The first botanical NDA, MediGene's Veregen (kunecatechins), illuminated gaps in the emerging regulatory framework for plant-derived prescription drugs, FDA review documents indicate.

"We are now setting precedents with the first botanical NDA," Botanical Review Team Leader Shaw Chen stated in a Sept. 15, 2006, memo.

Green tea-derived Veregen was approved Oct. 31, 2006, for topical treatment of external genital and perianal warts (¹ Pharmaceutical Approvals Monthly January 2007, p. 7).

FDA began laying the groundwork for botanical NDAs with a guidance process that started over a decade ago. CDER released its final guidance on botanical drug products in June 2004.

"Relatively little attention was paid to the requirements for approval of botanical NDAs at the time of drafting, probably because few were sure that following the guidance would lead to successful NDA submission," Chen said. "It was hard to imagine what a botanical NDA package would look like."

"Thus some NDA-related issues emerged only after rare discussions of late phase studies with sponsors and with the submission of this application," Chen continued. "Our regulatory approaches to these issues were also evolving … and it was not surprising that some of the recommendations in the guidance may be ill-advised and should be changed."

Irreducible Complexity

The guidance "provides that both purification and identification of the active ingredients in botanicals are optional," Chen noted. "While this provision has facilitated clinical studies of botanicals that have been used extensively in alternative medical practice, it does pose difficult regulatory issues for quality control of botanical products as most of our regulations were designed for pure chemical drugs."

"Veregen is a relatively simple botanical derived from a single part of a single plant (green tea leaves), containing a class of well-studied chemical entities as the major active ingredients (catechins)," he noted.

However, even a "relatively simple botanical" poses a challenge to established thinking on chemistry, manufacturing and controls issues, Chen suggested.

"As products of natural complex mixtures, the botanical new drugs can rarely have CMC specifications as precise as that of pure chemical drugs," Chen said.

"One critical question for approval of botanical drugs is whether the future marketing batches will have the same therapeutic effects as that observed in clinical trials," he said. Therapeutic consistency is "a unique botanical review issue not under the care of other disciplines and may require new regulatory thinking."

Specifying Specifications

During the Veregen review, FDA stood firm against MediGene's requests to broaden acceptance criteria. "There was an extensive communication between the applicant and FDA on the subject of acceptance criteria" for ensuring batch-to-batch consistency, Division of Dermatologic & Dental Drug Products Director Susan Walker emphasized in her review.

"The fundamental concept is that acceptance criteria for the drug substance batches are linked to demonstration of clinical efficacy via the clinical trials," Walker stated in her Oct. 28, 2006 memo.

Because Veregen's active component(s) have not been identified, "the whole drug substance is considered active," minutes of an Aug. 1, 2006, teleconference explain. "To establish meaningful specifications, we focused on the amount of each component in the pivotal clinical batches." FDA allowed a range of +10 percent for each component.

MediGene responded that the specifications were "extremely difficult and inquired if the agency would consider other batches besides the ones used in the clinical trials," the Aug. 1 minutes continue.

In response, FDA "stressed that the specifications for both the drug substance and the drug product must be derived from the clinical batches proven to be efficacious." Reiterating this stance, FDA went on to reject MediGene's proposal to add a non-pivotal Phase II/III trial to the clinical batch data.

"FDA will not change their minds on the specifications," the agency declared in a Sept. 8, 2006 teleconference. Other specifications "would result in an 'approvable' letter on the PDUFA date, with the need for additional clinical trials."

While MediGene conceded to FDA's specifications during a Sept. 21 teleconference, a pre-meeting submission suggests that MediGene's agreement may be more of an agreement to disagree.

"After approval of the NDA, MediGene would like to continue the discussion with the Division to resolve the issues related to our proposed acceptance criteria for drug product and drug substance specifications which were rejected during this review cycle," the Sept. 14, 2006, submission concludes.

- Bridget Silverman (b.silverman@elsevier.com)

No FDA Compromise On Veregen Specifications In First Botanical NDA Review

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