The EU Directive Really Doesn't Work!

I know, I know, you've heard it all before. But you're going to hear it again—and it's still very fresh. Ever since the European Union adopted its clinical trials directive back in 2001, it has been under repeated attack because, say many of its critics, it does little or nothing to harmonize conditions for multinational trials, while increasing costs and often delays.

Nearly 10 years on, the EU has timorously ventured into a renewed discussion of what's wrong and what can be done to fix it. And this consultation process has unleashed a tidal wave of comment from organizations and companies across Europe—most of it negative, and all of it demonstrating that not only do the rules on clinical trials continue to differ across Europe, but so too do attitudes among countries, companies, authorities, professional organizations, and ethics committees.

Peter O'Donnell

Persistent difficulties

For the sake of concision, the outline provided by the Association of the British Pharmaceutical Industry (ABPI) neatly summarizes some of the persistent difficulties. It says that differing requirements remain for submission components, and that there is a need for EU harmonization of content. "We also need harmonization of definitions and interpretation," continues ABPI. "Variations in definitions and interpretations of some issues, such as substantial amendments, noninvestigational medicinal products or reporting requirements for suspected and unsuspected serious adverse reactions, cause difficulties for applicants trying to implement a global study protocol."

In addition, specific national legal requirements create more hurdles. For instance, in France, detailed data related to biotech compounds are required due to local law. In Sweden, the nonacceptance of a qualified person declaration and the requirement for GMP certificates create hurdles. In Poland, genetic testing is not allowed, which results in national tailoring of the protocol due to the need to omit certain text on genetic testing. The administrative workload has undoubtedly increased and with it, the cost of conducting clinical research in Europe. Delays in approval times for clinical trial authorizations are mainly due to resourcing and sometimes complex procedural set-up of ethics committee reviews per country or region or site.

Nevertheless, ABPI believes that there has been some small benefit. Harmonizing minimum requirements at the EU level has increased the protection of patients across all member states, because the same degree of regulatory scrutiny is applied to all study applications, it says—adding that "adequate national resources are still needed to enforce the requirements in all EU countries."

Other views

According to the Association of Clinical Research Organizations (ACRO), the lack of harmonization means that very detailed regulatory intelligence, together with practical experience of the implementation in each respective country, is required for definitive national authority information, which is not readily available. This is very labor intensive and obliges companies to maintain dedicated regulatory groups focusing on the management of trials in the EU.

ACRO does not believe that the different application of the regulatory framework by member states has led, in the majority of cases, to divergent decisions on trial applications. But the questions raised by national authorities on an identical scientific dossier prior to reaching a final decision frequently differ widely, indicating a significantly divergent approach to assessment.

It says that France, Germany, and the Netherlands request much more detailed viral safety info for biologics than other countries. "In Hungary you need hospital budgets agreed before you submit, while the UK and Belgium require very little. Some countries like Germany have additional national requirements, which appear to relate primarily to advancing broader governmental policies than to the actual review."

The European Federation of Pharmaceutical Industries and Associations (EFPIA) takes an aggressive view of divergences. "There are many occasions when divergent decisions are adopted in different member states, and these situations can be extremely disruptive to the conduct of the trial," it says. "Experience of multicountry studies is that it is very unusual not to receive divergent assessments and that these do lead to different requested changes in the protocol. This may lead either to a trial not being run in the member state or to having to make multiple amendments to the protocol, thereby delaying access to treatment for patients and increase in administrative burden and costs."

European Biopharmaceutical Enterprises (EBE), an association representing the interests of smaller firms, wants to see an end to divergent requests from member states for changes to protocols, which delay the initiation of multinational trials in rare disease and complicate their management. It is dismayed by regulatory processes and administrative requirements that still vary significantly between EU member states, and by the difficulty in accessing information about additional national requirements.

Smaller firms do not usually have in-house resources to track and manage national regulatory documentation, translations, and approval processes, says EBE, and "the necessity to turn to consultants and contract research organizations for help to solve the issues above drives up the costs" to disproportionate levels.

Divergence in practice

The problems do not always arise because member states have adopted laws that are inconsistent with the EU directive. But even when the formal rules are not the cause, there are plenty of examples where the national practice with those rules creates difficulties.

EFPIA says that in the troubled discussion of what constitutes a substantial amendment to a protocol, it requires no more than "a modicum of subjectivity" to create different interpretations, which are driven, it says, "by organizations or individuals' differing tolerance to risk. Thus, it is likely that in the case of substantial amendments, the different implementation is driven by case-by-case application of different interpretation."

One of the obvious responses to divergence is centralization—but this approach has so far found no favor among EU member states, who, at the end of the day, make the rules. Nonetheless, the arguments about possible greater centralization continue to rage, and cover a host of topics—with very little unanimity.

The Danish ministry of health favors a common procedure for authorizing multinational trials. Meeting the requirements of multiple national procedures can hamper new drug development, it says. For BPI, the German Pharmaceutical Industry Association, the primary need is for a centralized authorization procedure with a single and unique clinical trial application dossier, which would be additional to the current procedures.

ABPI favors a single authorization for the entire EU for multinational trials, supported by adequate expert resources to handle single applications submitted centrally, resulting in an approval valid across the 27 member states. It also favors an opinion from a central ethics committee on the methodology of a clinical trial, valid for the EU as a whole. Local ethics committees, it concedes, might play a role in judging suitable investigators and sites.

This view is not endorsed by the Permanent Working Party of Research Ethics Committees in Germany. It says "a one-stop shop for submission of assessment dossiers will not work, given that the national requirements for documents and records differ due to different national laws, jurisdiction, and prior experiences." Some harmonization on a voluntary basis "might be achievable," it concedes, but "any attempts to limit the independence of research ethics committees have to be avoided."

But not all ethics committees oppose greater centralization. The Portuguese Ethical Committee for Clinical Research says it can agree on a one-stop-shop for submitting applications, "provided that all the needs for an adequate assessment of all aspects related with the ethics of clinical trials research are met." The Belgian Association of Phase I Units underlined the "strong need to create a unique European central registration system, used in all European countries, regulating the participation of healthy volunteers in clinical trials and setting a minimum exclusion period between trials."

And EFPIA believes that invocations of national cultural issues as a reason to reject centralization are simply not valid in the Europe of today.

Strong defense

Many organizations mount a strong defense of their own position. The Permanent Working Party of Research Ethics Committees in Germany attacks how the Commission is going about promoting discussion of the directive. It says the Commission approach is "biased" and that its principal concern "is to speed up the process of getting a clinical trial approved at almost all costs. The 'bad guys' are the national competent authorities and the research ethics committees, and to 'prove' this the Commission publishes questionable data," it complains. It is particularly dismissive of the quality of the data that much of the discussion is based on, claiming it is derived from a questionnaire with a very low response rate.

The new European Commissioner for Health, John Dalli, promised the European Parliament in January that he would look again at the clinical trials rules in Europe. He may not have realized what he was letting himself in for. But at least he will not be able to complain that he doesn't have enough views on which to base his review.

Peter O'Donnell is a freelance journalist who specializes in European health affairs and is based in Brussels, Belgium.