Masterstudiengang "Drug Regulatory Affairs"

Master-Thesis

Comparison of CMC requirements for Clinical Trials in the US and the European Union ***

Ingrid Schulz (Abschlußjahr: 2005)

Language: English

The conduct of clinical trials in the European Union as well as in the US require authority approval prior to commencement of the investigation. Both regulatory systems foresee review of chemistry, manufacturing and control (CMC) data by the respective authority, beginning with phase 1 of clinical investigations. However the approach to handle the applications for various stages of development differ: In the US usually only one Investigational New Drug Application (IND) is covering the complete development. Once in effect, it is amended with the respective data for subsequent phases of the investigation. In contrast, the European regulations foresee a submission of a new Clinical trial Application (CTA) for each of the subsequent steps of development.

Guidance in US as well as in the EU acknowledge that the amount of data that is available to support the application strongly depends on the stage of development. The expected data for both depends on the nature of the product, the type and duration of the trial and on the nature of the disease that is intended to be treated.

The review generally takes a risk based approach focussing on safety aspects.
With regards to the required format for the submission, the European detailed guidance document issued by the commission (ENTR/CT 1) refers to the ICH Common Technical Document (CTD) format which in Europe is mandatory for submission of marketing authorisation applications. The US guidance does not specifically refer to the CTD format, however the FDA is accepting submissions in CTD format as well.

Regarding the cooperation of the sponsor with the authority, in the US there is an established procedure of contacting the authority at certain time points in development to discuss scientific questions and to agree on further steps in development. This contact to the authority during development is not that strongly formalised according to specific milestones in the clinical development with the competent authorities of the member states of the European Union.
Examining the detailed CMC requirements that have to be fulfilled at the different stages of development, similarities are observed to a large extend.

For US INDs, guidance for CMC requirement is provided by the FDA for phase 1, 2 and 3 clinical trials, where the different phases are addressed separately.
The CHMP draft guidance chooses a more general approach, addressing the different sections of CMC information for all phases, highlighting additional aspects that have to be provided in more detail in phase 2 or phase 3.
As the EU draft guidance emphasizes that the level of detail will depend on the stage of development, this general approach leaves considerable flexibility to the sponsor when preparing the submission package.

CMC documentation for phase 1 for both the US and the EU has to be provided to a limited extend. Whilst phase 1 trials in the US require an effective IND and guidance regarding CMC requirements is in place in the US for several years, phase 1 trials in Europe in the past in most of the member states did not require submission of CMC data, but are only addressed since the implementation of the clinical trial directive.
Consequently, for the EU, the additional requirement of providing CMC information impacts the preparation of phase 1 trials to a considerable extend in terms of costs, timelines and administrative burdens.

Since the clinical trial directive and corresponding national guidance was only implemented recently, there is limited experience for both the applicant and the reviewing authorities so that the implications of the implementation of the clinical trials directive with regards to phase 1 clinical trials cannot yet be completely overseen.
Comparing the detailed requirements for the US and the EU, it may be concluded that the level of detail to be provided according to the draft CHMP guideline to some extend goes beyond the documentation that would support a US phase 1 IND.
Even though these differences in some cases may not present major hurdles, their impact for the conduct of phase 1 clinical trials in Europe with respect to timelines needed to prepare the appropriate data and documentation should be closely monitored, especially considering that the FDA is presently working on improvements for early drug product development and has recently provided a draft guidance for industry on exploratory INDs.
The future implementation of this guidance may turn out to present advantages to sponsors that may lead them to consider a US trial site the more attractive place to conduct exploratory trials.

For phase 2, the level of detail required for the EU and the US compares to a large extend. However some aspects are addressed in the US guidance which are not required according to the CHMP draft guidance and vice versa. With regards to the information to be provided to describe the drug substance manufacture, the US guidance is more detailed, whereas in the EU draft guideline some requirements regarding the drug product are more detailed and lead to a restricted flexibility in the drug product development process.

Considerable differences are observed regarding the documentation to be submitted for phase 3 clinical trials, where US requirements in a number of aspects exceed those for the EU.
This may stem from the fact that the focus in the US especially for phase 3 is not only on safety aspects but also on suitability of the data for subsequent market approval.
The level of detail differs mainly with regards to the information to be provided for the manufacture of the drug substance. Further difference can be observed in the concept of addressing excipients and packaging materials (container closure system) where the EU draft guidance allows for more flexibility.

Overall it can be concluded that with the implementation of the clinical trial directive the requirements for US and EU became comparable to a considerable extend. This may provide for synergies in preparing data and documentation to support trials that are intended to run in EU countries and the US. However, differences are observed, that in practice are likely to result in the need for preparation of different sets of documents. In the US currently efforts are made by the FDA in various areas to provide for a more effective development process e.g. with the critical path initiative. For the EU however the process of harmonisation will be the decisive factor to successfully strengthen the conduct of clinical research in Europe.
The approach of harmonizing CMC requirements with the CHMP directive is a valuable steps towards harmonisation throughout the member states. However as the guideline provides for flexibility and room for interpretation, the success of harmonisation will strongly depend on the member states interpretation and their readiness to handle flexible approaches in routine review.

Pages: 70,
Annexes: 20