2024 Volume 47 Issue 7 Pages 1345-1349
The Accelerated Approval (AA) Program of the United States (US) Food and Drug Administration (FDA) was established to facilitate and expedite access to new drugs for serious or life-threatening conditions. Although many drugs have granted AAs in the US, the number of approvals under the conditional approval system in Japan remains limited. This study aimed to examine whether confirmatory trials after the US AA are conducted in accordance with the design of postmarketing requirements and assess the timing of regular approval (RA) in Japan for drugs that have been granted US AA. Utilizing FDA databases and Japanese regulatory data from 1992 to 2023, we analyzed indications, postmarketing requirements, and clinical trial designs. Our findings indicate that the AA program in the US is well-managed as most AAs were converted to RAs based on confirmatory study data that met the designations. From the Japanese perspective, our findings show that the over half of Japanese RAs can be obtained without waiting for confirmatory trial results. By granting RA, instead of conditional approval, based on exploratory trial data in the US AA, the opportunity to evaluate postmarketing confirmatory trial results might be lost in Japan. Therefore, further improvements are needed to actively utilize the conditional approval system, which could allow for the rapid introduction of innovative drugs and also the verification of their efficacy and safety at an appropriate time.
The Accelerated Approval (AA) Program of the United States (US) Food and Drug Administration (FDA) was established in 1992 to facilitate and expedite access to promising new drugs for serious or life-threatening conditions. It is an alternative pathway to the regular approval (RA) to grant marketing approval based on a surrogate endpoint that is reasonably likely to predict a clinical benefit.1,2) Confirmatory trials are necessary for drugs with AA because of the uncertainty of the relationship between the surrogate endpoint and clinical benefits.3) As the AA program has been in place for over 30 years, knowledge and experience have accumulated. Thus far, hundreds of drugs have been approved under the program, and half of the approvals have already been converted to RAs after the submission of confirmatory trial data to the FDA.4–6)
The program has not always been the same and has been continually modified and clarified. According to the Consolidated Appropriations Act 2022, the FDA has more authority to determine the details of postmarketing confirmatory trials, requiring that they are ongoing at the time of AA, impose fines if the trials are unreasonably delayed or not completed, and expedite the withdrawal of the drug from the market for the indication if confirmatory trials fail.7) In March 2023, the FDA published a new draft guidance for the industry titled “Clinical Trial Considerations to Support Accelerated Approval of Oncology Therapeutics,” which provides additional guidance on the design and conduct of oncology clinical trials.8)
These changes make the requirements for AA and the design of confirmatory trials more important in the US. In contrast, in Japan, regulatory reforms are needed to utilize the existing “conditional approval system” actively. This is because although Japan’s “conditional approval system” started in 2017 to approve drugs deemed highly medically necessary, such as those for rare diseases, without the requirement for confirmatory trials, unlike the US, where the AA pathway is frequently utilized, the number of approvals under this system in Japan has been limited to five products to date.9) This lack of progress in the conditional approval system in Japan highlights the need for a comprehensive examination from both the government and industry perspectives. The government must ensure that confirmatory trials are conducted in accordance with the designated protocol required for conditional approval, while the industry needs to evaluate the benefits brought about by the conditional approval system.
Among several published reports on clinical trial characteristics for AA and confirmatory trials in the US,10–13) only few studies documented the design of confirmatory trials to meet postmarketing design requirements. The impact of the US AA on the speed of approval in Japan has been studied14); however, benefit of the Japanese conditional approval system for the industry, compared to the RA system, remains unclear. If the Japanese RA is granted immediately after the US AA without the need for confirmatory trials, there may create little incentive to use the conditional approval system from the industry’s perspective. Therefore, this study aimed to investigate whether confirmatory trials after the US AA are conducted in accordance with the design in the postmarketing requirements and to clarify the timing of RA in Japan for drugs granted AA in the US.
The FDA databases were searched from December 1992 to March 2023 to identify drugs approved by the FDA’s Center for Drug Evaluation and Research (CDER). Data sources included approval letters, labels, and review documents from Drugs@FDA.15) The following information was extracted for the AA and subsequent confirmatory trials from the data sources: date of AA, indication, postmarketing requirements, date of RA (if applicable), and trial design for both AA and RA (phase, randomized, blinded, sample size, and primary endpoint). If trial design information was missing, ClinicalTrials.gov, an official website of the US Department of Health and Human Services, and websites of the National Institutes of Health, the National Library of Medicine, and the National Center for Biotechnology Information were used.16) When multiple trials were submitted for approval, the later-stage trial was selected. If the clinical phase was the same, the trial was selected based on endpoints that were more relevant to the clinical benefit, larger sample size, randomization, or blinded design. To compare approval timelines for each product (indication) in the US and Japan, we investigated the approval status and date in Japan by searching the Japan Pharmaceuticals and Medical Devices Agency (PMDA) and Japan Pharmaceutical Manufacturers Association (JPMA) websites.17,18)
We identified 295 indications for which AAs were granted between December 1992 and March 2023 (Table 1). Of these, 53 (18%), 203 (69%), and 39 (13%) patients had infectious diseases, oncology, and other diseases, respectively. Forty (14%), 61 (21%), and 194 (66%) AAs were granted in the 1990s, 2000s, and 2010 and later, respectively. Furthermore, AAs for 161 (55%) indications were converted to RAs, and 35 (12%) were withdrawn.
| Variable | Indications, No. (%) | |||
|---|---|---|---|---|
| Overall | Therapeutic category | |||
| Infectious disease | Oncology | Others | ||
| Total number of accelerated approvals granted | 295 | 53 | 203 | 39 |
| Trends by decades | ||||
| 1990s | 40 (14) | 25 (47) | 11 (5) | 4 (10) |
| 2000s | 61 (21) | 22 (42) | 32 (16) | 7 (18) |
| 2010s and beyond | 194 (66) | 6 (11) | 160 (79) | 28 (72) |
| Conversion–withdrawal status | ||||
| Converted | 161 (55) | 38 (72) | 106 (52) | 17 (44) |
| Withdrawn | 35 (12) | 9 (17) | 24 (12) | 2 (5) |
| Not yet converted | 99 (34) | 6 (11) | 73 (36) | 20 (51) |
Table 2 summarizes the postmarketing requirements of AAs. Among the 295 indications for which AAs were granted, continuation of clinical trials whose data were partially submitted for AAs was required for 58 (20%) indications, and additional studies were required for the remaining 237 (80%). Regarding the study design for the latter 237 indications, 163 (69%), 49 (21%), 143 (60%), and 30 (13%) indications required randomization, blinding, specified endpoints, and a minimum number of patients in the approval letter, respectively. In addition, when focusing on the 194 indications for which AAs were granted after 2010, the continuation of clinical trials whose data were partially submitted for AAs was required in 29 (15%) indications, and additional studies were required for the remaining 169 (85%). Regarding the study design for the latter 169 indications, 125 (74%), 34 (20%), 131 (78%), and 28 (17%) indications required randomization, blinding, specified endpoints, and a minimum number of patients in the approval letter, respectively.
| Requirements | Accelerated approval for all period, No. (%) | Accelerated approval after 2010, No. (%) |
|---|---|---|
| Total number of accelerated approvals granted | 295 | 194 |
| Continuation of accelerated approval trials | ||
| Yes | 58 (20) | 29 (15) |
| No | 237 (80) | 169 (85) |
| Requirements for a new confirmatory trial (multiple) | ||
| Subtotal | 237 | 169 |
| Randomized trial | 163 (69) | 125 (74) |
| Blinded trial | 49 (21) | 34 (20) |
| Designation of an end point | 143 (60) | 131 (78) |
| Designation of the minimum number of participants | 30 (13) | 28 (17) |
We explored the clinical trial data submitted for AA (295 indications), as well as the confirmatory trial data for RA (161 indications) whose AAs were converted to RA (Table 3). Among the clinical trials for AA, 116 (39%) were randomized, and 76 (26%) were blinded. Of the 161 indications for which confirmatory trials were conducted, 119 (74%) were randomized, and 57 (35%) were blinded. The sample sizes of the test drug group in trials for AAs were as follows: 1–50 patients, 78 indications (26%); 51–100 patients, 77 indications (26%); 101–200 patients, and 45 indications (15%); 201–300 patients. The sizes of the actual drug groups in confirmatory studies were as follows: 42 indications (26%), 101–200 patients; 35 indications (22%), 201–300 patients; and 31 indications (19%), 301–500 patients.
| Variable | No. (%) | |
|---|---|---|
| Trial for accelerated approval | Confirmatory trial* | |
| Total | 295 | 161 |
| Randomized | ||
| Yes | 116 (39) | 119 (74) |
| No | 152 (52) | 32 (20) |
| Unknown | 27 (9) | 10 (6) |
| Blinded | ||
| Yes | 76 (26) | 57 (35) |
| No | 192 (65) | 94 (58) |
| Unknown | 27 (9) | 10 (6) |
| Trial phase | ||
| Phase 4 | 1 (0) | 10 (6) |
| Phase 3 | 79 (27) | 107 (66) |
| Phase 2/3 | 3 (1) | 2 (1) |
| Phase 2 | 104 (35) | 11 (7) |
| Phase 1/2 | 45 (15) | 1 (1) |
| Phase 1 | 9 (3) | 15 (9) |
| Observational study/Literature review | 28 (9) | 0 (0) |
| Unknown | 26 (9) | 15 (9) |
| Number of participants in the test drug group | ||
| 1–50 | 34 (12) | 4 (2) |
| 51–100 | 78 (26) | 9 (6) |
| 101–200 | 77 (26) | 42 (26) |
| 201–300 | 45 (15) | 35 (22) |
| 301–500 | 18 (6) | 31 (19) |
| 500– | 15 (5) | 27 (17) |
| Unknown | 28 (9) | 13 (8) |
* Confirmatory trial submitted for conversion to a regular approval.
Of the 295 indications for which AAs were granted in the US, 170 were also approved in Japan, and 125 were not. Regarding the breakdown by therapeutic area, among the 170 indications, 124, 28, and 18 were oncology, infectious diseases, and other indications, respectively (Fig. 1). Figure 2 shows the timing of Japanese approval compared to that of US AAs and RAs. Eighteen indications were approved in Japan before corresponding AAs were granted in the US. Furthermore, 102 indications were approved in Japan between the AA and its conversion to RA in the US, and the remaining 46 were approved in Japan after the RA in the US. Approval was not required in Japan for the remaining four indications and was addressed by revisions to the package inserts.
Our study suggests that confirmatory trials after the US AA were conducted in accordance with the design in the postmarketing requirements. RAs were obtained for more than half of the indications for which AAs were granted (Table 1). For an AA to be converted to a RA, postmarketing requirements must be met at the time of RA. While the designation of a randomized postmarketing study is required for approximately 70% of the products (Table 2), randomized confirmatory studies are conducted for more than 70% of the products for which AAs are converted to RA that meet designations. In confirmatory studies, sample size increased compared to those of studies for AA, and most phase 2 studies advanced to phase 3, confirming that the clinical trial design met postmarketing requirements (Table 3).
Our results align with those of previous studies that have shown that the approval system is relatively well-managed.5,6) Nevertheless, the US AA program is not without shortcomings. Discussions include the pros and cons of AAs with surrogate endpoints and the fact that despite delays in conducting confirmatory studies, some AA products had remained on the market for a long time.13,19) However, the FDA’s authority over postmarketing studies has been strengthened by the Consolidated Appropriations Act, and guidelines for oncology drugs are currently being developed.
Our study suggests that, from the industry’s perspective, there may be little incentive to use the conditional approval system compared to RA in Japan. Approximately 60% of the indications for which AAs were granted in the US were also approved in Japan (Fig. 1), and most of the AA indications approved in Japan also obtained Japanese approval between the AA and its conversion to RA in the US (Fig. 2). Although our results do not provide substantial evidence of the impact of the US AA on the Japanese approval, if the Japanese RA can be obtained without waiting for the result of the confirmatory trial, it is understandable why the industry does not use conditional approval. However, by granting RA in Japan without confirmatory trial data, instead of conditional approval, the opportunity to evaluate postmarketing confirmatory trial results might be lost in Japan. Furthermore, Japan should consider the fact that approximately 40% of indications for which AAs have been received in the US have not been granted in Japan. The absence of approval in Japan could stem from a transition in drug development dynamics, shifting from large multinational companies to smaller entities focusing only on the US markets. Addressing these findings necessitates harmonizing the pharmaceutical affairs system with fewer Japan-specific requirements, improving the environment for conducting multiregional clinical trials, and improving the market environment through the drug pricing system under the National Health Insurance to avoid hindering new drug development in Japan.
Our study has some limitations. First, we relied only on publicly available information and did not evaluate the details of the clinical trial design or validity. Thus, other types of studies may have been conducted for approval in both Japan and the US. Second, we only focused on confirmatory trials that resulted in successful conversion to RA; therefore, there might be a different trend in the trial design for withdrawn indications. Third, since CDER-approved drugs were explored in this study, products approved by the Center for Biologics Evaluation and Research (CBER), such as vaccines, blood products, and gene therapies, were not included in this study. Finally, it should be noted that the clinical data packages submitted for approval in Japan could not be identical to those submitted for approval in the US. However, we believe that this does not affect the considerations when comparing approval timings.
In conclusion, our study revealed that the AA program in the US is well-managed, as AAs have been converted to RAs for most indications based on confirmatory studies in accordance with the trial design required for postmarketing. From the Japanese perspective, improvements are needed to actively utilize the conditional approval system, which could allow for the rapid introduction of innovative drugs and also the verification of their efficacy and safety at an appropriate time.
This work was supported by the Health Labour Science Research Grant 23CA2027 from the Ministry of Health, Labour and Welfare, Japan.
The authors declare no conflict of interest.
