Impact of pharmaceutical industry involvement in the external review of clinical practice guidelines-A case study.

RATIONALE AND AIM: External review is important when developing clinical practice guidelines. Involving pharmaceutical companies may influence guideline recommendations in their favour and is therefore controversial. Our study aimed to measure stakeholder participation in the external review of the 2016 European acne guideline and assess the extent to which comments submitted by pharmaceutical companies suggested changes favouring their own products. METHODS: Retrospective, partially blinded case study using qualitative analysis of comments submitted during external review. RESULTS: Four stakeholder groups participated in the review: pharmaceutical company representatives (five out of five invited), professional association members (2/222), journal reviewers (n = 2), and visitors to the project website (n = 1). Of 78 comments submitted, 48 were from company representatives, 24 from journal reviewers, and six from others. Each comment suggested one change to the guideline. Of the comments submitted by companies, 41.7% related to "writing or formatting," 16.7% to "presentation of results," 12.5% to "background information for main recommendations," and 12.5% to the "strength of treatment recommendation". In 54.2% (26/48) of these comments, a change was suggested that put the companies' own products in a more positive light. Five of these changes were implemented by the guideline authors in the way suggested by the company representatives. CONCLUSION: Participation of professional societies, patients, and the general public in the external review of the 2016 European acne guideline was unacceptably low. This is in concordance with reports of low participation of these groups in other European dermatology guidelines. While involving the pharmaceutical industry in the review substantially increased the number of comments received, many of these sought changes that would have put companies' own products in a more favourable light. Our findings underscore the need to manage reviewer comments in a robust and transparent fashion. Solutions to encourage participation of all relevant stakeholders are needed.

Decision-Analytic Modeling for Time-Effectiveness of the Sequence of Induction Treatments for Moderate to Severe Plaque Psoriasis.

Importance: Systemic psoriasis treatments vary in efficacy and cost but also in time until onset of action. Patients with no response to a first induction treatment are typically switched to another, and some patients require several treatments before they see an improvement. Objective: To determine the most cost-effective sequence of induction treatment through a comparative time-effectiveness analysis of different systemic treatment sequences currently licensed in Germany for moderate to severe plaque psoriasis. Design, Setting, and Participants: This time-effectiveness analysis used a decision-analytic model set in the German health care system. The population simulated to receive the treatment sequences consisted of adult men and women with psoriasis vulgaris or plaque type psoriasis eligible for systemic treatment. Systematic reviews were performed to generate model input values. Data were collected from November 1 through December 15, 2017, and analyzed from January through August 2018. Interventions: Five treatment sequences frequently used in Germany, identified through an online expert survey (response rate, 10 of 15 [66.7%]), and 4 theoretical sequences starting with a biological agent. Treatments included methotrexate sodium (MTX), cyclosporine (CSA), fumaric acid esters (FAE), adalimumab (ADA), ixekizumab (IXE), infliximab (INF), and secukinumab (SEC). Main Outcomes and Measures: Two health states were defined: responder (patients achieving a Psoriasis Area Severity Index [PASI] ≥75) and nonresponder (PASI <75). Probability values were defined as response rates of PASI-75. Treatment effects were determined by the mean change in Dermatology Life Quality Index (DLQI) score. Time until onset of action was assessed as weeks until 25% of patients reach PASI-75. Individual time-effectiveness ratios were calculated per treatment sequence as time until onset of action (in weeks) per minimally important difference (MID) in DLQI and were subsequently ranked. Results: Treatment sequences starting with a biological agent, including IXE-INF-SEC (1.4 weeks per DLQI-MID), INF-IXE-SEC (2.05 weeks per DLQI-MID), SEC-IXE-ADA (2.1 weeks per DLQI-MID), and ADA-IXE-SEC (2.8 weeks per DLQI-MID) were more time-effective than frequently used treatment sequences, including MTX-SEC-ADA (6.8 weeks per DLQI-MID), MTX-ADA-IXE (7.0 weeks per DLQI-MID), MTX-ADA-SEC (7.2 weeks per DLQI-MID), MTX-FAE-ADA (10.05 weeks per DLQI-MID), and FAE-MTX-CSA (11.5 weeks per DLQI-MID). The results were robust to deterministic sensitivity analyses. Conclusions and Relevance: When allocating monetary resources, policy makers and regulators may want to consider time until patients experience an MID in their quality of life as an additional outcome measure. Trial Registration: PROSPERO Identifier: CRD42017074218.

Off-label prescriptions and decisions on reimbursement requests in Germany - a retrospective analysis.

BACKGROUND AND OBJECTIVES: "Off-label use" is defined as the prescription of pharmaceutical products outside their approved indications. Rare diseases frequently lack "on-label" treatment options. In order to avoid reimbursement claims following the prescription of off-label drugs, physicians in Germany can - on a case-by-case basis - file an application for cost coverage with the competent health insurance prior to treatment initiation. PATIENTS AND METHODS: We conducted a chart review for cost coverage requests submitted by two outpatient clinics at a university-affiliated dermatology department between 2010 and 2012 (clinic for autoimmune diseases and urticaria clinic). Insurance providers, acceptance rates, reasons for rejection, and processing times were analyzed. RESULTS: The analysis showed that 56.8 % of applications for off-label use (n = 44) were approved during the first round. The rate increased to 75.0 % when including approvals granted after up to two rejections. The time between initial application and the response of health insurers was 49 days (median). In case of cost coverage approval, treatments were initiated 92 days (median) after the initial request. CONCLUSIONS: The present case series shows that, in the majority of cases, health insurers in Germany have agreed to reimburse the costs of proposed off-label therapies. A prospective study is required in order to evaluate whether current changes to legal regulations (GKV-Versorgungsstrukturgesetz, Patientenrechtegesetz) adequately address the problems identified.

Cost-effectiveness of systemic treatments for moderate-to-severe psoriasis in the German health care setting.

Systemic treatments of moderate-to-severe psoriasis differ substantially in terms of effectiveness and costs. Comprehensive economic-evaluations of all systemic treatments for psoriasis from a societal perspective are missing. The objective of our study was to compare the cost-effectiveness all systemic treatments approved for moderate-to-severe psoriasis from a societal perspective, by including all cost categories. An incremental cost-effectiveness-analysis was performed for all systemic treatments for psoriasis, currently recommended by the German S3-Guideline i.e. methotrexate, cyclosporine, fumaric acid esters, and retinoids, adalimumab, etanercept, infliximab and ustekinumab. We used a Markov model with time-dependent transition probabilities and a time horizon of 2 years to investigate incremental cost-effectiveness ratios. Both direct and indirect costs were considered to reflect the societal perspective. Effectiveness outcome was PASI-75 response. One-way and probabilistic sensitivity analyses explored the effect of treatment duration, discount rate, effectiveness, and the perspective (societal vs. healthcare system) on the findings. According to the base-case analysis a cost-effective treatment pathway for moderate-to-severe psoriasis starts with methotrexate, followed by ustekinumab 90 mg and infliximab, if methotrexate does not achieve or maintain PASI-75 response. Sensitivity analyses confirmed the general robustness of these findings with methotrexate being most cost-effective. However, from a third-party-payer perspective (without indirect cost) conventional therapies were generally more cost-effective than biologics. From a value-based healthcare perspective, methotrexate should be the systemic treatment of first choice, ustekinumab 90 mg second choice and infliximab third choice for patients with moderate-to-severe psoriasis. From a societal perspective, the other treatments are less efficient according to our model. From a third-party-payer perspective conventional therapies are more cost-effective than biologics.