Clinical trials authorisation

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. 

With a view to harmonising the conduct of clinical trials across the European Union, Directive 2001/20/EEC was finally agreed on 14 December 2000 and was formally adopted in May 2001 with a 3-year transition period for its implementation. The Directive is now fully implemented in the United Kingdom and further information on clinical trials there can be accessed at the MHR A website. Under the provisions of the Directive, all clinical trials now require a Clinical Trial Authorisation (CTA). This is discussed in detail in Chapter 17. 

Paal, T. L. 1997. Changes in Clinical Trial Authorisation in Eastern Europe. Drug Information Journal 1, 151-155. 

The clinical trial authorisation from SIDC is needed for all clinical trials in the Slovak Republic. 

There are a number of other regulations/directives that you will need to consult, as appropriate. These address topics such as Good Laboratory Practice (GLP), Good Manufacturing Practice (GMP), the conduct of clinical trials, variations to authorised drugs, and the use of genetically modified organisms. A list of the most relevant directives is shown in Table 1.5. 

Figure4.2 How some non-clinical activities can continue into the clinical trial and marketing authorisation phases.

Figure 5.1 Summary of clinical trials conducted as a prelude to a marketing authorisation application.

The manufacture of all investigational medicinal products (including placebo) that are intended for a clinical trial must be authorised and conducted according to Good Manufacturing Practice (GMP). This should be supervised and certified by a Qualified Person . An import authorisation is required for any product from outside the EU, which should also be manufactured to GMP standards. (See Ghapters 11 and 12 for information on GMP, manufacturing authorisations and Qualified Persons.)... 

Requests for permission to conduct clinical trials with pharmaceuticals in the US are termed Investigational New Drug Applications (INDs). The applications are actually a request for an exemption to supply a drug without a marketing authorisation. A cover sheet (Form 1571) must accompany the application. This cover sheet should also be used with each subsequent communication with the FDA, with each form consecutively numbered, starting at 000 for the initial submission. A copy of the form is shovm in Figure 5.6. 

It is worthwhile to note that, in the US, where the applicant will just be dealing with a single authority, there is no need to re-submit data that was previously submitted as part of an IN D application to conduct clinical trials. Instead, the applicant can cross-reference the IND file. This does not apply in Europe, because clinical trial applications will have been submitted to individual Competent Authorities, whereas marketing authorisation applications are usually submitted either centrally to the European Medicines Agency (EMEA) or collectively to a number of Competent Authorities. Thus, the files need to be self-supporting. 

Before initiating a clinical investigation, the manufacturer (or his/her authorised representative) must prepare a statement containing the information outlined in Figure 10.2, and notify the relevant Competent Authorities of the proposed study. The manufacturer must also keep available for inspection by the Competent Authorities the information outlined in Figure 10.3. Unlike for clinical trials, a standard application form has not been developed. Instead, appropriate application forms are... 

The use by the medical profession of medicines with no current marketing authorisation and of authorised medicines outside the terms of their marketing authorisation raises various regulatory issues. Leaving aside use in a clinical trial, such products are also used to treat the particular clinical needs of individual patients. This is known variously as named patient, particular patient or compassionate use supply. The first of these terms is misleading, because there has never been any requirement to identify a particular patient and for the purposes of this chapter the term particular patient supply is used instead. 

Supply on a particular patient basis encompasses various categories of unauthorised use of medicinal products. A product maybe imauthor-ised because it has been specially formulated for use it may be at the clinical trial stage of development, but be requested by doctors for use outside a trial it may have been authorised previously and then withdrawn from the market for commercial reasons, or because of safety, efficacy or quality concerns or it may be authorised currently, but for a different indication or patient population, or in a different country. 

A specified party must hold or obtain (and maintain) all necessary authorisations, for example, under the UK Medicines for Human Use (Clinical Trial) Regulations 2004, and sub-ordinate/related legislation, the Data Protection Act 1998 and the Animals (Scientific Procedures) Act 1986. 

Patent protection under general law usually lasts for up to around 20 years. This creates a difficulty in relation to medicinal products, as it can take some 12 years for the products to undergo research, development, the extensive clinical trials that are required in order to obtain a marketing authorisation and the authorisation process itself. These steps are also extremely expensive. The amount of time that remains during which the patent holder can exploit his patent and recoup his massive investment can be severely curtailed in relation to medicinal products. For this reason, the European Community has provided a form of additional patent-related protection for medicinal products authorised within the European Community, by means of a Supplementary Protection Certificate. A patent holder may apply for a certificate that takes effect at the end of the term of the basic patent, for a period equal to the period that elapsed between the date on which the application for the basic patent was lodged and the date of the first authorisation to place a product derived from the patent on the market in the Community, reduced by a period of 5 years. The maximum duration of the certificate is 5 years. The certificate applies to all medicinal products derived from the basic patent, but the additional time that can be obtained under the SPC is calculated in relation to the first product derived from the patent, authorised in the EU. 

The UK MEIRA has recently drawn special attention to several areas of interest and have highlighted adverse reactions in children and the elderly. Children pose a particular problem because they are seldom studied in clinical trials that form the basis of marketing authorisation submissions. The consequence of this is that children are prescribed medicines which are not licensed for that age group and little experience of possible adverse effects is available. The elderly are also under-represented in pre-marketing clinical trials and are also subject to diminished metabolic activity in respect of numerous commonly used drugs. 

The LA did not lay down rigid requirements concerning the data that must be provided before authorisation can be given for a certificate for the clinical trial of a new drug. It did, however, issue guidelines for applicants. 

Where a clinical trial was proposed with a marketed product then the CTMP scheme could be used. This was a streamlined process based on the fact that there were no quality issues with a product that had already been granted a marketing authorisation. The applicant submitted a copy of the trial protocol, provided information on the investigators and, depending on whether or not the applicant was the MAH, information on the procedures for reporting adverse drug reactions. It was only possible to use this procedure for UK marketed products. It did not apply to unauthorised products manufactured specifically for trial or to products, which were licensed only in countries other than the United Kingdom. 

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