Investigational medicinal product , clinical trial authorizations

The Competent Authorities are obliged to appoint Inspectors for checking that all activities associated with clinical trials are conducted in compliance with the regulations. The inspectors can inspect any sites concerned with the clinical trial, particularly the trial site (GCP), the manufacturing site of the investigational medicinal product (GMP), any laboratory used for analyses in the clinical trial (GLP), and/or the sponsor s premises. 

Most of the information sought is similar to the FDA s IND requirements. One major difference is that a Qualihed Person has to certify that the investigational medicinal product (IMP) is manufactured according to GMP The Competent Authority has the right to inspect the manufacturing facility for GMP compliance, the preclinical facility for GLP compliance, and the clinical trial sites for GCP compliance. 

The application for a clinical trial authorisation (CTA) for the first administration of a NME to man comprises the same elements as all other CTAs but, of course, there will be no clinical data. The regulatory authority known as the competent authority (CA) of the EU member state requires receipt of confirmation of the EU clinical trials database (EUDRACT) number, a covering letter, a completed application form, the protocol with all current amendments, the IB and a full Investigational Medicinal Product Dossier (IMPD) (see below). If the study is to be conducted in more than one member state, a list of CAs should be included. If the opinion of the lEC is available, it should be provided. 

Clinical trials are regulated by individual member states in the European Union. An applicant (or sponsor) submits data on the investigational medicinal product (IMP), and details of the proposed clinical trial, to the competent authority in the country in which the trial is to be carried out. The ethics committee responsible for the site where the trial is to take place also needs to give approval. 

Clinical trials and clinical trial authorizations in the European Union are controlled under the Clinical Trial Directive, 2001/20/EC [9], and all member states are bound by its requirements. Under the provisions of the Directive, a clinical trial is an investigation in human subjects that is intended to discover or verify the clinical, pharmacological, and/or other pharmacodynamic effects of one or more medicinal products, identify any adverse reactions or study the absorption, distribution, metabolism, and excretion, with the object of ascertaining the safety and/or efficacy of those products. This definition includes pharmacokinetic studies. 

Guide to Good Manufacturing Practices, Annex 13, Manufacture of Investigational Medicinal Products, July 2003. The Rules Governing Medicinal Products in the European Community, Vol. 4, Biostatistical Methodology in Clinical Trials in Applications for Marketing Authorizations for Medicinal Products, Committee for Proprietary Medicinal Products [CPMP] EEC 111/3630/92-EN, 1994. 

Readers are also urged to refer to the Commission Directive on the requirements to obtain an authorization to manufacture or import an investigational medicinal product and the requirements to be met by the holder of this authorization to implement the directive on Clinical Trials on medicinal products for human use (10). 

The regulatory procedure involved is a so-called Clinical Trial Authorization appH-cation (CTA) and consists, in addition to a Clinical Trial Protocol (CTP) and Investigator s Brochure (IB), of an Investigational Medicinal Product Dossier (IMPD) in CTD format. The IMPD consists of quality data, nonclinical pharmacology and toxicology data, clinical trial and previous human experience data, and an overall risk-benefit assessment. A copy of the CTA is sent to each EU Member State where the study is conducted, as well as to the Ethics Committees for approval. These also have to be notified in case of any amendments, study termination and adverse reactions. The contents of the IMPD are case specific and may be simplified or even replaced by the... 

Both a manufacturing license (GMP certificate includes the manufacturing license, see below) and a product approval, i.e., the marketing authorization, are required in order to get a biopharmaceutical product on the market. In the EU, GMP compliance has been compulsory as of 1993 for all manufacturers license holders as stated in Directive 93/356/EEC. More recently, these requirements have been extended by Directive 2003/94/EEC on GMP for Investigational Medicinal Products for Human Use. This Directive goes hand in hand with Directive 2001/20/EC on GCP in the Conduct of Clinical Trials on Medicinal Products for Human Use. 

As a consequence of the new legislation for clinical trials, documentation on the quality and preclinical (i.e., toxicological) data of investigational medicinal products, including radiopharmaceuticals, needs to be submitted to obtain approval from the national health authorities in the member states prior to initiating a clinical study in humans. Furthermore, all clinical trials which started in the European Union after 1 May 2004 need to be recorded in the European EudraCT database (European Commission 2003 b). 

INVESTIGATIONAL MEDICINAL PRODUCT A pharmaceutical form of an active ingredient or placebo being tested or used as a reference in a clinical trial, including a product with a marketing authorization when used or assembled (formulated or packaged) in a way different from the approved form, or when used for an unapproved indication, or when used to gain further information about an approved use. 

The year 2003 saw the launch of the European Clinical Trials (EudraCT) Database (https //eudract.emea.eu.int/eudract/index.do). The database is interfaced with the Eudravigilance Clinical Trial Module (EVCTM), and is used to facilitate communication on clinical trials between authorities in the oversight of clinical trials and investigational medicinal product development, and to provide for enhanced protection of clinical trial participants receiving investigational medicinal products. 

Clinical trials are divided into three phases. A phase I trial is carried out with 10-30 subjects, mostly healthy adults and a few appropriate patients, all on a voluntary basis, to find out the optimum dosage and route of administration. Early phase II trials are carried out as comparative studies, using double-blind methodology. Late phase II trials are carried out at medical institutions (not less than three) and more than 300 patients should be included and validated. Immediately after the new medicinal product has been approved by the Health Authorities for provisional production, phase III clinical trials should be carried out to conduct a community investigation and evaluation of the product. 

Unfortunately, the GCP guidelines are not always applied to other biomedical research and rarely to independent studies on marketed products initiated by clinicians without support from the manufacturer. There is still a double standard in therapeutic research and therefore in published papers arising from them. Editors and reviewers do not see the full documentation of non-sponsored biomedical research, whereas the regulatory authorities and their expert advisers will expect to see all data in the support of new medicines. The extent of the differences in standards is recognised when a potential investigating site is visited and one realises that there are no SOPs, that documentation of laboratory procedures is suboptimal and that staff are not properly trained. These facets are mentioned because the training that clinicians, scientists and technicians receive from company-based staff before and during a sponsored clinical trial adds considerably to the quality standards. 

In the US, an IND (Investigational New Drug) application has to be filed with the FDA. For other countries, a notification has to be submitted to the respective regulatory authorities. For example, Clinical Trial Exemption (CTX) applications are required for the UK, Clinical Trial Notification (CTN) and CTX for Australia, and a Clinical Trial Certificate (CTC) for Singapore and the European Agency for the Evaluation of Medicinal Products (EMEA). A more extensive discussion concerning regulatory authorities and the processes and procedures of applications is presented in Chapters 7 and 8. The relevant authority will review the application. A positive response from the authority is required before the trial can commence. 

---