The efficacy and safety of a treatment for Seborrhoeic Dermatitis shall be tested in a placebo-controlled clinical phase III study. The name of the investigational product is ABC-cream 0,25%. The multi-centre trial is designed as randomized and double-blinded study, with the subjects being divided into parallel groups. Participating subjects have to be over 20 years old. Minors or subjects who are incapable of giving consent are excluded from the study.
A phase III study is performed in order to evaluate efficacy and safety of the ABC-cream 0,25%. Several hundred to several thousand subjects are included. The purpose of a phase III trial is to assess the risk-benefit ratio of the drug considering the adequate labelling for the future marketing approval (Food and Drug Administration [FDA], 2009).
The trial will be performed in the United States and in the European Union. Therefore differences in the submission and approval processes have to be considered.
2 Submission and Approval in the United States
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The submission process in the U.S. begins even before the phase I study of the Investigational New Drug (IND) is conducted (see figure 1). The sponsor provides the Food and Drug Administration (FDA) with an Investigational New Drug Application requesting permission to perform a clinical trial in the United States. The FDA is a regulatory authority within the American Department of Health and Human Services. Basic content of the IND Application is stated in The Code of Federal Regulations (CFR) Title 21 Part 312 Section 23 states. It is also given on page two of the FDA-1571 form, which is also an important element of the application (see appendix 1).
Subsequently, the IND Review Process of the FDA commences and the sponsor is urged to wait 30 days to begin the clinical trial (see figure 2). When the review period of 30 days has expired, the clinical study can be initiated unless the FDA has placed a clinical hold. The FDA's primary concern is the safety of the subjects. Considering that the ABC-cream trial is a phase III study the FDA additionally reviews the study design for assessing efficacy of ABC-cream.
Furthermore, the study protocol has to be reviewed by an Institutional Review Board (IRB). Each institution conducting a clinical trial on humans must organise an IRB. It is a committee consisting of at least 5 experts and lay members from varying background. A qualified IRB should ensure that institutional commitments and regulations, standards of professional conduct and practise, community attitudes, and laws are acceptable in the study. Primary concern of the IRB is the protection of human rights (Food and Drug Administration [FDA], 21 CFR Part 56, 2008).
The ABC-cream has already passed these stages and is now - after finishing Phase II - ready to enter the phase III. Beforehand, a Sponsor/FDA Meeting with the focus on the "end of phase II" has to be held. It is necessary to ascertain the safety of the ABC-cream before beginning phase III testing. The purpose of the Sponsor/FDA Meeting is also to find conventions between the agency and the sponsor according to the overall plan, design and objectives for the ABC-cream study in phase III. An effective meeting can avoid additional expenditures of time and money (see figure 3).
It is the sponsor's obligation to provide background information and protocols for phase III one month prior to the Sponsor/FDA Meeting. In conformity with the CDER Handbook (1998, p.10), the following contents should be provided: data supporting the claim of the new drug product, chemistry data, animal data and proposed additional animal data, results of phase I and II studies, statistical methods being used, specific protocols for phase III studies and, if available, a copy of the suggested labelling for the ABC-cream.
Further detailed information on procedures for clinical trials is given in the Manual of Policies and Procedures (MaPPs) (Food and Drug Administration [FDA], 2009).
During the study, the sponsor has the responsibility to choose an experienced investigator and to ensure appropriate training. The sponsor is obliged to monitor the investigation(s) in order to ensure compliance with the general investigational plan and the study protocol. Maintenance of the IND and immediate information of FDA and investigators in case of new adverse effects is also obligatory (Food and Drug Administration [FDA], 21 CFR 312 Section 50, 2008).
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The investigator, on the other hand, is responsible for conducting investigations according to the signed investigators statement (FDA-1572: see appendix 2), the investiÂgational plan, and applicable regulations (Food and Drug Administration [FDA], 21 CRF 312.60, 2008)
3 Submission and Approval in the European Union
Basic principles for the EU submission of a clinical trial are the 'EU Directive 2001/20/EC of the European Parliament and of the Council of 4 April 2001' and the 'Commission Directive 2005/28/EC of 8 April 2005'. The documents were implemented to standardise procedures and administrative activities within the EU. In addition, the Directives' primary goal is the protection of the human subject. They are based on the Good Clinical Practise (GCP) for the use of investigational medicinal products on humans.
First and foremost, a EudraCT number should be obtained from the EMEA for the submission of the ABC-cream trial. The EudraCT number is a unique reference in order to identify the specific study. Subsequently, a Clinical Trial Authorisation Application (CTA) should be completed. It contains the following core information: The EudraCT number, a covering letter, the application form, the protocol, the Investigators Brochure (IB), the Investigational Medicinal Product Dossier (IMPD), a list of Competent Authorities to which the submission has been made, and a copy of the EC approval. The Clinical Trial Authorisation Application Form with a detailed checklist of further requirements is attached to the appendix 3.
According to the Directive 2001/20/EC Article 9.2, the CTA shall be submitted to the Competent Authorities (CA) of the Member States. The period until the CA informs the sponsor about acceptance or non-acceptance of the ABC-cream trial shall not exceed sixty days (see figure 4). In case the sponsor receives a notification of non-acceptance, the sponsor may amend a request. If no request is provided by the sponsor, the trial is considered as rejected (Directive 2001/20/EC, 2001, Article 9).
The Competent Authorities can be either national (e.g. BfArM) or supranational (e.g. EMEA). Reason for the division of those regulatory authorities is the country-specific handling of clinical trials in the EU Member States (Harman, 2004, p. 15). The different national and supranational regulatory authorities are listed in table 1. Further differences are reflected in the different ways the Directives were adopted to the requirements and procedures of the individual Member States.
Besides the application to the CA, a submission should be made to the responsible Ethics Committee (EC). The EC is an independent body of a Member State. Members of an EC are medical and non-medical professionals. The function of the EC is to ensure the well-being and safety of human trial subjects. In addition, the EC shall ensure further protection for the subject by giving an opinion on the study protocol as well as on the documents for subjects (e.g. documents to inform the subject and informed consent forms) and the qualification of the Investigators (Directive 2001/20/EC, 2001, Section 2).
After receipt of the submission, the EC should have a maximum of sixty days to give a consequential opinion to the sponsor and the Competent Authority in the Member State. If the EC requests further information, the period can be extended to a maximum of 35 days beginning with receipt of the amendments. The 35-day period can additionally prolonged by a request of the Competent Authority (Clumeck & Dorethy, 2004). The individual approval times are regulated by the single Member States (see table 2)
Furthermore, the ABC-cream trial is a multi-centre trial and can be conducted in more than one Member State. In this case, the Ethics Committee of each involved Member State must give their single opinion about the Phase III study (Directive 2001/20/EC, 2001, Article 7).
The sponsor should attend to the following duties and responsibilities: Compile the protocol and informed consent document including the Directive, submit and provide documentation to Ethics Committee and Competent Authority, report SUSARs to investigators and ethics committee, and respond to any request of the EC and the CA (Clumeck & Dorethy, 2004).
4 Comparing Summary of the United States and the European
In general, the fundamental guidelines for both the European Union and the United States are the Declaration of Helsinki and the ICH-GCP guidelines. These guidelines apply to sponsor, investigators, responsible Ethics Committees and regulatory authorities (Food and Drug Administration [FDA], 2009) (Directive 2001/20/EC, 2001).
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Based on the Good Clinical Practise (GCP) provided by the International Conference on Harmonisation (ICH), the Code of Federal Regulations contains guidelines for the U.S., whereas the EU proceeds according to the EU Directives.
To summarise, the application process differs between the U.S. and the EU. The regulatory authorities in the European Union are national and supranational Competent Authorities, which are generally located in the participating Member States. In contrast, the regulatory authority in the U.S. is the Food and Drug Administration.
The Ethics committees of the United States and the European Union vary in their organisational structure. The American Ethics Committee, the Institutional Review Board, is organised by the institution which conducts the clinical trial. On the contrary, the Ethics Committee in the EU is an independent body located in the Member States in which the study is performed.
Even the applications for the clinical trial differ from each other. The Investigational New Drug (IND) Application includes only the submission for a clinical trial in the U.S. The IND Application is provided once before phase I trial can be approved. For the implementation of the ABC-cream trial - which is a phase III study - a sponsor/FDA Meeting with focus on the "end of Phase II" is required.
In contrast, in the EU the sponsor applies for Clinical Trial Authorisation before the phase III of the ABC-cream trial commences. The review period is sixty days at maximum and can be extended by further 35 days or even longer, depending on the CA.
Finally, approval of the regulatory authority and the Ethics Committee is required in both the European Union and the United States.
Approval times in the different Member States of the EU
4-12 weeks (EC and time of acknowledgement of receipt of notification)
4-8 weeks (EC only)
1-2 months (EC and receipt of notification number)
6-12 months (depends on whether the product is new or known)
2-4 weeks (important permit time)
2-12 months (EC and authorization)
5-9 weeks (+1-2 months for EC approval)
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