Core outcome set for gene therapy in haemophilia: Results of the coreHEM multistakeholder project.

BACKGROUND: Gene therapy trial results show potential to cure haemophilia A and haemophilia B. Securing broad access to a cure for a lifelong chronic disease is anticipated to face barriers at the individual and healthcare system levels, which can be partly mitigated by harmonized planning of clinical research studies. The aim of the coreHEM project was to determine the set of outcome measures required to evaluate efficacy, safety, comparative effectiveness and value of gene therapy for haemophilia. METHODS: Modified Delphi consensus process, based on methods adapted from the COMET Initiative. RESULTS: Forty-nine participants (five patients, five clinicians, five researchers, four regulators, three research agencies, six health technology assessors, nine payers and 12 drug developers) took part in the study, with over 90% participation. The frequency of bleeds, factor activity level, duration of expression, chronic pain, healthcare resource use and mental health were identified as the core outcomes to be measured in addition to regulatory-mandated adverse effects. CONCLUSIONS: For the first time in haemophilia, a core outcome set has been developed, with the involvement of representatives of all relevant stakeholder groups. The core set has been expanded to include outcomes supporting assessment of comparative effectiveness and value, with the goal of streamlining regulatory approval, health technology assessment and market access decisions. Patient involvement ensures that outcomes are meaningful and relevant to those living with haemophilia. Active dialogue among drug developers, regulators and payers throughout the process is expected to facilitate broad uptake of the core outcomes in forthcoming clinical trials.

The COMET Initiative database: progress and activities update (2015).

This letter describes the substantial activity on the Core Outcome Measure in Effectiveness Trials (COMET) website in 2015, updating our earlier progress reports for the period from the launch of the COMET website and database in August 2011 to December 2014. As in previous years, 2015 saw further increases in the annual number of visits to the website, the number of pages viewed and the number of searches undertaken. The sustained growth in use of the website and database suggests that COMET is continuing to gain interest and prominence, and that the resources are useful to people interested in the development of core outcome sets.

From adaptive licensing to adaptive pathways: delivering a flexible life-span approach to bring new drugs to patients.

The concept of adaptive licensing (AL) has met with considerable interest. Yet some remain skeptical about its feasibility. Others argue that the focus and name of AL should be broadened. Against this background of ongoing debate, we examine the environmental changes that will likely make adaptive pathways the preferred approach in the future. The key drivers include: growing patient demand for timely access to promising therapies, emerging science leading to fragmentation of treatment populations, rising payer influence on product accessibility, and pressure on pharma/investors to ensure sustainability of drug development. We also discuss a number of environmental changes that will enable an adaptive paradigm. A life-span approach to bringing innovation to patients is expected to help address the perceived access vs. evidence trade-off, help de-risk drug development, and lead to better outcomes for patients.

Accelerated access to innovative medicines for patients in need.

There is broad agreement among health-care stakeholders that more must be done to ensure that patients have timely access to new and innovative medicines. Assuming that industry will continue to develop such medicines at a sustainable rate, regulators and payers become the gatekeepers. Regulators, starting in the late 1980s/early 1990s, and, more recently, payers have implemented a variety of early-access pathways or initiatives, and this practice is continuing even today. This article describes the specific approaches that have been taken in four economically developed regions, reviews their success rates, and suggests possible new directions.

Methodological recommendations for comparative research on the treatment of chronic wounds.

OBJECTIVE: To provide specific recommendations to product developers and clinical researchers on the design of comparative effectiveness studies for the treatment of chronic wounds, specifically those pertaining to arterial and venous-disease related ulcers, diabetic foot ulcers, pressure ulcers and burn wounds. METHOD: The recommendations were developed based on a process defined by the Center for Medical Technology Policy (CMTP). After selecting the subject area, semi-structured phone interviews were conducted by one of the authors (SSS) with representatives of payers, manufacturers, clinicians, clinician/researchers and patient advocates. Next, a broad range of stakeholders participated in a meeting convened by CMTP to determine their needs. A technical working group comprising key stakeholders then participated in clarifying recommendations developed by CMTP staff and adding important considerations for their implementation. The resulting draft document was finalised based on public and solicited comment from individual manufacturers; a consortium of product developers and manufacturers; and an alliance of physicians, providers, manufacturers and patient organisations. This article is a summary of the full effectiveness guidance document. RESULTS: To address the needs of patients, clinicians, guideline developers, payers and other post-regulatory decision makers, this work makes ten recommendations to guide comparative effectiveness research for chronic wound care. These recommendations fall into four categories: study design, population, comparators and outcomes. CONCLUSION: This paper suggests that using the recommendations outlined to conduct comparative effectiveness research on treatments for chronic wound therapies would facilitate trials that provide patients, clinicians, and payers with the information they need to make optimal treatment decisions. These recommendations focus on design changes that would have the largest impact in improving the usability of the results by decision makers and provide specific guidance on the design of prospective studies intended to inform decision making by patients, clinicians and payers. DECLARATION OF INTEREST: There were no external sources of funding for these recommendations. The Value Institute and the Center for Medical Technology Policy (CMTP) are both private, non-profit organisations. The authors have no financial, commercial or social conflicts of interest to declare with respect to the article or its content.

Current and future state of FDA-CMS parallel reviews.

The US Food and Drug Administration (FDA) and the Centers for Medicare and Medicaid Services (CMS) recently proposed a partial alignment of their respective review processes for new medical products. The proposed "parallel review" not only offers an opportunity for some products to reach the market with Medicare coverage more quickly but may also create new incentives for product developers to conduct studies designed to address simultaneously the information needs of regulators, payers, patients, and clinicians.

Controlled trial of interventions to increase testing and treatment for Helicobacter pylori and reduce medication use in patients with chronic acid-related symptoms.

BACKGROUND: Many symptomatic patients take proton pump inhibitors or histamine-2 blockers for years and those without gastro-oesophageal reflux disease might benefit from Helicobacter pylori eradication. AIM: To increase testing and treatment of H. pylori and reduce chronic use of proton pump inhibitors and histamine-2 blockers. METHODS: We conducted a three-armed controlled trial in 14 managed care practices. We included adults who used proton pump inhibitors or histamine-2 blockers for >1 year and excluded those with gastro-oesophageal reflux disease or previous endoscopy. We compared usual care (n = 312 patients from 6 practices) to low-intensity (n = 147 from 3 practices) and high-intensity (n = 122 from 5 practices) interventions. Low-intensity intervention consisted of guidelines, patient-lists, and a "toolkit"; high-intensity intervention added academic group detailing by a gastroenterologist with reinforcement by pharmacists. RESULTS: Compared with usual care, the high-intensity intervention increased H. pylori test-ordering (29% versus 9% at 12 months, P = 0.02). About half (23 of 58) of patients tested positive and 22 received eradication treatments. The high-intensity intervention decreased proton pump inhibitor use by 9% per year (P = 0.028), but did not alter histamine-2 blocker use. The low intensity intervention was ineffective. CONCLUSIONS: Providing guidelines, patient-lists, and toolkits was no better than usual care. Adding group detailing and pharmacist reinforcements led to improvements in H. pylori management and decreases in proton pump inhibitor use.

Medication prescribing patterns for patients with bipolar I disorder in hospital settings: adherence to published practice guidelines.

OBJECTIVE: The purposes of this paper were to examine the medication prescribing patterns for bipolar I disorder in hospital settings and to compare them to recently published expert consensus guidelines for medication treatment of bipolar disorder. METHODS: Data were obtained from the 1996-2000 CQI+SM Outcomes Measurement System, on patients age 18 or older admitted to psychiatric inpatient units from over 100 medical-surgical hospitals. A total of 1864 patients with a primary discharge diagnosis of bipolar I or II disorder were identified from a large cohort of hospitalized patients. Patient characteristics were assessed at hospital admission and medication usage, at discharge. The medication analysis focused on the 1471 individuals with bipolar I mania or bipolar I depression (with or without psychotic features), representing 54% and 25% of admitted bipolar patients, respectively. RESULTS: At admission, the typical bipolar patient (mean age 57) had experienced a relatively severe and chronic course of illness. The array of psychotropic agents used was broad, with no single prescribing pattern predominant. Only one in three bipolar I (manic or depressed) patients with psychotic features was discharged on medications recommended by expert guidelines as preferred or alternate recommended treatment. Absent psychotic features, this dropped to one in six patients. Surprising was the relatively high use of antidepressants for patients with mania, particularly those without psychotic symptoms. CONCLUSIONS: Results suggest that a substantial proportion of patients with bipolar I disorder are discharged from hospitals on medications not generally recommended by current practice guidelines.

Antipsychotic treatment of behavioral and psychological symptoms of dementia in geropsychiatric inpatients.

Behavioral/psychological symptoms of dementia (BPSD) affect caregiver burden and transition from home to hospital or long-term care. The authors examined change in BPSD for dementia patients (from hospital admission to discharge) who were prescribed haloperidol (n= 289), olanzapine (n=209), or risperidone (n=500). Olanzapine was associated with significantly greater overall improvement in BPSD (based on the Psychogeriatric Dependency Rating Scale total score) than risperidone or haloperidol. Olanzapine was significantly superior on measures of active-, verbal-, and passive-aggression and delusions/hallucinations to risperidone or haloperidol, and, on manipulative behavior and noisiness, to risperidone. Results support the effectiveness of olanzapine in improving several BPSD in hospitalized dementia patients.

The outcomes of outcomes and effectiveness research: impacts and lessons from the first decade.

OBJECTIVE: To assess the outcomes of the Agency for Healthcare Research and Quality's (AHRQ; formerly the Agency for Health Care Policy and Research, AHCPR) first decade of focus on outcomes and effectiveness research (OER) and to identify needs and opportunities for the study of OER in the coming years. DATA SOURCE: Study findings were collected in response to an inquiry by the Center for Outcomes and Effectiveness Research at AHRQ in July 1997 to all principal investigators (PIs) funded between 1989 and 1997. The request was for investigators to identify their "most salient findings" and supply material for up to three slides. STUDY DESIGN: A taxonomy of 11 non-mutually exclusive categories was used to group the investigators' salient findings by characteristics of methodology or purpose. Two health services researchers assigned findings to up to three categories for each discrete study. PRINCIPAL FINDINGS: Responses were received from 61 (64 percent) of the 91 PIs, reporting on 115 studies. Of the 246 category assignments made, descriptive epidemiology was the most common (24 percent), followed by comparative effectiveness (17 percent) and economic assessments (12 percent). Most studies were retrospective analyses of administrative data. Viewed within a conceptual framework for assessing the impact of research, OER has built a solid foundation for future quality improvement efforts by identifying problems, generating hypotheses, and developing new methodologies and has had limited impact on health care policies, practices and outcomes. CONCLUSIONS: OER has had moderate but significant success meeting initial expectations for the field. Challenges for the next generation of OER include advancing from hypothesis generation to definitive studies of effectiveness, and acceleration of the process by which findings effect policy, practice, and outcomes.

Designing naturalistic prospective studies of economic and effectiveness outcomes associated with novel antipsychotic therapies.

The cornerstone of recent pharmacoeconomic work in schizophrenia is the hypothesis that the improved efficacy of novel antipsychotic medications will lead to a reduction in medical services utilization, thereby reducing direct medical costs associated with treatment. Creating the most valid design to prospectively examine the effectiveness and costs of competing pharmacotherapies requires a dialectic of opposing research paradigms. The final protocol must represent a series of decisions that strike a careful balance between being scientifically sound (internal validity) and generalizable to the real world of clinical treatment (external validity). The results must be useful to decision-makers in determining to what extent reductions in healthcare expenditures can offset higher drug acquisition costs within their type of treatment environment. This article is a review of several methodological challenges in the design of medical effectiveness trials, including whether to blind the study, definition of the patient population, degree of physician discretion in treatment, and how to collect and analyze data for patients who discontinue their originally assigned medication. The article also provides a discussion of how clinical practices can inform decisions made to meet these challenges. The issues are illustrated through a prospective study designed to evaluate the cost-effectiveness of the newer antipsychotics in general and olanzapine in particular. Cost-effectiveness studies of novel antipsychotic medications, particularly those with naturalistic designs, will increase in importance as the use of these second-generation agents continues to expand.

Changes in perceived health and functioning as a cost-effectiveness measure for olanzapine versus haloperidol treatment of schizophrenia.

We utilize data from a large, double-blind, randomized clinical trial of treatment for schizophrenia to compare the effect of therapy with the second generation antipsychotic olanzapine versus therapy with the conventional agent haloperidol on the perceived functioning and well-being of patients over 1 year as measured by the Medical Outcome Study Short Form (SF-36). We also compare the total cost of care between the treatment groups over 1 year and combine cost and functional outcomes information to estimate the incremental cost-effectiveness of both therapies in this sample. Over 1 year of therapy, patients receiving olanzapine experienced a mean of 5.75 units greater improvement than did haloperidol-treated patients on the physical health and functioning factor of the SF-36 and 1.66 units greater improvement on the mental health and functioning factor. The mean annual total cost of care, including the cost of medication therapies, was $9386.87 less for olanzapine-treated patients than for haloperidol-treated patients. The incremental cost-effectiveness ratio for olanzapine versus haloperidol treatment indicated a savings of $1632.50 per unit of improvement in the SF-36 physical health and functioning score and a savings of $5654.74 per unit of improvement in the mental health and functioning composite. Improvements in perceived health and functioning were also associated with reduction in hospital costs in the full sample. These findings suggest that patient-centered measures of functioning such as the SF-36 are an important component of the evaluation of the cost-effectiveness of novel treatments for schizophrenia.

Reliability, validity, and application of the medical outcomes study 36-item short-form health survey (SF-36) in schizophrenic patients treated with olanzapine versus haloperidol.

UNLABELLED: Schizophrenia leads to impairments in mental, social, and physical functioning, which should be included in evaluations of treatment. OBJECTIVES: This study was designed to determine the reliability and validity of the Medical Outcomes Study Short Form Health Survey (SF-36) for schizophrenic patients, to characterize perceived functioning and well being and to compare short-term change in SF-36 scores for patients treated with olanzapine or haloperidol. RESEARCH DESIGN: Data were obtained from a randomized, double-blind trial comparing these agents for safety, efficacy, and cost effectiveness. A 6-week acute treatment portion preceded a 46-week "responder extension" phase. SUBJECTS: A subsample (n = 1,155) completing a pre-treatment SF-36 provided data for this study. MEASURES: Psychometric analyses were conducted, and perceived level of functioning was compared with that for the US adult population. Change from baseline to 6 weeks was examined by treatment group. RESULTS: Clear evidence was obtained for the instrument's reliability and validity for these patients. There were marked deficits in General health, Vitality, Mental health, Social functioning, and in Role limitations resulting from both physical and emotional problems. Olanzapine-treated patients improved in 5 of 8 domains to a significantly greater degree than did haloperidol patients. CONCLUSIONS: The SF-36 can be a reliable and valid measure of perceived functioning and well being for schizophrenic patients. The perceptions of functioning can be valuable indices of disease burden and can help to demonstrate the effectiveness of newer antipsychotic medications such as olanzapine.

Lansoprazole compared with histamine2-receptor antagonists in healing gastric ulcers: a meta-analysis.

To compare the gastric ulcer healing rates of lansoprazole with histamine2-receptor antagonists (H2RAs) (ranitidine, famotidine, cimetidine, and roxatidine), a meta-analysis was performed using data from five published and eight unpublished randomized controlled trials. Analyses were performed using (1) both evaluable patients (n = 1527) and all randomized patients (n = 1655) (assuming that patients lost to follow-up were treatment failures); (2) all studies and a subset of studies that received high methodologic quality scores; and (3) fixed-effects, random-effects, and Bayesian statistical models. In all cases, lansoprazole was associated with a significantly higher rate of endoscopic healing at both 4 and 8 weeks compared with the H2RAs. When the most conservative Bayesian statistical model and intent-to-treat analysis were used, lansoprazole was associated with a 33% higher healing rate at 4 weeks (risk ratio = 1.33; 95% confidence interval [CI] = 1.19 to 1.49) and a 12% higher healing rate at 8 weeks (risk ratio = 1.12; 95% CI = 1.06 to 1.19) than were the H2RA agents. Similar results were obtained when the meta-analysis was performed on evaluable rather than all randomized patients and using the three different analytical techniques noted above. Slightly lower, though still highly significant, improvement in ulcer healing rates was obtained when the meta-analysis was performed using a subset of six studies that received high methodologic quality scores. These results support the conclusion that lansoprazole heals ulcers more quickly than do the H2RAs and also achieves higher overall rates of healing. The eradication of Helicobacter pylori associated with gastric ulcers was not assessed in individual studies.

Practice guidelines. What are internists looking for?

To determine features of the presentation of clinical practice guidelines that may enhance their use by internists, we conducted a cross-sectional survey to which 1,513 (60%) of 2,513 eligible internists responded. Endorsements by respected colleagues and by major organizations were identified as very important by 72% and 69% of respondents, respectively. Respondents preferred short pamphlets and manuals summarizing a number of guidelines and felt that concise recommendations (86%), synopsis of supporting evidence (85%), and quantification of benefit (77%) were important in guideline presentation. We conclude that guideline developers should gain the endorsement of major organizations and present key aspects in brief, easily assimilated formats.

The relationship of counselor and peer alliance to drug use and HIV risk behaviors in a six-month methadone detoxification program.

The purpose of this study was to examine the relationship of treatment outcomes in opioid detoxification to levels of counselor and peer alliance. Forty-one subjects were recruited from a larger, 180-day study of psychosocial treatment. Beginning at day 90, subjects completed monthly measures of alliance. Outcome measures included treatment retention, drug use and self-reported HIV risk. Measures of alliance were found to be internally consistent and moderately stable over time. During the final 30 days of the methadone taper, higher levels of both types of alliance were associated with less use of illicit opioids. Alliance with counselor was associated with less frequent needle sharing. For subjects who could be located for 30-day follow-up, greater alliance with peers was associated with more frequent HIV (sexual) risk behaviors. Results suggest that treatment outcome may be improved through approaches that address a patient's alliance with both counselor and peers.

The adoption of preventive care practice guidelines by primary care physicians: do actions match intentions?

OBJECTIVE: To measure primary care physicians' familiarity with, attitudes toward, and confidence in preventive care practice guidelines for the elderly and to determine whether their attitudes are associated with implementation of guidelines into clinical practice. DESIGN: A self-administered survey of physicians employed by a health maintenance organization (HMO) and of patients cared for by those physicians. Medical records were also reviewed to assess compliance with practice guidelines. SETTING: An HMO in Southern California. PARTICIPANTS: Forty-eight primary care physicians completed the survey (100% response rate). The medical records of 3,249 randomly selected elderly patients (65 to 75 years old) were studied. Of these patients, 2,799 completed a preventive care survey (response rate 86.1%). MEASUREMENT AND RESULTS: Most HMO primary care physicians agreed or strongly agreed that guidelines will improve quality of medical care (88%) and that guidelines have caused them to change their care of patients (73%). Although the physicians' general attitudes about guidelines did not often correlate with their use of preventive care guidelines, the physicians who stated that practice guidelines had changed their practices were more likely to offer their patients clinical breast examinations (75.9% vs 67.2%, p = 0.04) and to counsel their patients to exercise (70% vs 58%, p = 0.01) than were the physicians who did not. There was a significant association between physicians' support for and adoption of specific practice guidelines regarding mammography (r = 0.34, p = 0.02) and immunizations against influenza (r = 0.42, p < 0.005), pneumococcal pneumonia (r = 0.47, p < 0.001), and tetanus (r = 0.31, p = 0.03). CONCLUSIONS: Physicians employed by an HMO were familiar with and hopeful about the role of guidelines for improving patient care. Physicians' attitudes toward specific preventive care guidelines and admission that guidelines had caused them to change their practice did at times, but not always, correlate with their implementation of guidelines into clinical practice.