Marketing Authorization Application Research Articles

Insights into the mechanisms of serplulimab: a distinctive anti-PD-1 monoclonal antibody, in combination with a TIGIT or LAG3 inhibitor in preclinical tumor immunotherapy studies.

With more than 20 anti-PD-1/PD-L1 antibodies currently marketed, anti-PD-1 therapy has become a cornerstone of tumor immunotherapy. These agents, however, exhibit notable disparities in their characteristics and clinical performance. For instance, in the field of small cell lung cancer (SCLC) where the majority of anti-PD-1 antibodies have yielded limited success, serplulimab produced impressive survival improvements and was approved for this indication by China's National Medical Products Administration. Serplulimab's marketing authorization application also received a positive opinion from the European Medicines Agency. Nevertheless, the molecular mechanism underpinning serplulimab's superiority over its competitors remains elusive. We characterized the differences between serplulimab with approved PD-1/PD-L1 inhibitors (pembrolizumab and nivolumab) in terms of their binding features and functions in vitro and anti-tumor activity in vivo. Cellular pathways underlying the efficacy of serplulimab were also investigated. In comparison to competitors, serplulimab robustly induces PD-1 receptor endocytosis while fostering weaker PD-1-CD28 cis interactions. This phenomenon could mitigate the dephosphorylation of CD28 by SHP2, thereby facilitating sustained and robust T cell activation. While serplulimab and pembrolizumab exhibited similar performance in vitro and in vivo studies, serplulimab consistently demonstrated superior tumor killing efficacy compared to pembrolizumab upon co-administration with anti-TIGIT or anti-LAG3 inhibitors. Mechanistically, the serplulimab combination effectively reduces tumor microenvironment Treg cell populations, augments effector and memory T cell populations, and more potently modulates genes associated with diverse facets of the immune system, surpassing the effects of the pembrolizumab combination. In summary, our data underscore serplulimab as a differentiated PD-1 monoclonal antibody with best-in-class therapeutic potential.

Evaluation of orphan maintained biological medicinal products in the European Union between 2018 to 2023: a regulatory perspective

ABSTRACT Objectives Orphan medicinal products (OMPs) authorized in the European Union (EU) benefit from market exclusivity, fee waivers, and national incentives. Maintaining orphan status during the marketing authorization application (MAA) requires meeting eligibility criteria, especially demonstrating significant benefit (SB), which is challenging. This study identifies key features linked to successful orphan status maintenance for biological OMPs approved in the EU between 2018 and 2023. Methods Data from European public assessment reports and orphan maintenance assessment reports were analyzed. Results Among the 50 biological OMPs granted orphan designation, 68.0% had to demonstrate SB over existing treatments, with 91.2% leveraging the clinically relevant advantage area, utilizing better clinical efficacy (83.8%) and subpopulation (38.7%) sub-domains. However, 32% did not need to demonstrate SB due to a lack of alternative treatments, most of which were ultra-orphan drugs. Advanced therapy medicinal products and monoclonal antibodies were the most numerous OMP categories, whereas oncology and immunomodulation were the preferred therapeutic areas. Conclusion The Orphan Regulation plays a critical role in advancing treatments for rare diseases, fostering innovation while addressing unmet medical needs. Nonetheless, the insufficient return on investment criterion remains underused, whereas refining major contribution to patient care guidelines and incorporating real-world evidence may enhance regulatory evaluations.

Revisions to the requirement of the Japanese clinical study data for biosimilar developments in Japan

ABSTRACT Background The ‘Questions and Answers (Q&A)’ document regarding Japanese biosimilar guideline elucidated that Japanese participant enrollment in at least one comparative clinical study was required for the marketing authorization application (MAA) of biosimilars in Japan. Research design and methods To discuss the requirement of Japanese clinical study data for biosimilar development, the trend in comparative clinical studies conducted for approved biosimilars of monoclonal antibodies and fusion proteins was analyzed, and the consistency of the results between the overall population and the Japanese population according to the publicly available information was reviewed. Results The number of comparative clinical studies enrolling Japanese participants was 25 cases, and the type and percentage were 13 (52%) and 12 (48%) cases of comparative pharmacokinetic study and comparative efficacy study, respectively. In all comparative clinical studies, consistent results between the overall population and the Japanese population were shown. Conclusions Our study indicated that Japanese participant enrollment in comparative clinical studies may not always be necessary for biosimilar development when certain conditions are satisfied. This has been described in the revised Q&A document published by the Ministry of Health, Labour and Welfare in January 2024.

Effect of Project Orbis participation by the Swiss regulator on submission gaps, review times, and drug approval decisions between 2020 and 2022: a comparative analysis

Expedited market access for novel and efficacious drugs is warranted for patients. Since 2020, Swissmedic (The Swiss Agency for Therapeutic Products) has been participating in Project Orbis, a collaborative parallel-review programme launched by the US Food and Drug Administration (FDA) in 2019 to expedite patient access to cancer drugs. This programme allows regulatory agencies to remain independent in their decisions. We aimed to evaluate the effect of the first 2 years of Project Orbis from the Swissmedic perspective. In this comparative analysis, we compared submission gap (time between submission at the FDA and Swissmedic), review time, approval and consensus decision rate, and the approved indications between Swissmedic and the FDA for marketing authorisation applications (MAAs) in oncology submitted to Swissmedic through Project Orbis (Orbis MAAs) or outside of Project Orbis (non-Orbis MAAs) from Jan 1, 2020, to Dec 31, 2021. Swissmedic review time was evaluated with a decision until June 30, 2022. For the decision comparison analysis, non-Orbis oncology MAAs submitted and evaluated from Jan 1, 2009, to Dec 31, 2018 (referred to as the pre-Orbis era) were also considered. Inferential statistics were done using Wilcoxon rank-sum test and the 95% CI for the median was based on binomial distribution. For each hypothesis testing, the significance level was set to 5%. No correction for multiple testing was performed. We analysed the submission gap, review time, and regulatory decision for 31 Orbis MAAs and 41 non-Orbis MAAs during the Orbis era. The median submission gap was 33·0 days (95% CI 19·0-57·0) for Orbis MAAs versus 168·0 days (56·0-351·0) for non-Orbis MAAs (p<0·0001). The median review time at Swissmedic was 235·5 days (198·0-264·0) for Orbis MAAs versus 314·0 days (279·0-354·0) for non-Orbis MAAs (p=0·0002). Approval rates at Swissmedic were consistent between Orbis MAAs (20 [77%] of 26) and non-Orbis MAAs (31 [76%] of 41). The rate of consensus decisions between Swissmedic and the FDA was 21 (81%) of 26 for Orbis MAAs and 31 (76%) of 41 for non-Orbis MAAs. Swissmedic approval rates were lower for indication extensions than for new active substances for Orbis MAAs (13 [72%] of 18 vs seven [88%] of eight) and non-Orbis MAAs (17 [71%] of 24 vs 14 [82%] of 17). Divergent decisions between agencies were predominantly observed for indication extensions (11 [73%] of 15 divergent decisions). During the pre-Orbis era, Swissmedic approved 61 (88%) of 69 MAAs for new active substances. Submission gap and review time for oncology applications at Swissmedic were significantly reduced by participation in Project Orbis, and approval consensus decisions were increased between agencies. These findings suggests that participating in Project Orbis could lead to faster patient access to drugs. None.

Real-World Evidence to Support the Registration of a New Osteoporosis Medicinal Product in Europe

AbstractReal-World Evidence (RWE), which has historically been used to support post-approval safety studies, has recently gained acceptance for new drug applications as supportive evidence or as new clinical evidence for medicinal products with orphan designation and/or in disease areas with high unmet need. Here, we present a case study for the use of RWE in the approval of abaloparatide in the European Union (EU) under the tradename Eladynos. In addition to data from the pivotal Phase 3 study, the marketing authorization application (MAA) included clinical data from additional interventional and observational studies, as well as post-marketing data obtained from the United States (US) market since approval of abaloparatide by the Food and Drug Administration (FDA) in 2017. The new interventional studies were not designed to assess fracture efficacy and cardiovascular safety which were topics of concern raised by the Committee for Medicinal Products for Human Use (CHMP) during their review of the initial MAA submitted in 2015. However, these studies taken together with the RWE formed the basis for a new MAA. Prior to the planned resubmission in the EU, national Scientific Advice (SA) was sought on the proposed clinical program, specifically on the relevance of Real-World Data (RWD) derived from an observational study to support and complement the efficacy and safety data already available from prospective randomized clinical trials. This case study demonstrates successful use of RWE to address a previously identified gap raised by the CHMP during the review of an earlier MAA, which led to the approval of Eladynos for the treatment of osteoporosis in the EU.

Innovative Genoceuticals in Human Gene Therapy Solutions: Challenges and Safe Clinical Trials of Orphan Gene Therapy Products.

The success of gene therapy attempts is controversial and inconclusive. Currently, it is popular among the public, the scientific community, and manufacturers of Gene Therapy Medical Products. In the absence of any remedy or treatment options available for untreatable inborn metabolic orphan or genetic diseases, cancer, or brain diseases, gene therapy treatment by genoceuticals and T-cells for gene editing and recovery remains the preferred choice as the last hope. A new concept of "Genoceutical Gene Therapy" by using orphan 'nucleic acid-based therapy' aims to introduce scientific principles of treating acquired tissue damage and rare diseases. These Orphan Genoceuticals provide new scope for the 'genodrug' development and evaluation of genoceuticals and gene products for ideal 'gene therapy' use in humans with marketing authorization application (MAA). This perspective study focuses on the quality control, safety, and efficacy requirements of using 'nucleic acid-based and human cell-based new gene therapy' genoceutical products to set scientific advice on genoceutical-based 'orphan genodrug' design for clinical trials as per Western and European guidelines. The ethical Western FDA and European EMA guidelines suggest stringent legal and technical requirements on genoceutical medical products or orphan genodrug use for other countries to frame their own guidelines. The introduction section proposes lessknown 'orphan drug-like' properties of modified RNA/DNA, human cell origin gene therapy medical products, and their transgene products. The clinical trial section explores the genoceutical sources, FDA/EMA approvals for genoceutical efficacy criteria with challenges, and ethical guidelines relating to gene therapy of specific rare metabolic, cancer and neurological diseases. The safety evaluation of approved genoceuticals or orphan drugs is highlighted with basic principles and 'genovigilance' requirements (to observe any adverse effects, side effects, developed signs/symptoms) to establish their therapeutic use. Current European Union and Food and Drug Administration guidelines continuously administer fast-track regulatory legal framework from time to time, and they monitor the success of gene therapy medical product efficacy and safety. Moreover, new ethical guidelines on 'orphan drug-like genoceuticals' are updated for biodistribution of the vector, genokinetics studies of the transgene product, requirements for efficacy studies in industries for market authorization, and clinical safety endpoints with their specific concerns in clinical trials or public use.

Comparison of Three Regional Medicines Regulatory Harmonisation Initiatives in Africa: Opportunities for Improvement and Alignment.

The African Medicines Regulatory Harmonisation (AMRH) Initiative was formed in 2009 and subsequently, three regional initiatives (East African Community Medicines Regulatory Harmonisation [MRH], Southern African Development Community [SADC]/ZaZiBoNa MRH, and the Economic Community of West Africa States MRH) were established. As these initiatives serve as a foundation for the African Medicines Agency (AMA), the aim of this study was to compare their operating models, successes and challenges to identify opportunities for improvement and alignment. A mixed method approach was used for the data collection using a questionnaire, the Process, Effectiveness and Efficiency Rating (PEER), developed by the authors specifically for this study and semi-structured interview techniques. There were 23 study participants (one from each agency of the member countries of the three regions). It was hoped that data generated from this study would lead to a series of recommendations, which would then be ratified by the regulatory authorities. Most respondents stated that AMRH contributed to the strengthening of regulatory systems and harmonising regulatory requirements across economic regions of Africa, potentially resulting in improved access to quality-assured medicines. Although established at different times and at the discretion of each region, the marketing authorisation application review processes are largely similar, with a few differences noted in the eligibility and submission requirements, type of procedures employed, the timelines and fees payable. The challenges identified in the three regions are also similar, with the most noteworthy being the lack of a binding legal framework for regional approvals. In this study, we compared the process, successes and challenges of these three regional harmonisation initiatives in Africa addressing the areas of legal frameworks, information management systems, the accessibility and affordability of medicines and reliance that will bring greater alignment and efficiency in their operating models, thereby strengthening the foundation of the soon-to-be-operationalised AMA.

Psychotropics: A scientific, regulatory, and public view on the medicinal uses of cannabinoids and psilocybin

Research on psychotropics is gaining more popularity worldwide and support from drug regulatory agencies, which recognise the unmet medical needs of certain patient communities, such as patients with mental disorders and patients with cancer who experience depression. Cannabinoids and psilocybin have shown promising results in preclinical studies and clinical trials, but the current clinical evidence is scarce, and the regulatory requirements are strict due to high potential for drug abuse. The US FDA has recently released a draft, non-binding guidance on clinical trials with psychedelics. Europe is currently falling behind the US and Canada in terms of regulating psychotropic substances. The article provides a general introduction on conducting clinical trials with psychotropics and the regulatory requirements (as of October 2023) when submitting marketing authorisation application. In the near future, as more data becomes available, research on psychotropics will definitely shape the European regulatory landscape.

Do the Outcomes of Clinical Efficacy Trials Matter in Regulatory Decision-Making for Biosimilars?

There is an increasing body of evidence supporting a more flexible approach in clinical data requirements for the approval of more complex biosimilar substances such as monoclonal antibodies (mAbs). The aim of this paper is to further analyse the role of quality/chemistry, manufacturing and controls (CMC) and clinical data for the conclusion on biosimilarity and the decision on marketing authorisation (MA). In the present study, we analysed the MA applications (MAAs) of all 33 mAbs and three fusion proteins evaluated by the European Medicines Agency (EMA) between July 2012 and November 2022 with special emphasis on all submitted rituximab (four products) and trastuzumab (seven products) biosimilar candidates, including withdrawn applications. For the two withdrawn applications, the comparative efficacy trials suggested biosimilarity, but the quality/CMC package was not accepted by EMA. We therefore investigated whether a negative MAA outcome could have been predicted based on the evidence generated in the quality/CMC packages, regardless of clinical trial data. For this purpose, we reviewed the respective European Public Assessment Reports (EPARs) or withdrawal assessment reports, and the first regulatory assessments for all these 36 MAAs (i.e. day 120 of the centralized procedure), which are not publicly available. During EMA review, where significant issues are identified which would preclude a marketing authorisation, these issues are raised as questions to the applicant and are classified as major objections (MO). In 67% of cases, the outcome of the quality and clinical assessment was the same, i.e. both the quality and clinical assessments either supported approval or did not support approval. In 11% of cases, MO were identified in the quality part of the submission but not in the clinical data. In 22% of cases, MO were raised on the clinical data package but not on the quality data. However, we found no instance where seemingly negative clinical data, including failed efficacy trials, led to a negative overall decision. In each instance, the failure to confirm similar clinical performance in all investigated aspects was eventually viewed as not being related to the biosimilar per se but as being due to imbalances in the trial arms, immaturity of secondary endpoint results, change in the reference product, or even chance findings. Furthermore, when performing an in-depth analysis of the quality and clinical packages of trastuzumab and rituximab biosimilars, we found that in no case were clinical trial data necessary to resolve residual uncertainties regarding the quality part. The results further support the argument that sufficient evidence for biosimilarity can be obtained from a combination of analytical and functional testing and pharmacokinetic studies which may also generate immunogenicity data. This calls into question the usefulness of comparative efficacy studies for the purposes of regulatory decision-making when approving biosimilar mAbs and fusion proteins.

Analysis of Errors Identified during Regulatory Review of Risk Management Plans Submitted as Part of Registration Dossiers

Scientific relevance. On 6 December 2022, an updated version of the Rules for Good Pharmacovigilance Practice of the Eurasian Economic Union (EAEU GVP) came into force. The greatest changes were made to the requirements for pharmacovigilance documents, particularly the risk management plan (RMP). In practice, the changed EAEU GVP has resulted in multiple errors, creating the need to thoroughly analyse their structure and causes and to develop recommendations for their prevention.Aim. This study aimed to identify, analyse, and collate inconsistencies between the information submitted by marketing authorisation holders in their RPMs and the updated EAEU GVP requirements.Materials and methods. The Scientific Centre for Expert Evaluation of Medicinal Products analysed 50 RMPs received after 6 December 2022 as part of registration dossiers aimed to support marketing authorisation applications and/or align the registration dossiers with the EAEU requirements.Results. The errors made by applicants when preparing RMPs were categorised according to their influence on the interpretation of a medicinal product’s safety profile. The errors leading to incorrect safety profile interpretations were considered type 1 errors (63% of the cases). The errors affecting the perception of the RMP but not the interpretation of the safety profile (e.g., grammatical errors, notes and comments by applicants, incorrect translation of terms) were deemed type 2 errors (37% of the cases). The majority of EAEU GVP noncompliance cases were detected in Part II of the RMP, the section providing the most information on the safety profile of a medicinal product.Conclusions. There are several ways to improve the quality of RMP preparation. The information included in the RMP should be compared with the information provided in the registration dossier. The RMP should be incorporated into the integrated pharmaceutical quality system according to the requirements of good practices.A responsible employee of the marketing authorisation holder’s quality assurance system should control the final RMP version. Employees of pharmacovigilance departments should receive regular training.

Comparison of the Latin America Regulation Landscape and International Reference Health Authorities to Hasten Drug Registration and Clinical Research Applications

IntroductionPromptly providing new drugs to fulfill unmet medical needs requires changes in drug development and registration processes. Health Authorities (HAs) considered as reference due to their experience and acknowledgement (Food and Drug Administration [FDA] among others) already consider innovative clinical trial (CT) designs and flexible approval procedures, but Latin America (LATAM) regulations are still far. A comparison was performed to identify gaps.Materials and MethodsCT requirements for drug Marketing Authorization Application (MAA) and CT approval regulations were compared between LATAM and reference HAs (FDA/European Medicines Agency [EMA]/Health-Canada/Swissmedic/Therapeutic Goods Administration [TGA]/Pharmaceuticals and Medical Devices Agency [PMDA]), as of August 2022. Procedure included reference HAs regulations review, item selection, identification in LATAM regulations, and International Council for Harmonisation of Technical Requirements for Pharmaceuticals for Human Use (ICH) guidelines (ICH-E6[R2]/ICH-E8[R1]) implementation revision.ResultsFor MAA, specific application requirements or ICH guideline M4(R4) on common technical document (CTD) adoption are generally stated, and phase-I/III performance is mandatory (explicitly/implicitly). Faster patient access procedures are infrequent: Priority-drug programs, conditional authorizations, or expedited procedures are scarce or non-existent. Regulatory reliance procedures are adopted through different pathways. Regarding CT approval, innovative/complex CT designs are not prohibited but usually omitted. Some countries implemented adapted CT conducting during the COVID-19 pandemic. Early scientific advice meetings (HA-sponsor) are occasionally considered. Most countries are not formally ICH-joined.ConclusionsLATAM regulations must adapt to new regulatory standards (FDA/EMA/ICH) through implementation of frequent updates, reliance/expedited procedures, early HA-sponsor interactions, innovative/complex CTs, mandatory phase-III reaching elimination, and decentralized elements for CT conducting.

Comparing pharmaceutical persistence across terrestrial and aquatic environments: do studies according to OECD 307 and OECD 308 lead to similar outcomes?

Information on transformation and persistence of chemical substances in the environment is important for hazard and risk assessment within a regulatory context or as a decision criterion in a safe and sustainable by design framework. Half-lives for human and veterinary medicinal products available from marketing authorization applications were compared between soil (OECD 307) and aquatic water/sediment systems (OECD 308). The comparison shows, that there is no obvious correlation between the total system half-lives in the two different compartments and that surpassing persistence criteria is compartment-specific in 45% of the cases.

How can patient preferences be used and communicated in the regulatory evaluation of medicinal products? Findings and recommendations from IMI PREFER and call to action.

Objective: Patients have unique insights and are (in-)directly affected by each decision taken throughout the life cycle of medicinal products. Patient preference studies (PPS) assess what matters most to patients, how much, and what trade-offs patients are willing to make. IMI PREFER was a six-year European public-private partnership under the Innovative Medicines Initiative that developed recommendations on how to assess and use PPS in medical product decision-making, including in the regulatory evaluation of medicinal products. This paper aims to summarize findings and recommendations from IMI PREFER regarding i) PPS applications in regulatory evaluation, ii) when and how to consult with regulators on PPS, iii) how to reflect PPS in regulatory communication and iv) barriers and open questions for PPS in regulatory decision-making. Methods: PREFER performed six literature reviews, 143 interviews and eight focus group discussions with regulators, patient representatives, industry representatives, Health Technology Assessment bodies, payers, academics, and clincians between October 2016 and May 2022. Results: i) With respect to PPS applications, prior to the conduct of clinical trials of medicinal products, PPS could inform regulators' understanding of patients' unmet needs and relevant endpoints during horizon scanning activities and scientific advice. During the evaluation of a marketing authorization application, PPS could inform: a) the assessment of whether a product meets an unmet need, b) whether patient-relevant clinical trial endpoints and outcomes were studied, c) the understanding of patient-relevant effect sizes and acceptable trade-offs, and d) the identification of key (un-)favorable effects and uncertainties. ii) With respect to consulting with regulators on PPS, PPS researchers should ideally have early discussions with regulators (e.g., during scientific advice) on the PPS design and research questions. iii) Regarding external PPS communication, PPS could be reflected in the assessment report and product information (e.g., the European Public Assessment Report and the Summary of Product Characteristics). iv) Barriers relevant to the use of PPS in regulatory evaluation include a lack of PPS use cases and demonstrated impact on regulatory decision-making, and need for (financial) incentives, guidance and quality criteria for implementing PPS results in regulatory decision-making. Open questions concerning regulatory PPS use include: a) should a product independent broad approach to the design of PPS be taken and/or a product-specific one, b) who should optimally be financing, designing, conducting, and coordinating PPS, c) when (within and/or outside clinical trials) to perform PPS, and d) how can PPS use best be operationalized in regulatory decisions. Conclusion: PPS have high potential to inform regulators on key unmet needs, endpoints, benefits, and risks that matter most to patients and their acceptable trade-offs. Regulatory guidelines, templates and checklists, together with incentives are needed to foster structural and transparent PPS submission and evaluation in regulatory decision-making. More PPS case studies should be conducted and submitted for regulatory assessment to enable regulatory discussion and increase regulators' experience with PPS implementation and communication in regulatory evaluations.

Bringing function to the forefront of cell therapy: how do we demonstrate potency?

Unlike conventional pharmaceuticals, biologics and Advanced Therapy Medicinal Products (ATMPs) are required to meet a standard of "potency" as part of the final release criteria at completion of manufacture. During early phase clinical trials, most regulatory agencies have been willing to accept very immature potency assays with an expectation that these will be improved, qualified and validated during the clinical development of the drug to Marketing Authorisation Application (MAA) or Biologics License Application (BLA) submission.This model of continuous development of potency assay in parallel with drug development has already led to at least two notable problem cases; namely Iovance and Mesoblast. Both companies completed successful phase III clinical trials but, in both cases, the initial BLA was rejected on the basis that their potency assay for drug product release was inadequate. Fortunately these issues appear to have been overcome in March of this year, with Mesoblast receiving acceptance of their BLA for Remestemcel and Iovance obtaining a rolling BLA approval for Lifileucel.

Historical Overview of Regulatory Approvals and PMDA Assessments for Biosimilar Products in Japan During 2009-2022.

A biosimilar product is defined as "a biological product that is highly similar to an existing, approved biological product (known as originator or reference product) in terms of structure, function, quality, and clinical efficacy and safety". Recently, biosimilar products have been actively developed around the world, and part of the reason for this is to combat the rapid growth of medical expenses in many countries, including Japan, the United States (US), and Europe. The use of biosimilar products has been promoted as a measure to address this issue. The review of marketing authorization applications for biosimilar products in Japan is conducted by the Pharmaceuticals and Medical Devices Agency (PMDA), which reviews the comparability of the quality, efficacy, and safety based on the data submitted by the applicants. As of December 2022, 32 biosimilar products have been approved in Japan. Through this process, the PMDA has gained much experience and knowledge regarding the development and regulatory approval of biosimilar products; however, details of the regulatory approvals for biosimilar products in Japan have not been reported until now. Therefore, in this article, we present the details of regulatory history and revised guidelines for approval of biosimilar products in Japan, questions and answers, other relevant notifications, and consideration for comparability evaluations for analytical, non-clinical, and clinical studies. In addition, we provide details about the approval history, number, and types of biosimilar products that have been approved between 2009 and 2022 in Japan.

Digital Tools-Regulatory Considerations for Application in Clinical Trials.

During the last few years, the pharmaceutical industry has adopted digital technologies/digital health technology (DHT) to improve the drug development process and the commercialization of new products. Technological advances are strongly supported by both the US-FDA and the EMA, but the regulatory landscape in the US seems to be more suitable to promote innovation in the digital health sector (e.g. Cures Act). In contrast, the new Medical Device Regulation sets high hurdles for Medical Device software to pass regulatory scrutiny.On both sides of the Atlantic, a digital tool must be fit-for-purpose for the intended use in the clinical drug trial. Irrespective of its status as a Medical Device, at least the basic safety and performance requirements according to local regulations should be met, quality system and surveillance requirements should be fulfilled, and the sponsor must ensure conformity with GxP and the local data privacy and cybersecurity legislations.There is an overlap in technical and clinical validation for drug development tool qualification in both regions to ensure that the digital tools deliver reliable data with tangible clinical benefits. Based on an analysis of the regulatory framework of the FDA and the EMA, this study proposes regulatory strategies for a global pharma company: It would be prudent for drug development companies to a) use approved solutions or b) consider qualification of drug development tools early and in parallel to clinical development. Early engagement with the FDA and the EMA/CA is recommended to define evidentiary standards and corresponding regulatory pathways for different contexts-of-use and to clarify regulator's expectations as to what extent data collected by digital tools are acceptable to support marketing authorization applications (MAA).Hence a harmonization of the partly disparate regulatory requirements in the US and the EU accompanied by further development of the regulatory landscape in the EU, could further foster the use of digital tools in drug clinical development. The outlook for the use of digital tools in clinical trials is hopeful.

Establishing a core dossier for multiple regulatory submissions: a case study in the Latin America region.

The Latin America region comprises several countries that do not follow harmonized regulatory requirements for drug product (DP) marketing authorization applications (MAA), resulting in customized registration dossiers for each country. Here, we established a core dossier for multiple MAA in the Latin America region by examining the similarities between regulatory requirements and reconciling their potential discrepancies through discussions among all national regulatory representatives. The core dossier was used in the submission of a new small molecule, NME1, to nine markets. Assessment of the process included the time to submission; the timing, number, and complexity of questions received; and timing of final national regulatory agencies (NRA) evaluation decisions. The core dossier resulted in an accelerated submission timeline for most markets and earlier receipt of NRA queries from some markets, compared with projections. One round of queries of a low or medium complexity was received from all agencies. The receipt of final NRA evaluation decisions was also accelerated in most markets, compared with the best-case approval timeframes. The core dossier approach was also evaluated against the standard submission of a similar small molecule, NME2. In contrast to the core dossier submission of NME1, a second round of questions, and high-complexity questions were received from two markets for NME2. In conclusion, a core dossier has the potential to simplify the regulatory process for both reviewers and applicants in regions that do not share harmonized regulatory requirements, with a consequential acceleration of DP approvals.

Clinical development time is shorter for new anticancer drugs approved via accelerated approval in the US or via conditional approval in the EU.

The US Food and Drug Administration (FDA) and the European Medicines Agency (EMA) offer expedited regulatory approval programs for drugs with high potential patient value applicable at different stages leading to marketing authorization: (i) drug development (fast track designation (FTD), breakthrough therapy designation (BTD), regenerative medicine advanced therapy designation in the United States, and priority medicines scheme in the European Union), (ii) review of marketing authorization application (priority review in the United States and accelerated assessment in the European Union), (iii) approval of drug (accelerated approval in the United States and conditional approval in the European Union). Typical clinical development time of 76 new anticancer drugs, for which the EMA gave a positive opinion between January 2010 and December 2019, was 6.7 years: 5.8 years for small molecules and 7.7 years for biotechnology-derived products. Drugs following only BTD (5.6 years) typically had a shorter clinical development time than drugs following only FTD (6.4 years) or both FTD and BTD (6.4 years), compared to drugs not following any expedited regulatory approval program at the drug development stage (7.7 years). Drugs following an expedited regulatory approval program at the stage of drug development and accelerated approval in the United States (FDA1 [4.5 years] and FDA3 [5.6 years]), and drugs following the standard procedure at the stage of drug development and conditional approval in the European Union (EMA5 [5.5 years] and EMA7 [4.5 years]) typically had a reduced clinical development time. These findings provide insight for the industry into combinations of expedited regulatory approval programs correlated with shorter clinical development time of new anticancer drugs.

The European Union’s current regulations for the licensing of generic and hybrid medications

In the European Union, the applicant must specify the legal justification for the application in any Marketing Authorization Application (MAA) for a pharmaceutical product. The dossier's content and the market exclusivity are significantly influenced by this legal foundation, which is outlined in Directive 2001/83/EC as modified. The right legal foundation must be chosen carefully for new development projects involving active chemicals that are already known, including novel strengths, dosage forms, administration methods, and indications. In accordance with Article 10 and the so-called "hybrid" and "generic" applications, this article describes the registration criteria and the procedure for obtaining a marketing authorization for applicants utilizing the Article 8(3) legal foundation.

Marketing Regulatory Oversight of Advanced Therapy Medicinal Products in Europe.

Advanced therapy medicinal products (ATMP) in the European Union (EU) are regulated by Regulation 1394/2007 and comprise gene and cell therapy and tissue-engineered products. Under this framework, ATMP are authorised by the centralised procedure, coordinated by the European Medicines Agency (EMA), whereas clinical trial authorisations remain at the remit of each National Competent Authority. The Committee for Advanced Therapies is responsible for the scientific evaluation of the marketing authorisation applications and for generating a draft opinion that goes to the Committee for Human Medicinal Products for a final opinion. For every application, data and information relating to manufacturing processes and quality control of the active substance and final product have to be submitted for assessment together with data from non-clinical and clinical safety and efficacy studies. Technical requirements for ATMP are defined in the legislation, and guidance for different products is available through several EMA/CAT guidelines.Due to the diverse and complex nature of ATMP, a need for some regulatory flexibility was recognised. Thus, a risk-based approach was introduced in Regulation 1394/2007 allowing adapted regulatory requirements. This has led, for instance, to the development of good manufacturing practice (GMP) guidelines specific for ATMP. This, together with enhanced regulatory support, has allowed an increasing number of successful marketing authorisation applications resulting in 25 licensed ATMP in the EU, mainly gene therapy medicinal products. The promise of messenger RNA and genome editing technologies as therapeutic tools make the future for these innovative medicinal products look even brighter.This chapter reviews the regulatory landscape together with some of the support initiatives developed for ATMP in the EU.