ANDA User Fees Will Fund Public Relations-focused Studies On Palatability Of Generics

One project will look at tablet size, odor and other characteristics that in the past have been a source of public complaints about generics.

User fees will pay for studies of taste and odor issues with generic drugs, a source of public relations problems as well as repeated FDA battles with manufacturers.

The Generic Drug User Fee draft commitment letter, released Dec. 7, includes a regulatory science plan for FY 2013, the program’s first year, if Congress approves it in 2012 as expected.

One of the projects will evaluate patient acceptability of drug products’ physical attributes. The draft letter states it will use lab and human studies of tablet size, shape, coating, odor perception, score configuration, and taste masking or color to determine their effect on a patient’s ability to use the drug or perceive quality.

Examples included the ability to swallow a tablet or tolerate its smell. The information will help FDA improve its guidance on physical attribute controls as well as how they should be compared to the reference product.

Another proposed study will include a post-marketing assessment of generic and branded drugs, which is intended to build public confidence in generics “because of pro-active responses to product concerns.” It also could allow for an “integrated response to product concerns involving laboratory investigations and post-marketing data collection,” according to the draft letter.

A third project is intended to conduct additional pharmacokinetic studies to improve public confidence in generic anti-epileptic drugs. That study appears to be a direct response to problems in late 2009 after media reports called into question the efficacy of some generic epilepsy products. At that time, FDA planned to issue scientific papers and possible approval guidance changes to boost public confidence (Also see "FDA Aims To Bolster Generics' Image With Research, Regulatory Changes" - Pink Sheet, 16 Nov, 2009.).

Generic drug confidence questions resurfaced again in 2010 when CDER Director Janet Woodcock said generics still were suffering from public perception problems and needed a brand make-over. She said complaints about bad taste, foul odor or rough coatings and size differences should be fixed.

At the same time, Woodcock further irritated generic industry officials by relating comments from manufacturing and drug development officials that some products may not actually be equivalent to their reference drugs. The Office of Generic Drugs, however, countered Woodcock’s statements that efforts to improve the public perception of generics were under way (Also see "FDA's Woodcock Expresses Concern Not All Generics Are Equivalent, But OGD May Have Solution" - Pink Sheet, 1 Nov, 2010.).

Product Development Studies Included

FDA plans to continue efforts to inform recommendations for generic product development, potentially cutting required time and costs, in the regulatory science plan.

The draft commitment letter includes study modeling and simulation to potentially eliminate the need for some in-vitro and/or in-vivo studies. Another project will look at excipient effects on permeability and absorption of BCS Class 3 drugs, which also could eliminate the need for some in vivo bioequivalence studies.

The agency also wants to study the impacts on quality caused by API manufacturing and control changes. It stated in the letter that a better understanding of the area will allow manufacturers and regulators to target assessments of high-risk areas.

Another project will expand collection of generic drug post-marketing surveillance data. The agency wants baseline adverse event data so it can better investigate new reports.

FDA also will look at usage patterns like popular drug strengths, the extent of switchability, medication errors and switches back to the reference product. The agency plans to use all the data to develop policies for excipients and impurities, according to the draft letter.

Regulatory science proposals also were included in the Prescription Drug User Fee Act reauthorization commitment letter, released earlier this year (Also see "PDUFA V Agreement Appears Set Between FDA And Industry" - Pink Sheet, 28 Apr, 2011.). FDA Commissioner Margaret Hamburg made expanding the agency’s regulatory science capacity a priority in 2010 (Also see "FDA Has Regulatory Science Plan; Now It Needs Funding" - Pink Sheet, 6 Oct, 2010.).

Application Quality Addressed

The GDUFA draft commitment letter also includes FDA pledges to investigate more long-standing regulatory science questions related to generics, including:

• Bioequivalence of local-acting orally inhaled drug products
• Bioequivalence of local-acting topical dermatological drug products
• Physiochemical characterization of complex drug substances

In all, there were 13 regulatory science topics listed in the draft letter. FDA is expected to begin working on them at the beginning of FY 2013, or whenever the program is launched.

Public comments on the projects and other aspects of the draft letter will be taken during a Dec. 19 hearing at FDA’s White Oak headquarters.

A working group of industry representatives and other stakeholders is expected to identify additional GDUFA regulatory science initiatives for consideration. The draft letter specifically mentioned draft guidances to “clarify FDA recommendations with regard to complex product development and help limit deficiencies in applications” will be part of the topics considered in FY 2014.

The agency also is expected to develop refusal to receive standards for ANDAs and related submissions by the end of the first program year, which also would promote increased application quality and limit problems.

Application quality also was a point of emphasis for FDA in the PDUFA reauthorization negotiations to help improve its record of first-cycle approvals (Also see "PDUFA V: FDA Application Completeness Crackdown Continues" - Pink Sheet, 7 Feb, 2011.).

Sponsor Communication Increased

Communication between sponsors and the agency is expected to increase through GDUFA, which also could improve ANDA submissions.

A number of review goals were included in the draft agreement for ANDAs, amendments and prior approval supplements as well as for controlled correspondence responses.

FDA agreed to begin issuing “complete response” letters instead of discipline-specific letters for generic applications once the user fee program launches and conduct 30-minute phone conversations with sponsors to discuss issues raised in them.

Reviewers also will be allowed to tell sponsors about “easily correctable deficiencies” for applicants, as in the new drug application review process.

Using foreign regulator inspections to support FDA requirements also will be studied during the program. The agency agreed to a goal of parity between domestic and foreign facility inspection frequency in FY 2017 (Also see "Generic User Fee Agreement Includes FDA Pledge To Determine Best Use Of Foreign Regulator Inspections" - Pink Sheet, 7 Dec, 2011.).

FDA will receive streamlined hiring authority to add the necessary staff to complete its goals and will aspire to maintain productivity at pre-implementation levels while training new employees.

At least 25% of staff will be hired and trained in FY 2013 and 50% in FY 2014. The goal is to complete all GDUFA-related hiring in FY 2015, according to the draft letter.