An EU and U.S. Integration Strategy

Few things unite the biotech industry more strongly than the desire for greater harmonization in regulatory and administrative requirements between the European Union (EU) and United States. Harmonization of regulatory guidelines and development principles through projects such as the International Conference on Harmonization of Technical Requirements for Registration of Pharmaceuticals for Human Use (ICH) is extremely valuable. But even with significant achievements such as the Common Technical Document (CTD), major administrative differences remain and continue to frustrate.

PHOTOGRAPHY: GETTY IMAGES ILLUSTRATION: PAUL A. BELCI

As highlighted by the "Framework for Advancing Transatlantic Economic Integration between the European Union and the United States of America," signed by Presidents Bush, Merkel, and Barroso in April 2007, the desire for greater harmonization has support at the highest political level. Of course, the practicalities of transforming this goodwill into tangible solutions for industry are extremely challenging, particularly when the key guiding principles for the proposal are that: No change to legislation should be required, and the simplifications should maintain or increase current levels of public health protection.

In November 2007, the European Commission (EC) hosted the Transatlantic Administrative Simplification Workshop, which it co-chaired with the FDA and organized with help from the European Medicines Agency (EMEA) and the Heads of the EU National Medicines Agencies (HMA).

The Workshop provided transatlantic pharmaceutical regulatory partners with the opportunity to hear the pharmaceutical and biotechnology industries' proposals for administrative simplification through transatlantic cooperation. More than 24 ideas for simplification presented by industry from both sides of the Atlantic highlighted the scope for administrative simplification, which were then categorized into "work done," "work in progress to be intensified," "proposals for careful consideration," and "visionary proposals involving possible legislative changes" (see Table 1). The more pertinent ideas for clinical research follow.

Administrative Simplification: International Proposals

Work done

The first achievement to date is the formal adoption of a common application form by the FDA and EMEA for sponsors seeking orphan drug designation. The idea is to allow sponsors to apply simultaneously to both jurisdictions with one application format, the impact of which should be comparable to the CTD for marketing applications. The format includes sections with common information required by both the EMEA and FDA, and sections with region-specific information.

The need for a common application form was due to the fact that submitting differing application formats to the EMEA and FDA represents a substantial burden for sponsors, particularly for small- and medium-size companies. Applying in both territories at the same time should not only reduce resources spent and thus costs on the sponsor's side but also benefit patients with rare diseases as a result of earlier designation. However, the first practical experience with the common form has shown that there is still a need for further improvement in the form's design.

For example, the form used by the FDA is an electronic version with editable fields, which do not always allow for the entering of EU-specific information such as phone numbers composed of more than 10 digits.In contrast, the EMEA form is a text version that seems more user-friendly. Also, there are still too many fields that need to be completed with information specific to the FDA and EMEA only, which not only makes the form longer than the previous EMEA one but it also implies that different content for the FDA and EMEA has to be entered.

Despite these teething problems in finding an optimal format, the common orphan drug designation application form is a step forward and provides an environment where the FDA and EMEA can share experiences, gain an understanding of the similarities and differences in their designation of orphan drug status, and ultimately continue the process of administrative harmonization.

Work in progress

There is still a substantial amount of "work in progress to be intensified." One example is the existing implementation plan for the U.S.–EU confidentiality arrangements, including the exchange of information on Good Clinical Practice (GCP) and Good Manufacturing Practice (GMP) inspections, pediatric development plans, and parallel scientific advice (under the existing pilot program), as well as staff exchanges and training between EU authorities and the FDA.

The purpose of the confidentiality arrangements is to allow FDA and EU authorities to share expertise, perspectives, and ideas for alternative approaches to regulation. The consequences for industry are considerable: The EU competent authorities and FDA will communicate more often and more intimately. The information exchange covers both regular and ad hoc exchanges, whereby regular exchanges can include information on preauthorization and postauthorization applications, as well as inspections and guidance documents, and it applies to all products that fall within the remit of the two agencies. For example, the exchange of inspection results is proposed to take place on a quarterly basis, comprising a list of inspections (GMP, GCP, and pharmacovigilance) performed the previous quarter and inspections likely to be performed during the next quarter.

Ad hoc exchanges between the agencies, which by definition are not subject to planning, will be classified into three categories: urgent, expedited, and standard. Examples include provision of scientific advice, encountered difficulties during evaluation of applications for marketing authorization not covered by regular planned exchanges, product-related pharmacovigilance issues prior to public release, advance notice of significant regulatory sanctions of mutual interest, and urgent issues of general public health concern.

A central effort of the confidentiality arrangements is the pilot program of parallel scientific advice that will ultimately be aimed at faster access to new medicines, especially those derived from new technology and intended for advanced therapy approaches. The goal is a so-called "joint scientific advice" procedure drawing on an infrastructure put in place for the EMEA, FDA, and pharmaceutical companies to facilitate the exchange of views on scientific issues during the development phase of new drugs.

Two initiatives are foreseen to ensure a smooth implementation: establishment of a coordination committee and a yearly evaluation of the implementation progress. The committee will consist of a representative from the EC, EMEA, and FDA and their main role will be handling organizational and operational aspects of the implementation. During the yearly evaluation, experiences gained will be discussed and proposals for further improvement will be identified. Evaluation is planned to continue into 2009.

Over the past few years, there have been several attempts by industry to seek parallel scientific advice from the FDA and EMEA, and it should be noted that the current procedure requires the sponsor, not the authority, to organize the joint meeting. Although the EMEA does assign a coordinator, the procedure is not standardized and can be slow, which is especially cumbersome for smaller sponsors with reduced resources. Also, it should be kept in mind that the FDA considers parallel scientific advice only for drug products at the pre-IND and end of Phase II stages, rather than at the beginning of clinical development or for nonpivotal studies. It is advisable to check with the relevant agency beforehand if an advice request relating to an early stage of drug development is indeed eligible for the procedure.

Another example of "work in progress to be intensified" is the harmonization at the ICH level on topics such as clinical trial annual safety reports and the development of an international standard for pharmacovigilance case reports. Exchange of information on pharmacovigilance topics (either product or nonproduct related issues) through teleconferences is another objective. Harmonization efforts so far have included clinical trial annual safety reports per product rather than per trial, which allows a clearer identification of safety issues and better evaluation of the risk–benefit ratio of a given product. Efforts are currently being made to reinforce the use of the EudraVigilance database as a common repository for all suspected unexpected serious adverse events (SUSARs) from clinical trials and postmarketing in order to become an even more efficient tool for identification and generation of safety signals.

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Proposals for consideration

"Proposals for careful consideration" by the EC, EMEA, and FDA are, firstly, increased bilateral collaboration on EU- and U.S.-located inspections, formalization of the exchange of information, and coordination of inspections in third-party countries. Secondly, they include the use of one bioequivalence study to support a generic registration in the EU and United States. Finally, tasks such as individual risk management plans, scientific guidelines, and information on pediatric development plans.

Industry fully supports the concept of a mutually recognized inspection report, which would not only honor the fact that Good Laboratory Practice (GLP), GCP, and GMP guidelines apply in all ICH regions but would also facilitate site changes by the sponsor, which currently occurs in practice. Having one competent authority from a single region inspecting a manufacturing or research site would not only reduce resources and time spent by the authorities, it would also save costs incurred by the sponsor, which is of particular interest for smaller-size companies.

Mutual acceptance of bioequivalence studies for generics would help in bringing generic products onto the market faster and thus improve medical care, especially from a pharmacoeconomic point of view, which is a major focus of today's national health care systems.

Visionary proposals

A number of further proposals that might require legislative changes are also under consideration, including minimizing the EU retesting of medicinal products on importation from outside of the EU, harmonization of time frames for assessment of clinical trial authorizations (thus having one decision serve both sides of the Atlantic), harmonization of the timelines for submission of pediatric investigational plans (PIPs), creating one global pharmacopoeia, agreement on pharmacovigilance rules for well-established products, and harmonization of regulatory terminology.

Such topics are unlikely to be resolved during the current harmonization efforts due to the likely need for legislative changes. For example, although certainly desirable, the creation of one global pharmacopoeia will be a major undertaking and work has been in progress since the early 1990s. The Pharmacopoeial Discussion Group (PDG) within the European Directorate of the Quality of Medicines meets twice yearly at various locations around Europe, Japan, and the United States. At each meeting, the PDG organizes a hearing for representatives of the excipient and pharmaceutical industry (e.g., national associations of manufacturers of pharmaceutical products), to promote synergy and exchanges of compendial contents and standards.

The goal is for consensus to be reached by consulting relevant user groups through public surveys and, if necessary, by organizing conferences with all pharmacopoeial groups and any parties concerned. Harmonized compendial standards are critical if the goal of registration, market surveillance, and free movement and trade of medicines is to be achieved among as many countries as possible.

Initially Targeted Plans

Officially the next steps will be careful public health and legal and practical consideration of the proposals by the EU and U.S. regulators with a view to release, in the context of the bilateral collaboration, joint prioritized roadmaps for administrative simplification. In a joint press release dated June 17, 2008, the EMEA, EC, and FDA published a Transatlantic Administrative Simplification Action Plan, which details the 18 specific projects that will be initially targeted (see Table 2).

These transatlantic activities provide both opportunities and challenges for industry. There are real opportunities for industry to reduce the barriers to transatlantic product development, but there is also a challenge to ensure the simplification solutions do not become tomorrow's barriers. Furthermore, industry must ensure that its current clinical development plans consider these regulatory advances.

Stuart Mudge, PhD, is general manager & project director, Voisin Consulting Australia Pty Ltd. Christiane Fertig,* PhD, is Project Leader, Voisin Consulting, 3, rue des Longs Prés, 92100 Boulogne-Billancourt, France, email: fertig@voisinconsulting.com

*To whom all correspondence should be addressed.