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.

The future with the UK Medical Devices Agency.

The medical device industry is facing a period of profound change and opportunity. This is partly arising from rapid developments in various fields of science and technology and partly from sociological and perceptual changes in society. One regulatory agency describes how it is responding to the challenge.

Sympathetic activity in patients with panic disorder at rest, under laboratory mental stress, and during panic attacks.

BACKGROUND: The sympathetic nervous system has long been believed to be involved in the pathogenesis of panic disorder, but studies to date, most using peripheral venous catecholamine measurements, have yielded conflicting and equivocal results. We tested sympathetic nervous function in patients with panic disorder by using more sensitive methods. METHODS: Sympathetic nervous and adrenal medullary function was measured by using direct nerve recording (clinical microneurography) and whole-body and cardiac catecholamine kinetics in 13 patients with panic disorder as defined by the DSM-IV, and 14 healthy control subjects. Measurements were made at rest, during laboratory stress (forced mental arithmetic), and, for 4 patients, during panic attacks occurring spontaneously in the laboratory setting. RESULTS: Muscle sympathetic activity, arterial plasma concentration of norepinephrine, and the total and cardiac norepinephrine spillover rates to plasma were similar in patients and control subjects at rest, as was whole-body epinephrine secretion. Epinephrine spillover from the heart was elevated in patients with panic disorder (P=.01). Responses to laboratory mental stress were almost identical in patient and control groups. During panic attacks, there were marked increases in epinephrine secretion and large increases in the sympathetic activity in muscle in 2 patients but smaller changes in the total norepinephrine spillover to plasma. CONCLUSIONS: Whole-body and regional sympathetic nervous activity are not elevated at rest in patients with panic disorder. Epinephrine is released from the heart at rest in patients with panic disorder, possibly due to loading of cardiac neuronal stores by uptake from plasma during surges of epinephrine secretion in panic attacks. Contrary to popular belief, the sympathetic nervous system is not globally activated during panic attacks.

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.

Social phobia. The most common anxiety disorder.

Social phobia, the avoidance of social situations for fear of humiliation and embarrassment, has historically been under-recognised. Today, social phobia is the third most common psychiatric disorder that, left untreated, has been shown to have a marked impact upon the quality of life and success of sufferers. Specific pharmacotherapy and psychological therapies used simultaneously or alone, have been shown to be efficacious in the treatment of this disorder.

Nitric oxide modulates retention of immobility in the forced swimming test in rats.

Although originally developed as a possible screen for antidepressants, the Porsolt forced swimming test has more recently been extensively used as a model for studying the involvement of the endocrine system in the acquisition and retention of behavioural responses. In previous studies we have shown that while adrenalectomised rats acquire the immobile response normally, they are unable to retain it on retest next day. In the present study we show that retention of the immobile response in the Porsolt swim test is impaired in intact rats given the nitric oxide (NO) inhibitor L-N-arginine methyl ester (L-NAME), in a dose- and time-dependent manner. At a dose of 50 mg/kg levels of immobility are similar to those in adrenalectomised animals, an effect reversed by the simultaneous administration of L-arginine (50 mg/kg). L-Arginine also reverses the behavioural effect of adrenalectomy, and L-NAME blocks the ability of dexamethasone or the kappa-selective opioid ketocyclazocine to reverse the effect of adrenalectomy on retention of the immobile response. We conclude that the kappa-opioid and glucocorticoid mediated pathways previously shown to independently facilitate retention are mediated by nitric oxide.

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.

Trichotillomania. A common hidden disorder.

Trichotillomania is a chronic impulse control disorder that has recently seen increased public awareness resulting in more sufferers seeking treatment. Use of SSRIs, or cognitive behavioural interventions either alone or in combination, brings about a reduction in symptoms for most who, until recently, have been a silent group of sufferers who believed they alone plucked their hair.

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.

The effect of water temperature on immobility in the forced swimming test in rats.

In the Porsolt swimming test intact rats acquire and retain the immobile response indistinguishably at 25 and 30 degrees C; at both temperatures retention is abolished by administration of the glucocorticoid antagonist RU38486 and the kappa-selective opiate receptor antagonist MR2266 when given together, but not when either is given alone. At 20 degrees C, however, the animals do not acquire the response, and have levels of retention significantly lower than at the higher temperature. This deficit is not restored by administration of glucocorticoids, kappa-opioid receptor-selective agonists, thyroid hormone or glucose.

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

Regulation of medicines in the United Kingdom has changed considerably since the establishment of the Medicines Control Agency in 1989, and other changes will take place throughout the European Community (EC) over the next few years. 1995 will see the introduction of a centralised procedure, applicable to a small number of innovative drugs, and a decentralised procedure, based on mutual recognition of licences granted by existing control authorities in other EC countries.

The thyroadrenal axis, food deprivation and retention of a behavioural response.

The effects of adrenalectomy on retention of the immobile response in the Porsolt swimming rat test are equally reversed by dexamethasone, ketocyclazocine and thyroxine; the effects of hypothyroidism are similarly equally well reversed by all three agents, or by adrenalectomy. Animals food deprived for 24 h lose the response, but retain it after 48 h food deprivation; the latter effect is blocked by adrenalectomy. These counterintuitive findings suggest hitherto unrecognized commonalities and/or interactions in the metabolic effects of the thyroid and adrenal glands.

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.

Obsessive compulsive disorder. An update.

Developments in the neurosciences, neuropharmacology and in cognitive/behavioural therapy have helped in providing effective treatment for OCD. That OCD can be treated successfully is likely to lead to greater public demands on clinicians for diagnosis and treatment. It is thus hoped that the quality of life for sufferers will improve and the secretiveness and shame they now feel about their illness will no longer occur.

The forced swimming test: effects of glucose administration on the response to food deprivation and adrenalectomy.

Rats food deprived for 24 h prior to a 15 min swimming test have no difficulty in acquiring the immobile response but showed significantly reduced levels of immobility (40%) on retest compared with controls (70%). This effect of food deprivation was reversed, by glucose (100 mg/kg), dexamethasone (6 micrograms/rat) and ketocyclazocine (25 micrograms/rat). Adrenalectomised animals also acquire but cannot retain the immobile response, however, adrenalectomised rats given 1000 mg/kg glucose within 2 h of the initial swimming test are immobile for 75-85% of the retest period. We interpret these findings as suggesting a complex interplay of endocrine and metabolic factors are necessary for retention of the behavioural response.

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.

Thyroid hormones and the acquisition and retention of behavioural responses.

Naive rats placed in a plexiglass cylinder from a 15 minute test period show progressive immobility, and retain the immobile response when given a 5-minute retest 24 hours later. In the present study we show that hypothyroidism markedly attenuates the acquisition of the immobile response; that this effect on acquisition is reversed 5-10 minutes after the administration of thyroxine; and that hypothyroid rats treated with a single dose of thyroxine up to 2 hours after the initial test show levels of immobility on re-test indistinguishable from intact rats.

Glucocorticoids, adrenal medullary opioids, and the retention of a behavioral response after stress.

In the Porsolt model swimming test, naive rats become progressively more immobile over a 15-min initial test (0-5 min, approximately 30% immobile; 5-10 min, approximately 50%, 10-15 min, approximately 70%). Twenty-four hours later, rats have retained the response, being immobile for about 70% of a 5-min retest period. We previously reported that in this test adrenalectomized rats are indistinguishable from intact rats over the 15-min test period, but are immobile for only approximately 30% of a 5-min retest period 24 h later. The finding that this behavioral effect of adrenalectomy can be reversed by glucocorticoids or kappa-selective opioids led us to hypothesize that retention of the immobile behavior can be effected by glucocorticoids from the adrenal cortex or kappa-selective opioids from the adrenal medulla. To test this hypothesis, we have given intact rats the antiglucocorticoid RU38486 and the anticholinergics atropine and mecamylamine to block adrenal medullary discharge, either alone or simultaneously. Administered alone, neither class of antagonist affected the response; administered together, they profoundly reduced immobility to levels seen in adrenalectomized rats. Additional evidence for medullary kappa-selective opioids mediating the behavioral effect was that the administration to hypophysectomized rats of atropine plus mecamylamine or the kappa-selective antagonist MR2266 reduced immobility to the levels seen in adrenalectomized animals. We conclude that secretion from either the adrenal cortex or medulla is sufficient for the incorporation of this learned response after stress, and that in intact animals input from both zones may contribute to the terms of this behavioral response.