The impact of parallel regulatory–health technology assessment scientific advice on clinical development. Assessing the uptake of regulatory and health technology assessment recommendations

Tafuri, Giovanni; Lucas, Inês; Estevão, Steve; Moseley, Jane; d’Andon, Anne; Bruehl, Hannah; Gajraj, Elangovan; Garcia, Sonia E.; Hedberg, Niklas; Massari, Marco; Molina, A. Gonzalez; Obach, Mercè; Osipenko, Leeza; Pétavy, Frank; Petschulies, Marco; Pontes, Caridad; Russo, Pierluigi; Schiel, Anja; Casteele, Marc Van de; Zebedin-Brandl, Eva-Maria; Rasi, Guido; Vamvakas, Spiros

doi:10.1111/bcp.13524

Cited by 35 publications

(43 citation statements)

References 5 publications

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“…In 60% of cases, the comparators implemented would meet the needs of regulators and at least one HTA body involved in the advice and in 100% of cases for the primary endpoints. This supports the need to gather external input to support decision making for clinical trial design …”

Section: Parallel Advice Between European Regulators and European Htamentioning

confidence: 75%

Multistakeholder Advice at the European Medicines Agency: Is It Still Needed?

Vamvakas¹,

Moseley²,

Vetter³

2019

Clin Pharma and Therapeutics

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To address clinical trials conducted for regulators and other decision-making purposes the European Medicines Agency offers different multistakeholder platforms (parallel advice with Health Technology Assessment (HTA) bodies or with the US Food and Drug Administration (FDA)) in which different decision makers can provide simultaneous feedback on proposals for evidence generation. In this article, we present the case for seeking such advice, how they work in practice, and which products are best targeted for which procedures. PARALLEL ADVICE BETWEEN EUROPEAN REGULATORS AND EUROPEAN HTA BODIESHealth technology assessment now features in a majority of European Member States with 48 organizations having a defined role in directly advising a decision maker with regard to HTA of new medical technologies. Different methodologies among HTA bodies are also recognized 1 but all require that the evidence for HTA addresses relative effectiveness domains, including clinical effectiveness but potentially also issues of transferability to local contexts and wider components (economic and patient aspects) when relevant. Building on the success of standard scientific advice from regulators, in which scientific advice is a tool to drive adequate data for the benefit-risk assessment at the time of marketing authorization (MA), parallel advice with HTA bodies was introduced to facilitate adequate evidence generation to meet the needs of different stakeholders and to avoid unnecessary trial duplication.In a parallel advice on a particular product, European regulators and HTA bodies give their views on the evidence generation plans at the same time. As an upstream decision maker, the regulator's position can be informative. For many HTAs, the licensed indication is a critical starting point for the appraisal process.Levels of alignment between regulators and HTA bodies on the trial designs for a product are a marker for the efficiency of the evidence generation. For a cohort of parallel advice procedures, a high level of agreement/partial agreement between the regulators and HTA bodies on the nature of the evidence to be collected was found at the end of the process supporting the potential for efficient evidence generation. 2 The current procedure provides for discussion meetings with the developers, HTA, and regulatory representatives on the most controversial aspects of the proposals. We have tracked programs that have been the subject of parallel advice with HTA bodies to see if the clinical trials were compliant with the advice given. Developers frequently changed comparators (81% of studies) and primary endpoints (74%) compared to those initially proposed in advices. In 60% of cases, the comparators implemented would meet the needs of regulators and at least one HTA body involved in the advice and in 100% of cases for the primary endpoints. This supports the need to gather external input to support decision making for clinical trial design. 3 Alignment between regulators and HTAs cannot be reached on the trial design in all case...

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Section: Parallel Advice Between European Regulators and European Htamentioning

confidence: 75%

Multistakeholder Advice at the European Medicines Agency: Is It Still Needed?

Vamvakas¹,

Moseley²,

Vetter³

2019

Clin Pharma and Therapeutics

Self Cite

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“…Similar initiatives to PRIME exist elsewhere, such as the breakthrough therapy designation program in the USA and the Sakigake Designation in Japan [33]. Increased early contacts and joint scientific advice with both regulators and HTA bodies should also be encouraged to identify the best comparator in clinical trials and facilitate the choice of primary end points that deliver added therapeutic value, which would ultimately accelerate access to new treatment options for cancer patients [34,35].…”

Section: • Improve Early Contacts Between Clinicians Regulators and Htamentioning

confidence: 96%

Biased by design? Clinical trials and patient benefit in oncology

2019

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trial design • drug development • drug registration • patient benefit • risks of bias Pivotal clinical trials: biased? A recent study by Naci et al. examined the design characteristics, risks of bias and reporting adequacies of pivotal randomized controlled trials of cancer drugs approved by the EMA in the period 2014-2016 [1]. During this period, 32 new cancer drugs were approved by the EMA on the basis of 54 pivotal trials-of these, 41 (76%) were randomized controlled trials and 13 (24%) were non-randomized or single arm trials. The study reported that 49% of trials were judged to be at high risk of bias based on aspects of their design, conduct or analysis. Furthermore, only 10 (26%) randomized controlled trials measured overall survival as a primary end point, with the majority of trials evaluating surrogate metrics such as progression free survival or response rates. Furthermore, there were also discrepancies between scientific publications and regulatory documentation, thereby raising concerns of reporting inadequacies and risks of bias in both sources of information. These findings raise serious questions regarding clinical trial design and the drug registration process, particularly with regards to patient benefits. The problem is not restricted to Europe alone; previous studies have also raised concerns with US FDA approvals. For example, a study that assessed all FDA approvals of novel drugs, across all areas of medicine in the period 2005-2012, reported wide disparities in pivotal trial characteristics across different therapeutic areas [2]. While overall 219 of 448 (48.9%) pivotal trials included a surrogate end point, for cancer it was 46 of 55 (83.6%). Pivotal trials in cancer were also less likely to be randomized, double-blinded or to not include a placebo or active comparator. Another notable finding was that most cancer approvals were on the basis of a single pivotal trial, whereas for other therapeutic areas, approvals were based on two to four pivotal trials. A different study examining FDA cancer drug approvals based on response rate showed that many cancer drugs are approved based on low or modest response rates, typically tested in single-arm studies [3]. It could be argued that the surrogate end points used in such pivotal trials are acceptable as they correlate to overall survival and/or quality of life in the long term [4]. However, the data to support such an argument is lacking [5]. A recent systematic review of the association between surrogate end points and overall survival in oncology showed that the vast majority (82%) are low or moderate in strength [6]. A study of FDA approvals of cancer drugs during 2008-2012, a period in which 67% of approvals were made on the basis of a surrogate end point, assessed whether subsequent data emerged to show an increase in overall survival [7]. With a median follow-up of 4.4 years, the study reported that of 36 drugs approved with surrogate end points, only five subsequently reported improved overall survival in a randomized controlled trial, 18...

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“…Following examination of comparator nonalignment, representative cases ( Table ) exemplifying impact of timely PSA on comparator divergence resolution have been highlighted by the EMA, whereby solutions obtained earlier in development yielded plans to satisfy the EMA and HTAB . A 2018 analysis revealed that the EMA and HTA collective comparator advice is implemented in only 60% of cases, with regulator advice being followed otherwise …”

Section: Ema‐htab Psa Pilot Case Studies and Program Development Impactmentioning

confidence: 99%

“…This begs for direct questions applicable and open to both the EMA and HTABs to discuss toward possible convergence and divergence clarification. Recent analyses on alignment of the EMA and HTAB feedback and degree of agreement by specific question domain (e.g., patient population and comparator) outline good examples to consider . The PC platform can then uncover views of each stakeholder on elements crucial to registration and market access and allow discussion on acceptable alternatives in cases of divergence.…”

Section: Ema‐htab Psa Pilot Case Studies and Program Development Impactmentioning

confidence: 99%