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The 505(b)(2) process was established at the same time that Congress created the generic drug industry with passage of the Drug Price Competition and Patent Term Restoration Act (Hatch-Waxman) in 1984. This legislation included section 505(b)(2) to encourage further innovation for drugs that have already received FDA approval. Specifically, this section permits submission of a new drug application containing one or more investigations necessary to approval that were not conducted by the applicant and for which the applicant has no right of reference. Innovations that may qualify for 505(b)(2) treatment include modifications to: dosage form, formulation, strength, route of administration, dosing regimen, indication for use, active ingredient and others. What makes this section unique is that it opens up the door to data leveraging, which may include both non-clinical and clinical studies as well as a resource that is often overlooked: the published scientific literature. And, unlike the case with generic drugs, section 505(b)(2) also provides for potential approval exclusivity of three to five years if clinical trial data is a requirement for approval. When a 505(b)(2) NDA qualifies for orphan drug designation, the award of exclusivity may be as much as seven years.
The 505(b)(2) Concept
Applications Covered by Section 505(b)(2). This guidance, issued October 1999, describes the type of information that can be relied upon from a reference listed drug and what can and can’t be submitted in a 505(b)(2) application.
Providing Regulatory Submissions in Electronic Format – Certain Human Pharmaceutical Product Applications and Related Submissions Using the eCTD Specifications. This guidance, issued January 2013, describes the substance and format of the data submission requirements for traditional NDAs, ANDAs and 505(b)(2) applications.
Formal Meetings Between the FDA and Sponsors or Applicants. This guidance, issued May 2009, provides basic information for requesting and conducting meetings with the FDA to seek its input on product development plans.
Getting Started: The Pre-IND Meeting
First and most important is the need to confirm that 505(b)(2) is a suitable path. The FDA can and will refuse to file an NDA for a drug that is a duplicate and therefore eligible for approval as an ANDA (505(j)). During pre-IND discussions, sponsors can also establish the product’s value and define the target label. Having the FDA’s buy-in to the proposed development strategy or at least having the agency’s input into the plan can save time and money and significantly accelerate the development process.
Additionally, the FDA can provide valuable input on your plans to leverage data from the approved drug. The FDA’s guidance “Formal Meetings Between the FDA and Sponsors” provides an excellent road map for beginning the necessary dialogue with the FDA to streamline your development path. The data needed in a 505(b)(2) NDA can usually be limited to demonstrating the value of the particular innovation or variation of the already approved product. The data needed can range anywhere from a simple demonstration of bioequivalence to a full verification of clinical safety and efficacy. Additionally, an objective assessment of available data in respect to how this data supports proposed labeling claims is imperative.
Also by meeting with the FDA, any significant objections or data gaps can be identified and addressed, thereby facilitating development or making any early go/no-go decision much more apparent. Unfortunately, data gaps are sometimes not terribly obvious. Take, for example, a product improvement made to an “old” NDA — that is, one approved prior to the enactment of the GLP regulations. A 505(b)(2) applicant wanting to rely on such an “old” reference listed drug will likely be asked to fill even non-clinical data gaps if a complete line of GLP toxicology data is not available for reference from the precursor NDA. The FDA must apply today’s approval standard when approving a product modification in a 505(b)(2), and this may require backfilling data that was not required at the time of the original NDA approval.
While data leveraging should be considered an opportunity, it needs to be realistically balanced against any data gaps identified. It pays to be optimistic but optimism should be tempered with a realistic assessment of probability of success. Your meeting with the FDA should clarify your assessment.
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