common (>200,000) disease there exists a smaller population of less than 200,000 AND the drug for which orphan designation is requested CANNOT be used outside of the identified subset (examples: by reasons of toxicity, inefficacy or other mitigating circumstances). 

Medical Rationale Criterion

The efficacy standard required to secure Orphan Drug Designation. Usually, this will require either some positive clinical experience or an efficacy signal demonstrated in an acceptable preclinical animal model of the human rare disease. This criteria must be satisfied by testing with the particular moiety submitted for designation. 

Moiety 

This is the term of art used in the orphan drug act to describe the drug substance receiving orphan designation. Do note that designated moieties are agnostic as to formulation or route of administration. 

Non Profitability Criterion

Since the original drafting of the orphan drug act in 1983, the law has provided for orphan designation through satisfaction of EITHER the prevalence criterion OR  the non profitability criterion. This non profitability criteria is arcane, very infrequently used (less than 7 times of the almost 7,000 existing orphan designations) and unlikely to present a viable work-around to the prevalence criterion. Nevertheless, this criterion remains an existing part of the law. 

Rare Pediatric Disease Designation (RPDD)

This designation identifies that a particular drug is an FDA-acknowledged candidate for a pediatric rare disease. Moreover, it provides assurances that should this product receive marketing authorization for said pediatric rare disease (and should the moiety still be a new chemical entity at the time of marketing award) then along with NDA or BLA, delivery of a Priority Voucher (PRV) is expected. This designation removes regulatory uncertainty for investors who seek the PRV as part of their return on investment. 

Priority Review Voucher (PRV)

This voucher is issued to the developer of a drug for a pediatric rare disease as an incentive for the creation of more such drugs. This voucher holds innate value because, when applied to any marketing application, it entitles the sponsor of that application to a priority review, even if that application otherwise would not be so entitled. At this writing, the estimated value of a PRV is $150MM. 

Market Exclusivity

This means that FDA promises not to award market authorization for the same drug for the same rare disease to any other sponsor for a seven year period following the awarded market authorization to a sponsor who previously had an orphan designation. This exclusivity is different from the “data exclusivity” awarded through Hatch-Waxman exclusivity. Orphan drug market exclusivity, while a form of market protection, is far superior to conventional intellectual property protections, i.e. patents. 

Fast Track Designation

This is an award of administrative expediences that accelerate FDA’s processing of products for an unmet medical need which is serious and for which a specific product offers the promise of meeting that need. Fast Track Designation does not require clinical data and can be applied for as early as the initial IND application.   

Breakthrough Therapy Designation

Like Fast Track Designation, this is an award of administrative expediencies to accelerate the development of new drugs for unmet medical needs. The benefits of breakthrough therapy designation embrace all benefits awarded with Fast Track Designation, and go far beyond those awards. However unlike Fast Track Designation Breakthrough Therapy Designation requires early, promising clinical data. It should be noted that where Fast track designation has reasonably objective and standardized criteria, Breakthrough Therapy Designation is comparatively subjective with vague criteria and a smaller proportion of applications are successful. However, the pharmacoeconomic benefits of Breakthrough Therapy Designation far surpass those of Fast Track; Breakthrough therapy designation awardees instantaneously realize dramatic increases in their asset valuation. 

Investigational New Drug (IND) Application

This is the formal mechanism through which clinical trials for new drugs can legally be investigated in the United States of America. The European synonym is CTA. 

Biologics License Application (BLA)

This is the means by which biologics are authorized in the United States of America. While it used to be that all BLAs were handled by the Center for Biologics Evaluation and Research (CBER), for the past 20 years BLAs for many macromolecules are also processed by the Center For Drugs Evaluation and Research (CDER). 

INTERACT Meeting

This recently invented meeting format is sometimes called the “Pre-Pre-IND meeting”. This alternative moniker reflects the “blue sky” nature of the INTERACT Meeting; it is an opportunity to envision a drug’s broad development plan without getting bogged down with many details. 

Type A, B, C, D Meeting

FDA categorizes meetings on the basis of the rapidity with which they respond to meeting requests and set a meeting date, the format of meeting requests and briefing packets (together or separated) and the anticipated meeting format (written response only or in person/virtual). Type B Meetings include a selection of standardized meeting milestones such as Pre-IND, end of phase II, and Pre-NDA. Type A Meetings are matters of grave urgency such as a meeting to end a clinical hold or a meeting following a complete response letter (i.e. denial). Type C Meetings used to be all meetings that are not A or B and still is the term for miscellaneous/general meetings. Type D Meetings is a recent invention focused on rapid responses to narrow questions, typically from a single discipline.

Pre-IND Meeting

See Type B Meetings above.

Prescription Drug User Fee Act (PDUFA) 

The Prescription Drug User Fee Act (PDUFA) was originally established by the Reagan Administration as a means by which to expedite severe review backloads at FDA. Industry accepted the implementation of fees and FDA accepted binding agreements for review timelines in meetings, minutes and application processing. A large proportion of the budget for FDA reviewers now comes from PDUFA sources. However, orphan drugs are exempt from paying PDUFA filing fees which at this writing is 4.3 million dollars. 

Pediatric Research Equity Act (PREA)

The Pediatric Research Equity Act is a law requiring companies to consider and include the pediatric population in their drug development plans. For orphan drugs, this requirement is waived. 

Deficiency Letter

OOPD/FDA almost never denies or rejects an application for Orphan Designation. Rather, it is OOPD practice to either award Orphan Designation or to send a letter outlining the deficiencies in the application which have prevented such award and holding the applicant in abeyance pending satisfaction of those deficiencies. In truth, roughly 40 percent of all applications are held in perpetual abeyance, despite multiple amendments, which admittedly is indistinguishable from a denial or rejection. 

Orphan Products Clinical Trials Grants Program

This grants program is original to the 1983 statute to the Orphan Drug Act. It offers funds for clinical trials for orphan drugs and award is based on the likelihood that an applicant can advance a product into the market. In addition to the substantial funds this program offers, an even more attractive feature is that grants reviews are often not conducted by far flung academic KOLs, but rather, by the same FDA reviewers who are ultimately responsible for licensing decisions. 

Natural History Studies Grants Program

This is a newer program designed to illuminate ill defined natural histories from rare diseases with the hope that such information will advance drug development for these diseases.

505b(1) and 505b(2)

These are two means by which a new drug application (NDA) can be issued. In a 505b(1) the sponsor is responsible for submitting all elements to satisfy the Agencies safety and efficacy criteria. In contrast, in a 505b(2) application data satisfying some part of the criteria is derived from sources external to the application itself. For example, a new formulation of an old drug for a new indication might receive an NDA through a 505b(2) process in which the sponsor augments new efficacy data for the new indication and some new clinical pharmacology data for the new formulation with safety data from the previously licensed product. 

Qualified Infectious Disease Product (QIDP)

This is a special designation to incentives the development of new products for infectious diseases, an especially poignant need in this era of microbial resistance to existing antibiotics.

The International Conference on Harmonization (ICH)

The International Conference on Harmonization is a forum through which regulators in the US, Europe and Japan regularly meet to streamline their requirements for regulated industry. While ICH guidelines do not supersede any member states existing statutes and regulations, ICH guidelines do synthesize these various requirements into a single document which can allow international pharmaceutical companies to utilize common data in common formats (e.g. eCTD).

The Regenerative medicine advanced therapy Designation RMAT 

This designation awarded to tissue based cellular and gene therapies is similar to the Breakthrough Therapy Designation established for drugs. Like BTD, RMAT identifies especially promising products deserving of special care and acceleration and rewards such products with added attention.