Perspectives on how to build bridges between regulation, health technology assessment and clinical guideline development: a qualitative focus group study with European experts.

OBJECTIVE: Improving synergy among regulation, health technology assessment (HTA) and clinical guideline development is relevant as these independent processes are building on shared evidence-based grounds. The two objectives were first to assess how convergence of evidentiary needs among stakeholders may be achieved, and second, to determine to what extent convergence can be achieved. DESIGN: Qualitative study using eight online dual-moderator focus groups. SETTING: Discussions had a European focus and were contextualised in four case studies on head and neck cancer, diabetes mellitus, multiple sclerosis and myelodysplastic syndromes. PARTICIPANTS: Forty-two experienced (over 10 years) European regulators, HTA representatives and clinicians participated in the discussion. INTERVENTIONS: Participants received information on the case study and research topic in advance. An introductory background presentation and interview guide for the moderators were used to steer the discussion. RESULTS: Convergence may be achieved through improved communication institutionalised in multistakeholder early dialogues, shared definitions and shared methods. Required data sets should be inclusive rather than aligned. Deliberation and decision-making should remain independent. Alignment could be sought for pragmatic clinical trial designs and patient registries. Smaller and lower-income countries should be included in these efforts. CONCLUSION: Actors in the field expressed that improving synergy among stakeholders always involves trade-offs. A balance needs to be found between the convergence of processes and the institutional remits or geographical independence. A similar tension exists between the involvement of more actors, for example, patients or additional countries, and the level of collaboration that may be achieved. Communication is key to establishing this balance.

Interchangeability of biosimilars: A study of expert views and visions regarding the science and substitution.

Healthcare systems have reached a critical point regarding the question of whether biosimilar substitution should become common practice. To move the discussion forward, the study objective was to investigate the views of experts from medicines agencies and the pharmaceutical industry on the science underpinning interchangeability of biosimilars. We conducted an empirical qualitative study using semi-structured interviews informed by a cross-disciplinary approach encompassing regulatory science, law, and pharmaceutical policy. In total 25 individuals with experience within biologics participated during September 2018-August 2019. Eight participants were EU national medicines authority regulators, and 17 had pharmaceutical industry background: five from two originator-only companies, four from two companies with both biosimilar and originator products, and eight from seven biosimilar-only companies. Two analysts independently conducted inductive content analysis, resulting in data-driven themes capturing the meaning of the data. The participants reported that interchangeability was more than a scientific question of likeness between biosimilar and reference products: it also pertained to regulatory practices and trust. Participants were overall confident in the science behind exchanging biosimilar products for the reference products via switching, i.e., with physician involvement. However, their opinions differed regarding the scientific risk associated with biosimilar substitution, i.e., without physician involvement. Almost all participants saw no need for additional scientific data to support substitution. Moreover, the participants did not believe that switching studies, as required in the US, were appropriate for obtaining scientific certainty due to their small size. It is unclear why biosimilar switching is viewed as scientifically safer than substitution; therefore, we expect greater policy debate on biosimilar substitution in the near future. We urge European and UK policymakers and regulators to clarify their visions for biosimilar substitution; the positions of these two frontrunners are likely to influence other jurisdictions on the future of biosimilar use.

Improving Interactions Between Health Technology Assessment Bodies and Regulatory Agencies: A Systematic Review and Cross-Sectional Survey on Processes, Progress, Outcomes, and Challenges.

The need to optimize drug development and facilitate faster access for patients has ignited discussions around the importance of improving interactions between health technology assessment (HTA) bodies and regulatory agencies. In this study, we conducted a systematic review to examine processes, progress, outcomes, and challenges of harmonization/interaction initiatives between HTA bodies and regulatory agencies. MEDLINE, EMBASE, and the International Pharmaceutical Abstracts database were searched up to 21 October 2019. Searches for gray literature (working papers, commissioned reports, policy documents, etc.) were performed via Google scholar and several institutional websites. An online cross-sectional survey was also conducted among HTA (n = 22) and regulatory agencies (n = 6) across Europe to supplement the systematic review. Overall, we found that while there are areas of divergence, there has been progress over time in narrowing the gap in evidentiary requirements for HTA bodies and regulatory agencies. Most regulatory agencies (4/6; 67%) and half (11/22, 50%) of the HTA bodies reported having a formal link for "collaborating" with the other. Several mechanisms such as early tripartite dialogues, parallel submissions (reviews), adaptive licensing pathways, and postauthorization data generation have been explored as avenues for improving collaboration. A number of pilot initiatives have shown positive effects of these models to reduce the time between regulatory and HTA decisions, which may translate into faster access for patients to life-saving therapies. Thus, future approaches aimed at improving harmonization/interaction between HTA bodies and regulatory agencies should build on these existing models/mechanisms while examining their long-term impacts. Several barriers including legal, organizational, and resource-related factors were also identified, and these need to be addressed to achieve greater alignment in the current regulatory and reimbursement landscape.

Are ECG monitoring recommendations before prescription of QT-prolonging drugs applied in daily practice? The example of haloperidol.

PURPOSE: Monitoring of the QT duration by electrocardiography (ECG) prior to treatment is frequently recommended in the label of QT-prolonging drugs. It is, however, unknown how often general practitioners in daily clinical practice are adhering to these risk-minimization measures. We assessed the frequency of ECG measurements in patients where haloperidol was initiated in primary care. METHODS: Patients (≥18 years) with a first prescription of haloperidol in the UK Clinical Practice Research Datalink (2009-2013) were included. The proportion of ECGs made was determined in two blocks of 4 weeks: during the exposure period when haloperidol was initiated, and during the control period, 1 year before. Conditional logistic regression analysis was applied to calculate the relative risk of having an ECG in the exposure period compared with the control period. Subgroup analyses were performed to assess the proportion of ECG measurements in patients with one or more additional risk factors for QT prolongation. RESULTS: In total, 3420 patients were prescribed haloperidol during the exposure period, and 1.8% of them had an ECG at treatment initiation, compared with 0.8% during the control period (relative risk [RR] 2.4 [1.5-3.8]). Of the patients with additional risk factors for QT prolongation, 1.9% of the patients had an ECG at initiation of the prescription, compared with 1.0% during the control period (RR 2.1 [1.2-3.5]). CONCLUSIONS: Compliance with recommendations to perform an electrocardiogram when starting a new QT-prolonging drug is extremely low, when haloperidol is taken as an example.