Joining the parallel lines

Along with the scientific uncertainty inherent in developing new drugs, companies seeking approval for their products must deal with the worry of navigating the diverse regulatory systems around the world.

However, the establishment of the Transatlantic Economic Council (TEC) by European Commission President José Manuel Barroso, German Chancellor Angela Merkel and US President George W. Bush at the EU/US Summit in April 2007 aimed to combat some of these problems, at least between the US and Europe, by fostering transatlantic economic integration, and allowing companies to express their concerns and to push for more transparent cooperation.

On 13 May 2008, US Cabinet members and European Commissioners met for a second session of TEC and decided to intensify the cooperation between the US and the European Union in the pharmaceutical arena. In theory, this can be regarded as an important date for pharmaceutical companies engaged in the marketing of products on both sides of the Atlantic. In practice, however, it might not be quite the milestone it could be.

On the go...

Pharma objectives of TEC

TEC aims to achieve better regulation, barrier-free and secure trade, protection of intellectual property rights and integration of financial markets. To achieve these objectives, it has several permanent members, comprising the EU Commissioners for External Relations, Trade, and Internal Market and Services, and, from the US, the Secretaries of the Treasury and Commerce and the Trade Representative. A group of advisers has been tasked to articulate the views of manufacturers, as well as citizens and consumers, on both sides of the Atlantic, on the priorities that should be pursued.

During the high-level meeting in May, it was announced that, among other things, the EU and the US had agreed to strengthen collaboration on medicine regulation, and to conduct joint inspections of pharmaceutical manufacturing facilities. The intention is to simplify and harmonize administrative procedures in the pharmaceutical area, as well as to ensure the safety of products manufactured in third countries.

Transatlantic Administrative Simplification Action Plan

The European Commission (EC), the European Agency for the Evaluation of Medicinal Products (EMEA) and FDA should, under this agreement, pilot joint inspections of companies manufacturing finished medicinal products in the EU and the US, as well as companies producing APIs in other countries. According to an EC spokesman, these inspections should start at the end of the year, but preliminary discussions have already been initiated to determine the pharmaceutical manufacturing facilities where they are needed.

On both sides of the Atlantic, it is stressed that doubling up on inspections should ensure high standards are maintained and reassure companies that they are dealing with a united regulatory front. The programme requires that FDA and EMEA share inspection schedules, results and information on inspected manufacturing facilities.

It is also expected that this cooperation will allow the regulatory bodies to better identify sites making APIs in third countries and ensure that these facilities are adhering to GMPs. This increased vigilance is intended to lead to higher regulatory standards and increased supply chain security.

The harmonization of administrative procedures and the safety of the medicinal product are the prime objectives of the new joint inspection programme. By pooling their resources, the EU and the US will inspect more sites and increase pressure on pharmaceutical companies, both at home and abroad, that do not respect GMPs.

This is very good news for those pharmaceutical companies that do respect GMPs. A single inspection by?a joint EU–US team could provide simpler, quicker and more effective access to the US and European markets.

Problems in parallel

This new regulatory development was first discussed in an administrative simplification workshop, held in Brussels (Belgium) in November 2007, as part of the ongoing confidentiality arrangements between the EU and the US.

The sharing of information on inspection outcomes was already part of the confidentiality arrangements and is currently done on an ad hoc basis. The types of information covered by the arrangements include legal and regulatory issues, scientific advice, orphan drug designation, inspection reports, marketing authorization procedures and post-marketing surveillance. The implementation plan allows for regular exchange of GMP, GCP and pharmacovigilance inspection information. As far as the new inspections initiative is concerned, the EC wants to look at how these exchanges can be expanded upon.

In practice, however, there are doubts regarding the real efficiency of a programme that focuses on ad hoc exchange of nonemergency information. Indeed, too many differences already hinder the collaboration between the two regulatory bodies and these issues have been highlighted with the setback of another similar EU–US initiative that did not achieve the anticipated results: the Parallel Scientific Advice (PSA) Programme.

The PSA Programme began in January 2005. It sought to better coordinate regulatory approval of medicinal products by allowing companies to seek parallel scientific advice on testing their new medicinal products (that is, new human drugs and biologics) from both EMEA and FDA simultaneously. Claiming, perhaps prematurely, the success of this pilot programme, it was decided in March 2006 to extend the pilot phase, and to intensify transatlantic cooperation in the area of medicinal products, with particular focus on vaccines (including preparedness for influenza pandemic), medicines for children, medicines for rare diseases, oncology and pharmacogenomics.

The programme was expected to: increase dialogue between agencies and sponsors from the beginning of the product life cycle; optimize product development by avoiding unnecessary testing replication or unnecessary diverse testing methodologies; allow for additional critical issues to be identified and shared by both agencies; and streamline development and facilitate access, for example, for orphan drugs and products eligible for accelerated review.

However, in practice, uptake was disappointing and experience varied widely between companies. One problem that arose from the process is the institutions' disparate approaches. While EMEA is a scientific institution, whose role is to examine the adequacy of elements of a clinical trial authorization submitted in support of an application for marketing authorization, FDA's responsibilities are much broader and the association perceives itself as having a different role.

Furthermore, EMEA has even acknowledged that companies were reluctant to be 'guinea pigs' in the PSA process. In addition, some companies complained that what they received was not joint advice or combined advice but parallel advice, without coherence, and that the procedure added to the administrative burden rather than lightening it. The systematic differences inherent in the regulatory bodies partly explain this disparity — while the EMEA had one group dealing with scientific advice, the FDA split the process among various divisions.

Perfecting the Plan

For the new initiative, however, the regulatory bodies seem to have opted for a more efficient approach by launching joint — not parallel — inspections to try to avoid facing the criticisms that plagued the PSA.

But it seems that the PSA's poor results have not affected the regulatory bodies' morale. On 17 June 2008, FDA and EC together unveiled their new Transatlantic Administrative Simplification Action Plan, under which they demonstrated their willingness to develop closer collaboration in a number of pharmaceutical areas including biomarkers, innovative medicines initiatives, product specific risk management, biosimilars and advanced therapy medicinal products, as well as inspections, which they aim to streamline through closer collaboration based on the 'cluster' concept. This involves bringing together experts in the field to discuss the issues and formulate ideas and recommendations.

Towards 2009

So does this mean the EU and the US have learned the lesson of the PSA setbacks? Are companies now likely to have more confidence in the efficiency of these collaboration projects?

Caution must be the key word for the time being and expectations must always be put into perspective. The PSA example highlighted the problems in transatlantic collaboration and those weaknesses could continue to plague the new inspections initiative. While in theory unity leads to strength, FDA and EMEA will now have to show that they are able to manage this initiative in practice.

According to the EC, the pilot joint inspection phase will help to evolve procedural ways of cooperation; for example, with regard to conducting the inspections or drafting the inspection reports. The first joint inspection results are expected at the end of 2009. Only then will we know if this plan can really come together.

Fabien Roy is a Legal Assistant at the law firm Hogan & Hartson, Brussels, Belgium. He can be contacted at froy@hhlaw.com