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.

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.

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.

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.

Variation in utilization of procedures for treatment of peripheral arterial disease. A look at patient characteristics.

OBJECTIVE: To examine associations between demographic characteristics and use of interventional procedures in patients with peripheral arterial disease. DESIGN: Case series drawn from a statewide hospital discharge database. SETTING: Nonfederal acute-care hospitals in Maryland. PATIENTS AND INTERVENTIONS: A total of 7080 cases of angioplasty, bypass surgery, or amputation for lower-extremity peripheral arterial disease in 1988 through 1989. MAIN OUTCOME MEASURE: Use of angioplasty, bypass surgery, and lower-extremity amputation. RESULTS: A total of 1185 angioplasties, 4005 bypass operations, and 1890 amputations were identified. Population-based annual rates showed that angioplasty use peaked at about 70 per 100,000 at the age of 65 to 74 years, bypass surgery use peaked at more than 250 per 100,000 at 75 to 84 years of age, and amputation use peaked at about 225 per 100,000 at 85 years of age and older. The age-adjusted likelihood of having a procedure for peripheral arterial disease was 1.7 times higher in men than in women and 1.6 times higher in blacks than in whites. Compared with patients who had angioplasty or bypass surgery, patients who had amputations were more likely to be more than 65 years old, to be black (odds ratio, 2.5), to have Medicaid or no insurance (odds ratio, 1.7), to have diabetes mellitus (odds ratio, 3.0), and not to have hypertension (odds ratio, 3.1). Compared with patients who had bypass surgery, patients who had angioplasty were more likely to be under 65 years old, to be white (odds ratio, 1.7), and not to have diabetes mellitus (odds ratio, 1.3). CONCLUSION: Patient race is associated with differences in the frequency with which angioplasty, bypass surgery, and amputation are performed for peripheral arterial disease, and insurance status is associated with the likelihood of having amputation.

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.

Factors related to subsequent reproductive outcome in couples with repeated pregnancy loss.

Specific factors in a couple's history may influence the recurrence risk following repeated pregnancy loss (RPL). Couples with RPL were contacted several years following evaluation and information concerning subsequent pregnancies was obtained. Linear regression analysis was utilized to determine which factors in the history were significant predictors of pregnancy outcome following evaluation. A family history of RPL or a "genetic defect" was a highly significant predictor of subsequent unsuccessful pregnancies. Surgical, but not medical, treatment for RPL was a significant predictor of eventual successful outcome. The number of abortions prior to evaluation for RPL, presence of a liveborn child, maternal age at evaluation, and intercurrent infertility all failed to be significant predictors of pregnancy outcome after evaluation.

Patterns of mood states in pregnant women undergoing chorionic villus sampling or amniocentesis.

The purpose of this study was to compare patterns of self-reported mood states of women having chorionic villus sampling (CVS) (n = 151) to those of women electing amniocentesis (n = 30) with the indication of advanced maternal age. Mood states were defined as scores on the 6 subscales of the Profile of Mood States (POMS). Women at 4 U.S. prenatal diagnostic facilities completed the POMS at 4 assessment periods. These were a) at their initial genetic counseling session, b) 2 weeks post CVS results (or an equivalent time), c) 2 weeks post amniocentesis results (or an equivalent time), and d) at 30 weeks gestation. Repeated measures analysis of variance revealed that anxiety, fatigue, and confusion decreased, and vigor increased in both groups as the pregnancy progressed. Depression decreased in both groups and then increased at assessment 4 in women in the amniocentesis group but not in those electing CVS. Results should be interpreted in conjunction with obstetrically and genetically-oriented findings regarding safety and accuracy to help women decide between the 2 procedures.

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.

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.

Insurance coverage for experimental technologies.

As the number and cost of new technologies grow, it is increasingly important that we develop sound policies for payment for those technologies while their clinical impacts are being defined. Such policies need to balance social interests in promotion of innovation, early access to promising technology, patient safety, control of health care costs, and return on investment. We present a rationale, policy options, and a proposal for insurance coverage of experimental technology.

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.

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.

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.

Health care technology in the United States.

The US health care system reflects the free market of the US economy--there is no fixed budget and no limit on expenditures in the loosely structured matrix of largely private-sector health industry components. Mainly because of the inaccessibility of adequate health care for a large segment of the population, and because of the enormous cost of care threatens financial ruin for many more people, the first major reform of the system was debated in Congress for most of 1994, though, in the end, no leglislation was passed. One focus of the debate on spending has been the problem of excessive use of expensive medical technology and the need for some control, which, by and large, is lacking in the existing system. Health care technology assessment itself is a thriving industry in the United States, used by government, insurers, medical societies, hospitals, and other groups for their own purposes. At the national policy level, few opportunities for technology assessment to affect the health care industry exist, so most effort is directed at trying to affect medical practice at the level of the individual hospital and practitioner. The discernible effect of technology assessment has been minimal.

Episode-of-care physician payment: a study of coronary artery bypass graft surgery.

Paying physicians for an episode of care is a possible alternative to current fee-for-service payment. We studied physician billing patterns for 512 Medicare beneficiaries who received coronary artery bypass graft (CABG) surgery in 1983. Relatively elaborate decision rules had to be created to exclude services that were not part of a routine CABG. We found that 72% of charges for an episode were associated with services provided on the day of surgery. Forty-seven percent of charges were by the primary surgeon, 15% by the assistant surgeon(s), and 9% by the anesthesiologist. Our results suggest that episode-of-care payment is a complex, and somewhat costly, alternative to other methods of prospective payment to physicians, although selective contracting by a health insurer for an episode of care for certain procedures might both reduce costs and improve quality.

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.

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.