Product licence application

Potential new drugs that show acceptable toxicity in animals are usually first tested in healthy human volunteers before being investigated in patients. Chapters 3-6 deal with these aspects of new drug development, and it is the purpose of this chapter to consider how safety should be evaluated at the time of the product licence application and in the post-marketing phase. 

By the time that an application for a product licence is ready, a certain amount of evidence on the safety of the drug will be available. In a review of product licence applications to the Committee on Safety of Medicines (CSMs), Rawlins and Jefferys presented data on the number of patients who were available for the assessment of safety and efficacy (Table 15.5). When it is considered that many of the patients included would have been in short-term clinical trials (up to 28 days), and that other trials would have been conducted on formulations and doses that were different from those recommended in the product licence application, then the relevant numbers are substantially reduced. 

In view of the regulatory delay that was caused by the need to apply for a CTC, a Statutory Order (SI 1974/498) was made during 1974, to provide an exemption from the need to hold a CTC in such cases, subject to certain conditions. This order applied to trials conducted by doctors and dentists on their own responsibility (DDX). The basis of the clinical trial exemption (CTX) scheme, introduced in 1981, to include studies initiated by the pharmaceutical industry, was that together with a detailed clinical trial protocol and summaries of chemical, pharmaceutical, pharmacological, pharmacokinetic, toxicological and human volunteer studies, a clinical trial in patients may proceed without the need for the additional details normally required for a CTC or Product Licence application. This exemption scheme was based on the requirements that ... 

Product licence holders are required to inform the Ministry of Health (MOH) of any changes to the details that were previously submitted in their product licence applications. Approval by MOH is required before the changes can be effected, with the exception of some minor amendments that require only notification to MOH. 

Change of product physical characteristics (e.g., inclusion or deletion of superficicd marking of tablet) (Note Change of product s colour, shape and coating, a new product licence application is required.) Major (DRA-3) Product sample C2(e)... 

Requesting scientific advice from the CHMP can be sought irrespective of whether the product licence application will be made using the centralized or mutual recognition procedures (see below). For products that are not required to pass through the centralized procedure (CP), careful, case-by-case consideration is needed when deciding which authority to approach with a request for scientific advice. 

If data are available on 1000 patients, then on the assumption that there were no confounding factors, an adverse effect with an incidence of about 1 in 300 might be detected. If there were confounding factors, such as a significant background level of the ADE, not associated with the drug, then the level of detection could fall to 1 in 100 or even less. Most ADEs that have caused problems occur less frequendy than 1 in 1000 patients, and may be as rare as 1 in 10 000 or 50 000, so the evidence available in the product licence application is wholly inadequate for such an assessment. The need for the continuing evaluation of safety is therefore a matter of considerable importance, and has been the subject of numerous publications. ... 

Rawlins MD, Jefferys DB. Study of United Kingdom product licence applications containing new active substances. BATJ 1991 302 223-5. 

The basis of the CTX scheme is that, following an evaluation of a detailed clinical trial protocol and summaries of chemical, pharmaceutical, pharmacological, pharmacokinetic, toxicological and, when appropriate, human volunteer studies, a clinical trial may be permitted. This obviates the provision of the additional details normally required for a Clinical Trial Certificate or Product Licence application. 

A standard format of product licence application has been adopted, making the preparation of regulatory documents much simpler. The format and data requirements of the EU are being adopted by several countries outside the union, so reducing the number of types of application necessary. 

These, along with the requirements of the European Pharmacopoeia, provide guidance for the data requirements for packaging and its format for presentation in the product licence application. 

The main pharmaceutical Directives 65/65 and 75/318 do not actually spell out in detail what is required in a Product Licence Application. These key directives require that applications be made, and define only in outline the data requirements. It is therefore necessary to expand the guidance and this is done in the Notice to Applicants (1986) and its subsequent amendments. The Notice to Applicants prepared by the European Commission has no legal standing, but gives additional advice over and above that given in the various EU Directives. The notice actually forms volume 2 of 9 volumes of the Rules Governing Medicinal Products in the European Union, and has two parts ... 

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