The impact of FDA and EMEA guidelines on drug development in relation to Phase 0 trials.

Br J Cancer. 2007 Aug 28;97(5):577-81

Authors: Marchetti S, Schellens JH

An increase in the number of identified therapeutic cancer targets achieved through recent biomedical research has resulted in the generation of a large number of molecules that need to be tested further. Current development of (anticancer) drugs is a rather inefficient process that for an average new molecule takes around 10-15 years. It is also a challenging process as it is associated with high costs and a low rate of approval. It is known that less than 10% of new molecular entities entering clinical Phase I testing progress beyond the investigational programme and reach the market; this probability is even lower for anticancer agents. In 2003, the US Food and Drug Administration (US FDA) declared the urgent need for new toolkits to improve the critical development path that leads from scientific discovery to the patient. In this scenario, Phase 0 (zero) trials should allow an early evaluation in humans of pharmacokinetic and pharmacodynamic profiles of test compounds through administration of sub-pharmacological doses and for a short time period to a low number of humans. Typically, Phase 0 studies have no therapeutic or diagnostic intent. Owing to the low doses administered and the low risk of toxicity, shorter preclinical packages to support these studies are required. Phase 0 trials have been proposed to help in making an early selection of promising candidates for further evaluation in Phase I-III trials, providing a potentially useful instrument for drug discovery, particularly in the field of oncology. Phase 0 studies are expected to reduce costs of drug development, and to limit the preclinical in vitro and in vivo testing and the time period of drug development. However, there are also concerns about the utility and feasibility of Phase 0 studies. In January 2006, guidelines on exploratory investigational new drug studies in humans have been published by the US FDA, and currently a Phase 0 programme is ongoing at the National Cancer Institute to evaluate the impact (feasibility and utility) of Phase 0 studies on drug development. In Europe, a Position Paper produceArticles

Falling on stony ground? A qualitative study of implementation of clinical guidelines’ prescribing recommendations in primary care.

Health Policy. 2007 Sep 1;

Authors: Rashidian A, Eccles MP, Russell I

OBJECTIVES: We aimed to explore key themes for the implementation of guidelines’ prescribing recommendations. METHODS: We interviewed a purposeful sample of 25 participants in British primary care in late 2000 and early 2001. Thirteen were academics in primary care and 12 were non-academic GPs. We asked about implementation of guidelines for five conditions (asthma, coronary heart disease prevention, depression, epilepsy, menorrhagia) ensuring variation in complexity, role of prescribing in patient management, GP role in prescribing and GP awareness of guidelines. We used the Theory of Planned Behaviour to design the study and the framework method for the analysis. RESULTS: Seven themes explain implementation of prescribing recommendations in primary care: credibility of content, credibility of source, presentation, influential people, organisational factors, disease characteristics, and dissemination strategy. Change in recommendations may hinder implementation. This is important since the development of evidence-based guidelines requires change in recommendations. Practitioners do not have a universal view or a common understanding of valid ‘evidence’. Credibility is improved if national bodies develop primary care guidelines with less input from secondary care and industry, and with simple and systematic presentation. Dissemination should target GPs’ perceived needs, improve ownership and get things right in the first implementation attempt. Enforcement strategies should not be used routinely. CONCLUSIONS: GPs were critical of guidelines’ development, relevance and implementation. Guidelines should be clear about changes they propose. Future studies should quantify the relationship between evidence base of recommendations and implementation, and between change in recommendations and implementation. Small but important costs and side effects of implementing guidelines should be measured in evaluative studies.

PMID: 17767976 [PubMed - as supplied by publisher]

]]>

Many asthma patients experience persistent symptoms despite appropriate clinical and guideline-based treatment with inhaled corticosteroids.

J Am Acad Nurse Pract. 2007 Sep;19(9):459-70

Authors: Mogil J

Purpose: To review possible reasons for persistence of asthma symptoms despite appropriate use of clinical and guideline-based treatments, including the use of inhaled corticosteroids. Data sources: Review of the worldwide scientific literature on factors related to persistent symptoms in patients with asthma. Conclusions: Patients with asthma may not respond as expected to therapy because of factors that include poor adherence, improper inhaler technique, persistent exposure to symptom triggers, and limitations of current standard therapy, including steroid insensitivity or the steroid plateau effect. Persistent symptoms may also be associated with IgE-mediated airway inflammation, as current standard asthma therapies do not directly address the IgE-mediated component of the inflammatory cascade. Asthma is a complex disease and its treatment requires the full cooperation and participation of the patient. Implications for practice: Healthcare professionals can play a key role by educating patients and their family members about the nature of asthma and rationale for treatment, supporting the importance of strict adherence to prevention measures and the prescribed treatment regimen.

PMID: 17760570 [PubMed - in process]

]]>

Cystic Fibrosis Pulmonary Guidelines: Chronic Medications for Maintenance of Lung Health.

Am J Respir Crit Care Med. 2007 Aug 29;

Authors: Flume PA, O’sullivan BP, Robinson KA, Goss CH, Mogayzel PJ, Willey-Courand DB, Bujan J, Finder J, Lester M, Quittell L, Rosenblatt R, Vender RL, Hazle L, Sabadosa K, Marshall B

RATIONALE: Cystic fibrosis is a recessive genetic disease characterized by dehydration of the airway surface liquid and impaired mucociliary clearance. As a result, individuals with the disease have difficulty clearing pathogens from the lung and experience chronic pulmonary infections and inflammation. Death is usually a result of respiratory failure. Newly introduced therapies and aggressive management of the lung disease have resulted in great improvements to length and quality of life, with the result that the median expected survival age has reached 36 years. However, as the number of treatments expands, the medical regimen becomes increasingly burdensome in time, money, and health resources. Hence, it is important that treatments should be recommended on the basis of available evidence of efficacy and safety. OBJECTIVES: The Cystic Fibrosis Foundation therefore established a committee to examine the clinical evidence for each therapy and provide guidance for the prescription of these therapies. METHODS: The committee members developed and refined a series of questions related to drug therapies used in the maintenance of pulmonary function. We addressed the questions in one of three ways, based on available evidence: (i) commissioned systematic review (ii) modified systematic review or (iii) summary of existing Cochrane reviews. CONCLUSIONS: It is hoped that the guidelines provided in this manuscript will facilitate the appropriate application of these treatments to improve and extend the lives of all individuals with cystic fibrosis.

PMID: 17761616 [PubMed - as supplied by publisher]

]]>

Evaluation of menstrual bleeding patterns: a new proposal for a universal guideline based on the analysis of more than 4500 bleeding diaries.

Eur J Contracept Reprod Health Care. 2007 Sep;12(3):203-11

Authors: Gerlinger C, Endrikat J, Kallischnigg G, Wessel J

Objective To develop a universal guideline allowing the comparison of interventions like oral contraceptives and hormone replacement therapy with an impact on menstrual bleeding pattern. Methods Literature analysis and cluster analysis of 4612 bleeding diaries. Results We summarized key definitions needed for the evaluation of menstrual bleeding patterns from the literature. We developed a methodology to systematically evaluate menstrual bleeding patterns that distinguishes between cyclical and continuous hormonal regimens. Conclusion This universal guideline can be applied to all prospective clinical studies that affect menstrual bleeding patterns. It allows regulatory agencies and prescribing physicians to make meaningful comparisons of different products.

PMID: 17763258 [PubMed - in process]

]]>

Photopheresis in pediatric graft-versus-host disease after allogeneic marrow transplantation: clinical practice guidelines based on field experience and review of the literature.

Transfusion. 2007 Aug 30;

Authors: Kanold J, Merlin E, Halle P, Paillard C, Marabelle A, Rapatel C, Evrard B, Berger C, Stephan JL, Galambrun C, Piguet C, D’Incan M, Bordigoni P, Deméocq F

BACKGROUND: Extracorporeal photochemotherapy (ECP) gives positive results in the management of graft-versus-host disease (GVHD), but in children, specific difficulties can outweigh this benefit. These difficulties must be taken into consideration when establishing a standardized reproducible procedure for implementation under a quality management plan. STUDY DESIGN AND METHODS: Twenty-seven children underwent ECP for severe acute GVHD (aGVHD) or chronic GVHD (cGVHD) after allogeneic marrow transplantation. Data were collected prospectively, with particular emphasis placed on technical, biologic, immunologic, clinical, and long-term follow-up issues. RESULTS: The 27 children underwent a total of 750 sessions. Mononuclear cells were collected on a commercially available apheresis system (COBE Spectra, Gambro BCT). Overall survival was 73 percent, and ECP led to significant improvement in 21 of the 27 patients (11 with complete response and 10 with partial response, i.e., >50% of organ involvement). Tolerance was good overall, the main limiting factors being vascular access and the psychological impact of repeated apheresis procedures. Children weighing less than 25 kg were not more susceptible to side effects. CONCLUSION: A specifically pediatric-dedicated and -experienced team faces only limited difficulties when treating children with GVHD by ECP. Overall, ECP is efficient and well tolerated. Our experience was therefore pooled together with available pediatric data to establish clinical practice guidelines. These guidelines consider ECP as a first-line therapy in Grade IV aGVHD (in association with conventional pharmacologic approaches) and limited cGVHD and as a second-line therapy in steroid-resistant Grades II to III aGVHD and extensive cGVHD.

PMID: 17764513 [PubMed - as supplied by publisher]

]]>

Falling on stony ground? A qualitative study of implementation of clinical guidelines’ prescribing recommendations in primary care.

Health Policy. 2007 Sep 1;

Authors: Rashidian A, Eccles MP, Russell I

OBJECTIVES: We aimed to explore key themes for the implementation of guidelines’ prescribing recommendations. METHODS: We interviewed a purposeful sample of 25 participants in British primary care in late 2000 and early 2001. Thirteen were academics in primary care and 12 were non-academic GPs. We asked about implementation of guidelines for five conditions (asthma, coronary heart disease prevention, depression, epilepsy, menorrhagia) ensuring variation in complexity, role of prescribing in patient management, GP role in prescribing and GP awareness of guidelines. We used the Theory of Planned Behaviour to design the study and the framework method for the analysis. RESULTS: Seven themes explain implementation of prescribing recommendations in primary care: credibility of content, credibility of source, presentation, influential people, organisational factors, disease characteristics, and dissemination strategy. Change in recommendations may hinder implementation. This is important since the development of evidence-based guidelines requires change in recommendations. Practitioners do not have a universal view or a common understanding of valid ‘evidence’. Credibility is improved if national bodies develop primary care guidelines with less input from secondary care and industry, and with simple and systematic presentation. Dissemination should target GPs’ perceived needs, improve ownership and get things right in the first implementation attempt. Enforcement strategies should not be used routinely. CONCLUSIONS: GPs were critical of guidelines’ development, relevance and implementation. Guidelines should be clear about changes they propose. Future studies should quantify the relationship between evidence base of recommendations and implementation, and between change in recommendations and implementation. Small but important costs and side effects of implementing guidelines should be measured in evaluative studies.

PMID: 17767976 [PubMed - as supplied by publisher]

]]>

The effect of adherence to practice guidelines on depression outcomes.

Ann Intern Med. 2007 Sep 4;147(5):320-9

Authors: Hepner KA, Rowe M, Rost K, Hickey SC, Sherbourne CD, Ford DE, Meredith LS, Rubenstein LV

BACKGROUND: Few studies have assessed clinician adherence to depression practice guidelines and the relationship between clinician adherence and depression outcomes. OBJECTIVE: To estimate how frequently specific guideline recommendations are followed and to assess whether following guideline recommendations is linked to improved depression outcomes. DESIGN: Observational analysis of data collected from 1996 to 1998 in 3 randomized clinical trials. SETTING: 45 primary care practices in 13 U.S. states. PATIENTS: 1131 primary care patients with depression. MEASUREMENTS: Expert panel methods were used to develop a patient survey-based index that measured adherence to clinical practice guidelines on depression. Rates of adherence to the 20 indicators that form the index were evaluated. Multivariable regression that controlled for case mix was used to assess how index scores predicted continuous and dichotomous depression measures at 12, 18, and 24 months. RESULTS: Quality of care was high (clinician adherence > or =79%) for 6 indicators, including primary care clinician detection of depression. Quality of care was low (adherence, 20% to 38%) for 8 indicators, including management of suicide risk (3 indicators), alcohol abuse (2 indicators), and elderly patients; assessment of symptoms and history of depression; and treatment adjustment for patients who did not respond to initial treatment. Greater adherence to practice guidelines significantly predicted fewer depressive symptoms on continuous measures (P

PMID: 17785487 [PubMed - in process]

]]>

Turning Evidence into Recommendations:protocol for a study of guideline development groups.

Implement Sci. 2007 Sep 5;2(1):29

Authors: Michie S, Berentson-Shaw J, Pilling S, Dieppe P, Raine R, Cluzeau F, Alderson P, Ellis S, Feder G

ABSTRACT: BACKGROUND: Health care practice based on research evidence requires that evidence is synthesised, and that recommendations based on this evidence are implemented. It also requires an intermediate step: translating synthesised evidence into practice recommendations. There is considerable literature on evidence synthesis and implementation, but little on how guideline development groups (GDGs) produce recommendations. This is a complex process, with many influences on communication and decision-making, e.g., the quality of evidence, methods of presentation, practical/resource constraints, individual values, professional and scientific interests, social and psychological processes. To make this process more transparent and potentially effective, we need to understand these influences. Psychological theories of decision-making and social influence provide a framework for this understanding. Objectives This study aims to investigate the processes by which GDGs formulate recommendations, drawing on psychological theories of decision-making and social influence. The findings will potentially inform the further evolution of GDG methods, such as choice of members and procedures for presenting evidence, conducting discussion and formulating recommendations. METHODS: Longitudinal observation of the meetings of three National Institute of Health and Clinical Excellence (NICE) GDGs, one from each of acute, mental health and public health, will be tape recorded and transcribed. Interviews with a sample of GDG members at the beginning, middle, and end of the GDG’s work will be recorded and transcribed. Site documents including relevant e-mail interchanges, GDG meeting minutes, and stakeholders’ responses to the drafts of the recommendations will be collected. Data will be selected for analysis if they refer to either evidence or recommendations; the focus is on “hot spots”, e.g., dilemmas, conflicts, and uncertainty. Data will be analysed thematically and by content analysis, drawing on psychological theories of decision-making and social influence.

PMID: 17803806 [PubMed - as supplied by publisher]

]]>

Improved Treatment of Hospitalized Coronary Artery Disease Patients With the Get With The Guidelines Program.

Crit Pathw Cardiol. 2007 Sep;6(3):98-105

Authors: Labresh KA, Fonarow GC, Smith SC, Bonow RO, Smaha LC, Tyler PA, Hong Y, Albright D, Ellrodt AG,

Adherence to evidence-based interventions for hospitalized cardiovascular disease patients is not optimal. This study assesses the impact of a national quality improvement program on adherence to guidelines in these patients. Data from 92 hospitals from across the United States participating in the Get With The Guidelines program for at least 1 year for 11 acute and secondary prevention measures from a preintervention baseline period and the subsequent 4 quarters of a quality improvement intervention were analyzed. A patient group of 45,988 patients with acute myocardial infarction, unstable angina, revascularization, or peripheral vascular disease was included in this evaluation. Significant improvement from baseline was seen in 10 of 11 measures by the fourth quarter: use of early aspirin for acute myocardial infarction, 76.4% to 88.0% (P /=100 mg/dL, 60.4% to 67.0% (P

PMID: 17804969 [PubMed - as supplied by publisher]

]]>

Multidisciplinary Rounds (MDR): An Implementation System for Sustained Improvement in the American Heart Association’s Get With The Guidelines Program.

Crit Pathw Cardiol. 2007 Sep;6(3):106-16

Authors: Ellrodt G, Glasener R, Cadorette B, Kradel K, Bercury C, Ferrarin A, Jewell D, Frechette C, Seckler P, Reed J, Langou A, Surapaneni N,

INTRODUCTION:: Hospitals throughout the United States face the challenge of developing implementation systems able to sustain improved clinical care over years. The American Heart Association’s Get With The Guidelines (GWTGs) program helps hospitals address this challenge with a comprehensive approach to quality improvement for patients with CAD, heart failure and stroke. The Department of Medicine at Berkshire Medical Center, a 300-bed community teaching hospital, developed a clinical care improvement implementation system called multidisciplinary rounds (MDR). We report our performance in GWTGs using MDR. METHODS:: MDR is a patient-focused communication system integrating care delivered by multiple providers using concurrent feedback, redundancy, and rapid cycle improvement. Providers from multiple disciplines meet for 1 hour 3 times per week to coordinate care and assure adherence to evidence-based guidelines for all non-ICU medical patients. Following brief focused presentations, participants view our electronic medical record (EMR) projected on screens, which includes orders, diagnoses, laboratory, medications, cardiology reports, consultations, nursing documentation, smoking and immunization status, and other information. The leaders emphasize the importance of evidence-based order sets in our computerized provider order entry system (CPOE), checklists, and tools. Specific suggestions for interventions and documentation based upon AHA/ACC guidelines are provided. RESULTS:: MDR has rapidly improved adherence to evidence-based measures in all GWTGs programs. In addition, MDR has been associated with sustained improvement in all modules. Berkshire Medical Center has received more performance achievement awards than any other hospital in the United States. These awards include 6 consecutive awards in GWTGs CAD, 3 in stroke, and 2 in heart failure. Cardiovascular process improvements have been associated with a reduction in inpatient AMI mortality from 8.75% to 5.20% (with an expected severity-adjusted mortality of 10.18%). Berkshire Medical Center provides about 80% of the acute care in Berkshire County and thus influences the outcomes of a large proportion of our community’s patients. Between 1999 and 2004, Berkshire County had a 26.3% decrease in major CVD deaths compared with a Massachusetts decrease of 17.3% and a US decrease of 17.8%. We have seen a 44.4% decrease in AMI mortality, a 34.5% decrease in stroke mortality, and a 33.9% decrease in heart failure mortality. We have assisted multiple organizations in implementing GWTG and MDR. CONCLUSIONS:: MDR at Berkshire Medical Center is a clinical quality-improvement implementation system that has driven sustained high-level performance in the American Heart Association’s GWTGs. MDR has changed our culture, improved coordination of care, been flexible, and facilitated rapid and sustained process improvement. Improvement in evidence-based cardiovascular processes for CAD, stroke and heart failure have been associated with improved in hospital AMI mortality and decreased overall community cardiovascular, AMI, stroke and heart failure mortality. MDR can be used by multiple organizations to drive care improvement.

PMID: 17804970 [PubMed - in process]

]]>