Patient-reported, observer-reported and performance outcomes in qualification procedures at the European Medicines Agency 2013-2018.

AIMS: To describe characteristics of applicant, tool, outcomes, regulatory responses and general learnings from European Medicines Agency (EMA) Qualification Procedures on patient-reported outcomes (PROs), observer-reported outcomes (ObsROs) and performance outcomes (PerfOs) finalized between January 2013 and December 2018. METHODS: Descriptive analysis, and qualitative review of the regulatory outcomes of the study procedures. RESULTS: Seventeen qualification programmes for PROs, 6 for ObsRO tools and 11 for PerfO tools were submitted by consortia, large and small/medium companies. Gastroenterology and neurology were the most frequent therapeutic areas. There was a high level of regulators' partial agreement (above 70%) with applicant's approaches with constructive input; EMA published Letters of Support for PRO (6), ObsRO (2) and PerfO (4) tools, and Qualification Opinions on PROs (2) and PerfOs (1). General issues related to Qualification Procedures on PROs raised by EU regulatorsincluded: population, appropriate studies to demonstrate ability to detect change, tool validation in interventional trials, anchoring, identification of the minimally important difference, item selection, weighting, and multiple domains. In addition, specific issues for ObsROs and PerfO tools validation are identified. CONCLUSIONS: Regulators discussed principles and challenges of validation tailored to specific setting in tool development, providing constructive feedback. Regulatory outputs supportive of further development were published in over one-third of programs. We encourage applicants intending to use or develop novel PRO, ObsRO and PerfO tools that will generate evidence for regulatory submissions on medicines to consider Qualification procedures for novel methods to seek feedback on the development and validation of these tools.

Biomarker-Driven Developments in the Context of the New Regulatory Framework for Companion Diagnostics in the European Union.

The new In Vitro Diagnostic Regulation (EU) 2017/746 (IVDR) introduces important changes in the EU legal framework for companion diagnostics (CDx), including a new risk-based classification system for in vitro diagnostic tests (IVDs), a first legal definition for CDx and enhanced involvement of notified bodies in the conformity assessment and certification process of CDx. The IVDR also establishes an important link between the assessment of a CDx and the corresponding medicinal product by requiring the notified body to seek a scientific opinion from the medicines regulator on the suitability of the CDx for use with the concerned medicinal product(s) before issuing an IVD certificate. Whereas the IVDR aims at establishing a robust regulatory framework for IVDs, it is also associated with several challenges, such as insufficient capacity of notified bodies and readiness of manufacturers. To ensure timely access for patients to essential IVDs, a progressive roll-out for this new legislation has been introduced. In addition, the new consultation process for CDx requires increased collaboration and alignment of assessments performed by the different stakeholders involved in this process. The European Medicines Agency (EMA) and notified bodies are currently building experience based on the first CDx consultation procedures that have been submitted from January 2022 onward. In the current article, we describe the new European regulatory framework for certification of CDx and highlight several challenges for medicine and CDx co-development. In addition, we briefly touch upon the interplay between the Clinical Trial Regulation (EU) No. 536/2014 (CTR) and the IVDR.

The Added Value of Patient Engagement in Early Dialogue at EMA: Scientific Advice as a Case Study.

The European Medicines Agency provides Scientific Advice to medicines developers and patient input has been an integral part of this process for many years. As end users of medicines, patients bring their perspectives to many different processes along EMA's regulatory pathway, complementing the scientific expertise. While the value of including patients has been well-demonstrated over the years, requests for evidence of their impact continue. Using Scientific Advice as a case study, data was collected over a four-year period to assess the number of patients involved, where they contributed, as well as the impact and added value of their input. In this paper, we show that patients' contributions have a tangible impact on the recommendations provided to developers and in over half of the cases, this led to further discussion on relevant patient perspectives. These data provide quantitative evidence of the value of patient input in medicines development and supports EMA's continued inclusion of their voice throughout the medicine's lifecycle.

Randomized Controlled Trials Versus Real World Evidence: Neither Magic Nor Myth.

Compared with drugs from the blockbuster era, recently authorized drugs and those expected in the future present a heterogenous mix of chemicals, biologicals, and cell and gene therapies, a sizable fraction being for rare diseases, and even individualized treatments or individualized combinations. The shift in the nature of products entails secular trends for the definitions of "drugs" and "target population" and for clinical use and evidence generation. We discuss that the lessons learned from evidence generation for 20th century medicines may have limited relevance for 21st century medicines. We explain why the future is not about randomized controlled trials (RCTs) vs. real-world evidence (RWE) but RCTs and RWE-not just for the assessment of safety but also of effectiveness. Finally, we highlight that, in the era of precision medicine, we may not be able to reliably describe some small treatment effects-either by way of RCTs or RWE.

Clinical Trials for COVID-19: Can we Better Use the Short Window of Opportunity?

The scientific community has risen to the coronavirus disease 2019 (COVID-19) challenge, coming up with an impressive list of candidate drugs and vaccines targeting an array of pharmacological and immunological mechanisms. Yet, generating clinical evidence of efficacy and safety of these candidate treatments may be frustrated by the absence of comprehensive trial coordination mechanisms. Many small stand-alone trials and observational studies of single-agent interventions are currently running or in planning; many of these will likely not deliver robust results that could support regulatory and patient-level treatment decisions. In this paper, we discuss actions that all stakeholders in the clinical trial ecosystem need to take to ensure that the window of opportunity during this pandemic will not shut, both for patients in need of treatment and for researchers to conduct decision-relevant clinical trials.

Regulatory and health technology assessment advice on postlicensing and postlaunch evidence generation is a foundation for lifecycle data collection for medicines.

The understanding of the benefit risk profile, and relative effectiveness of a new medicinal product, are initially established in a circumscribed patient population through clinical trials. There may be uncertainties associated with the new medicinal product that cannot be, or do not need to be resolved before launch. Postlicensing or postlaunch evidence generation (PLEG) is a term for evidence generated after the licensure or launch of a medicinal product to address these remaining uncertainties. PLEG is thus part of the continuum of evidence development for a medicinal product, complementing earlier evidence, facilitating further elucidation of a product's benefit/risk profile, value proposition, and/or exploring broader aspects of disease management and provision of healthcare. PLEG plays a role in regulatory decision making, not only in the European Union but also in other jurisdictions including the USA and Japan. PLEG is also relevant for downstream decision-making by health technology assessment bodies and payers. PLEG comprises studies of different designs, based on data collected in observational or experimental settings. Experience to date in the European Union has indicated a need for improvements in PLEG. Improvements in design and research efficiency of PLEG could be addressed through more systematic pursuance of Scientific Advice on PLEG with single or multiple decision makers. To date, limited information has been available on the rationale, process or timing for seeking PLEG advice from regulators or health technology assessment bodies. This article sets out to address these issues and to encourage further uptake of PLEG advice.

Are Novel, Nonrandomized Analytic Methods Fit for Decision Making? The Need for Prospective, Controlled, and Transparent Validation.

Real-world data and patient-level data from completed randomized controlled trials are becoming available for secondary analysis on an unprecedented scale. A range of novel methodologies and study designs have been proposed for their analysis or combination. However, to make novel analytical methods acceptable for regulators and other decision makers will require their testing and validation in broadly the same way one would evaluate a new drug: prospectively, well-controlled, and according to a pre-agreed plan. From a European regulators' perspective, the established methods qualification advice procedure with active participation of patient groups and other decision makers is an efficient and transparent platform for the development and validation of novel study designs.

The Qualification of an Enrichment Biomarker for Clinical Trials Targeting Early Stages of Parkinson's Disease.

As therapeutic trials target early stages of Parkinson's disease (PD), appropriate patient selection based purely on clinical criteria poses significant challenges. Members of the Critical Path for Parkinson's Consortium formally submitted documentation to the European Medicines Agency (EMA) supporting the use of Dopamine Transporter (DAT) neuroimaging in early PD. Regulatory documents included a comprehensive literature review, a proposed analysis plan of both observational and clinical trial data, and an assessment of biomarker reproducibility and reliability. The research plan included longitudinal analysis of the Parkinson Research Examination of CEP-1347 Trial (PRECEPT) and the Parkinson's Progression Markers Initiative (PPMI) study to estimate the degree of enrichment achieved and impact on future trials in subjects with early motor PD. The presence of reduced striatal DAT binding based on visual reads of single photon emission tomography (SPECT) scans in early motor PD subjects was an independent predictor of faster decline in UPDRS Parts II and III as compared to subjects with scans without evidence of dopaminergic deficit (SWEDD) over 24 months. The EMA issued in 2018 a full Qualification Opinion for the use of DAT as an enrichment biomarker in PD trials targeting subjects with early motor symptoms. Exclusion of SWEDD subjects in future clinical trials targeting early motor PD subjects aims to enrich clinical trial populations with idiopathic PD patients, improve statistical power, and exclude subjects who are unlikely to progress clinically from being exposed to novel test therapeutics.

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

AIMS: The parallel regulatory-health technology assessment scientific advice (PSA) procedure allows manufacturers to receive simultaneous feedback from both EU regulators and health technology assessment (HTA) bodies on development plans for new medicines. The primary objective of the present study is to investigate whether PSA is integrated in the clinical development programmes for which advice was sought. METHODS: Contents of PSA provided by regulators and HTA bodies for each procedure between 2010 and 2015 were analysed. The development of all clinical studies for which PSA had been sought was tracked using three different databases. The rate of uptake of the advice provided by regulators and HTA bodies was assessed on two key variables: comparator/s and primary endpoint. RESULTS: In terms of uptake of comparator recommendations at the time of PSA in the actual development, our analysis showed that manufacturers implemented comparators to address both the needs of regulators and of at least one HTA body in 12 of 21 studies. For primary endpoints, in all included studies manufacturers addressed both the needs of the regulators and at least one HTA body. CONCLUSIONS: One of the key findings of this analysis is that manufacturers tend to implement changes to the development programme based on both regulatory and HTA advice with regards to the choice of primary endpoint and comparator. It also confirms the challenging choice of the study comparator, for which manufacturers seem to be more inclined to satisfy the regulatory advice. Continuous research efforts in this area are of paramount importance from a public health perspective.

Marketing authorisation of orphan medicines in Europe from 2000 to 2013.

An analysis was performed on a data set of 157 orphan designated medicines with an outcome for marketing authorisation application (MAA) between 2000 and 2013. The intention was to understand the factors associated with marketing authorisation success, the challenges developers face regarding orphan medicine development, and how scientific advice (SA) is used during development. The results demonstrated that orphan medicines have a lower success rate compared with non-orphan medicines and that determinants for marketing authorisation success were company size and compliance with SA. Compliance with SA could help orphan medicine developers overcome clinical development challenges.

Advanced Therapy Medicinal Products for Rare Diseases: State of Play of Incentives Supporting Development in Europe.

In 2008, the European Union introduced the Advanced Medicines Regulation aiming to improve regulation of advanced therapy medicinal products (ATMPs). We applied the ATMPs classification definitions in this Regulation to understand the link of this emerging group of medicinal products and the use of the Orphan Regulation. A total of 185 products that can be classified as ATMPs based on this Regulation have been submitted for orphan designation. Prior to its introduction in 2008, 4.5% of the products submitted for orphan designation met these criteria. This percentage went up to 15% after 2008. We analyzed several parameters associated with active ATMP ODDs focusing on sponsor type and EU-Member State origin, therapeutic area targeted, and ATMP classification [i.e., somatic cell therapy medicinal product, tissue-engineered product (TEP), or gene therapy medicinal product (GTMP)] and the use of regulatory services linked to incentives such as the use of protocol assistance (PA) and other Committees [Committee for Advanced Therapies (CAT) and the Pediatric Committee]. The aim here was to gain insight on the use of different services. The UK submits the largest number of ATMPs for ODD representing ~30% of the total to date. Few submissions have been received from central and Eastern European Member States as well as some of the larger Member States such as Germany (3.6%). ATMPs ODDs were primarily GTMPs (48.7%) and SCTMPs (43.3%). TEPs only represented 8% of all submissions for this medicinal class. This is different from non-ODDs ATMPs where GTMPs make only 20% of ATMPs. A total of 11.7% of ATMP ODDs had received formal CAT classification. A total of 29.8% of all orphan drug (OD) ATMPs requested PA. A total of 71.8% did not have an agreed pediatric investigation plan (PIP). Four products (Glybera one PA; Zalmoxis two; Holoclar one; Strimvelis three) have received a marketing authorization (MAA) and a 10-year market exclusivity. Strimvelis also completed their PIP, which was compliant and received the additional 2-year extension to their 10-year market exclusivity. One OD ATMP (Cerepro) received a negative opinion for MAA. The use of services linked to incentives offered by different legislations for ATMP ODDs is low, indicating a need for increasing awareness.

Clinician-Reported Outcome Assessments of Treatment Benefit: Report of the ISPOR Clinical Outcome Assessment Emerging Good Practices Task Force.

A clinician-reported outcome (ClinRO) assessment is a type of clinical outcome assessment (COA). ClinRO assessments, like all COAs (patient-reported, observer-reported, or performance outcome assessments), are used to 1) measure patients' health status and 2) define end points that can be interpreted as treatment benefits of medical interventions on how patients feel, function, or survive in clinical trials. Like other COAs, ClinRO assessments can be influenced by human choices, judgment, or motivation. A ClinRO assessment is conducted and reported by a trained health care professional and requires specialized professional training to evaluate the patient's health status. This is the second of two reports by the ISPOR Clinical Outcomes Assessment-Emerging Good Practices for Outcomes Research Task Force. The first report provided an overview of COAs including definitions important for an understanding of COA measurement practices. This report focuses specifically on issues related to ClinRO assessments. In this report, we define three types of ClinRO assessments (readings, ratings, and clinician global assessments) and describe emerging good measurement practices in their development and evaluation. The good measurement practices include 1) defining the context of use; 2) identifying the concept of interest measured; 3) defining the intended treatment benefit on how patients feel, function, or survive reflected by the ClinRO assessment and evaluating the relationship between that intended treatment benefit and the concept of interest; 4) documenting content validity; 5) evaluating other measurement properties once content validity is established (including intra- and inter-rater reliability); 6) defining study objectives and end point(s) objectives, and defining study end points and placing study end points within the hierarchy of end points; 7) establishing interpretability in trial results; and 8) evaluating operational considerations for the implementation of ClinRO assessments used as end points in clinical trials. Applying good measurement practices to ClinRO assessment development and evaluation will lead to more efficient and accurate measurement of treatment effects. This is important beyond regulatory approval in that it provides evidence for the uptake of new interventions into clinical practice and provides justification to payers for reimbursement on the basis of the clearly demonstrated added value of the new intervention.

How aligned are the perspectives of EU regulators and HTA bodies? A comparative analysis of regulatory-HTA parallel scientific advice.

BACKGROUND: In 2010, the European Medicines Agency (EMA) initiated a pilot project on parallel scientific advice with Health Technology Assessment bodies (HTABs) that allows manufacturers to receive simultaneous feedback from both the European Union (EU) regulators and HTABs on their development plans for medicines. AIMS: The present retrospective qualitative analysis aimed to explore how the parallel scientific advice system is working and levels of commonality between the EU regulators and HTABs, and among HTABs, when applicants obtain parallel scientific advice from both a regulatory and an HTA perspective. METHODS: We analysed the minutes of discussion meetings held at the EMA between 2010, when parallel advice was launched, and 1 May 2015, when the cutoff date for data extraction was set. The analysis was based on predefined criteria and conducted at two different levels of comparison: the answers of the HTABs vs. those of the regulators, and between the answers of the participating HTA agencies. RESULTS: The analysis was based on 31 procedures of parallel scientific advice. The level of full agreements was highest for questions on patient population (77%), while disagreements reached a peak for questions on the study comparator (30%). With regard to comparisons among HTABs, there was a high level of agreement for all domains. CONCLUSIONS: There is evident commonality, in terms of evidence requirements between the EU regulators and participating HTABs, as well as among HTABs, on most aspects of clinical development. Indeed, regardless of the question content, the analysis showed that a high level of overall agreement was reached through the process of parallel scientific advice.