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• W3033248840 abstract "Advanced therapy medicinal products (ATMPs) comprising cell therapy, gene therapy, and tissue-engineered products, offer a multitude of novel therapeutic approaches to a wide range of severe and debilitating diseases. To date, several advanced therapies have received marketing authorization for a variety of indications. However, some products showed disappointing market performance, leading to their withdrawal. The available evidence for quality, safety, and efficacy at product launch can play a crucial role in their market success. To evaluate the sufficiency of evidence in submissions of advanced therapies for marketing authorization and to benchmark them against more established biological products, we conducted a matched comparison of the regulatory submissions between ATMPs and other biologicals. We applied a quantitative assessment of the regulatory objections and divergence from the expected data requirements as indicators of sufficiency of evidence and regulatory flexibility, respectively. Our results demonstrated that product manufacturing was challenging regardless of the product type. Advanced therapies displayed critical deficiencies in the submitted clinical data. The submitted non-clinical data packages benefited the most from regulatory flexibility. Additionally, ATMP developers need to comply with more commitments in the post-approval phase, which might add pressure on market performance. Mitigating such observed deficiencies in future product development, may leverage their potential for market success. Advanced therapy medicinal products (ATMPs) comprising cell therapy, gene therapy, and tissue-engineered products, offer a multitude of novel therapeutic approaches to a wide range of severe and debilitating diseases. To date, several advanced therapies have received marketing authorization for a variety of indications. However, some products showed disappointing market performance, leading to their withdrawal. The available evidence for quality, safety, and efficacy at product launch can play a crucial role in their market success. To evaluate the sufficiency of evidence in submissions of advanced therapies for marketing authorization and to benchmark them against more established biological products, we conducted a matched comparison of the regulatory submissions between ATMPs and other biologicals. We applied a quantitative assessment of the regulatory objections and divergence from the expected data requirements as indicators of sufficiency of evidence and regulatory flexibility, respectively. Our results demonstrated that product manufacturing was challenging regardless of the product type. Advanced therapies displayed critical deficiencies in the submitted clinical data. The submitted non-clinical data packages benefited the most from regulatory flexibility. Additionally, ATMP developers need to comply with more commitments in the post-approval phase, which might add pressure on market performance. Mitigating such observed deficiencies in future product development, may leverage their potential for market success. The pharmaceutical industry is shifting focus toward disease areas with high unmet medical needs such as oncology and rare diseases.1Lee M. Ly H. Möller C.C. Ringel M.S. Innovation in regulatory science is meeting evolution of clinical evidence generation.Clin. Pharmacol. Ther. 2019; 105: 886-898Crossref PubMed Scopus (12) Google Scholar Advancements in biotechnology have enabled such a shift by introducing novel therapeutic approaches, particularly cell therapies, gene therapies, and tissue-engineered products, known in the European Union (EU) as advanced therapy medicinal products (ATMPs).2Fischbach M.A. Bluestone J.A. Lim W.A. Cell-based therapeutics: the next pillar of medicine.Sci. Transl. Med. 2013; 5: 179ps7Crossref PubMed Scopus (297) Google Scholar To date, 14 ATMPs have received marketing authorization (MA) in the EU; however, 5 have subsequently been withdrawn from the market. Most recently, Zalmoxis was withdrawn in October 2019 after unfavorable results reported from the post-approval phase III clinical trial,3Sharma V. Disappointing end for MolMed’s Zalmoxis cell therapy In EU. Inf. Pharma Intell.2019https://pink.pharmaintelligence.informa.com/PS140998/Disappointing-End-For-MolMeds-Zalmoxis-Cell-Therapy-In-EUGoogle Scholar a requirement for conditional MA, which was obtained in 2016. Reimbursement and commercial issues, limited market demand and manufacturing problems contributed to the other withdrawals.4Abou-El-Enein M. Elsanhoury A. Reinke P. Overcoming challenges facing advanced therapies in the EU market.Cell Stem Cell. 2016; 19: 293-297Abstract Full Text Full Text PDF PubMed Scopus (91) Google Scholar,5Jarosławski S. Toumi M. Sipuleucel-T (Provenge®)-autopsy of an innovative paradigm change in cancer treatment: why a single-product biotech company failed to capitalize on its breakthrough invention.BioDrugs. 2015; 29: 301-307Crossref PubMed Scopus (33) Google Scholar It is expected that pharmaceutical development programs generate safety and efficacy evidence that is not only sufficient to support MA decisions but also decisions made by health technology assessment (HTA) agencies and other relevant stakeholders.6Abou-El-Enein M. Hey S.P. Cell and gene therapy trials: are we facing an “evidence crisis”?.EClinicalMedicine. 2019; 7: 13-14Abstract Full Text Full Text PDF PubMed Scopus (20) Google Scholar, 7Tafuri G. Pagnini M. Moseley J. Massari M. Petavy F. Behring A. Catalan A. Gajraj E. Hedberg N. Obach M. et al.How aligned are the perspectives of EU regulators and HTA bodies? A comparative analysis of regulatory-HTA parallel scientific advice.Br. J. Clin. Pharmacol. 2016; 82: 965-973Crossref PubMed Scopus (44) Google Scholar, 8Jørgensen J. Kefalas P. Reimbursement of licensed cell and gene therapies across the major European healthcare markets.J. Mark. Access Health Policy. 2015; 3: 29321Crossref Google Scholar, 9Wang T. McAuslane N. Liberti L. Leufkens H. Hövels A. Building synergy between regulatory and HTA agencies beyond processes and procedures—can we effectively align the evidentiary requirements? A survey of stakeholder perceptions.Value Health. 2018; 21: 707-714Abstract Full Text Full Text PDF PubMed Scopus (24) Google Scholar However, such alarming numbers of withdrawals can indicate that there is a gap between the evidence presented for MA and the evidence deemed sufficient for market and patient access. ATMPs are also biological medicinal products,10European Parliament and CouncilDirective 2001/83/EC of the European Parliament and of the Council of 6 November 2001 on the Community code relating to medicinal products for human use.2001https://eur-lex.europa.eu/LexUriServ/LexUriServ.do?uri=CELEX:32001L0083:EN:HTMLGoogle Scholar a family of products extracted from or manufactured from biological sources. These products include monoclonal antibodies, enzymes, and hormones, the majority of which are produced by recombinant DNA technologies (hereafter referred to as other biologicals). After 30 years of experience with recombinant proteins, their development path has become well established.11Lu R.-M. Hwang Y.-C. Liu I.-J. Lee C.-C. Tsai H.-Z. Li H.-J. Wu H.-C. Development of therapeutic antibodies for the treatment of diseases.J. Biomed. Sci. 2020; 27: 1Crossref PubMed Scopus (685) Google Scholar In contrast, ATMPs are a more diverse group of products, often with little in common with each other, and many of them are a poor fit for existing development and business models. This situation challenges developers to identify an appropriate development strategy and determine how much evidence is needed to increase the probability of success in acquiring MA and achieving commercial viability.12Ten Ham R.M.T. Hoekman J. Hövels A.M. Broekmans A.W. Leufkens H.G.M. Klungel O.H. Challenges in advanced therapy medicinal product development: a survey among companies in Europe.Mol. Ther. Methods Clin. Dev. 2018; 11: 121-130Abstract Full Text Full Text PDF PubMed Scopus (48) Google Scholar The expected evidence that should be collected on a therapeutic candidate during its development for inclusion in a MA application (MAA) is laid down in Annex I of Directive 2001/83/EC (hereafter referred to as data requirements). Sections for specific types of therapeutics, such as ATMPs, are provided in the Annex to acknowledge the complexity of these products and guide developers on how to comply with additional requirements, whenever applicable. Moreover, to emphasize the need for flexibility when developing and testing ATMPs, which are very diverse in nature, Annex I encourages the use of a risk-based approach.10European Parliament and CouncilDirective 2001/83/EC of the European Parliament and of the Council of 6 November 2001 on the Community code relating to medicinal products for human use.2001https://eur-lex.europa.eu/LexUriServ/LexUriServ.do?uri=CELEX:32001L0083:EN:HTMLGoogle Scholar,13Salmikangas P. Schuessler-Lenz M. Ruiz S. Celis P. Reischl I. Menezes-Ferreira M. Flory E. Renner M. Ferry N. Marketing regulatory oversight of advanced therapy medicinal products (ATMPs) in Europe: the EMA/CAT perspective.Adv. Exp. Med. Biol. 2015; 871: 103-130Crossref PubMed Scopus (37) Google Scholar Such risk analysis can be conducted by the applicant to determine the extent of quality, non-clinical, and clinical evidence to be included in the MAA, and to provide scientific justification when deviating from the requirements of this Annex (hereafter referred to as divergence).10European Parliament and CouncilDirective 2001/83/EC of the European Parliament and of the Council of 6 November 2001 on the Community code relating to medicinal products for human use.2001https://eur-lex.europa.eu/LexUriServ/LexUriServ.do?uri=CELEX:32001L0083:EN:HTMLGoogle Scholar However, the degree of divergence of ATMPs from the expectations in Annex I and its effect on the sufficiency of the evidence and ability to reach a conclusion on the overall risks and benefits of the product have not been thoroughly investigated. Previous studies have attempted to investigate the evidence in ATMP submissions through the quantification of objections raised by regulatory authorities during the assessment procedure of MAAs.14de Wilde S. Coppens D.G.M. Hoekman J. de Bruin M.L. Leufkens H.G.M. Guchelaar H.-J. Meij P. EU decision-making for marketing authorization of advanced therapy medicinal products: a case study.Drug Discov. Today. 2018; 23: 1328-1333Crossref PubMed Scopus (17) Google Scholar, 15Carvalho M. Martins A.P. Sepodes B. Hurdles in gene therapy regulatory approval: a retrospective analysis of European marketing authorization applications.Drug Discov. Today. 2019; 24: 823-828Crossref PubMed Scopus (20) Google Scholar, 16Barkholt L. Voltz-Girolt C. Raine J. Salmonson T. Schüssler-Lenz M. Regulatory watch: European regulatory experience with advanced therapy medicinal products.Nat. Rev. Drug Discov. 2019; 18: 8-9Crossref PubMed Scopus (18) Google Scholar, 17Bravery C.A. Ball O. Robinson S. EU market authorisation strategy: lessons from the first 22 ATMP submitted to the EMA.Cell Gene Ther. Insights. 2019; 5: 759-791Crossref Google Scholar de Wilde et al.14de Wilde S. Coppens D.G.M. Hoekman J. de Bruin M.L. Leufkens H.G.M. Guchelaar H.-J. Meij P. EU decision-making for marketing authorization of advanced therapy medicinal products: a case study.Drug Discov. Today. 2018; 23: 1328-1333Crossref PubMed Scopus (17) Google Scholar and Carvalho et al.15Carvalho M. Martins A.P. Sepodes B. Hurdles in gene therapy regulatory approval: a retrospective analysis of European marketing authorization applications.Drug Discov. Today. 2019; 24: 823-828Crossref PubMed Scopus (20) Google Scholar relied on the European public assessment report (EPAR), a document published by the European Medicines Agency (EMA) for all submissions that reach the first stage of assessment, whether approved, refused, or withdrawn. Barkholt et al.16Barkholt L. Voltz-Girolt C. Raine J. Salmonson T. Schüssler-Lenz M. Regulatory watch: European regulatory experience with advanced therapy medicinal products.Nat. Rev. Drug Discov. 2019; 18: 8-9Crossref PubMed Scopus (18) Google Scholar at the EMA quantified the objections for the first 20 MAAs for ATMPs. The study by de Wilde et al.14de Wilde S. Coppens D.G.M. Hoekman J. de Bruin M.L. Leufkens H.G.M. Guchelaar H.-J. Meij P. EU decision-making for marketing authorization of advanced therapy medicinal products: a case study.Drug Discov. Today. 2018; 23: 1328-1333Crossref PubMed Scopus (17) Google Scholar showed considerable discrepancies in the results compared to the other two studies15Carvalho M. Martins A.P. Sepodes B. Hurdles in gene therapy regulatory approval: a retrospective analysis of European marketing authorization applications.Drug Discov. Today. 2019; 24: 823-828Crossref PubMed Scopus (20) Google Scholar,16Barkholt L. Voltz-Girolt C. Raine J. Salmonson T. Schüssler-Lenz M. Regulatory watch: European regulatory experience with advanced therapy medicinal products.Nat. Rev. Drug Discov. 2019; 18: 8-9Crossref PubMed Scopus (18) Google Scholar that performed a more thorough analysis, with Barkholt et al. deemed to be the most reliable data source, as they relied on internal EMA data.16Barkholt L. Voltz-Girolt C. Raine J. Salmonson T. Schüssler-Lenz M. Regulatory watch: European regulatory experience with advanced therapy medicinal products.Nat. Rev. Drug Discov. 2019; 18: 8-9Crossref PubMed Scopus (18) Google Scholar Nevertheless, to benchmark the sufficiency of submitted evidence for ATMPs, a comparison with more established biological products is needed, as suggested by Bravery et al.17Bravery C.A. Ball O. Robinson S. EU market authorisation strategy: lessons from the first 22 ATMP submitted to the EMA.Cell Gene Ther. Insights. 2019; 5: 759-791Crossref Google Scholar This approach can help ATMP developers mitigate deficiencies in evidence by identifying the weaknesses in existing submissions and understanding the impact on post-approval commitments and performance. To our knowledge, no existing research has attempted to assess the sufficiency of evidence presented for ATMPs in MAA submissions against other biologicals, by not only the quantification of objections, but also by identifying areas of regulatory flexibility, where applicants diverged from data requirements in Annex I. In this study, we conducted a retrospective, head-to-head, nearest neighbor matched comparison of submitted evidence between ATMPs and other biologicals using data extracted from the EPARs. We accounted for several confounding factors that may impact the extent and the source of the evidence expected in the MAA by matching them in both groups. The data requirements provided in Directive 2001/83/EC, Annex I, were clustered into four evidence domains: the manufacturing and quality testing domain, the experimental design and conduct of studies domain, the efficacy and mode of action (MoA) domain, and the safety and toxicity domain. We then employed the quantitative assessment of the objections and divergence in each domain as indicators of evidence sufficiency and compared them between both groups. The differences in the timing of addressing the detected objections between the authorized cohorts were then explored. Finally, we investigated the possible reasons for the observed differences in evidence sufficiency. Screening of 1,604 submissions (data cutoff, July 1, 2019) in the EMA databases (authorized or refused submissions, 1,382; withdrawn submissions, 222) identified 22 ATMP submissions (Tables 1 and S1). Out of the 22 submissions, 12 were for gene therapy products (55%, including genetically modified cells), 6 were for tissue-engineered products (27%), and 4 were for somatic cell therapy products (18%). Products that contained autologous cells were 11/22 (50%), while 3/22 products contained allogeneic cells (14%). The first submission was for Cerepro in 2005, while the last identified submission was in 2018 for Zynteglo. The average number of ATMP submissions per year was 1.6 (standard deviation [SD], 0.9; range, 0–3). MA was granted to 14/22 submissions (Table 1), 10 of which were full MA (72%), 3 were conditional MA (CMA) (21%), while 1 (Glybera) was authorized under exceptional circumstances (7%). 21/22 (95%) EPARs were available since one product (Raligize) was withdrawn before the end of the first stage of evaluation (day 120), meaning that no EPAR was released. Out of the 14 approved ATMPs, 5 have been subsequently withdrawn. The screening of the EMA databases and selection of the ATMP submissions is depicted in (Figure S1).Table 1Basic Characteristics of the Matched CohortsATMPs/ Total (N = 22)ATMPs/ Matched (n = 17)Other Biologicals/Matched (n = 17)MAA outcome (%)authorized14 (64)12 (71)12 (71)failed (refused and/or withdrawn)8 (36)5 (29)5 (29)MA type (%)full authorization10 (45)10 (59)10 (59)conditional marketing authorization3 (14)1 (6)1 (6)marketing authorization under exceptional circumstances1 (5)1 (6)1 (6)withdrawn (pre-approval)aWithdrawn refers to the withdrawal of the marketing authorization application before issuing a final opinion from the Committee for Medicinal Products for Human Use (CHMP).7 (32)4 (24)4 (24)refused1 (5)1 (6)1 (6)Orphan designation (%)13 (60)11 (65)11 (65)Disease area (%)non-hematological malignant neoplasms7 (32)5 (29)5 (29)musculoskeletal diseases4 (18)4 (24)4 (24)hematological malignant neoplasms3 (14)3 (18)3 (18)endocrine, nutritional, and metabolic diseases2 (9)2 (12)2 (12)digestive system diseases1 (5)1 (6)1 (6)eye diseases3 (14)1 (6)1 (6)diseases of blood, blood-forming organs, and certain immune disorders2 (9)1 (6)1 (6)MAA, marketing authorization application; MA, marketing authorization.a Withdrawn refers to the withdrawal of the marketing authorization application before issuing a final opinion from the Committee for Medicinal Products for Human Use (CHMP). Open table in a new tab MAA, marketing authorization application; MA, marketing authorization. The same EMA databases were screened to identify suitable matches to ATMPs from other biologicals. In total, 17/21 (81%) ATMPs were matched to other biologicals submissions (Tables 1 and S2) and compared statistically for objections and divergence. In the authorized ATMP cohort, 12/14 (86%) ATMPs were matched to other authorized biologicals. Two products (Zynteglo and Holoclar) could not be matched, as they received a CMA, and biological products with a CMA in the same disease areas (blood diseases and eye diseases, respectively) could not be identified. In the failed authorization cohort, 5/7 (71%) ATMPs were matched. Contusugene Ladenovec Gendux (CLG) and OraNera could not be matched due to the unavailability of other withdrawn biological products for eye diseases and non-hematological malignancies (not orphan), respectively. Of the 17 matched biologicals, 16 were recombinant products (94%), while the remaining product (Oncophage) was an autologous tumor-derived protein-peptide complex (6%). The 16 recombinant products, comprised, nine monoclonal antibodies (56%), three enzymes (19%), three hormones, cytokines, or growth factors (19%) and one coagulation factor (6%). Out of the 12 approved matched biologicals, only 1 has been subsequently withdrawn. The matching characteristics of the ATMPs and the other biologicals are summarized in Table 1. To examine whether each ATMP and matched biological underwent the regulatory evaluation at a close time frame, the duration between the dates of the regulatory decisions (authorization, withdrawal, or rejection) for each matched pair was calculated. In the authorized cohorts, the average duration between the date of authorization of matched pairs was 15.6 months (SD, 21.8 months; range, 0–67). In the failed cohorts, the average duration between the withdrawal or rejection date of matched pairs was 41.4 months (SD, 30.9 months; range, 11–86). The available information in the EPARs on the objections raised on the submitted evidence was then extracted and sorted according to the corresponding evidence domains as defined (Table S3). When comparing the authorized matched paired products (n = 24), the total number of the identified objections in the EPARs of the ATMPs was significantly higher (p = 0.013) (Table 2; Figure S2). When comparing the objections in each evidence domain, objections in the experimental design and conduct of studies domain were significantly higher in authorized ATMPs (p = 0.021). Furthermore, a greater number of objections were raised on the evidence of efficacy and MoA in authorized ATMPs (p = 0.031) (Table 2; Figure S2). In contrast, no significant differences were observed in the product manufacturing and quality domain (p = 0.186) or issues related to product safety (p = 0.727) (Table 2; Figure S2). For the failed submissions (withdrawn or rejected, n = 10), no statistically significant differences were found in either the total number of objections or within any of the four domains (Table 2; Figure S3).Table 2Matched Comparison of Objections between ATMP and Biologicals SubmissionsEvidence DomainDifferences in Objections between Successful ATMPs and Biologicals Submissions (n = 24)Differences in Objections between Failed ATMPs and Biologicals Submissions (n = 10)Zp (Two-Tailed)Zp (Two-Tailed)Manufacturing and quality−1.3800.186−0.6740.625Experimental design and conduct of the studies−2.2210.021∗−0.6740.625Efficacy and MoA−2.1080.031∗−0.1371Safety and toxicity−0.4310.727−0.5520.750Total number of objections−2.3960.013∗−0.6740.625∗p < 0.05. p values were determined by a Wilcoxon signed-rank test. Open table in a new tab ∗p < 0.05. p values were determined by a Wilcoxon signed-rank test. The impact of the regulatory flexibility on the evidence was evaluated by estimating the degree of divergence from the data requirements and then comparing them between groups. This was achieved by quantifying the studies that were not submitted in the application, as stated in the EPARs. When comparing the authorized cohorts, in total, significantly more divergence was detected in the EPARs of the ATMPs as compared to the other biologicals (p = 0.0001) (Table 3; Figure S4). Divergence in authorized ATMPs was significantly higher than in other biologicals, in the safety and toxicity evidence domain (p = 0.006), as well as in the clinical efficacy and MoA domain (p = 0.0001) (Table 3; Figure S4). Despite the application of more novel technologies and methods for ATMP manufacture and testing as compared to other biologicals, no divergence from the data requirements was detected in this domain. Additionally, no significant difference in divergence was found in the experimental design and conduct of studies evidence (p = 0.063), despite being greater in authorized matched ATMPs than in matched biologicals (Z = −2.081) (Table 3; Figure S4). No statistically significant differences were observed between the failed authorization cohorts (n = 10) (Table 3; Figure S5).Table 3Matched Comparison of Divergence between ATMPs and Biologicals SubmissionsEvidence DomainsDifferences in the Divergence between Authorized ATMPs and Biologicals Submissions (n = 24)Differences in the Divergence between Failed ATMPs and Biologicals Submissions (n = 10)Zp (Two-Tailed)Zp (Two-Tailed)Experimental design and conduct of the studies−2.0810.06301.000Efficacy and MoA−3.0700.0001∗−1.6330.188Safety and toxicity−2.6690.006∗−1.2140.313Total number of divergence−3.0630.0001∗−1.4830.188∗p < 0.05. p values were determined by a Wilcoxon signed-rank test. Open table in a new tab ∗p < 0.05. p values were determined by a Wilcoxon signed-rank test. The distribution of the objections among the products and evidence domains revealed a clear heterogeneity in the distribution within the ATMP cohort (Figure 1). Most of the objections in both groups were concentrated in the manufacturing and quality domain, followed by the experimental design, and then the efficacy and safety domains. The spread of the objections across the products was greater in the ATMPs for most of the data requirements (Figure 1). The most commonly identified objections in ATMP submissions were on compliance with good clinical practice (GCP) and clinical trial protocols (Figure 1, domain II, row 1). Such objections were due to substantial changes in the trial protocols, inadequate documentation of studies, and GCP non-compliance. These issues were not detected as frequently in the EPARs of the other biologicals (Figure 1, domain II, row 1). Another common objection for ATMPs was related to the efficacy results of the main clinical studies (Figure 1, domain III, row 1). Out of the 12 ATMPs with such detected objections, 7 were successful submissions. Objections in the manufacturing and quality domain were mostly related to validation of the analytical methods, design and control of the manufacturing process, and comparability (Figure 1, domain I, rows 1–3). Most objections in the design and control of the manufacturing of ATMPs were due to deficiencies in microbiological control (8/12, 67% of the products). Other notable manufacturing objections were related to the choice and justification of the analytical methods (Figure 1, domain I, row 5). The most frequent reason for these objections was the choice of the potency assays (8/11, 73%). Objections around characterization and specifications of ATMPs were also common; however, they were slightly more common in other biologicals (Figure 1, category I, row 4). Safety-related objections were not common and were closely similar in both cohorts. Sources of divergence were primarily identified in non-clinical studies and, to a lesser degree, in clinical studies (Figure 2). The inability to undertake in vivo toxicity studies such as toxicokinetics, reproduction toxicity, local tolerance, and, in some cases, carcinogenicity studies in the ATMP safety and toxicity domain led to a greater number of divergences (Figure 2). Moreover, a full understanding of MoA was not achievable by conducting animal studies, particularly in cell-based product submissions. Difficulties in the application of good laboratory practice (GLP) principles in non-clinical studies of ATMPs has led to the acceptance of non-compliant studies in the submissions, a divergence not seen with other biologicals (Figure 2). The absence of pharmacokinetics/biodistribution studies in human subjects (Figure 2) resulted in a significantly higher number of divergences for ATMPs (especially those approved). Absorption, distribution, metabolism, and excretion studies are not expected to be conducted in the case of ATMPs, but other studies such as target organ distribution, migration, and persistence were not conducted in human subjects for some of the products. In those cases, the study was not technically possible, and the available non-clinical evidence was considered sufficient. Furthermore, for only 6/17 (35%) of ATMPs, dose-escalation studies were conducted, while for 15/17 (88%) of other biologicals, traditional dose-escalation studies were carried out. Raised regulatory objections can be solved during the MAA procedure with the submission of new data, additional analysis, additional risk minimization measures, or modifications of the summary of product characteristics. Where such solutions are not possible during the procedure and the issue does not preclude approval, applicants can be asked to commit to solving the outstanding issues after approval through submission of more data on the quality, safety, or efficacy of the product. When comparing the approaches to address outstanding objections in successful applications, post-approval commitments were more frequent for ATMP submissions than for other biologicals (Figure 3). Further analysis showed that more manufacturing and quality objections for ATMPs were mentioned in the EPAR to be addressed in the post-approval phase as compared to other biologicals (Figure 3). These objections were mostly related to validations of the analytical methods, improving process control, developing new analytical methods, performing further characterization, and tightening of the proposed specifications. Furthermore, developers of ATMPs committed to more post-approval approaches to address issues related to the pivotal trial results, long-term efficacy and long-term safety, as compared to biologicals (Figure 3). These approaches mainly included the obligation to perform post-authorization safety studies (PASSs) and post-authorization efficacy studies (PAESs) (Figure 3). Additionally, ATMP developers were obliged to collect specific safety and efficacy information through the use of patient registries. Possible differences in the development strategy in both cohorts were explored. The nature of the organization that developed the product was considered and divided into two categories: established large biopharma and micro, small, and medium-sized enterprises (SMEs). The use of scientific advice is reported in the EPAR, so those data were also collected. Most of the ATMP submissions came from SMEs, with only 4/17 (24%) of ATMP submissions from large companies, as compared to 15/17 (88%) for other biologicals. Despite ATMPs being more complex products that may require regulatory advice at several stages of development, EMA scientific advice was sought at nearly equal frequency. On average, developers of authorized ATMPs sought EMA scientific advice 3.0 times (SD, 1.3; range, 1–5), while the developers of the other approved biologicals sought scientific advice 3.1 times (SD, 2.0; range, 0–7). The main clinical studies utilized for the benefit-risk assessment also showed signif" @default.
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• W3033248840 title "Mitigating Deficiencies in Evidence during Regulatory Assessments of Advanced Therapies: A Comparative Study with Other Biologicals" @default.
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