Cell and Gene Therapy Product Approvals in China: Insights into Clinical Trials and Regulatory Advances.

The Orphan Drug Act incentivizes medication development for rare diseases, offering substantial financial benefits to the manufacturer. Orphan products constitute most new drug approvals in oncology, but safety and efficacy questions have emerged about some of these agents. To define characteristics of orphan cancer drugs and their pivotal clinical trials and to compare these with nonorphan drugs. We identified all new orphan and nonorphan drugs approved between 2004 and 2010 to treat cancer. We then collected data on key development variables from publicly available information on the US Food and Drug Administration's Web site and in the Code of Federal Regulations. We assessed clinical testing dates, approved indications, and regulatory characteristics (regular vs accelerated review, advisory committee review, postmarketing commitments). We then compared design features (randomization, blinding, primary end point) of pivotal trials supporting approval of orphan and nonorphan drugs and rates of adverse safety outcomes (deaths not attributed to disease progression, serious adverse events, dropouts) in pivotal trials. Fifteen orphan and 12 nonorphan drugs were approved between January 1, 2004, and December 31, 2010. Pivotal trials of orphan drugs had smaller participant numbers (median, 96 [interquartile range {IQR}, 66-152] vs 290 [IQR, 185-394] patients exposed to the drug; P < .001) and were less likely to be randomized (30% vs 80%; P = .007). Orphan and nonorphan pivotal trials varied in their blinding (P = .04), with orphan trials less likely to be double-blind (4% vs 33%). Primary study outcomes also varied (P = .04), with orphan trials more likely to assess disease response (68% vs 27%) rather than overall survival (8% vs 27%). More treated patients had serious adverse events in trials of orphan drugs vs trials of nonorphan drugs (48% vs 36%; odds ratio, 1.72; 95% confidence interval, 1.02-2.92; P = .04). Compared with pivotal trials used to approve nonorphan cancer drugs, pivotal trials for recently approved orphan drugs for cancer were more likely to be smaller and to use nonrandomized, unblinded trial designs and surrogate end points to assess efficacy.

Background The number of pharmaceutical companies developing cell and gene therapy (CGT) products, categorized into cell therapy products (CTPs) and gene therapy products (GTPs), has increased, expanding patient access to approved treatments. Compared to conventional modalities, such as chemical compounds and biopharmaceuticals, both CTPs and GTPs pose significant challenges in their development. This study analyzed the characteristics of pharmaceutical companies associated with entry into CGT product development. Methods Focusing on 309 pharmaceutical companies worldwide with marketed products, we analyzed entry into development and the numbers of CTPs and GTPs. We explored firm characteristics associated with entry into CTP and GTP development, as well as their respective proportions within company pipelines, using multiple regression models. Results Approximately 30% of firms included CTPs or GTPs in their product baskets. Larger firms were more inclined to pursue CGT product development. Compared with companies headquartered elsewhere, Japanese companies were more likely to develop CTPs, maintaining a higher proportion of these agents in their baskets. The tendency towards home market entry was more pronounced for CTPs and GTPs than for chemical moieties and proteins. Firms with experience in biopharmaceuticals were more likely to develop GTPs, demonstrating higher proportions of these agents than firms without such experience. While larger sales tended to enhance entry into both CTP and GTP development, research and development expenditure played a greater role in driving entry into CTP development than into GTP development. Conclusions These findings underscore the distinct characteristics of CTPs and GTPs and offer valuable insights into pharmaceutical innovation research.

BACKGROUND: Health plans apply utilization management criteria to guide their enrollees' access to prescription drugs. Patient subgroup restrictions (ie, clinical prerequisites for drug coverage) are a form of utilization management that have not been thoroughly investigated. OBJECTIVE: To examine the frequency with which large US commercial health plans impose patient subgroup restrictions beyond the US Food and Drug Administration (FDA) label in their coverage policies for orphan drugs and for drugs included in 1 or more FDA-expedited programs. To determine how consistently these patient subgroup restrictions align with eligibility criteria specified in each drug's pivotal clinical trial(s). METHODS: The Tufts Medical Center Specialty Drug Evidence and Coverage (SPEC) database was used, which includes coverage policies issued by 17 large US commercial health plans. SPEC contained 3,786 orphan drug policies and 4,027 FDA-expedited drug policies (current as of December 2020). SPEC data on plans' patient subgroup restrictions were assessed for the first objective. Each patient subgroup restriction was benchmarked against the corresponding eligibility criteria for a drug's pivotal clinical trial(s) for the second objective. To do so, the "Clinical Studies" section of the drug's FDA label was reviewed or, if necessary, the published manuscript describing the drug's pivotal trial(s). Patient subgroup restrictions were categorized as follows: (1) "consistent," the restriction and trial eligibility criterion are equivalent; (2) "same measure, more stringent," the restriction and trial eligibility criteria depend on the same measure, but the plan coverage is more restrictive; (3) "same measure, less stringent," the restriction and trial eligibility criteria depend on the same measure, but the plan coverage is less restrictive; and (4) "not consistent," the restriction and trial eligibility criteria depend on different measures. RESULTS: Health plans imposed patient subgroup restrictions in 20.2% of orphan drug policies (frequency varied by health plan, 11.7%-36.6%), and in 21.8% of FDA-expedited drug policies (frequency varied by health plan, 11.1%-47.9%). Of the 936 patient subgroup restrictions in orphan drug policies, 60.3% were categorized as consistent; 7.3% as same measure, more stringent; 12.0% as same measure, less stringent; and 20.5% as not consistent. Of the 1,070 patient subgroup restrictions in FDA-expedited drug policies, 57.5% were categorized as consistent; 6.7% as same measure, more stringent; 16.0% as same measure, less stringent; and 19.8% as not consistent. CONCLUSIONS: Patient subgroup restrictions for orphan drugs and FDA-expedited programs varied substantially across health plans, potentially resulting in inconsistent access to a given therapy across the approved patient population. Patient subgroup restrictions tend to be consistent with eligibility criteria specified in pivotal clinical trials. DISCLOSURES: This study was funded by Sarepta Therapeutics, Inc. Alexa C Klimchak and Lauren E Sedita are employees of Sarepta Therapeutics, Inc., and may own stock/options in the company.

PCN231 - Comparative Analysis of Clinical Trial Attributes in Pivotal Studies for Orphan vs. Non-Orphan Oncology Products FDA-Approved between 2011 and 2015

Recognizing the challenges faced by researchers and clinicians working in the field of cellular therapy, the National Heart, Lung, and Blood Institute (NHLBI), National Institutes of Health, established the Production Assistance for Cellular Therapies (PACT) program in 2003 and expanded it in 2010. The PACT program provides both clinical product manufacturing support that furthers the mission of NHLBI in the areas of cardiac, lung, and blood diseases and broad support of translational development across all disease areas to serve the entire cell therapy community. The program also provides access to expertise in project management, regulatory affairs, and quality assurance and control. Education initiatives include webinars, cell processing facility-hosted workshops, national workshops, and active participation and leadership within the cell therapy community through collaboration with other cell therapy organizations and academia. So far, over 650 PACT-manufactured cell therapy products have been administered in 32 clinical trials for a range of illnesses and diseases such as acute myocardial infarction, sickle cell disease, and graft-versus-host disease.

Drug time lags occur between the date that new drugs are first approved, often in the USA, and approval is granted in other countries. Multi-regional clinical trials (MRCTs) are a key strategy for simultaneous global development and regulatory submission of new drugs. However, no studies have evaluated the impact of MRCT versus local development on key time points in the drug development lifecycle between the USA and Japan. It is important for pharmaceutical companies planning drug development in Japan to understand when they can start development, when they can catch up in case of development initiation delay, length of time the development period might take, and amount of time that market exclusivity is lost, if Japan does not participate in the MRCT. The aim of this study was to investigate differences in drug lag in development initiation, New Drug Application (NDA) submission and drug approval, as well as differences in the development and review periods, by local trials and MRCTs between Japan and the USA. We also assessed the advantages and disadvantages of MRCTs for these lags in Japan. We analyzed drug approvals in Japan between 2016 and 2020 and divided them into local and MRCT groups. Lags in development initiation, NDA submission, and approval of new drugs were calculated by subtracting each date in Japan from the corresponding date in the USA. Our study period was divided into three periods based on the International Conference on Harmonization (ICH) E17 guideline, published in 2017, and the guideline for the Phase I trials in the Japanese population prior to MRCTs, published in 2014. In addition, subgroup analyses by therapeutic area, regulatory background, modality, capital style, and sales ranking (2020) were conducted. We analyzed 174 approvals in Japan and the USA. The differences in the drug lags for development initiation, NDA submission, and approval between the local and MRCT groups were 4.9, 3.5, and 3.2 years, respectively. All three lag times were shorter for the MRCT group than the local group. A development initiation lag in the local group has expanded since publication of the guidelines. For the people of Japan, important drug lags were identified in development initiation, NDA submission, and drug approval dates between local trials and MRCTs that include Japan. It is difficult to recover fully from the delay caused by local development, and it is important to understand the further expansion of drug lags, in cases where Japan is not involved in the MRCT.

BackgroundA pronounced disparity exists in the accessibility of orphan drugs between China and developed countries, such as the United States. Identifying and analyzing the critical determinants that contribute to this gap is essential for enhancing the availability of orphan drugs and promoting equitable access for patients.MethodsWe included all new orphan drugs approved by the US Food and Drug Administration (FDA) between 2013 and 2023 and collected their approval information in China and the United States. Major factors of interest included accelerated review pathway, locations where pivotal clinical trials were conducted, therapeutic category, and other factors affecting the delay in drug launch. They were analyzed using multinomial logistic regression, analysis of covariance, and the Mann-Whitney U test.ResultsThe FDA approved a total of 242 new orphan drugs between 2013 and 2023. Among these, 119 (49.2%) of these drugs had been approved in China as of 1 January 2025, with a median lag time of 1,004 days (2.75 years). Among them, 47 drugs (41.2%) were included in the China’s List of Rare Diseases. Multinomial logistic regression analysis revealed that the conduct of pivotal trials supporting FDA approval in mainland China was associated with whether such drugs were launched in China (odds ratio = 10.53, 95% confidence interval 3.67–40.79; P < 0.001). Furthermore, the Mann-Whitney U test indicated that such characteristics as the inclusion of indications in China’s List of Rare Diseases, the granting of breakthrough therapy designation by the National Medical Products Administration (NMPA), and the inclusion of pivotal clinical trials in mainland China were all associated with the shortening of drug lag time.DiscussionOur findings suggest that orphan drug approval delays in China have improved significantly, but still face significant challenges. China’s involvement in the global collaborative development of drugs not only helps shorten the relative lag time for drugs to obtain approval in China but also avoids repeated trials and significantly improves R&D efficiency. We recommend that pharmaceutical companies include Chinese patients in the drug development stage so that they can enjoy cutting-edge innovative therapies more quickly.

The State of Gene Therapies: The FDA Perspective

ImportanceMany investigational drugs fail in late-stage clinical development. A better understanding of why investigational drugs fail can inform clinical practice, regulatory decisions, and future research.ObjectiveTo assess factors associated with regulatory approval or reasons for failure of investigational therapeutics in phase 3 or pivotal trials and rates of publication of trial results.Design, Setting, and ParticipantsUsing public sources and commercial databases, we identified investigational therapeutics that entered pivotal trials between 1998 and 2008, with follow-up through 2015. Agents were classified by therapeutic area, orphan designation status, fast track designation, novelty of biological pathway, company size, and as a pharmacologic or biologic product.Main Outcomes and MeasuresFor each product, we identified reasons for failure (efficacy, safety, commercial) and assessed the rates of publication of trial results. We used multivariable logistic regression models to evaluate factors associated with regulatory approval.ResultsAmong 640 novel therapeutics, 344 (54%) failed in clinical development, 230 (36%) were approved by the US Food and Drug Administration (FDA), and 66 (10%) were approved in other countries but not by the FDA. Most products failed due to inadequate efficacy (n = 195; 57%), while 59 (17%) failed because of safety concerns and 74 (22%) failed due to commercial reasons. The pivotal trial results were published in peer-reviewed journals for 138 of the 344 (40%) failed agents. Of 74 trials for agents that failed for commercial reasons, only 6 (8.1%) were published. In analyses adjusted for therapeutic area, agent type, firm size, orphan designation, fast-track status, trial year, and novelty of biological pathway, orphan-designated drugs were significantly more likely than nonorphan drugs to be approved (46% vs 34%; adjusted odds ratio [aOR], 2.3; 95% CI, 1.4-3.7). Cancer drugs (27% vs 39%; aOR, 0.5; 95% CI, 0.3-0.9) and agents sponsored by small and medium-size companies (28% vs 42%; aOR, 0.4; 95% CI, 0.3-0.7) were significantly less likely to be approved.Conclusions and RelevanceRoughly half of investigational drugs entering late-stage clinical development fail during or after pivotal clinical trials, primarily because of concerns about safety, efficacy, or both. Results for the majority of studies of investigational drugs that fail are not published in peer-reviewed journals.

7026 Background: CAR T cell therapies have shown remarkable efficacy in B-cell NHL. Here, we report CRS and ICANS timing in 1579 patients (pt) treated with liso-cel in clinical trials across indications or in the standard of care (SOC) setting to inform safety monitoring requirements. Methods: Data from pivotal trials (TRANSCEND NHL 001, TRANSCEND CLL 004, TRANSFORM, PILOT, TRANSCEND FL) included pts treated with liso-cel for R/R LBCL, CLL/SLL, MCL, and FL; data from the Center for International Blood and Marrow Transplant Research (CIBMTR) Registry included pts who received commercial liso-cel for R/R LBCL and had ≥ 1 assessment after infusion. Outcomes were incidence, onset, grade (gr), and duration of CRS and ICANS from pivotal trials and the CIBMTR Registry. Results: Of 702 pts treated with liso-cel in 5 clinical trials, 46% had no CRS, 54% had any-gr CRS (gr ≥ 3 at onset, 1%); 98% of events had onset ≤ 2 wk after infusion and median duration was 5 d (Table). Of 7 pts with CRS onset &gt; Day 15 (gr 1, n = 5; gr 2, n = 2), all resolved. Most (69%) pts had no ICANS, 31% had any-gr ICANS (gr ≥ 3 at onset, 5%); 88% of events had onset ≤ 2 wk after infusion and median duration was 7 d (Table). Of 27 pts with ICANS onset &gt; Day 15 (gr 1, n = 20; gr 2, n = 6; gr 3, n = 1), all resolved except 1 pt with gr 2 leukoencephalopathy. Of 877 liso-cel–treated pts from the CIBMTR Registry, 51% had no CRS, 49% had any-gr CRS (gr ≥ 3, 3%); 97% of events had onset ≤ 2 wk after infusion and median duration was 4 d (Table). Of 15 pts with CRS onset &gt; Day 15 (gr 1, n = 9; gr 2, n = 2; gr 3, n = 1; unknown, n = 3), 13 resolved (missing, n = 2). Most (73%) pts had no ICANS, 27% had any-gr ICANS (gr ≥ 3, 7%). Of 150 pts with reported onset date, 95% had onset ≤ 2 wk after infusion and median duration was 5.5 d. Of 8 pts with ICANS onset &gt; Day 15 (gr 1, n = 5; gr 2, n = 1; gr 4, n = 2), 5 resolved (missing, n = 3). Further characterization/management of CRS/ICANS events will be presented. Conclusions: Data from the liso-cel pivotal clinical trials and SOC setting from the CIBMTR Registry demonstrated that most CRS/ICANS events occurred ≤ 2 wk after infusion and were not severe. For the few pts who experienced onset of CRS/ICANS after Day 15, most events were low grade and resolved. Clinical trial information: NCT02631044 , NCT03331198 , NCT03483103 , NCT03575351 , NCT04245839 . CRS and ICANS in liso-cel–treated pts. Pivotal clinical trials (N = 702) CIBMTR Registry (N = 877) CRS ICANS CRS ICANS Any gr, n (%) 381 (54) 220 (31) 430 (49) a 234 a,b (27) Gr 3/4/5, c n (%) 4 (0.6)/3 (0.4)/0 29 (4)/3 (0.4)/0 4 (0.5)/13 (1)/7 d (0.8) 43 (5)/17 (2)/5 (0.6) Median (range) time to onset, d 5 (1–63) 8 (1–63) 4 (IQR, 3–6) 6 (IQR, 4–9) Median (range) duration from onset, d 5 (1–37) 7 (1–119) 4 (IQR, 2–6) 5.5 (IQR, 2–11) Onset &gt; Day 15, n/N (%) 7/381 (2) 27/220 (12) 15/430 (3) 8/150 (5) a Gr was to be determined for 3 pts; b A total of 150/234 had a reported onset date; c Gr at onset for clinical trials; maximum gr during reporting period for CIBMTR; d Three pts had PD and 1 had ICANS reported as primary cause of death.

The Need for Increased Clarity and Transparency in the Regulatory Pathway for Gene Medicines in the European Union

The increasing attrition rates of new drug research and development have become a global problem. To tackle this problem as well as the problem of "drug lag" in Japan, strategies utilizing multiregional clinical trials (MRCTs) are now being commonly applied. It is important to determine whether clinical data in a specific country and region have tendencies or patterns that will help us to consider an appropriate strategy for drug development in the specific region as well as worldwide. However, little has been studied on strategies and methods for drug development to pursue simultaneous development taking into account these characteristics. It would be valuable to determine and characterize the safety profile of Japanese clinical trial data. To characterize the overall safety profile of Japanese data in terms of the frequency of adverse events (AEs), serious AEs, and discontinuation due to AEs compared with non-Japanese data, 73 pharmaceutical products recently approved in Japan were selected. Their clinical trial safety data, derived from comparable studies conducted in Japan and Western countries using the bridging strategy and MRCTs, were reviewed and analyzed. Japanese data are similar to non-Japanese data in terms of overall frequency of AEs; however, the sample size of Japanese patients in the bridging studies and MRCTs was generally smaller than that in non-Japanese data. The safety profile in Japanese clinical data was shown to be similar to that of non-Japanese data from the standpoint of overall frequency of AEs. This finding should be encouraging to pharmaceutical companies and the health authority in Japan to accelerate participation in MRCTs.

Background: Cell and gene therapy products belong to a diverse class of biopharmaceuticals known as advanced therapy medicinal products. Cell and gene therapy products are used for the treatment and prevention of diseases that until recently were only managed chronically. The objective of this study was to examine the characteristics of market authorizations, discontinuations, and prices of cellular and gene therapy products worldwide. Data and Methods: We conducted an electronic search of authorized cell, tissue-engineered, and gene therapy products from the databases of the main drug regulatory agencies. The analysis excluded hematopoietic progenitor cell cord blood products authorized by the U.S. Food and Drug Administration. Price information was derived from the Red Book (Truven Health Analytics) for the United States, health technology assessment agencies for Europe, and other public sector sources and company news for other countries. We also searched the scientific literature for authorizations, discontinuations, and price information using MEDLINE/PubMed, Cochrane Library, Google Scholar, and EMBASE databases. All cost data were converted to U.S. dollars. Descriptive analysis was conducted in this study. Results: There were 52 different cell, tissue engineering and gene therapy products with 69 market authorizations in the world as of December 31, 2018. The products included 18 (34%) cell therapies, 23 (43.4%) tissue engineered products, and 12 (22.6%) gene therapies. There were 21 (30.4% of all authorizations) cell therapy, 26 (37.7%) tissue-engineered, and 22 (31.9%) gene therapy market authorizations. The EMA withdrew the authorization for two tissue engineering products, one cell therapy and one gene therapy, and New Zealand lapsed approval of one cell therapy. Most products were first authorized after 2010, including 10 (83.3%) gene therapies, 13 (72.2%) cell therapies, and 13 (56.5%) tissue-engineered products. The treatment price for four allogenic cell therapies varied from $2,150 in India to $200,000 in Canada. The treatment price for three autologous cell therapies ranged from $61,500 in the United Kingdom to a listed price of $169,206 in the United States. Tissue-engineered treatment prices varied from $400 in South Korea to $123,154 in Japan. Gene therapy treatment prices ranged from $5,501 for tonogenchoncel-L in South Korea to $1,398,321 for alipogene tiparvovec in Germany. Conclusions: A significant number of new cell, tissue, and gene therapies have been approved in the past decade. Most products were conditionally authorized and targeted rare cancers, genetic diseases, and other debilitating diseases. However, there are also products approved for cosmetic reasons. Cell, tissue, and gene therapies are among the most expensive therapies available. Healthcare systems are not prepared to assume the cost of future therapies for a myriad of rare diseases and common diseases of epidemic proportions.

ObjectivesLittle is routinely disclosed about the costs of the pivotal clinical trials that provide the key scientific evidence of the treatment benefits of new therapeutic agents. We expand our earlier...

1435O_PR - Comparison of the European Society for Medical Oncology Magnitude of Clinical Benefit Scale (ESMO-MCBS) in clinical trials supporting US Food and Drug Administration (FDA) approval of orphan vs. non-orphan drugs