Product licences

Figure 7.10 Outiine of requirements for a Veterinary Bioiogics Product Licence Appiication.

As discussed in the introduction to this chapter, results of ED are intended to give a clear indication that the drug is a serious candidate for FD to product licence, or that it is not viable and development should be stopped forthwith. Sometimes it takes a little longer before the picture becomes clear but the aim should be to make a go/no-go decision at the earliest opportunity. 

It is often not appreciated how much work is required to ensure that the marketing authorisations are kept up to date through being renewed and amended as necessary. Similarly, it may not be realised that a simple variation to a product licence, such as a small change in the amormt of excipient, will require the submission of a variation document to the authorities. 

Finally, the representative must learn the details of the product licence and thus know how, when promoting the product, to avoid being in breach of either the Medicines Act or the ABPI Code of Practice, which is written specifically to assist company personnel in promoting products to prescribers in an appropriate manner. 

Pharmaceutical companies have recourse to aU the art of sophisticated advertising, promotion, public relations and specialist agencies, as well as having their own trained marketing professionals. Consequently written, documentary and published promotional items are usually reviewed and scrutinised by the company medical advisers for conformity with the known data and the ABPI Code of Practice, while the regulatory affairs professionals usually ensure conformity with the product licence. A pharmaceutical... 

This is the name of what we used to know simply as the data sheet, or colloquially as the package insert. The SPC is the document that must be submitted in draft by companies to the MHRA/Reference Member State/European Medicines Evaluation Agency upon application for a marketing authorisation and, once approved, must then be provided to prescribers or suppliers of medicines, either with the product or at the time of promotion or within the previous 15 months of promotion of the product, written or verbal. The SPC includes the prescribing information for the product and represents the product licence approval for the medicine (see Section 12.2.1.1). It is the definitive statement between the competent authority and the company and, more importantly, is becoming the common basis of communication between the... 

The original provisions date back to the early 1970s. Under section 7(2) of the Medicines Act 1968, it was necessary to hold a product licence in order to sell, supply, export or import a medicinal product to procure those activities or for the manufacture or assembly of the product. However, various exemptions from the licensing requirements, including those relating to particular patient supply, were provided for in the act and in related statutory instruments. The most important exemptions were contained in sections 9 and 13 of the act, the Medicines (Exemption from Licences) (Special and Transitional Cases) Order 1971, the Medicines (Exemption from Licences) (Special Cases and Miscellaneous Provisions) Order 1972 and the Medicines (Exemptions from Licences) (Importation) Order 1984. ... 

Regulation 3(1) of the 1994 Regulations states that no medicinal product may be placed on the market or distributed by way of wholesale dealing, unless it has a marketing authorisation. This replaces the product licence requirement in section 7 of the act. The exemptions to this requirement are provided for by regulation 3(2) and Schedule 1 to the regulations. They permit supply for individual patients and also enable practitioners to hold limited supplies of stocks of imauthorised medicines. The provisions apply equally to doctors and dentists. 

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. 

The granting of a product licence in the United Kingdom, or its equivalent in other countries, is a dividing line that places firm constraints on what studies can and cannot be done in the pre- and post-marketing periods. Because it would be medically and ethically unacceptable to permit doctors (investigators) to use an unapproved drug in unrestricted circumstances, it is essentially impossible to conduct clinical trials... 

RawUns MD, Jefferys DB. Study of United Kingdom product licence apphcations containing new active substances. BMJ 1991 302 223-5. 

The products already on the market on 1 September 1971, the date for implementation of the Medicines Act, were given the Product Licences of Right (PLR) that were subject to a review process at a later date. This proposal for review of PLRs is reminiscent of the FDA contract with the National Academy of Sciences/National Research Council (NAS/NRC) in 1966, to evaluate the effectiveness of some 4000 different drug formulations approved on the basis of safety alone between 1938 and 1962 - the year of the Kefauver-Harris Amendment. 

The LA was already empowered by the Medicines Act to suspend, revoke or vary licences under section 28 and to control clinical trials in patients under section 36. At the outset in 1971, the Committee recognised the need to adhere to the policy stated by the CSD in respect of considering efficacy but took a much firmer line in 1972, bearing in mind section 19 of the Act. The Committee stated explicitly that, in future, it would require applications to be supported by some evidence of efficacy before advising that a product licence should be granted. 

In 1974, the Health Ministers consulted the UK Medicines Commission on a proposal to set up a committee under section 4 to advise the LA on applications for product licences for dental and other surgical materials. 

The number of PLRs that were allowed to lapse by the manufacturers or were revoked or suspended in the United Kingdom between 1971 and 1982 was 22 376, and by 1988 this number had increased to 27 938. By 1982, the number of PLRs that were converted into full product licences was only 598. At the completion of the review in 1990, the number of applications received for full product licences was 6272 and of these just under 5300 were converted into full licences, most after changes had been agreed to the terms of the licences. Of the 6272 applications, only 706 required referral to CRM or CDSM for advice. The CRM was deemed to have completed its work in 1991 and was disestablished on 31 March 1992 (SI 1992/606) while similarly, the CDSM was disestablished on 31 December 1994 (SI 1994/15). 

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 ... 

New products introduced following a major apphcation for a product licence from the United Kingdom Licensing Authority may be priced at the discretion of the company on entering the market. This will have to take account of costs of research and development and the competition in the marketplace. 

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