Guidance synthesis. Medical research for and with older people in Europe: proposed ethical guidance for good clinical practice: ethical considerations.

INTRODUCTION: In Europe the population is ageing rapidly. Older people are taking many medicinal products daily and these may not necessarily be suitable for them. Publications show that older patients are underrepresented in clinical trials, especially those over 75 years, with multiple co-morbidities, concomitant treatments and/or frailty. This document provides a summary of recommendations on ethical aspects of clinical trials with older people, who may in some cases be considered a vulnerable patient population. The EFGCP's Geriatric Medicine Working Party (GMWP) has developed this guidance to promote such research and to support health care professionals in their efforts. ETHICAL, SCOPE AND CONTEXT: The definition of a geriatric patient is reviewed. Frail and vulnerable patients, who are a minority of geriatric patients, should be included whenever it is relevant. The legal context is described. THE PROCESS OF INFORMED CONSENT: All adults should be presumed capable of consent, unless proven otherwise; informed consent must be sought for all older people who are able to consent. A simple, short and easy-to-understand information sheet and consent form will contribute to improving the readability and understanding of the older participant. A participant guide and the use of a simple tool to ensure decision making capacity, are recommended. Whenever older people are unable to consent, their assent should be sought systematically using adequate information, in addition to seeking the consent of their legal or authorised representative as appropriate. ETHICS COMMITTEES: Research ethics committees need internal and/or external geriatric expertise to balance the benefits and risks of research in older people and to appreciate and recognise their autonomy. DESIGN AND ANALYSES: Design and Analyses should be adapted to the objectives with appropriate outcomes and are not different from other clinical trials. CONCLUSIONS: The absence of proper recruitment or insufficient presence of older patients in clinical development plans for new medicinal products is detrimental; there is a need to improve evidence-based knowledge, understanding and management of their conditions and treatment. The aim of this guidance is to facilitate clinical research for and with the older patient population. The long version of the guidance will be available on the EFGCP's website: www.efgcp.be/.

Guiding Principles for Pharmaceutical Physicians from the Ethical Issues Committee of the Faculty of Pharmaceutical Medicine of the Royal Colleges of Physicians of the UK.

Medical practitioners practising in the field of pharmaceutical medicine, whether in industry, regulatory bodies or an academic environment, are bound by the same ethical standards which apply to all doctors. Their work, however, leads to some very specific ethical considerations which may not be fully explored in ethical codes based in clinical medicine. This document aims to establish some guiding principles which should underpin a working ethical framework for pharmaceutical physicians. It clearly places the protection of patients (and research subjects) and the doctor's duties to wider society ahead of responsibilities to an individual employer while emphasising the importance of adherence to high standards of research, including dissemination of findings. These principles form the basis of a fuller report which offers more specific practical advice on possible ethical conflicts or dilemmas.

Ethics and pharmaceutical medicine -- the full report of the Ethical Issues Committee of the Faculty of Pharmaceutical Medicine of the Royal Colleges of Physicians of the UK.

The practice of pharmaceutical medicine brings with it ethical challenges and dilemmas often very different from those encountered in the practice of clinical medicine. Having established a framework of guiding ethical principles, this report aims to look in some detail at specific areas of possible ethical concern to pharmaceutical physicians, offering practical advice and guidance on good practice. The report covers issues related to pharmaceutical research, including dissemination of research findings, communication with other health professionals and patients and involvement of pharmaceutical physicians and companies in the provision of patient services. The primacy of the interests of patients and the wider public is emphasised, and the possible impact of new developments in pharmaceutical technology is explored. It is hoped that the report will help those working in pharmaceutical medicine and act as a stimulus for wider discussion and debate.

[Contribution of explanatory notes. Efficacy of the ICH plan for international clinical development of a new drug]. / Contribution des notes explicatives. Efficacité d'ICH au plan de développement clinique international d'un nouveau médicament.

After the achievement of the Phase 1 of the ICH process (ICH4, Brussels, July 1997) and the recent adoption of two new Efficacy Guidelines (E5, E9) by the ICH Steering Committee, the Pharmaceutical Industry and CROs have today the necessary tools and standards of reference, to set up a Global Plan of Clinical Development for any New Molecular Entity for Human Use, within the three ICH Regions, Europe, Japan and the USA. However to achieve such a goal, the Efficacy Guidelines must officially be integrated in the Regulatory requests of each of the 3 ICH Regions ans implemented by Industry. The use of these Guidelines which concern the Clinical Development Plan and most of the content of the Clinical Documentation for Registration of New Medicinal Products, will show the qualities and defects of ICH texts, leading in the future to possible amendments, during the maintenance phase of these Guidelines (Step6 of ICH process?). The Efficacy texts cannot be separated from other ICH Guidelines concerning Quality, Safety ans above all the Multidisciplinary texts which are of great interest for the clinical development plan, registration and follow up after MAA of any New Medicinal Product. Referring to Ethnic differences between the three ICH Regions, topic E5 is the most innovative of Efficacy Guidelines for both Regional Regulatory Authorities, accepting or not foreign clinical data and International Companies, setting up Global Clinical Plan and Registration Dossier. The paper is also looking at the future impact of the other Efficacy (E10) and Multidisciplinary (M1 to M4) Guidelines which are still under consideration.

Interaction between roxithromycin and cyclosporin in heart transplant patients.

Cyclosporin is an immunosuppressive agent commonly used in transplant patients. It is actively metabolised by the cytochrome P450 system and interactions with drugs metabolised by the same system are predictable. This is particularly relevant since cyclosporin has a low therapeutic index and its renal toxicity is concentration-related. Roxithromycin, a new, well-tolerated macrolide with a weak interactive profile, uses the same isoenzyme of the P450 system as cyclosporin. To evaluate its interaction potential in clinical practice, 8 heart transplant recipients treated with cyclosporin for at least 1 month received roxithromycin for 11 days (150 mg twice daily). Bi-weekly controls of plasma cyclosporin concentrations and creatinine levels were carried out before, during and after roxithromycin treatment. A slight nonsignificant rise in cyclosporin concentrations was observed, but creatinine levels remained stable during roxithromycin treatment. Values of cyclosporin concentrations diminished after withdrawal of roxithromycin. Cyclosporin dosage adjustment was not necessary. There was a minor pharmacokinetic interaction, which can be considered safe for the usual therapeutic dosage of roxithromycin used.

Prevention of the transient adverse effects of a gonadotropin-releasing hormone analogue (buserelin) in metastatic prostatic carcinoma by administration of an antiandrogen (nilutamide).

Gonadotropin-releasing hormone (GnRH) analogues administered for the treatment of advanced prostatic cancer induce a transient increase in plasma testosterone levels during the first week of treatment, often with a secondary rise in plasma levels of prostatic acid phosphatase and a flareup of disease. To determine whether the antiandrogen nilutamide (Anandron) blocks these effects, we carried out a multicenter, placebo-controlled study of nilutamide in men with prostatic cancer treated with the GnRH analogue buserelin. Thirty-six men with disseminated prostatic cancer and elevated plasma levels of prostatic acid phosphatase were randomly assigned to two groups. Group 1 included 17 men who received buserelin (500 micrograms daily subcutaneously) and nilutamide (300 mg daily by mouth); group 2 included 19 men treated with buserelin and placebo. Symptoms were assessed, and plasma was collected before treatment, daily for 14 days, and on days 18, 22, and 29 after the initiation of treatment. Bone pain appeared or worsened in 5 of the 17 men in group 1 and in 12 of the 19 men in group 2 (P less than 0.05). Acute urinary obstruction occurred in one man in group 2. Despite similar changes in the plasma testosterone levels in both groups, the median concentration of plasma prostatic acid phosphatase decreased almost immediately in group 1, but increased transiently, then decreased on day 14 in group 2. Median levels of prostate-specific antigen decreased immediately in group 1 and decreased on day 8 in group 2. We conclude that nilutamide can prevent the adverse consequences of the buserelin-induced transient rise in plasma testosterone levels in men with advanced prostate cancer treated with a GnRH analogue.

Pituitary-adrenal response to the antiglucocorticoid action of RU 486 in Cushing's syndrome.

RU 486 [17 beta-hydroxy-11 beta-(4-dimethylaminophenyl)17 alpha-(prop-1-ynyl)estra-4,9-dien-3-one] is a steroid analog which antagonizes glucocorticoid action at the receptor level. The pituitary-adrenal response to RU 486 was evaluated in patients with Cushing's syndrome. The acute administration of 400 mg RU 486 at 0800 h in five patients with Cushing's disease induced no significant change in plasma cortisol during the next 10 h compared with the administration of placebo. However, prolonged administration (400 mg daily for 3 days) caused activation of the pituitary-adrenal axis; urinary cortisol increased the most from 727 to 5720, 830 to 8200, 610 to 1020, 110 to 570, and 300 to 990 micrograms/day. Plasma cortisol and lipotropins increased to a lesser extent. Hormone changes appeared on the second day of drug administration and lasted up to 3-4 days after the drug was discontinued. In two patients with nonpituitary-dependent Cushing's syndrome, RU 486 induced no significant change in steroid secretion. We conclude that RU 486 induced a delayed and prolonged pituitary-adrenal response in Cushing's disease; whether the resulting cortisol overproduction will overcome the peripheral effect of RU 486 remains to be determined.

Assessment of the antimineralocorticoid effect of RU 28318 in healthy men with induced exogenous and endogenous hypermineralocorticism.

The antimineralocorticoid effect of a single dose of RU 28318, has been assessed in healthy men with exogenous or endogenous hypermineralocorticism. For exogenous hypermineralocorticism induced by ingestion of 9 alpha-fluorohydrocortisone (9 alpha-FHC) and aldosterone infusion, RU 28318 100 mg (9 alpha-FHC ingestion) or 200 mg (aldosterone infusion) was administered, and its effect compared with identical doses of spironolactone or a placebo. For endogenous hypermineralocorticism induced by ingestion of furosemide, RU 28318 100 and 300 mg was tested in comparison with 100 mg spironolactone or placebo. In all 3 studies, both RU 28318 and spironolactone significantly raised the urinary Na/K ratio when compared to placebo administration. No significant difference was apparent between RU 28318 and spironolactone. Thus, a single dose of RU 28318 in man has an antimineralocorticoid effect identical to those produced by the identical molar dose of spironolactone. In addition, the results show that furosemide-induced hyperaldosteronism constitutes a simple and reproducible test for assessing the antimineralocorticoid effect of a drug.

The new steroid analog RU 486 inhibits glucocorticoid action in man.

RU 486 [17 beta-hydroxy-11 beta-(4- dimethylaminophenyl )-17 alpha-(prop-1- ynyl )-estra-4,9-dien-3-one] is a new steroid analog which antagonizes glucocorticoid action at the receptor level in animals. To assess its potential antiglucocorticoid activity in man we studied the pituitary-adrenal response to RU 486 in normal men. The compound was administered at 0200 h and plasma cortisol and lipotropins (LPH) were measured hourly for 10 h. After 400 mg RU 486 significant and sustained elevation of both hormones occurred during the 0700-1200 h period: mean (+/- SE) plasma levels after placebo or RU 486 during this interval were, respectively, for cortisol (ng/ml), 63.4 +/- 8.2 and 112.7 +/- 2.9 (P less than 0.02); and for LPH (pg/ml), 34.8 +/- 11.3 and 71.6 +/- 15.4 (P less than 0.01). The 200- and 100-mg doses induced only transient cortisol and LPH increases. Administration of RU 486 (400 mg) at 1400 h induced no increase in plasma cortisol compared to placebo in the corresponding 2000 to 2400 h period. When RU 486 was administered concomitantly with dexamethasone (1 mg) at 2400 h, dose-dependent blockade of the dexamethasone-induced cortisol suppression at 0900 h was found (r = 0.62, P less than 0.01); this blockade was partial after the 100-mg dose, but complete after the 400-mg dose. Plasma LPH and ACTH showed parallel variations. We conclude that RU 486 antagonizes the negative pituitary feedback of both the nocturnal endogenous cortisol rise and exogenously administered dexamethasone. These actions are consistent with an antiglucocorticoid activity of this compound in man.

RU 16117, an orally active estriol-like weak estrogen.

RU 16117, the 11 alpha-methoxy derivative of ethynyl estradiol, is an orally active weak estrogen potentially effective in the treatment of estrogen-deficiency in postmenopausal women (climacteric symptoms and severe osteoporosis). Biochemical studies have shown that RU 16117, like estriol, possesses the properties characteristic of a partial estrogen agonist/antagonist. RU 16117 binds to the cytosol estrogen receptor (ER) to form a complex which dissociates much faster than the estradiol complex. This explains its lower nuclear uptake. Furthermore, the nuclear RU 16117 complex also dissociates faster than the estradiol complex. Consequently, although low doses of RU 16117 can induce the majority of the effects of estradiol (increased polymerase A and B activities, cytosol ER replenishment, progestin receptor induction, increased uterine weight), these effects are long-lived only if the dose is considerably increased or if the compound is administered repeatedly or continuously. Since RU 16117 transiently occupies available estrogen binding sites, it can prevent the full response of estradiol. Thus, under appropriate kinetic conditions, it acts as an estrogen antagonist on the above parameters and also on DMBA-induced mammary tumors in the rat. At a daily dose of 24 micrograms for a period of 4 weeks RU 16117 led to 65% reduction in the number of already-established tumors. RU 16117 inhibits basal gonadotropin secretion and decreases the LH response to LHRH. Injection of 5 micrograms s.c. to the rat in estrus markedly inhibited the spontaneous peaks of LH, FSH and PRL measured on the afternoon of expected proestrus. Low doses which block ovulation by 100% had no detectable effect on vaginal cornification, thus suggesting a greater sensitivity at the hypothalamo-pituitary level.(ABSTRACT TRUNCATED AT 400 WORDS)

Franco-Belgian cooperative study of ursodeoxycholic acid in the medical dissolution of gallstones: a double-blind, randomized, dose-response study, and comparison with chenodeoxycholic acid.

A double-blind randomized, multicenter study was carried out to determine the efficacy and safety of ursodeoxycholic acid (UDCA) at 4 doses of 2.1 to 16.2 mg X kg-1 X day-1, and chenodeoxycholic acid (CDCA) at the dose of 16.9 mg X kg-1 X day-1, in 197 patients treated for up to 1 year for radiolucent gallstones in functioning (opacified) gallbladders. There was confirmed complete dissolution in 5.9% of patients receiving UDCA at the dose of 2.1 mg X kg-1 X day-1, 18.9% in those receiving 4.2, 28.9% in those receiving 8.4, 14.6% in those receiving 16.2, and 20.0% in patients receiving CDCA. Partial (over 50%) or complete dissolution occurred in 29.4% of patients receiving 2.1 mg X kg-1 X day-1 of UDCA, 37.8% of those receiving 4.2, 55.2% in those receiving 8.4, 48.7% in those receiving 16.2, and 50.0% in patients receiving CDCA. Complete dissolution occurred significantly more frequently in small (less than 5 mm in diameter) than in large (5 to 15 and more than 15 mm) stones. There was no significant influence of treatment on serum cholesterol and triglycerides in any of the groups. Serum aminotransferases remained normal (or lower than twice the upper normal limit) in all patients treated with UDCA. Diarrhea leading to cessation of treatment occurred in 5% of patients receiving UDCA, but was significantly less frequent than in those receiving CDCA. These results confirm that, within a 1-year period, UDCA is equally effective and induces diarrhea less frequently than CDCA, with an optimal dose (8 mg X kg-1 X day-1) approximately twice lower than that of CDCA.

New hormonal treatment in cancer of the prostate: combined administration of an LHRH agonist and an antiandrogen.

At doses which have no or minimal inhibitory effect when administered alone, the LHRH agonist [D-Ser(TBU)6,des-Gly-NH10(2)] LHRH ethylamide (HOE-766) and the antiandrogen RU-23908 administered simultaneously cause a marked inhibition of ventral prostate and seminal vesicle weight after 5 months of treatment. The effect of the LHRH agonist is due to a blockage of the testicular steroidogenic pathway. The same LHRH agonist administered to adult men with cancer of the prostate causes a marked inhibition of serum testosterone and dihydrotestosterone to castration levels within 1-2 weeks. Administration of the pure antiandrogen to men with cancer of the prostate already receiving the LHRH agonist does not interfere with the LHRH agonist-induced blockage of androgen biosynthesis: Moreover, objective signs of remission of the disease were rapidly observed in 8 out of 10 patients. The ease of application of this new form of hormonal therapy which neutralizes androgens from all sources should facilitate its early administration and thus minimize the development of metastases and androgen-resistant cell clones.

[Epidemiologic relations between arteriopathy of the lower extremities and chronic gastroduodenal ulcer]. / Relations épidémiologiques entre artériopathie des membres inférieurs et ulcère gastro-duodénal chronique.

The authors report the results of a study of 3 565 consecutive patients over 30 years of age, of French nationality living in the Paris region, hospitalised over a 5 year period in a Department of internal medicine and vascular pathology. The incidence of gastroduodenal ulcer was compared in each sex in 10 year age groups in 764 patients with arterial disease and 2 801 patients without arterial disease. The incidence of ulcers was higher in patients with occlusive arterial disease in men in the 50 to 59 year age group (20,4 p. 100 compared to 9 p. 100, p less than 0,01), and in the 60 to 69 year age group (20,3 p. 100 compared to 9,8 p. 100, p less than 0,001), and after 70 years of age in females (12,8 p. 100 compared to 4 p. 100, p less than 0,01). The overall incidence in all patients with arterial disease (16,7 p. 100 of all 591 males, and 12,1 p. 100 of all females) was higher than in a corresponding control group (9,7 p. 100, p less than 0,0001, and 4,8 p. 100, p less than 0,001 respectively). These results only concern chronic ulcers. There was no difference in the incidence of acute ulcers.

New approach in the treatment of prostate cancer: complete instead of partial withdrawal of androgens.

To completely eliminate androgens of both testicular and adrenal origin, 37 previously untreated patients with advanced (stages C or D) prostatic cancer received the combination therapy using an LHRH agonist (HOE-766) and a pure antiandrogen (RU-23908). The response criteria developed by the National Prostatic Cancer Project were used. A positive response (assessed by bone scan and/or serum prostatic acid phosphatase measured by radioimmunoassay was observed in 29 of the 30 cases who could be evaluated by these objective criteria (97%). The objective response was parallel to a rapid and marked improvement of the clinical signs and symptoms related to prostate cancer (prostatism, bone pain, and general well being). In marked contrast, the same combination therapy applied to patients previously treated with high doses of diethylstilbestrol (13 patients) showed a positive objective response in only 55% of cases. In 23 previously castrated patients showing relapse, an objective response was seen in only 25% of cases after neutralization of adrenal androgens by the antiandrogen. Previous treatment with chlorotrianisene (TACE) had no detectable effect on prostatic cancer and patients having previously received such treatment had a rate of positive response similar to previously untreated patients (five of five). In the previously untreated patients receiving the combination therapy, a 60% fall in serum prostatic acid phosphatase was observed as early as five days after starting treatment, at a time when the serum androgen concentration was 100% to 200% above control. Combined treatment with the pure antiandrogen completely prevents flare-up of the disease, a complication previously found in a significant proportion of patients treated with an LHRH agonist alone. The present data show that complete withdrawal of androgens by combined hormonal therapy with the LHRH agonist (or castration) and a pure antiandrogen leads to a positive objective response in more than 95% of cases as opposed to 60%-70% as reported by many groups using the previous partial hormonal therapy (castration or high doses of estrogens). Adrenal androgens are most likely responsible for this difference. The present study also shows that the proportion of androgen-sensitive cells decreases from more than 95% in untreated patients to 25% to 55% after previous partial hormonal therapy. Such data clearly indicate that the previous partial hormonal therapy exclusively aimed at neutralizing testicular androgens left 25% to 55% of cancer cells having a relatively low sensitivity to androgens in a hormonal milieu compatible with their continuous growth. No clinical or biochemical side effect could be detected except those related to reduced serum androgen levels.(ABSTRACT TRUNCATED AT 400 WORDS)

New hormonal therapy in prostate cancer: combined use of a pure antiandrogen and an LHRH agonist.

Treatment with an LHRH agonist (HOE-766) alone causes an almost complete blockage of testicular testosterone formation in rat and man. In order to neutralize androgens of adrenal origin, a pure antiandrogen (RU-23908) was given in combination with the LHRH agonist in the rat. At doses where each drug has no or minimal effect alone, prostate and seminal vesicle weight were reduced to 9 and 15% of control after 5 months of combined treatment, respectively. Among the species studied, man is the most sensitive to the inhibitory effect of treatment with LHRH agonists on testicular steroidogenesis. Near castration levels of serum testosterone and 5 alpha-dihydrotestosterone are obtained within 1-2 weeks of daily subcutaneous administration of the LHRH agonist [D-Ser(tbu)6, des-Gly-NH2(10)]LHRH ethylamide (HOE-766) in adult men with cancer of prostate. The decrease in serum androgen levels is accompanied by objective remission of the cancer in approximately 75% of cases. In a preliminary study where the LHRH agonist was administered in combination with the pure antiandrogen RU-23908, it was shown that the antiandrogen does not interfere with the LHRH-induced inhibition of serum androgen levels. The ease of application of this new form of hormonal therapy should permit its use at early stages of the disease and thus reduce the development of metastases and androgen-resistant cell clones.