In April 2014, the European Parliament and European Council will officially adopt a new regulation on clinical trials of medicinal products (the Regulation). The Regulation is expected to take effect in May 2016 and will replace Directive 2001/20/EC,  which failed to harmonize the national rules on the authorization and conduct of clinical trials in the European Union (EU). Lack of harmonization and heavy red tape have contributed to a drastic decline of clinical trials in Europe; however, implementation of the Regulation will help restore competitiveness in the field.

The text of the Regulation has already been agreed upon through informal negotiations between European institutions. Barring any unexpected opposition by an EU Member State, the future legal landscape for clinical trials in Europe can be anticipated based on the agreed-upon text of the Regulation. The Regulation is more comprehensive and detailed than its predecessor; it contains more than 90 Articles and several Annexes, which revise existing clinical trial rules, make significant changes to clinical trial authorization procedures, codify the European Commission’s current guidelines, and introduce new principles. Although the Regulation will modify the current clinical trial regime in a number of ways, we will focus on the most significant modification — revisions to clinical trial authorization procedures.

Compared to Directive 2001/20, the Regulation represents a victory for harmonization efforts because it will apply identical rules to clinical trials in all 28 EU countries. The clinical trial authorization procedures will be initiated through a single internet portal and coordinated among the Member States. While these changes are expected to facilitate the authorization of multinational trials, the revisions may not be comprehensive enough to attract more clinical trials to Europe. In particular, concerns remain about whether the Regulation will bring with it a more efficient, less time-consuming clinical trial authorization process.

The Initial Authorization Procedure
Currently, a clinical trial application is submitted to, and approved by, the competent authority and an ethics committee in each Member State where a sponsor intends to conduct its trial, with the authorization procedures conducted concurrently in each Member State. The Regulation replaces those parallel national procedures with a coordinated procedure, leaving only the organization of the national assessment to the individual Member States.

Application Dossier: Annex I to the Regulation lists the information and documents to be provided by the sponsor in its application dossier. Unfortunately, despite the EU counting 25 official languages, the Regulation only encourages, but does not mandate, Member States to accept documents in English language.

Submission of the Application: The Regulation creates one centralized EU portal through which a sponsor will submit its application dossier. By integrating the filing and exchange of all communications and documentation relating to a clinical trial into one centralized portal, the portal serves as a cornerstone of the new clinical trial landscape. The date of the Regulation’s ultimate implementation hinges on the portal’s functionality, which is entrusted to the European Medicines Agency (EMA).

Validation: The sponsor chooses a reporting Member State (Reporting Member State) to which it submits the application. The Reporting Member State must validate that the application contains a complete dossier and complies with the Regulation within 10 days of the application’s submission, or within 25 days if comments or additional information is requested from the sponsor. A Reporting Member State’s failure to reply within the proscribed time limit will be considered a tacit validation of the sponsor’s application. In addition to review by the Reporting Member State, other concerned Member States (Concerned Member States) may also comment on the validity of a sponsor’s application to the Reporting Member State.

Assessment: The new procedure for evaluating clinical trial applications distinguishes between components of an application that Member States must evaluate together (Part I of the assessment) from aspects that necessitate individual Member State evaluation, (Part II of the assessment). The bulk of the review falls under Part I; Part II concerns ethical, local and national considerations such as clinical trial agreements, informed consent, or biological samples.

Part I. – The Reporting Member State must prepare a Part I assessment report within 45 days of the validation date. The period may extended up to 31 days if the Reporting Member State requests additional information from the sponsor, plus as much as an additional 50 days if the application concerns complex medicinal products (such as advanced therapy or biotechnology products) that require expert assistance. In the case of multinational trials, the 45-day period is divided as follows: the Reporting Member State conducts an initial assessment and prepares a draft Part I assessment report within 26 days, the Concerned Member States perform a coordinated review of the application within 12 days, and the Reporting Member State takes the Concerned Member States’ comments into account, finalizes the Part I assessment report and submits it to the Concerned Member States and the sponsor within seven days.

Part II. – Part II assessments are completed by each Concerned Member State separately. The Regulation specifies that every clinical trial is subject to an ethical review by an independent ethics committee. Each Member State decides, at its discretion, how to effectively conduct this review. The Part I assessment timelines apply to Part II assessments as well.

A sponsor may request that the assessment of its application be limited to a Part I review. In such instances, the determination of the Part I assessment report will remain valid for two years. During this period, the sponsor may apply for an evaluation limited to Part II, provided that it certifies to a lack of new substantial scientific information that could impact the results of the previous Part I assessment.

Decision: Each Concerned Member State notifies the sponsor of its Parts I and II determinations within five days of the date of the Part I assessment report, or by the last day of the Part II assessment, whichever is later.

A Concerned Member State may refuse to approve a clinical trial: (i) where an ethics committee has issued a negative opinion which, in accordance with national law, is valid for the entire Concerned Member State; (ii) if it finds, on duly justified grounds, that the aspects of the Part II requirements are not complied with; or (iii) if it disagrees with the Reporting Member State’s Part I assessment report conclusion. A Concerned Member State only has three grounds for disagreeing with the Reporting Member
State’s Part I assessment report conclusion:

1. significant differences in normal clinical practice between the Concerned Member State and the Reporting Member State would result in a clinical trial subject receiving treatment inferior to than which would be provided in normal clinical practice in the Concerned Member State;
2. infringement of the national legislation referred to in Article 86 (use of cells, supply or use of cell-derived products, abortives or narcotics);
3. disagreement with the conclusion of the Reporting Member State based on safety and data reliability and robustness considerations submitted during the assessment.

If a Concerned Member State does not notify the sponsor of its decision within the five-day deadline, the Reporting Member State’s Part I assessment conclusion automatically becomes the Concerned Member State’s decision on the application.

Substantial Modification to the Clinical Trial
A clinical trial may be modified after it has been authorized. Non-substantial amendments are recorded in an EU database, whereas substantial modifications must receive authorization.

The Regulation defines a substantial amendment as “any change to any aspect of the clinical trial which is made after notification of the decision referred to in Articles 8, 14, 19, 20 and 23 and which is likely to have a substantial impact on the safety or rights of the subjects or on the reliability and robustness of the data generated in the clinical trial.” Aside from the change of the principal investigator or the addition of a site, no further description or examples of a substantial modification are given. The current Commission guideline may therefore remain applicable.

The procedure for introducing a substantial modification to the clinical trial is the same as the initial authorization procedure, but with shorter timelines. Annex II to the Regulation lists the information and documents to be provided by the sponsor in its application dossier.

If the substantial modification concerns Part I, the original Reporting Member State has six to 21 days for validation and then 38 to 69 days for the assessment report, depending on whether comments or additional information is requested from the sponsor. An additional period of 50 days applies for more complex products. The time limit for decision is five days. If the Concerned Member State does not provide a decision by this deadline, the substantial modification is considered as accepted.

If the substantial modification concerns Part II, only the Concerned Member State is involved, but the time limits are the same as for a substantial modification to an aspect of Part I. The Concerned Member State may refuse the modification (i) if it finds, on duly justified grounds, that aspects of Part II are not complied with; or (ii) where an ethics committee has issued a negative opinion that, in accordance with national law, is valid for the entire Concerned Member State.

If the substantial modifications involve both Parts I and II concerns, both procedures above apply in parallel.

Addition of a Member State
The procedure for extending the trial to a new Member State (New Member State) shares the basic features of the initial authorization procedure, but excludes the validation component and imposes shorter decision-making timelines. To add a Member State, a sponsor submits its application to the New Member State, and that New Member State has 52 days to notify the sponsor of its decision, or 83 days if additional information is requested from the sponsor. If the New Member State does not adhere to this timeframe, the conclusion of the original Part I assessment report applies to this application as well.

When a sponsor applies to add a Member State, the Reporting Member State remains the same, but its role is limited as there is no re-assessment or further discussion of the issues evaluated in Part I unless additional information is requested from the sponsor.
The new authorization procedures apply to both national and multinational clinical trials, even in situations where the initial application was made in one Member State only. This allows sponsors to adopt a two-step approach and, by doing so, avoids losing the benefit of shorter timelines afforded by one Member State where they envision a multinational trial.

Conclusion
The timeframes imposed by the Regulation represent an improvement over the current clinical trial approval timeframes, as the new procedures include a tacit approval mechanism for Member States who would not otherwise comply with approval deadlines. Still, the timeframe for approval of a clinical trial application in the EU remains longer than in other countries, which may jeopardize Europe’s ability to regain its competitive edge in the field of clinical trials. 

References

1. Directive 2001/20/EC of the European Parliament and of the Council of April 4, 2001 addresses the laws, regulations and administrative provisions of the Member States relating to the implementation of good clinical practice in the conduct of clinical trials on medicinal products for human use.

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Geneviève Michaux
Hunton & Williams LLP

Geneviève Michaux is counsel in the Brussels office of Hunton &Williams LLP (www.hunton.com) and a member of the Firm’s Food and Drug Practice. She can be reached at gmichaux@hunton.com