The regulation of medical devices and the role of the Medical Devices Agency.

This article reviews the regulation of medical devices in the UK and Europe and compares the regulatory regime with that for pharmaceuticals. The regulation of devices follows the 'New Approach' policy of the EC Commission and involves more self-regulation and conformity assessment. The controls are relatively recent beginning in 1993 for Active Implantable Devices and concluding with the In Vitro Diagnostic Directive implemented in June 2000. The article describes how the directives have been implemented in the UK, the role of the Notified Bodies and the role of the Medical Device Agency (MDA) as the competent authority. In particular the Agency's compliance and standards work is described along with the strategy and post marketing surveillance and adverse incident scheme. The MDA is a key international device regulatory agency and its international role is discussed. So too is its device evaluation programme for the NHS and how this complements the work of NICE. The article also considers the future direction of the MDA and changes in the device sector.

New active substances authorized in the United Kingdom between 1972 and 1994.

AIMS: The study was undertaken to assemble a list of all new active medicinal substances authorised in the United Kingdom between 1972 and 1994; to assess whether the pattern of introductions had changed; and to examine withdrawal rates and the reasons for withdrawal. METHODS: The identities of those new active substances whose manufacturers had obtained Product Licences between 1972 and 1994 were sought from the Medicines Control Agency's product data-base. For each substance relevant information was retrieved including the year of granting the Product Licence, its therapeutic class, whether currently authorised (and, if not, reason for withdrawal), and its nature (chemical, biological etc.). RESULTS: The Medicines Control Agency's data-base was cross-checked against two other data-bases for completeness. A total of 583 new active substances (in 579 products) were found to have been authorised over the study period. The annual rates of authorisation varied widely (9 to 40 per year). Whilst there was no evidence for any overall change in the annual rates of authorising new chemical entities, there has been a trend for increasing numbers of new products of biological origin to be authorised in recent years. Fifty-nine of the 583 new active substances have been withdrawn (1 each for quality and efficacy, 22 for safety, and 35 for commercial reasons). CONCLUSIONS: For reasons that are unclear there is marked heterogeneity in the annual rates of authorisation of new active substances. Their 10 year survival is approximately 88% with withdrawals being, predominantly, for commercial or safety reasons. This confirms the provisional nature of assessments about safety at the time when a new active substance is introduced into routine clinical practice, and emphasises the importance of pharmacovigilance.

The new pharmaceutical regulatory procedures for Europe.

Since the late 1980s there has been considerable debate and discussion over the so called 'future system proposals' for the regulation of additional products throughout the European Union. On 1 January 1995 the future system became the new system with the coming into force of the Council and the associated Commission directives. These proposals are complex and have evolved from the present procedures that originated in 1965. David Jefferys gives an overview of the new procedures and considers how they will affect both the regulation of medicines and the development of new products over the rest of this decade.

EMEA and the new pharmaceutical procedures for Europe. European Medicines Evaluation Agency.

The regulation of medicines throughout Europe has undergone significant change since the first pharmaceutical Directive in 1965. 1995 will bring the next major stage in this evolution with the introduction of the so-called "Future System proposals". These will see the creation of the EMEA (the European Medicines Evaluation Agency), the introduction of a Centralized Procedure, applicable to a small number of innovative drugs, and a Decentralized Procedure, based on mutual recognition of licences granted by existing control authorities in other EC countries. The regulation of medicines in the United Kingdom has also changed considerably since the establishment of the Medicines Control Agency in 1989. This article looks at the new licensing arrangements for Europe and the development of medicines control in the UK over the last few years.

United Kingdom Product Licence applications involving new active substances, 1987-1989: their fate after appeals.

1. The overall fate of Product Licence applications for new active substances considered by the Committee on the Safety of Medicines between 1987 and 1989 is described. 2. Fifty-one applications were the subject of appelate procedures and 44 (86%) were successful. In 19 (43%) of the latter, applicants sought either decreased dosage regimens, substantially reduced indications, or (once) topical rather than systemic treatment. 3. Overall 57% of Product Licence applications considered between 1987 and 1989 either do not reach the market (23%) or only with substantial restrictions on dosage or indications (34%). Drug regulation, in the United Kingdom, thus plays a significant role in promoting public health rather than merely delaying the entry of new products to the market. 4. The number of volunteers and patients exposed to new active substances at the time of marketing varied widely within and between therapeutic classes. The median number of patients (1528) available for the assessment of safety underlies the importance of postmarketing safety surveillance.

Study of United Kingdom product licence applications containing new active substances, 1987-9.

OBJECTIVES: To investigate the fate of product licence applications containing new active substances in relation to their degree of innovation and therapeutic category. To assess the numbers of volunteers and patients exposed to a new active substance when marketing autorisation is first sought. DESIGN AND SETTING: Observational study of records for each licence application submitted to the United Kingdom licensing authority for marketing authorisation from 1987 to 1989. SUBJECTS: 118 product licence applications containing one or more new active substances. MAIN OUTCOME MEASURES: Success of application for product licence as assessed by the decision of the Committee on Safety of Medicines to advise the granting of a licence (with or without conditions) or provisionally advise its refusal on the grounds of quality, safety, or efficacy. Assessment of numbers of volunteers and patients exposed to each substance during premarketing studies and clinical trials, and the numbers of treated patients available for an assessment of safety. RESULTS: 118 relevant product licence applications were submitted during the review. Although 60% (52/86) of semi-innovative products fell into one of three therapeutic categories (cardiovascular, central nervous system, or anti-infective agents), only 41% (13/32) of fully innovative products fell into these categories. 47 applications were granted (conditionally or unconditionally) but the success rate for fully innovative products (56%, 18/32) was greater than that for semi-innovative products (34%, 29/86). The number of volunteers and patients exposed to a new product at submission varied widely and tended to be greater for successful applications. CONCLUSION: The results suggest a broadening of the pharmaceutical industry's research and development programmes and that a more liberal licensing policy exists for fully innovative products than for semi-innovative products. The relatively limited exposure of patients to new active substances at licensing underlines the importance of rigorous postmarketing surveillance.

An investigation of the role of the specific opioid antagonist naloxone in clinical toxicology.

1 An assessment of the current role of naloxone in clinical toxicology has been made in a series of three separate epidemiological studies. 2 Through the National Poisons Information Service we found that the role of naloxone in opioid poisoning is often not appreciated by the enquirer and that toxicological screening is often requested before the diagnostic use of naloxone. 3 The recommended dose of naloxone (0.4--1.2 mg i.v.) is not always adequate. In 51 cases where naloxone was effective, doses of up to 3.2 mg were necessary (mean 1.8 +/- 0.3 mg SEM i.v.). 4 In 31 cases of non-opioid poisoning, naloxone in doses of 0.4--1.2 mg i.v. caused no deterioration, whilst six patients in whom no opioids were detected showed clinical improvement. 5 In 300 cases of suspected ethanol-induced coma, 49 showed reversal of coma with naloxone, and in 38 cases ethanol was the sole cause of coma (mean plasma concentration 3.54 +/- 0.62 g/l SEM). 6 These results suggest that the role of naloxone in clinical toxicology is not fully appreciated. There is a need for further education as to its indications in opioid poisoning, together with additional studies to define more accurately the dose/response relationship. In addition, the role of naloxone in coma induced by ethanol and certain other non-opioids needs to be evaluated further.

Formic acid poisoning.

Forty-five cases of formic acid poisoning are reviewed. The metabolic and pathological consequences of such overdoses are considered. The consequences are discussed in relation to the amount of the acid ingested. The problems likely to be encountered in the management of such patients are highlighted.

Corticosteroid treatment, serum lipids and coronary artery disease.

Serum lipids and the cholesterol concentrations in the high density lipoprotein (HDL) fractions were measured in patients receiving long-term corticosteroid treatment for connective tissue disorders and asthma. Patients who were not receiving corticosteroid treatment had blood lipid levels which did not differ from those of healthy people. However, female (but not male) patients who had received prednisolone for a mean period of 3.1 years had a significant elevation in total cholesterol and a large decrease in HDL cholesterol. It seems possible that high levels of corticosteroids may increase the incidence of premenopausal ischaemic heart disease in females.

Blockade of chlorpropamide alcohol flush by aspirin.

The blocking effects of aspirin, chlorpheniramine, and cimetidine were tested against the flush provoked by alcohol in twenty-four chlorpropamide-treated patients with non-insulin-dependent diabetes mellitus. Active preparations were compared in a double-blind manner with an indistinguishable placebo. Aspirin significantly decreased the number of patients who flushed. Five patients studied in detail all showed suppression of chlorpropamide/alcohol flush by aspirin, with a mean facial temperature increase during the flush of 2.4 degrees C after pretreatment with placebo and an increase of 0.4 degrees C after pretreatment with aspirin.