Follow-up to the Stakeholder Meeting of August 19, 1998
Issues Relating to New Animal Drug Review
Several stakeholders expressed concern about the implementation of the Animal Drug Availability Act (ADAA), particularly in the context of improving the timeliness of new animal drug review, suggesting that this might be addressed through better communication with industry, clarification of requirements, increased staffing and decreased levels of review and regulation.
The Center is also concerned about implementation of the ADAA and has worked hard to publish implementing regulations in a timely manner. The final regulation defining adequate and well-controlled studies was published in advance of the statutory due date, and the proposed rule defining substantial evidence was published within weeks of the deadline. Unfortunately, the final rule on substantial evidence has been delayed, in part, to incorporate a definition of "antibacterial" enacted on October 21, 1998, as part of the Omnibus Consolidated and Emergency Supplemental Appropriations Act, Pub. L. 105-277. These rules go a long way toward clarifying the requirements regarding proof of effectiveness for new animal drugs. The Center anticipates that a series of guidance documents further clarifying ways and means to establish effectiveness will be issued as resources permit.
In the meantime, the enactment of the ADAA has allowed CVM to exercise greater flexibility in determining the number and types of adequate and well-controlled studies that will provide substantial evidence of effectiveness for a new animal drug and that flexibility has had a favorable effect on 78% of the new animal drugs on which decisions were made after the enactment of the ADAA. However, the increase in the workload of the Office of New Animal Drug Evaluation (ONADE) and the decrease in review staff has had a far more significant impact on the review process. In addition to performing review activities associated with New Animal Drug Applications (NADAs), abbreviated NADAs, and the investigational use of new animal drugs, ONADE review staff are needed to assist in writing implementing regulations and guidances for the Food and Drug Administration Act (FDAMA) and the ADAA. Between October 1996 and December 31, 1998, the number of reviewers with duties relating to the review of submissions decreased from 88 to 78 and the amount of time reviewers spent performing review activities decreased from 82 to 74 percent. Therefore, review times and overdue rates (both of which are increasing) are simply not a good indicator of ADAA implementation.
With respect to improving communication between CVM and new animal drug sponsors, long before enactment of the ADAA, CVM initiated the use of presubmission conferences between Center personnel and drug sponsors to discuss what information sponsors would need to provide to CVM to demonstrate that a new animal drug is safe and effective and considered any agreement reached to be binding upon CVM. Because both CVM and sponsors found these presubmission conferences to be a valuable tool that allows each to use its resources more efficiently and effectively, the availability of presubmission conferences was codified in the ADAA.
CVM is developing regulations and guidance, as needed, to establish formal procedures for requesting, holding, and documenting presubmission conferences pursuant to the ADAA. At the same time, CVM has continued to hold such conferences, as provided under the ADAA. CVM records the substance of presubmission conferences, including any agreements acceptable to CVM that are reached during the conference, in memoranda of conference and such memoranda are typically shared with involved sponsors.
Since passage of the ADAA in October, 1996, CVM has participated in 363 presubmission conferences with sponsors to discuss the effectiveness requirements for new animal drugs. These conferences were generally held in person, but some were conducted via telephone or video-link. This count includes meetings in which the focus is the establishment of effectiveness data requirements; the count does not include meetings relating to administrative processes, protocol development or label development. In some instances, the presubmission conferences included in the count addressed both safety and effectiveness data requirements. In other instances, separate presubmission conferences were held to discuss the safety requirements for the new animal drug. Thus, additional presubmission conferences, not reflected in the 363, were held to discuss target animal and/or human food safety data requirements for a new animal drug.
With respect to the concern expressed by stakeholders regarding the ADAA requirement to announce proposals for legislative and regulatory changes to facilitate the approval of new animal drugs intended for minor species and for minor uses, FDA published in the Federal Register in June, 1997 a request for comment regarding the kinds of changes that stakeholders would propose. Consideration of the many comments received and extensive deliberations of an internal Agency working group resulted in the publication of a discussion draft of options for legislative or regulatory changes in December, 1997 and the subsequent report "Proposals to Increase the Legal Availability of Animal Drugs for Minor Species and Minor Uses." This report is now available for consideration by interested parties, including Congress, industry, and other animal health advocates. A notice of its availability, including Internet access, was published in the October 29, 1998, Federal Register (63 FR 58056). The proposals depend heavily on legislative changes because over thirty years of experience since passage of the Animal Drug amendments to the Food, Drug & Cosmetic Act in 1968 have demonstrated that the new animal drug review and approval process required under the current statute is simply not amenable to the approval of products for minor use or minor species. Fundamental change is needed and that can only be accomplished by amending the statute.
Aside from comments regarding the impact of the ADAA on the new animal drug review process, there were a series of suggestions relating to other aspects of the review process, with particular concern being expressed regarding whether the NADA review process was given sufficient priority in terms of CVM resource allocation, whether the review process, or various parts thereof, could be streamlined to improve effectiveness and whether some parts of the process might better be accomplished by utilizing third-party resources.
The Center has traditionally considered new animal drug approval to be among its very highest priorities, and that position is very firmly supported by current CVM management. CVM has taken cuts in resources in its NADA review program only with great reluctance and as a last resort. The decrease in review resources noted above is reflective of just how serious the overall decrease in Center resources has been over the last several years (with the exception of resources specifically earmarked for the Food Safety Initiative).
CVM has routinely assessed its new animal drug review processes not only with respect to the establishment of reasonable scientific standards that will support the sound scientific decision-making required by the statute (and strongly supported by a number of stakeholders), but also with respect to the Center’s administrative processes, in an effort to increase the efficiency and effectiveness of those processes. The Center will continue to improve in both respects. In particular, the Center is very actively engaged in trying to improve the processing of so-called administrative NADAs. "Administrative" NADAs are the end product of fundmental changes to the review process intitiated by CVM several years prior to ADAA passage which permitted the independent review of subsets of the information supporting NADA approval in the Investigational New Animal Drug (INAD) file before an NADA is ever submitted. For products reviewed in this manner, most, if not all, of the scientific judgments associated with NADA approval are made before the NADA is submitted, and the process of approving the NADA becomes largely an administrative process. CVM and NADA sponsors are convinced that this fundamental change represents a significant improvement which will speed up the review process. CVM is currently seeking to further improve the last step in this new review process--approval of the NADA itself.
The Center is also taking a close look at the statistical review process. Additional resources have recently been reallocated to this critical area. The Center has initiated a process of performing pathology reviews in support of food safety determinations by contracting that effort out to third parties. CVM is considering whether other parts of the review process can also be cost-effectively performed in this manner.
As suggested by several stakeholders, CVM continues to devote significant resources to efforts to internationally harmonize approval standards. This includes work through the Joint Expert Committee on Food Additives (JECFA) and the Codex Alimentarius Commission. The JECFA is a scientific advisory body to the Codex Alimentarius Commission, an international food standard-setting organization established by the World Health Organization and the Food and Agriculture Organization of the United Nations. CVM currently has two full-time members on the JECFA committee and routinely sends two additional scientists as temporary advisors. The Center’s participation at these meetings has lead to the development of science-based standards for several products or products classes including the tetracyclines, eprinomectin, bovine somatotropin, and the endogenous hormones.
The Center is also involved in the Veterinary International Committee on Harmonization (VICH) process. This process, involving the European Union, Japan and the United States (with the participation of Australia and New Zealand), is designed to develop harmonized standards for drug approval and surveillance activities. CVM employees are involved in every one of the VICH working groups as members, topic leaders, or chairmen. To date, several harmonized guidance documents relating to the animal drug approval process have been forwarded to the VICH Steering Committee from the working groups for public comment prior to adoption.
As suggested by many stakeholders, the Center continues to improve its communication with stakeholders. CVM is currently working with other Federal agencies to share expertise or resources on issues relating to international harmonization of standards, international trade, and public health, including food safety. The Center is also laying the groundwork for possible future use of such resources in the review of particular NADAs, most notably those related to aquaculture. CVM totally supports the principles put forth in the agency’s Good Guidance Practices and is completely committed to establishing or revising guidance in accordance with those principles--one of the most significant of which is the involvement of stakeholders in the development of guidance documents. Unfortunately, resource constraints continue to impede CVM’s efforts to establish and revise guidance in a timely manner.
The Center looks forward to continuing its dialog with stakeholders, whether in the form of additional meetings such as the general stakeholder meeting of August 19, 1998 to which this document responds, or in the form of more focused meetings dealing with particular issues or involving particular stakeholders.
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