Analytical Methods for Comparing Uncontrolled Trials with External Controls from Real-World Data: a Systematic Literature Review and Comparison to European Regulatory and Health Technology Assessment Practice.

OBJECTIVES: To provide an overview of analytical methods in scientific literature for comparing uncontrolled medicine trials to external controls from individual patient-level real-world data (IPD-RWD). In addition, to compare these methods with recommendations made in guidelines from European regulatory and health technology assessment (HTA) organizations and with their evaluations described in assessment reports. METHODS: A systematic literature review (until March 1st 2023) in PubMed and Connected Papers was performed to identify analytical methods for comparing uncontrolled trials with external controls from IPD-RWD. These methods were compared descriptively to methods recommended in method guidelines and encountered in assessment reports of the European Medicines Agency (2015-2020) and four European HTA organizations (2015-2023). RESULTS: Thirty-four identified scientific articles described analytical methods for comparing uncontrolled trial data to IPD-RWD-based external controls. The various methods covered controlling for confounding and/or dependent censoring, correction for missing data; and analytical comparative modelling methods. Seven guidelines also focused on research design, RWD quality and transparency aspects, and four of those recommended analytical methods for comparisons with IPD-RWD. The methods discussed in regulatory (n=15) and HTA (n=35) assessment reports were often based on aggregate data and lacked transparency due to the few details provided. CONCLUSION: Literature and guidelines suggest a methodological approach to comparing uncontrolled trials with external controls from IPD-RWD similar to target trial emulation, using state-of-the-art methods. External controls supporting regulatory and HTA decision-making were rarely in line with this approach. Twelve recommendations are proposed to improve the quality and acceptability of these methods.

Harmonizing regulatory market approval of products with high safety requirements: Evidence from the European pharmaceutical market.

We causally analyzed whether being a member of the European Union (EU) and having access to a centralized marketing authorization procedure (centralized procedure [CP]) affects availability and time to launch of new pharmaceuticals. We employed multiple difference-in-differences models, exploiting the eastern enlargement of the EU as well as changes in the indications that fall within the compulsory or voluntary scope of the CP. Results showed that countries experienced a mean decrease in launch delay of 10.9 months (p = 0.004) after joining the EU. Effects were higher among pharmaceuticals that belong to indications that might voluntarily participate in the CP but are not obliged to. These are often financially less attractive to manufacturers than pharmaceuticals within the compulsory scope. Availability of new pharmaceuticals launched remained unaffected. We found signs that the magnitude of the country-specific effect of centralized marketing authorization on launch delay may be influenced by strategic decisions of manufacturers at the national level (e.g., parallel trade or reference pricing).

Regulatory Aspects for Approval of Advanced Therapy Medicinal Products in the EU.

In the European Union (EU), advanced therapy medicinal products (ATMPs) undergo evaluation by the European Medicines Agency's (EMA) Committee for Advanced Therapies (CAT) to obtain marketing authorization under the centralized procedure. Because of the diversity and complexity of ATMPs, a tailored approach to the regulatory process is required that needs to ensure the safety and efficacy of each product. Since ATMPs often target serious diseases with unmet medical need, the industry and authorities are interested in providing treatment to patients in a timely manner through optimized and expedited regulatory pathways. EU legislators and regulators have implemented various instruments to support the development and authorization of innovative medicines by offering scientific guidance at early stages, incentives for small developers and products for rare diseases, accelerated evaluation of marketing authorization applications, different types of marketing authorizations, and tailored programs for medicinal products with the orphan drug designation (ODD) and the Priority Medicines (PRIME) scheme. Since the regulatory framework for ATMPs was established, 20 products have been licenced, 15 with orphan drug designation, and 7 supported by PRIME. This chapter discusses the specific regulatory framework for ATMPs in the EU and highlights previous successes and remaining challenges.

Fast-tracking development and regulatory approval of COVID-19 vaccines in the EU: A review of ethical implications.

The rapid spread of SARS-CoV-2 worldwide has triggered intense activity in the field of biotechnology, leading to the development and regulatory approval of multiple COVID-19 vaccines in less than 1 year while raising sustained scrutiny as to the ethical issues associated with this process. This article pursues a twofold objective. First, it reconstructs and provides a thorough overview of the different steps, from clinical trial design to regulatory procedures, underpinning the "fast-tracking" of COVID-19 vaccine R&D and approval. Second, drawing on a review of published literature, the article identifies, outlines, and analyzes the most ethically challenging aspects related to such process, including concerns around vaccine safety, issues in study design, the enrollment of study participants, and the challenges in obtaining valid informed consent. By scrutinizing relevant aspects of COVID-19 vaccine development and regulatory processes leading to market authorization, this article ultimately aims to provide a comprehensive overview of the regulatory and ethical issues underpinning the roll-out of this key pandemic-containment technology worldwide.

Regulatory Frameworks for Advanced Therapy Medicinal Products in Thailand.

Advanced Therapy Medicinal Products (ATMPs) are a new class of medicinal products that fall under the Drug Act. B.E.2510. The Medicines Regulation Division, a regulatory unit under the Thai Food and Drug Administration, takes responsibility for the regulation of ATMPs. This includes importing or manufacturing of ATMPs for clinical trials, GMP inspection, and marketing authorization. In Thailand, ATMPs have been classified into four groups: cell therapy medicinal products, gene therapy medicinal products, tissue-engineered products, and combined ATMPs. At present, the guidelines for biological products are applied to ATMP in clinical trials and marketing authorization applications. At the same time, the specific guidelines for ATMPs are under development. This chapter provides an overview of the Thai FDA regulatory oversight of ATMPs, which covers investigational ATMPs, GMP certification, and marketing authorization.

From the Integrity of Potency Assays to Safe Clinical Intervention: Legal Perspectives.

Potency assays associated with the efficacy of investigational pharmaceutical products are one of the critical quality attributes that need to be carefully monitored during advanced therapy medicinal product (ATMP) development projects. Ensuring integrity of relevant potency assays for stem cell-based ATMPs is of paramount importance for safety and efficacy of clinical interventions. Yet, due to the complex and heterogeneous nature of stem cell-based ATMPs, creation of an appropriate set of potency assays is associated with a number of specific challenges ranging from intrinsic and operational to legal and regulatory ones. This chapter provides an overview of the EU regulatory landscape for advanced therapies, highlighting important aspects that need to be taken into consideration when preparing a strategic plan to meet the EU regulatory requirements.

The Regulation of Cell Therapy and Gene Therapy Products in Switzerland.

This chapter describes the regulation of cell and gene therapy products (CGTPs) in Switzerland and its legal basis. The Swiss Agency for Therapeutic Products, Swissmedic, is the lead Regulatory Authority and its ATMP Division is responsible for the regulation of these products at the level of clinical trials and marketing authorization. CGTPs are regulated similarly to medicinal products. The legal basis is set by the Therapeutic Product Act, the Transplantation Act, the Human Research Act, and associated ordinances. The ATMP Division is involved in processes such as scientific advice meetings, presubmission advice meetings, pharmacovigilance, market surveillance, import/export approvals, manufacturing license approval, and inspections. In Switzerland, guidance documents relevant for cell and gene therapy provided by PIC/S, OECD, ICH, Ph.Eur., EMA, or FDA are considered. In order to harmonize requirements for CGTPs, the ATMP Division is in constant exchange of information with foreign Regulatory Authorities and part of working groups of ICH, IPRP, and Ph.Eur. As CGTPs are biologically and technically complex, a risk-based approach is applied on a case-by-case basis for the evaluation of clinical trial and marketing applications. A substantial part of this chapter will provide requirements with respect to the manufacturing and quality, nonclinical and clinical evaluation of CGTPs. Furthermore, information will be provided regarding the use of real-world evidence in evaluation of clinical long-term efficacy and safety in case of rare diseases where the numbers of patients are too small for statistically meaningful analysis during clinical trials. Finally, the chapter will provide information on a health technology assessment (HTA) program that was launched in 2015 in Switzerland by the federal authorities.

Factors associated with early relapse of infantile haemangioma in children treated for at least six months with oral propranolol: A case-control study using the 2014-2021 French Ouest DataHub.

BACKGROUND: The factors associated with early relapse of infantile haemangioma (IH) after a first course of treatment with oral propranolol for at least six months (initiated after the marketing authorization had been granted) have not previously been investigated. OBJECTIVES: To identify factors associated with the risk of early relapse in children with IH treated with oral propranolol according to the current prescribing guidelines. METHODS: We performed a multicentre, retrospective, case-control study, using the Ouest Data Hub database. All children treated for at least 6 months with oral propranolol for IH between 31 June 2014 and 31 December 2021, and with a follow-up visit at least three months after treatment discontinuation were included. A case was defined as relapse of IH within three months of treatment discontinuation; each case was matched for age at treatment initiation and for centre, with four (relapse-free) controls. The association between relapse and treatment or IH characteristics was expressed as an odds ratio (OR) from univariate and multivariate conditional logistic regressions. RESULTS: A total of 225 children were included. Of these, 36 (16%) relapsed early. In a multivariate analysis, a deep IH component was a risk factor for early relapse [OR = 8.93; 95%CI: 1.0-78.9, p = 0.05]. A propranolol dosage level of less than 3 mg/kg/day protected against early relapse [OR = 0.11; 95%CI: 0.02-0.7, p = 0.02]. Tapering before propranolol discontinuation was not associated with a lower risk of early relapse. CONCLUSION: The risk factors for late and early relapse are probably different. Investigation of the risk factors for early vs. late IH relapse is now warranted.

Pre-approval and post-approval availability of evidence and clinical benefit of conditionally approved cancer drugs in Europe: A comparison with standard approved cancer drugs.

AIMS: Cancer drugs are increasingly approved through expedited regulatory pathways including the European conditional marketing authorization (CMA). Whether, when taking CMA post-approval confirmatory trials into account, the level of evidence and clinical benefit between CMA and standard approved (SMA) drugs differs remains unknown. METHODS: We identified all CMA cancer indications converted to SMA in 2006-2020 and compared these to similar SMA indications with regard to pivotal trial and CMA post-approval confirmatory trial design, outcomes and demonstrated clinical benefit (per the European Society for Medical Oncology Magnitude of Clinical Benefit Scale). We tested for differences in clinical benefit and whether substantial clinical benefit was demonstrated. To account for the clinical benefit of unconverted CMA indications, we performed sensitivity analyses. RESULTS: We included 15 SMA and 15 converted CMA cancer indications (17 remained unconverted). Approval of 11 SMA (73%) and four CMA indications (27%) was supported by a controlled trial. Improved overall survival (OS) was demonstrated for four SMA indications (27%). Improved quality of life (QoL) was demonstrated for three SMA (20%) and one CMA indication(s) (7%). Of subsequent CMA post-approval confirmatory trials, 11 were controlled (79%), one demonstrated improved OS (7%) and five improved QoL (36%). After conversion, CMA indications were associated with similar clinical benefit (P = .31) and substantial clinical benefit as SMA indications (risk ratio 1.4, 95% confidence interval 0.57-3.4). CONCLUSION: While CMA cancer indications are initially associated with less comprehensive evidence than SMA indications, levels of evidence and clinical benefit are similar after conversion from CMA to SMA.

Surrogate Endpoints for Late Kidney Transplantation Failure.

In kidney transplant recipients, late graft failure is often multifactorial. In addition, primary endpoints in kidney transplantation studies seek to demonstrate the short-term efficacy and safety of clinical interventions. Although such endpoints might demonstrate short-term improvement in specific aspects of graft function or incidence of rejection, such findings do not automatically translate into meaningful long-term graft survival benefits. Combining many factors into a well-validated model is therefore more likely to predict long-term outcome and better reflect the complexity of late graft failure than using single endpoints. If conditional marketing authorization could be considered for therapies that aim to improve long-term outcomes following kidney transplantation, then the surrogate endpoint for graft failure in clinical trial settings needs clearer definition. This Consensus Report considers the potential benefits and drawbacks of several candidate surrogate endpoints (including estimated glomerular filtration rate, proteinuria, histological lesions, and donor-specific anti-human leukocyte antigen antibodies) and composite scoring systems. The content was created from information prepared by a working group within the European Society for Organ Transplantation (ESOT). The group submitted a Broad Scientific Advice request to the European Medicines Agency (EMA), June 2020: the request focused on clinical trial design and endpoints in kidney transplantation. Following discussion and refinement, the EMA made final recommendations to ESOT in December 2020 regarding the potential to use surrogate endpoints in clinical studies that aim to improving late graft failure.

[Analysis and Suggestions on Status Quo of Commissioned Production under Medical Device Marketing Authorization Holder System in China].

OBJECTIVE: Sort out and analyze the current status and existing problems of the pilot work of the medical device marketing authorization holder system to provide reference opinions for the full implementation of the medical device marketing authorization holder system. METHODS: Use literature analysis, comparative analysis and field research to comprehensively analyze the status, advantages and risks of commissioned production under the medical device marketing authorization holder system. RESULTS: The commissioned production under the medical device marketing authorization holder system brings dividends and also brings risks. CONCLUSIONS: We should consider improving the medical device marketing authorization holder system from marketing authorization holder, the entrusted manufacturer, and the regulatory authority, and strengthen the quality supervision of the entrusted production of products.

Haemophilia, state of the art and new therapeutic opportunities, a regulatory perspective.

Haemophilia A and B are rare bleeding disorders. Over the past decades, they have been transformed from debilitating diseases to manageable conditions in the Western world. However, optimizing haemophilia care remains challenging in developing countries. Several challenges and unmet needs remain in the treatment of the haemophilia limiting the QoL of patients. These challenges are now being addressed by extended half-life recombinant factors, rebalancing and substitution therapies. Gene therapy and genome editing show promise for a definite clinical cure. Here, we provide an overview of new therapeutic opportunities for haemophilia and their advances and limitations from a regulatory perspective. The database on human medicines from the European Medicines Agency (EMA) was used and data from rare disease (orphan) designations and EPARs were retrieved for the analysis. Clinical trial databases were used to query all active studies on haemophilia. Gene therapy medicinal products based on AAV and lentiviral vectors are in development and clinical trials have reported substantial success in ameliorating bleeding tendency in haemophilia patients. The prospect of gene editing for correction of the underlying mutation is on the horizon and has considerable potential. With regard to the benefit of the gene therapy medicinal products, more long-term efficacy and safety data are awaited. We are entering an era of innovation and abundance in treatment options for those affected by bleeding disorders, but issues remain about the affordability and accessibility to patients.

Signals from the Dutch national spontaneous reporting system: Characteristics and regulatory actions.

PURPOSE: The aim of the study is to characterise safety signals based on the Dutch spontaneous reporting system (SRS) and to investigate the association between signal characteristics and Product Information (PI) update stratified by approval type: centrally authorised products (CAPs) versus nationally and decentralised authorised products (NAPs). METHODS: This study evaluates the full cohort of signals disseminated from the Dutch SRS in the period from 2008 to 2017. Each retrieved signal was characterised on a number of aspects. The signal management process from signal generation to a potential PI update was analysed in four steps: (1) signal characterisation; (2) proposed actions by the Dutch national competent authority (NCA) for the signals; (3) presence of PI update (yes/no) and association with signal characteristics; (4) timing from the moment the signal was issued to PI update. For step 1-3 we stratified products in CAPs and NAPs. RESULTS: Of all signals, 88.7% led to a proposed regulatory action by the NCA. Signals from the Dutch SRS for CAPs versus NAPs more often concerned biologicals, important medical events, class effects and shorter periods since marketing authorization. We detected PI updates for 26.2% of CAP signals and 61.3% of NAP signals. CONCLUSIONS: The Dutch SRSs remains an important source of signals. There are some notable differences in the characteristics of signals for CAPs versus NAPs. Signals for NAPs more frequently led to PI updates.

[Hybrid medicines in France. Hybrid medicines: Genesis and legal framework in Europe and in France]. / Les médicaments hybrides en France. Genèse des médicaments hybrides et cadre règlementaire en Europe et en France.

Hybrid medicines are defined as medicines that do not fill generic medicines' definition, forming a medicines group that stands half-way between reference medicinal products and generic medicines. The term "hybrid" was introduced in France in 2018, but the concept has existed for some fifteen years in Community legislation. The aim of this work is to expose hybrid medicines' legal framework, in Europe and in France. Hybrid medicines' European legal framework specifies in a guide of the European Medicines Agency, marketing authorization procedures that can be used for hybrid medicines, and what is required for marketing authorization applications. In France, a register of hybrid medicines' groups has been created, and registration procedures were specified in a decree at the end of 2019. Legal texts also underlined that substitution within hybrid medicines' group would be possible for some specific medical cases. Decrees specifying hybrid medicines' groups list and specific medical cases allowing substitution, are not appeared yet at the end of February 2021. Moreover, some elements have never been raised, particularly medical and economic assessment modalities.

[Study on Technical Risks and Primary Responsibility of Medical Artificial Intelligence Diagnosis Products under Strategy of "Healthy China"].

OBJECTIVE: It provides reference for accurate and efficient supervision of medical artificial intelligence industry. METHODS: By summarizing the main responsibility dilemma of medical artificial intelligence diagnosis products, sorting out relevant researches at home and abroad, the primary responsibility system of medical artificial intelligence diagnosis products is constructed. RESULTS: A medical artificial intelligence diagnosis products primary responsibility system with the marketing authorization holder as the "first responsible person" is established, and three safeguard measures are proposed, namely, algorithm transparency and interpretability, classification supervision mode and social co-governance supervision mode. CONCLUSIONS: The medical artificial intelligence diagnosis products primary responsibility system is helpful to implement the primary responsibility, to build "responsible and beneficial" artificial intelligence, and to realize "self-discipline", "good governance" and "in good order".

An overview of international regulatory frameworks for mesenchymal stromal cell-based medicinal products: From laboratory to patient.

Human mesenchymal stromal cells (hMSCs) are emerging as one of the most important cell types in advanced therapies and regenerative medicine due to their great therapeutic potential. The development of hMSC-based products focuses on the use of hMSCs as biological active substances, and they are considered medicinal products by the primary health agencies worldwide. Due to their regulatory status, the development of hMSC-based products is regulated by specific criteria that range from the design phase, nonclinical studies, clinical studies, to the final registration and approval. Patients should only be administered hMSC-based products within the framework of a clinical trial or after the product has obtained marketing authorization; in both cases, authorization by health authorities is usually required. Considering the above, this paper describes the current general regulatory requirements for hMSC-based products, by jurisdiction, to be implemented throughout their entire development process. These measures may provide support for researchers from both public and private entities and academia to optimize the development of these products and their subsequent marketing, thereby improving access to them by patients.

An assessment of the hospital exemption landscape across European Member States: regulatory frameworks, use and impact.

The hospital exemption (HE) (Article 28(2) of Regulation (EC) No 1394/2007; the "ATMP Regulation") rule allows the invaluable opportunity to provide patients with access to innovative, potentially life-saving treatments in situations of unmet clinical need. Unlicensed, developmental advanced therapy medicinal products (ATMPs) - cell-, gene- or tissue-based therapies - can be used to treat patients under certain conditions. Such products should be produced on a non-routine basis, custom-made for an individual patient under the responsibility of the requesting physician, for use in a hospital setting within the same Member State in which they are manufactured. The HE rule, and the specific requirements permitting its use, is further regulated at the Member State level, which has led to divergence in the implementation of HE across the European Union (EU). As a result, HE use varies significantly across Member States depending on their respective national legal implementation, policy makers' interpretation of HE, clarity of guidance at the national level, reimbursement opportunities and level of ATMP research and development activities carried out by academic and commercial organizations. With important variations in how quality, safety and efficacy standards are implemented and controlled across EU Member States for ATMPs provided via the HE rule and a lack of transparency around its use, the HE rule draws concern around its potential impact on public health. In this article, the authors report results of a legal analysis of the implementation of HE across the UK, France, Germany, Italy, Spain, Poland and the Netherlands and research findings on its current utilization, highlighting divergences across countries as well as gaps in legislation and control in these countries. The significance of these divergences and the differing levels of enforcement are discussed as well as their associated impact on patients, industry and health care professionals.

In-vivo diagnostic test allergens in Europe: A call to action and proposal for recovery plan-An EAACI position paper.

Diagnostic allergens are defined as medicinal products in the EU. Marketing authorization by national authorities is necessary; however, diagnostic allergens are not homogeneously regulated in different EU member states. Allergen manufacturers argue with increasing costs forcing them to continuously reduce the diagnostic allergen portfolios offered to allergists. In contrast, EAACI and national European Allergy Societies see the need for the availability of a wide range of high-quality diagnostic allergens for in vivo diagnosis of IgE-mediated allergies not only covering predominant but also less frequent allergen sources. In a recent EAACI task force survey, the current practice of allergy diagnosis was shown to rely on skin tests as first option in almost 2/3 of all types of allergic diseases and in 90% regarding respiratory allergies. With the need to ensure the availability of high-quality diagnostic allergens in the EU, an action plan has been set up by EAACI to analyse the current regulatory demands in EU member states and to define possible solutions stated in this document: (a) simplification of authorization for diagnostic allergens; (b) specific regulation of special types of diagnostic allergens; (c) new models beyond the current model of homologous groups; (d) simplification of pharmacovigilance reporting; (e) reduction of regulation fees for diagnostic allergens; (f) reimbursement for diagnostic allergens. Joining forces of allergists, manufacturers and authorities are of high importance to ensure remaining relevant allergens in the EU markets to facilitate a sustainable and comprehensive service for the diagnosis and treatment of allergic diseases.

Efficacy gap between phase II and subsequent phase III studies in oncology.

AIMS: There is a trend for more flexibility in timing of evidence generation in relation to marketing authorization, including the option to complete phase III trials after authorization or not at all. This paper investigated the relation between phase II and III clinical trial efficacy in oncology. METHODS: All oncology drugs approved by the European Medicines Agency (2007-2016) were included. Phase II and phase III trials were matched based on indication and treatment and patient characteristics. Reported objective response rates (ORR), median progression-free survival (PFS) and median overall survival (OS) were analysed through weighted mixed-effects regression with previous treatment, treatment regimen, blinding, randomization, marketing authorization type and cancer type as covariates. RESULTS: A total of 81 phase II-III matches were identified including 252 trials. Mean (standard deviation) weighted difference (phase III minus II) was -4.2% (17.4) for ORR, 2.1 (6.7) months for PFS and -0.3 (5.1) months for OS, indicating very small average differences between phases. Differences varied substantially between individual indications: from -46.6% to 47.3% for ORR, from -5.3 to 35.9 months for PFS and from -13.3 to 10.8 months for OS. All covariates except blinding were associated with differences in effect sizes for at least 1 outcome. CONCLUSIONS: The lack of marked average differences between phases may encourage decision-makers to regard the quality of design and total body of evidence instead of differentiating between phases of clinical development. The large variability emphasizes that replication of study findings remains essential to confirm efficacy of oncology drugs and discern variables associated with demonstrated effects.

Differences in Health Technology Assessment Recommendations Among European Jurisdictions: The Role of Practice Variations.

BACKGROUND: Health technology assessment (HTA) plays an important role in reimbursement decision-making in many countries, but recommendations vary widely throughout jurisdictions, even for the same drug. This variation may be due to differences in the weighing of evidence or differences in the processes or procedures, which are known as HTA practices. OBJECTIVE: To provide insight into the effects of differences in practices on interpretation of intercountry differences in HTA recommendations for conditionally approved drugs. METHODS: HTA recommendations for conditionally approved drugs (N = 27) up until June 2017 from England/Wales, France, Germany, the Netherlands, and Scotland were included. Recommendations and practice characteristics were extracted from these five jurisdictions and this data was validated. The effect of nonsubmissions, resubmissions, and reassessments; cost-effectiveness assessments; and price negotiations on changes in the percentage of negative recommendations and the interpretation of intercountry differences in HTA outcomes were analyzed using Fisher exact tests. RESULTS: The inclusion of cost-effectiveness assessments led to significant increases in the proportion of negative recommendations in England/Wales (from 4% to 50%, P<.01) and Scotland (from 21% to 71%, P<.01). The subsequent inclusion of price negotiations led to significant reductions in the proportion of negative recommendations in England/Wales (from 50% to 14%, P<.01), France (from 31% to 3%, P=.012), and Germany (from 34% to 0%, P<.01). Results indicated that the inclusion of nonsubmissions and resubmissions might affect Scottish negative HTA recommendations (from 7% to 21%), but this effect was not significant. No significant effects were observed in the Netherlands, possibly owing to sample size. CONCLUSION: Variations in HTA practices between international jurisdictions can have a substantial and significant impact on conclusions about recommendations by HTA bodies, as exemplified in this cohort of conditionally approved products. Studies comparing international HTA recommendations should carefully consider possible practice variations between jurisdictions.