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Paediatric Clinical Research Best Practice Paediatric Trial Design, CRF and Ethical Aspects. Katarina Hellborg Johansson AstraZeneca R&D Mlndal Background: Testing medication in children presents a dilemma, and the society wants to spare children from the potential risks involved in research. However, children may be harmed if they are given medication that has been inadequately studied. Health professionals, the Pharmaceutical Industry and politicians, have all expressed their concern about this unsatisfactory situation. Therefore, to ensure both the efficacy and safety of medicines, paediatric clinical trials are important to collect information on all age groups. Objectives: The objectives of this thesis were: to identify difficulties and problems that can arise due to poor study designs, and during clinical trials in children: and to see what laws, guidelines and SOPs, govern the planning and conducting of paediatric clinical trials. Methods: Literature studies were combined with systematic database searching. Employees at AstraZeneca, Investigators and Study Nurses who had worked with paediatric studies and members of different Ethics Committees in Sweden, were interviewed in-depth. Results: Depending on the country from which the person originated, the answer to the questions varied. Employees at AstraZeneca, Investigators and Study Nurses did not always have the same opinions on what could create problems during clinical studies. Conclusions: A database for registration of paediatric studies, including unsatisfactory results should be developed. It is imperative that everything is carefully prepared within clinical practice and adapted to childrens needs before the start of a paediatric clinical trial. Specially designed paediatric CRFs to obtain accurate and relevant collection of data. Direct communication with personnel involved in paediatric studies is necessary. Keywords: clinical trials, children, design, CRF, ethical aspects.
IMS Prescribing Insights data are available only for the retail sector. We examined the diagnoses for which these products have been prescribed in the retail setting using the guidelines given in Figure 1. The following diagnoses were used to estimate the level of prescribing for the correct indication International Statistical Classification of Diseases and Related Health Problems procedural coding system ; , 10th edition ; . Osteoporosis and Paget's Disease Fosamax alendronate ; and Actonel risedronate ; : M819 Osteoporosis Unspecified M859 Diseases of Bone Density and Structure Unspecified M810 Postmenopausal Osteoporosis M898 Other Specific Diseases of the Bone M809 Osteoporosis and Pathological Fracture Paget's disease applies only to Fosamax alendronate ; and Actonel risedronate ; . Forteo teriparatide ; : M810 Postmenopausal Osteoporosis M809 Unspecified Osteoporosis with Pathological Fracture Alzheimer's Disease G30 Alzheimer's Disease F03 Unspecified Dementia Orphan Drugs Tracleer bosentan ; : I27 Other Pulmonary Heart Disease Agrylin anagrelide ; : D752 Essential Thrombocytosis D473 Essential Thrombocythemia C92 Myeloid Leukemia D45 Polycythemia Vera D46 Myelodysplastic Syndromes D471 Chronic Myeloprolific Disease D469 Myelodysplastic Syndrome Unspecified According to IMS retail data, these products are not co-prescribed. Tablets having the composition set forth above are prepared as follows: the tablets are prepared by sieving the risedronate active ingredient and the edta with 1 2 of the microcrystalline cellulose into a twin shell blender. Risedronate pharmacyFurther studies on cholesterol levels in the Johns Hopkins medical students: the effect of stress at examinations Chron. Dis. 8: 661, 1958. GASTROENTERITIS Gastroenteritis is the main cause of acute diarrhea and is a frequent disorder that usually heals spontaneously within a few days. Gastroenteritis can be due to several viral or bacterial pathogens or to parasites, but the most frequent cause in children is rotavirus infection. The use of oral rehydration solutions is the main treatment, but it does not shorten the duration of diarrhea. Curative treatment Several controlled randomized trials showed a beneficial effect of probiotics and fermented dairy products in infantile or, less often, adult gastroenteritis; however, this is not a general property of all probiotics 2628 ; . Lactobacillus rhamnosus GG L. GG, Valio, Finland ; has been shown to be effective in the treatment of infant rotavirus diarrhea Table 2 ; . L. rhamnosus GG repeatedly reduced the duration of diarrhea by about half in randomized controlled trials Table 2 ; . It also proved effective in the treatment of acute diarrhea in children in Asia 34, 35 ; . Guandalini et al 38 ; recently reported the results of a double-blind multicenter European trial in children with acute diarrhea. Two-hundred eightyseven children aged 136 mo with acute diarrhea were enrolled and fluticasone, for example, alendronate. Source: U Thadani, "The Pursuit of Optimum Outcomes in Stable Angina", Am. J. Cardiovas. Drugs, 3 2003 ; , Suppl. 1, pp. 1120. Risedronate sodium tablets in indiaRisedronate 150mg
Nursing and Midwifery Council April 2002 ; Code of professional conduct, London: NMC. Royal College of Nursing 2002 ; Breast palpation and breast awareness: the role of the nurse. London: RCN. Publication code: 001 754. The Postmenopausal Estrogen Progestin Intervention Trial PEPI ; 1995 ; Effects of estrogen or estrogen plus progestin regimens on heart disease risk factors in postmenopausal women. Journal of the American Medical Association 273: 199-208. Pols, H.A.P., Felsenberg, D., Hanley, D.A., et al 1999 ; Multinational, Placebo-Controlled, Randomised Trial of the Effects of Alendronate on Bone Density and Fracture Risk in Post Menopausal Women with Low Bone Mass; Results of the FOSIT Study. Osteoporosis International 9: 461 468. Powles, T.J., Hickish, T., Kanis, J.A., et al 1996 ; Effect of tamoxifen on bone mineral density measured by dual-energy X-ray absorptiometry in healthy premenopausal and postmenopausal women. Journal of Clinical Oncology Vol 14; No 1: 78 84. Rees, M., and Purdie, D.W. 2000 ; Management of the menopause: the handbook of the British menopause society. Marlow: BMS Publications Ltd. Reginster, Y-Y, Minne, H.W., Sorenson, O.H., et al 2000 ; Randomised trials of the effects of risedronate on vertebral fractures in women with established postmenopausal osteoporosis. Osteoporosis International 11: 83 91. Royal College of Physicians 1999 ; Osteoporosis. Clinical guidelines for prevention and treatment. London: RCP. Rymer, J. 2000 ; Relative and absolute contraindications to HRT, in: Studd J.W.W. Ed ; The management of the menopause millennium review pp 21-26. London: Parthenon. Siddle, N., Sarrel, P., Whitehad, M.I. 1987 ; The effect of hysterectomy on the age at ovarian failure: identification of a sub group of women with premature loss of ovarian function and literature review. Fertility and Sterility 47: 940100. Stevenson, J.C. 1996 ; Metabolic effects of the menopause and oestrogen replacement, in Barlow D.H. Ed ; The menopause: the key issues, Baillire's Clinical Obstetric Gynecology 10 3 ; , 449-68. Torgerson, D.J., Iglesias, C.P., Reid, D.M. 2001 ; The economics of fracture prevention. The Effective Management of Osteoporosis 2001a: 111 12. Utian, W.H. 1999 ; The international Menopause Society menopause related terminology definitions. Climacteric 2: 284-286. Van Staa, T.P., Abenhaim, L., Cooper, C. 1998 ; Use of cyclical etidronate and prevention of non-vertebral fractures. British Journal of Rheumatology 37: 87-94. Risedronate dosingUsing water of suitable microbiological quality and hardness see Section 5.2 below ; for: the dilution of cleaning agents and disinfectants; the rinsing of endoscopes following manual cleaning and prior to introduction into the automated machine; and the final rinsing of endoscopes following disinfection which is necessary to remove irritant and toxic disinfectant residues ensuring that tanks and fluid pathways of the machine are drained and left dry when not in use or leaving the fluid pathway in contact with fresh disinfectant solution; regularly cleaning and disinfecting the machine, i.e. at the beginning of each session and preferably during each cycle or as otherwise instructed by the manufacturer see MDA Safety Action Bulletin SAB 93 ; 32. TABLE 4. SIGNS AND SYMPTOMS OF BACTERIAL CONJUNCTIVITIS and glimepiride. The Energy FormulaTM is advertised to diminish fatigue and contains American, Korean, Siberian, and Tienchi ginsengs, kola nut, guarana, damiana, and wild ginger root. Both guarana and kola nut contain caffeine, and various over-the-counter products that contain these herbs have been found to contain very high amounts of caffeine. Because this is a liquid formula, the amount of caffeine in the product would be hard to regulate and difficult to label. If high amounts of caffeine are what is producing the "needed boost throughout the day, " green tea or another inexpensive source of caffeine may provide an economical alternative. HepaticoTM HepaticoTM is a botanical compound that was first used in Russia. It is a combination of three common plants plaintain, nettle, and immortelle ; in a base of three other plants turmeric, milk thistle, and dandelion root ; . Each capsule contains 250 mg of a combination of the first three plants in 250 mg of a combination of the base herbs. The manufacturer does not provide information about the individual action of the first three plants. However, none of them individually is commonly known to have any action on the liver or gall bladder. The base botanicals are known to have effects on the liver and bile ducts, but the doses unknown amounts, but less than 250 mg of each per capsule ; are low. The amount of HepaticoTM used in an unpublished study discussed below was one to two capsules three times daily. This means the amounts of the botanicals involved in the study were below the amounts commonly used in published research that has examined the individual action of turmeric, milk thistle, and dandelion root. The information available from the manufacturer includes a study done in Canada with 23 patients who had either hepatitis B or C, or both. The majority were chronic hepatitis C patients. Study participants were given one or two capsules of HepaticoTM three times daily depending on the patient's weight ; for a period of 20-40 days. At the end of the study period, four of 23 participants had normalization of their ALT levels, and three of 23 participants had normalization of their AST levels. Participants who experienced normalization of their liver enzymes had varying histories of hepatitis C infection from 2-24 years duration. There is no information about their individual disease progression. A second group of ten hepatitis C patients took HepaticoTM for the first month of a 7-month trial. Two had normalization of their ALT levels. The investigators reported the participants in this study had relief from digestive symptoms and insomnia, but they did not document when or for how long this occurred. The study gave incomplete information about the patients' medical conditions. The only other liver function test conducted was for GGT levels, which did not change significantly during treatment. Liver biopsy results were not available. The Internet site for HepaticoTM lists reports from specific institutions and health care providers in Russia who report alleviation of the symptoms of severe cirrhosis, chronic hepatitis B and C, gallbladder disease, and chronic colitis. The studies were done with people who took one capsule three times daily over a period of three to four weeks. The only Russian medical study was on the toxicity of this product when tested in animals. It was found to be nontoxic in doses much higher than the recommended dose. It is unknown whether the claims for this product could be reproduced in clinical trials conducted in the United States. According to the study done in Canada unpublished ; , improvement normalization of ALT levels ; occurred in only a small minority of patients. Treated with vehicle. Treatment of OVX rats with either estrogen, bFGF, and PTH or risedronate, bFGF, and PTH increased N.Nd and Nd.Nd relative to those in OVX rats treated with vehicle as well as OVX rats treated with PTH alone. Although N.Tm and Nd.Tm tended to be lower in all OVX rats compared with those in vehicle-treated sham rats regardless of treatment, the overall differences did not achieve statistical significance P 0.1 ; . The N.Nd N.Tm was lower in vehicle-treated OVX rats than in vehicle-treated sham rats, but the difference did not reach statistical significance Fig. 1E ; . Treatment of OVX rats with PTH alone had no significant effect on the N.Nd N.Tm, whereas treatment of OVX rats with bFGF and PTH as well as estrogen, bFGF, and PTH increased this measure of trabecular connectivity above that observed in vehicle-treated OVX rats. Treatment of OVX rats with risedronate, bFGF, and PTH increased the N.Nd N.Tm to a level above that observed in sham rats treated with vehicle, OVX rats treated with vehicle, and OVX rats treated with PTH alone. Oc.S BS was higher in vehicle-treated OVX rats than in vehicle-treated sham rats Fig. 2A ; . Oc.S BS in all other treatment groups did not differ from that of vehicle-treated OVX rats. Ob.S BS was greater in OVX rats treated with vehicle compared with that in sham rats treated with vehicle Fig. 2B ; . Treatment of OVX rats with PTH alone or with bFGF and PTH increased Ob.S BS to a level above that in vehicletreated OVX rats. Ob.S BS in OVX rats treated with estrogen, bFGF, and PTH was nearly identical to that in OVX rats treated with bFGF and PTH. Ob.S BS in OVX rats treated with risedronate, bFGF, and PTH was greater than that in vehicle-treated sham rats but lower than that in OVX rats treated with PTH alone or with bFGF and PTH. OS BS was also greater in vehicle-treated OVX rats than in vehicle-treated sham rats Fig. 2C ; . OS OVX rats treated with PTH alone, bFGF and PTH, or estrogen, bFGF, and PTH tended to be greater than that in vehicle-treated OVX rats, but statistical significance was not achieved. OS BS in rats treated with risedronate, bFGF, and PTH did not differ from that in vehicle-treated sham or OVX rats, but was lower than that in OVX rats treated with PTH alone or with bFGF and PTH. The BFR BS did not differ between vehicle-treated sham and OVX rats Fig. 2D ; . Treatment of OVX rats with PTH alone, bFGF and PTH, or estrogen, bFGF, and PTH increased BFR BS relative to that in vehicle-treated sham and OVX rats. Although BFR BS in OVX rats treated with risedronate, bFGF, and PTH was also increased relative to that in vehicletreated sham rats, it was lower than that in OVX rats treated sequentially with bFGF and PTH. Vertebral ash density was lower in vehicle-treated OVX rats than in vehicle-treated sham rats Fig. 5A ; . Treatment of OVX rats with PTH alone resulted in a mean value for ash density that was between those observed in vehicle-treated sham and OVX rats, but not different from that in either group. Sequential treatment of OVX rats with bFGF and PTH increased ash density to the level of vehicle-treated sham rats. Cotreatment with estrogen or risedronae did not suppress the effect of treatment with bFGF and PTH on ash density and anacin and risedronate. Patients with COPD have high rates of bone fracture 11% 14% ; and bone mineral density BMD ; an average of 10% lower compared with control patients.88 A 10% drop in BMD equates to a 2.6-fold increase in fracture risk.88 Greater deficits are seen in patients with more severe disease. The risk factors for low BMD in patients with COPD include periods of immobilisation or hospitalisation, low FEV1, use of corticosteroids, decreased weight-bearing activity, and smoking. Other risk factors relevant to the general population also apply. These include low calcium intake, low body mass index, alcohol abuse and hypogonadism. All patients who take corticosteroids should be advised to undertake regular, weight-bearing exercise eg, walking and light resistance training ; . Those who have had long-term steroid therapy at lower doses and who have other risk factors should be screened. Intervention should be targeted at men and women who are taking more than 15 mg daily of prednisolone or who have several risk factors for osteoporosis and whose BMD is 1.5 standard deviations below the young adult mean.88 Oral bisphosphonates, particularly risedronate, have been shown to be effective in preventing and treating bone loss in men and women taking corticosteroids.88 However, most patients in these studies did not have respiratory disease. The studies also showed a reduction in risk of spinal fracture, especially in postmenopausal women. Other agents that have been used with some success in patients with respiratory disease include calcium, vitamin D and medroxyprogesterone acetate. Selecting patients with COPD who may be at increased risk of osteoporosis is most appropriately done on the basis of conventional risk factors. Further refining of clinical predictors and more evidence for the cost-effectiveness of such programs still needs to be resolved before recommendations on a screening strategy in patients with COPD can be made. For more information on prevention and treatment of osteoporosis, see the current Australian guidelines.88. St. George's Hospital Medical School, St. George's Hospital, and Royal Free and University College Medical School, Windeyer Institute for Medical Science, London, United Kingdom and panadol.
We combined data from three randomized, double-blind, placebo-controlled, parallel group, phase III clinical studies conducted in parallel: the Vertebral Efficacy with Risedronate Therapy North America VERT-NA ; and Multinational VERT-MN ; clinical studies and the Hip Intervention Program HIP ; study. These three studies were used.
The following changes to the Formulary, approved at the May 16th meeting of the Pharmacy and Therapeutics Committee, will become effective on June 1, 2007. Formulary Additions: Amlodipine Norvasc ; Nifedipine XL Procardia XL ; Zolpidem Ambien Generic ONLY ; Meloxicam Mobic ; Nabumetone Relafen ; Formulary Deletions: Risedronate Actonel ; Azelastine Optivar ; If you have any questions about these changes, please contact Richard Johnson, Pharmacy Director, at 831-430-5553. TABLE 1. PEDIATRIC ANALGESIC MEDICATIONS FOR END-OF-LIFE PAIN, for example, forteo.
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