Public Citizen Comments on Pharmaceutical Annex to the U.S.-EU Mutual Recognition Agreement

April 28, 2000

Charles Gaylord
Office of International and Constituent Relations (HFG-1)
Food and Drug Administration
5600 Fishers Lane
Rockville MD 20857

Re: Docket Number 98S1064

Dear Mr. Gaylord,

On December 8, 1999, the Food and Drug Administration (FDA) held a public meeting to discuss the progress in implementing the Pharmaceutical GMP (Good Manufacturing Practices) Annex of the Agreement on Mutual Recognition (MRA) between the U.S. and the European Community. This letter expands upon concerns Public Citizen raised at the meeting.

The purpose of the GMP Annex is to permit foreign drug regulatory authorities to conduct GMP inspections in their nations on behalf of the FDA. To achieve this goal, the U.S. will examine the Pharmaceutical GMP regulatory systems of each of the E.U. member nations to determine whether or not each is “equivalent” to the U.S. regulatory system.

The GMP Annex defines equivalence as involving “systems [that] are sufficiently comparable to assure that the process of inspection and the ensuing inspection reports will provide adequate information to determine whether respective statutory and regulatory requirements of the authorities have been fulfilled. Equivalence does not require that the respective regulatory systems have identical procedures.” Several FDA representatives at the December meeting stressed that the agreement did not mean that standards would be harmonized. However, in response to an audience question, Joseph Famulare of the FDA’s Center for Drug Evaluation and Research responded, “There is certainly no prohibition against certain harmonizations taking place. I think it’s just a natural outcome of the process.”

Recommendation: Given these contradictory statements, the FDA should clarify whether and what harmonized standards are likely to result from the MRA. If indeed harmonization of standards is contemplated, FDA should plainly state the process it will use to incorporate public comment into the harmonization process. Public Citizen reminds the FDA that any change of any U.S. standard or adoption of a foreign standard, must be accompanied by notice and comment rulemaking.

Next, with regard to the pending equivalence determinations, Public Citizen rejects the notion of equivalence propagated by the North American Free Trade Agreement and World Trade Organization agreements. The very notion of equivalence allows for imprecise, subjective comparisons that are not appropriate when dealing with issues as important as public health and safety. However, given that equivalency decisions between nations are moving forward, we urge exacting criteria for making equivalence determinations. A standard or a regulatory system should only be declared equivalent if it provides precisely the same or greater level of substantive protection for public health and safety and after there is an appropriate opportunity for public comment.

In the case of the GMP Annex, the criteria identified in Appendix 4 of the MRA provide no assurance that determinations of equivalence will result in the same level of public safety for U.S. consumers. Rather, the criteria are strikingly vague and seem designed to assure maximum flexibility to facilitate a determination of equivalence. In the absence of specific criteria, any determination of equivalence will be meaningless from a public health standpoint.

Rather than discussing each of the criteria, we will review three examples. First, the criteria include “Authority to make inspections, review and copy documents and to make samples and collect other evidence.” There can be little question that many (if not all) regulatory bodies in Europe have such authority, but the real question is: Do they actually make these inspections? Rather than requiring “authority” for equivalence, there should be specific quantitative criteria that must be met: numbers of inspections per unit time, percentage of facilities inspected per unit time, length of inspections, numbers of inspectors per facility, etc. Moreover, there needs to be greater assurance that these inspections are of equivalent stringency: Do similar infractions receive similar penalties?

Second, the criteria also include “Mechanisms in place to assure appropriate professional standards and avoidance of conflict of interest.” While we certainly agree that these are relevant criteria, they must be broken down into their basic elements and each of these must be assured. How will conflict of interest be avoided? What specific mechanisms do the European countries have to avoid conflict of interest, and how do they compare with our own? What is the nation’s track record on enforcement? Without a detailed comparison of specific conflict of interest standards and enforcement histories, the criteria are meaningless.

A third and final example concerns “accountability of the regulatory authority.” This phrase, like the two above, is so nebulous as to be devoid of meaning. From Public Citizen’s perspective, an accountable regulatory authority is one that, at a minimum, has Freedom of Information standards no weaker than our own, has provisions for notice and comment rulemaking equivalent to our own, announces and then holds advisory committee meetings in public, and can be challenged in court, on either procedural or substantive grounds. Again, FDA must flesh out the details and assure that there is equivalence for each of these “sub-criteria” or else any determination of equivalence will not be credible.

The FDA is planning to examine the equivalency of each country on a case-by-case basis over the course of the next two years or more. However, at the December 8th meeting, in response to a question on whether or not the FDA will notice a pending equivalency decision as a proposed rule, the FDA indicated that it did not think further notice was necessary, but that it would maintain an open docket. It appears that the FDA believes the November 6, 1998 (63 FR 60121) notice of the MRA as a whole is sufficient public notification for these equivalency decisions.

In contrast, the FDA’s detailed procedure for determining equivalence in the food safety area (62 FR 30593, June 4, 1997) calls for a preliminary determination of whether equivalence exists for each particular country followed by notice and comment rulemaking. The FDA will not issue a final determination on the issue of equivalence without taking into account the comments received.

Recommendation: The FDA can greatly increase public confidence in the MRA equivalency process with early notice and comment rulemaking on each proposed equivalency decision. Such notices must lay out, in detail, the case for equivalency and must clearly identify all the sub-criteria examined, any aspect of the other nation’s regulatory system that differs from the U.S. system, and why the FDA believes that system affords an equivalent level of public protection. The FDA should respond to comments and concerns by the public on the record, before making a final equivalency determination.

At the December 8th meeting, the FDA indicated that if a determination of equivalence is made in a closed Joint Sectoral Committee meeting, the FDA will notify the public of its final decision via the Federal Register and give its reasoning for the decision. This is, of course, too late for meaningful public input. Moreover, if an equivalency determination is not made, the FDA will not notify the U.S. public, but will let the requesting country know about any problem areas the FDA has identified. Thus the public will be unaware of what problems were identified and will be unable to comment on those problems or measure progress on ameliorating the problems. While predecisional data regarding confidential business information are restricted in certain circumstances, it is illogical that information regarding another nation’s system of laws, regulations and enforcement history is being treated in the same manner.

Examining the equivalency of each nation’s regulatory system is a massive endeavor that will entail an enormous expenditure of public resources. The GAO estimated that the FDA will need $10 million for 125 full time staff and other expenses to reach the first year of the MRA’s implementation stage. Public Citizen wants to make sure that interested consumers and taxpayers enjoy the fruits of these investigations and analysis.

Recommendation:
The FDA should make predecisional information concerning any equivalence determination available to the public prior to a final determination and allow for notice and comment. At the very latest, this information should be released at the time an equivalence decision is made, pro or con.

Finally, we are concerned about which documents currently available to the U.S. public under the Freedom of Information Act would remain available after the FDA’s inspection duties are turned over to regulators of other nations.

Recommendation: The FDA should affirm that the following U.S. documents will continue to be made available to the public when the MRA is fully implemented and the documents are generated by regulatory authorities of other nations: 1) inspection reports (including 483s); 2) enforcement reports (bi-weekly list of recalls); 3) notices of violation; and 4) warning letters. For a foreign drug regulatory authority to be deemed equivalent to the FDA, there must be a guarantee that the foreign equivalents of these documents are also available. The FDA should also make plain the process by which U.S. citizens will gain access to these foreign documents.

The Joint Sectoral Committee will determine which regulatory authorities are ready to be deemed “equivalent.” The Joint Sectoral Committee is made up of representatives from the FDA and the European Commission who have responsibility for pharmaceutical GMPs. Each government has one vote on any equivalency decision, and all decisions are made by unanimous consent. Joint Sectoral Committee meetings will be closed to the public.

The events in Seattle at the end of November demonstrate that the U.S. public is fed up with the undemocratic and non-transparent manner in which the U.S. government conducts its trade policy. It is contrary to the culture of open and accountable governance touted by the FDA at the December 8th meeting to allow final decisions about equivalence to be reached behind closed doors.

Recommendation: Public Citizen asks that the meetings of the Joint Sectoral Committee and the Joint Committee, which may be involved in resolving disputes regarding equivalency, be open to public observation and transcripts of all committee business be posted on the websites of the FDA and the Office of the U.S. Trade Representative.

Attached please find a paper produced by the Transatlantic Consumer Dialogue (of which Public Citizen is a member) called Principles of International Harmonization. The TACD is comprised of 65 consumer groups on both sides of the Atlantic representing some 600 million consumers. The paper outlines consumer concerns with international harmonization, equivalency and Mutual Recognition Agreements. We hope the paper will be taken into consideration by the FDA as it moves forward with the implementation of the U.S.-E.U. MRA.

Sincerely,

Mary Bottari
Director, Harmonization Project
Public Citizen’s Global Trade Watch

Peter Lurie, M.D., M.P.H.
Deputy Director
Public Citizen’s Health Research Group

Sidney M. Wolfe, M.D.
Director
Public Citizen’s Health Research Group