Abstract
Abstract
Objective
The US Food and Drug Administration (FDA) and the European Medicines Agency (EMA) are leading benchmarks for reliance approval pathways, while many regulatory authorities streamline their review processes by referencing these authorities’ evaluations and decisions. Major postmarketing (MPM) modifications, reflecting benefit–risk updates, are often added to approved labels. This study aimed to identify variables associated with significant MPM safety modifications by FDA and EMA to understand their potential impact on regulatory decision-making in the reliance process.
Design
Retrospective cohort study of new drug applications and supplemental indications approved by the Israeli Ministry of Health (MOH) between 2014 and 2019. The primary outcome was time to first MPM safety modification by the FDA/EMA. Associated factors, including clinical and regulatory variables, were examined using both univariate and multivariable Cox regression analyses.
Setting
Applications with FDA and/or EMA approval at the time of assessment in Israel were included.
Results
467 applications met the inclusion criteria. Oncology therapeutics (HR 2.19 (95% CI 1.71 to 2.80)), approval based on early phase clinical trials data—phase 1 (HR 3.14 (95% CI 1.29 to 7.63)) and phase 2 (HR 1.97 (95% CI 1.47 to 2.64)), facilitated approval pathways (HR 1.68 (95% CI 1.31 to 2.17)) and approval based on a surrogate endpoint (HR 1.92 (95% CI 1.31 to 2.46)), were associated with higher rates of MPM modifications. MPM modifications were documented in 53.1% of applications that underwent a single Advisory Committee on Drug Registration (ACDR) review cycle, compared with 68.67% of applications that required multiple review cycles (HR 1.6, (95% CI 1.19 to 2.16), p=0.001). In multivariable analysis, oncology indications (HR 1.71 (95% CI 1.31 to 2.25)), facilitated approval pathways (HR 1.46 (95% CI 1.13 to 1.92)) and applications approved following multiple review cycles (HR 1.42 (95% CI 1.14 to 2.58)) were found to be predictive factors correlated with MPM modifications.
Conclusions
By considering these associated factors, regulators can strengthen the reliance pathway assessment process, supporting a balance between streamlined evaluation procedures and maintaining rigorous safety and efficacy standards.
Keywords: Medicine, Health policy, PUBLIC HEALTH
STRENGTHS AND LIMITATIONS OF THIS STUDY.
This study examined a comprehensive national database of drug approvals utilising a reliance pathway over a 6-year period.
The use of an exploratory multivariable Cox proportional hazards model facilitated the identification of key variables that can be considered by regulatory agencies using reliance-based approval.
The analysis integrates preapproval regulatory characteristics with subsequent post-marketing safety outcomes.
The study focused on the two leading reference regulatory authorities, Food and Drug Administration and European Medicines Agency, which maintain a publicly available online database, excluding drug applications authorised by other regulatory agencies.
The observational nature of the study is subject to residual confounding and inherent bias.
Introduction
Health regulatory authorities play a critical role in promoting public health by optimising and expediting the evaluation of new drugs and indications, thereby enhancing patient access and fostering innovation.1 Across global health regulatory authorities, efforts are focused on optimising resource utilisation and streamlining processes. One key strategy is reliance on leading authorities such as the FDA and the EMA, which serve as reference agencies for other regulators like Israel MOH, for new drug applications and supplemental indications. However, a reliance process necessitates careful consideration due to potential gaps between the regulatory agencies’ landscapes. The optimal supporting data for a new drug application in both the FDA and EMA are data derived from comparative phase 3 studies establishing efficacy and safety.2 However, in life-threatening diseases or conditions considered as an unmet medical need, marketing authorisation applications may be submitted with less robust clinical data, derived from early phase studies (phase 1 or 2) and/or interim analysis.3
Moreover, regulatory authorities use various strategies to expedite the evaluation and registration of new drugs and supplemental new indications, aiming to enhance patients access and promote the introduction of innovative treatments. These strategies often involve accepting data from early-phase trials or surrogate endpoints to support authorisation.4–6
The Pharmaceutical Registration Department in the Pharmaceutical division in Israel MOH is responsible for the assessment and authorisation of new drugs and supplemental indications and for PM modifications. This process employs a strategic reliance pathway, leveraging prior approvals from the FDA and/or EMA to streamline regulatory evaluations and accelerate market access.
The assessment process consists of a clinical review by assessors with regulatory and clinically relevant expertise. An evaluation of data supporting safety and efficacy is conducted by a pharmacist expert in regulatory and clinically relevant expertise. After a first assessment and subsequent deficiency letter (if needed), the application is reviewed by a wide forum of the ACDR members, which consists of expert physicians along with the Pharmaceutical Registration Department clinical assessors.
This completes one review cycle, and a recommendation regarding the approval or rejection of the application is provided with an outline of any conditions for approval.7 The evaluation relies solely on clinical data, independent of the drug’s setting (outpatient or hospital) and independent of its price. The cost of the medicine does not influence the ACDR’s discussions or decisions. The committee’s recommendation for each application can be either to accept, accept with modifications, accept with postapproval requirements, reject or defer pending further data or clarifications by the applicant. If further data are needed, a deficiency letter is issued, and the application is given pending status. The application will be rediscussed in a subsequent review cycle.
This study continues our previously published work, describing a two-fold risk of MPM modifications after multiple review cycles compared with approvals taken after a single review cycle (HR=1.98, 95% CI 1.26 to 3.09).8 In this study, we aimed to describe variables associated with MPM label modifications over a more extensive 6-year period (2014–2019). Given the absence of prespecified causal framework for variable selection in this context, and the exploratory nature of identifying factors associated with MPM modifications, we applied a data-driven approach in multivariable analysis.
Methods
Study design and setting
We conducted a retrospective cohort study based on regulatory drug applications submitted for registration in Israel between the years 2014 and 2019, allowing a follow-up period of at least 2 years of postapproval data collection and long-term safety evaluation. The final data cut-off was January 2022.
Inclusion criteria
Applications were included if they were authorised by the FDA and/or EMA before submission in Israel and applications that received ACDR approval. To minimise confounding factors and ensure the integrity and comparability of our datasets across all included applications, the analysis excluded applications for biosimilar drugs, drugs administered topically, ophthalmic drugs, coagulation factors and vaccines, as these types of applications constitute a minor part of the total applications.
Variables and data source
The study cohort was identified through a comprehensive and systematic search in the Israeli MOH pharmaceutical registration database. All regulatory submissions and ACDR protocols between 1 January 2014 and 31 December 2019 were manually reviewed. Each application that met the predefined inclusion criteria was included in the analysis to ensure a comprehensive and non-selective cohort. For each application, the following factors were recorded from the Drug registration department portal: the requested and authorised indication, reference regulatory authority (FDA and/or EMA), the reference regulatory authority assessment pathway (standard or facilitated), clinical trial’s phase, primary endpoint used (clinical or surrogate), number of discussions and deficiency letters (following committee discussions) and Israel MOH’s decisions (accept or reject).
The study cohort was reviewed by two researchers. Data extractions were performed by a predefined data collection framework. Differences of opinion between the researchers were resolved by further discussion and additional data collection. To ensure consistency and allow comparability of our findings to existing evidence, the variables selected were primarily based on those which were utilised in a previous study on this topic.8 The primary outcome was time to first MPM safety modifications by the FDA or EMA. MPM safety modifications were defined as the implementation of either a black box warning, a new contraindication, a new safety warning or precaution, a new adverse event (common, very common or severe), an indication that has been withdrawn or restricted, dosage limitation and withdrawal of an approved drug or indication from the market. To determine the regulatory approval pathway and to identify any MPM safety modifications, a comprehensive search of online regulatory databases was conducted. For detailed information on drugs approved by the FDA, the Drugs@FDA9 database was scanned, as were data regarding assessment pathways10–13 and the Drug Safety-related Labeling Changes page.14 For drugs approved by the EMA, the EMA’s website15 was scanned, as was the European Union registry database.16
Bias
Several measures were taken to minimise potential biases. To address selection bias, we included all drug applications that met predefined inclusion criteria, ensuring a comprehensive cohort. Information bias was minimised by relying on official regulatory databases from Israeli MOH, EMA and FDA, which provide valid data on the defined variables and outcomes. Multivariable Cox regression was conducted to examine the association between key variables and the occurrence of MPM safety modifications.
Study size
The study size was determined by the total applications that met the inclusion criteria during the designated study period (2014–2019). Out of 620 NDAs (New Drug Application) and supplemental indication applications reviewed by the Israeli ACDR between 1 January 2014 and 31 December 2019, 467 met inclusion criteria, which provided a robust sample for analysis.
Statistical analysis
Factors associated with MPM safety modifications were evaluated using univariate Cox regression to calculate HRs and 95% CIs. To identify independent factors, variables that demonstrated statistical significance in the univariate analysis (p<0.05) were included into a multivariable Cox regression. A backward elimination method (with a removal criterion of p>0.1) was employed to refine the final model. Given the exploratory nature of this study and the lack of a prespecified causal model, a data-driven approach was used to identify factors associated with the outcome. Statistical significance was defined as a two-sided p value <0.05. All analyses were conducted using SPSS Statistics for Windows, V.28.0 (IBM Corp).
Patient and public involvement statement
None.
Results
Out of 620 NDAs (New Drug Application) and supplemental indication applications reviewed by the Israeli ACDR between 1 January 2014 and 31 December 2019, 467 met inclusion criteria (75%).
The median follow-up time for occurrence of FDA/EMA MPM modification was 21.7 months (95% CI 21 to 29.3). The applications’ characteristics are presented in table 1.
Table 1. Application characteristics and number of Advisory Committee for Drug Registration discussions of approved applications.
| Variable | Total n=467 |
Single discussion n=384 |
Multiple discussions n=83 |
P value |
|---|---|---|---|---|
| Major modification n (%) | 292 (62.5%) | 204 (53.1%) | 57 (68.7%) | 0.01 |
| Drug indication n (%) |
||||
| Oncology | 157 (33.6%) | 119 (25.5%) | 38 (45.8%) | 0.01 |
| Haematology | 71 (15.2%) | 54 (14.1%) | 17 (20.5%) | 0.14 |
| Infectious disease | 63 (13.5%) | 52 (13.5%) | 11 (13.3%) | 0.94 |
| Endocrinology | 48 (10.3%) | 40 (10.4%) | 8 (9.6%) | 0.83 |
| Immunology | 34 (7%) | 31 (8.1%) | 3 (3.6%) | 0.24 |
| Rheumatology | 31 (6.6%) | 26 (6.8%) | 5 (6.0%) | 0.8 |
| Gastroenterology | 30 (6.4%) | 26 (6.8%) | 4 (4.8%) | 0.63 |
| Pulmonology | 29 (6.2%) | 26 (6.8%) | 3 (3.6%) | 0.45 |
| Dermatology | 27 (5.8%) | 24 (6.3%) | 3 (3.6%) | 0.44 |
| Neurology | 26 (5.6%) | 24 (6.3%) | 2 (2.4%) | 0.39 |
| Cardiology | 19 (4.1%) | 15 (3.2%) | 4 (4.8%) | 0.76 |
| Psychiatry | 17 (3.6%) | 15 (3.9%) | 2 (2.4%) | 0.75 |
| Medical genetics | 14 (3.0%) | 11 (2.9%) | 3 (3.6%) | 0.72 |
| Ophthalmology | 11 (2.4%) | 11 (2.9%) | 0 (0%) | 0.23 |
| Gynaecology | 9 (1.9%) | 7 (1.8%) | 2 (1.6%) | 0.66 |
| Urology | 7 (1.5%) | 7 (1.8%) | 0 (0%) | 0.61 |
| Nephrology | 3 (0.6%) | 2 (0.5%) | 1 (1.2%) | 0.44 |
| Reference agency n (%) | ||||
| Approved by EMA (only) | 72 (15.4%) | 65 (16.9%) | 7 (8.4%) | 0.16 |
| Approved by FDA (only) | 89 (19.1%) | 71 (18.5%) | 18 (21.7%) | 0.44 |
| Approved by EMA and FDA | 306 (65.5%) | 248 (64.6%) | 58 (69.9%) | 0.36 |
| Approval type n (%) |
||||
| Facilitated | 141 (30.2%) | 115 (29.9%) | 26 (31.3%) | 0.8 |
| Approved with limitation | 84 (18.0%) | 50 (13.0%) | 34 (41.0%) | <0.001 |
| Phase 1 trial data | 6 (1.3%) | 5 (1.3%) | 1 (1.2%) | >0.999 |
| Phase 2 trial data | 79 (16.9%) | 59 (15.4%) | 20 (24.1%) | 0.054 |
| Phase 3 trial data | 377 (80.7%) | 316 (82.3) | 61 (73.5%) | 0.065 |
| Surrogate endpoint | 211 (45.2%) | 164 (42.7%) | 47 (56.6%) | 0.021 |
| Type of application n (%) | ||||
| New drug application | 227 (48.6%) | 186 (48.4%) | 41 (49.4%) | 0.99 |
| Supplemental indication | 227 (48.6%) | 188 (49.0%) | 39 (47.0%) | 0.93 |
| Other* | 13 (2.8%) | 10 (2.6%) | 3 (3.6%) | 0.71 |
P values represent the statistical difference between drugs approved after a single Advisory Committee for Drug Registration discussion and those which required to or more cycles.
Other type of application—new formulation, new method of administration.
EMA, European Medicines Agency; FDA, US Food and Drug Administration.
Out of 467 included applications, the majority of indications belong to the following therapeutic areas: oncology (33.6%), haematology (15.2%) and infectious diseases (13.5%). Most applications (65.5%) were previously approved by both the EMA and FDA, and 48.6% of the applications were NDAs as well as new indications of approved drugs (48.6%). Facilitated regulatory assessment pathway was recorded in 30.2% of the applications. The majority of applications (80.7%) were approved based on phase 3 trial data, and 45.2% were approved based on surrogate endpoints. Conditional approval, ie, approval with limitations of use, was decided in 84/467 (18%).
Most approvals, 384 (82.2%), were granted following a single review cycle, and 83 (17.8%) were granted following multiple review cycles. Among applications with multiple review cycles, 73 (88%) had two, and 10 (12%) had more than two review cycles. Out of 384 applications approved following a single review cycle, in 204 applications (53.1%), MPM modification was recorded, while in applications approved following multiple review cycles, MPM modification was detected in 57 applications (68.7%), p=0.01.
The median time to MPM modification for applications approved following a single review cycle was 27.6 months (95% CI 22.4 to 32.8) versus 14.6 months for applications approved following multiple review cycles ((95% CI 9.2 to 19.9), p=0.01).
Univariate analysis (table 2) revealed a positive correlation between MPM modifications and several variables: applications within oncology therapeutic area (HR 2.19 (95% CI 1.71 to 2.80) p<0.001), haematology therapeutic area (HR 1.41 (95% CI 1.02 to 1.96) p=0.035), compared with other therapeutic areas, applications approved based on early phase clinical trials data—phase 1 (HR 3.14 (95% CI 1.29 to 7.63) p=0.008) and phase 2 (HR 1.97 (95% CI 1.47 to 2.64) p<0.001), facilitated approval pathways ((HR 1.68 (95% CI 1.31 to 2.17), p=0.001)), compared with standard approval and approval based on a surrogate endpoint (HR 1.92 (95% CI 1.51 to 2.46) p<0.001), compared with clinical endpoint. MPM modifications were documented in 53.1% of applications that underwent a single ACDR review cycle compared with 68.67% of applications that required multiple review cycles (HR 1.6 (95% CI 1.19 to 2.16), p=0.001). Prior approval by EMA or FDA only, as well as other therapeutic areas, rather than oncology and haematology were not detected as a predicting factor for MPM modifications (table 2).
Table 2. Univariate analysis of associated variables with postmarketing major modifications.
| Variable | No modification | Modification | HR (95% CI) |
P value |
|---|---|---|---|---|
| Therapeutic area of drug indication n (%) |
||||
| Immunology | 20 (9.7%) | 14 (5.4%) | 0.57 (0.33 to 0.97) |
0.037 |
| Dermatology | 10 (4.9%) | 17 (6.5%) | 1.18 (0.72 to 1.92) |
0.516 |
| Cardiology | 9 (4.4%) | 10 (3.8%) | 0.88 (0.466 to 1.65) |
0.683 |
| Oncology | 42 (20.4%) | 115 (44.1%) | 2.19 (1.71 to 2.80) |
<0.001 |
| Haematology | 27 (13.1%) | 44 (16.9%) | 1.41 (1.02 to 1.96) |
0.035 |
| Infectious disease | 32 (15.5%) | 31 (11.9%) | 0.82 (0.57 to 1.99) |
0.311 |
| Gastroenterology | 12 (5.8%) | 18 (6.9%) | 1.04 (0.64 to 1.68) |
0.873 |
| Nephrology | 2 (1%) | 1 (0.4%) | 0.48 (0.068 to 3.45) |
0.458 |
| Pulmonology | 21 (10.2%) | 8 (3.1%) | 0.37 (0.18 to 0.75) |
0.004 |
| Ophthalmology | 10 (4.9%) | 1 (0.4%) | 0.11 (0.015 to 0.78) |
0.007 |
| Endocrinology | 19 (9.2%) | 29 (11.1%) | 1.02 (0.70 to 1.51) |
0.905 |
| Psychiatry | 6 (2.9%) | 11 (4.2%) | 1.31 (0.71 to 2.39) |
0.384 |
| Rheumatology | 16 (7.8%) | 15 (5.7%) | 0.72 (0.43 to 1.21) |
0.21 |
| Urology | 4 (1.9%) | 3 (1.1%) | 0.59 (0.80 to 1.84) |
0.356 |
| Neurology | 13 (6.3%) | 13 (5%) | 0.92 (0.52 to 1.60) |
0.756 |
| Gynaecology | 5 (2.4%) | 4 (1.5%) | 0.68 (0.25 to 1.83) |
0.444 |
| Medical genetics | 11 (5.3%) | 3 (1.1%) | 0.28 (0.09 to 0.86) |
0.018 |
| Reference agency n (%) |
||||
| Approved by EMA (only) | 36 (17.5%) | 36 (13.8%) | 1 | 0.28 |
| Approved by FDA (only) | 37 (18%) | 52 (19.9%) | 1.39 (0.90 to 1.85) |
0.13 |
| Approval type n (%) |
||||
| Facilitated approval | 46 (22.3%) | 95 (36.4%) | 1.68 (1.31 to 2.17) |
0.001 |
| New drug application | 117 (56.8%) | 110 (42.1%) | 0.76 (0.59 to 0.97) |
0.029 |
| Supplemental indication | 83 (40.3%) | 144 (55.2%) | 1.33 (1.04 to 1.70) |
0.022 |
| New formulation | 6 (2.9%) | 6 (2.3%) | 0.77 (0.34 to 1.72) |
0.517 |
| Other | 0 (0%) | 1 (0.4%) | 1.76 (0.25 to 12.53) |
0.569 |
| Phase 1 trial data | 1 (0.5%) | 5 (1.9%) | 3.14 (1.29 to 7.63) |
0.008 |
| Phase 2 trial data | 20 (9.7%) | 59 (22.6%) | 1.97 (1.47 to 2.64) |
<0.001 |
| Phase 3 trial data | 183 (88.8%) | 194 (74.3%) | 0.52 (0.40 to 0.69) |
<0.001 |
| Surrogate endpoint | 52 (25.2%) | 143 (54.8%) | 1.92 (1.51 to 2.46) |
<0.001 |
| Approved with limitation | 35 (17%) | 49 (18.8%) | 1.20 (0.88 to 1.63) |
0.259 |
| Number of discussions>1 | 26 (12.6%) | 55 (21.8%) | 1.61 (1.19 to 2.16) |
0.001 |
| Required additional data or clarifications n (%) | ||||
| Efficacy data | 25 (12.1%) | 40 (15.3%) | 1.25 (0.89 to 1.74) |
0.203 |
| Safety data | 27 (13.1%) | 43 (16.5%) | 1.35 (0.97 to 1.87) |
0.075 |
HRs and 95% CIs were estimated using univariate Cox regression. Reference categories were defined as follows: therapeutic area: other therapeutic fields, which were included in the analyses; reference agency: approved by EMA and FDA; approval type: standard approval; application types and clinical trial phase were each analysed using separate binary indicators for each category, with the reference group defined as all other categories; primary endpoint: clinical endpoint; approved with limitation: approved without limitation; number of discussions >1: one discussion; required additional data: not required data.
New method of administration.
EMA, European Medicines Agency; FDA, Food and Drug Administration.
The variables significantly associated with a higher rate of MPM modifications were subsequently included in the multivariable model to determine independent predictors (table 3).
Table 3. Multivariable analysis of associated variable with postmarketing major modifications.
| Variable | HR (95% CI) | P value |
|---|---|---|
| Approved following multiple review cycles | 1.42 (1.14 to 2.58) | 0.024 |
| Drugs within the oncology therapeutic area | 1.71 (1.31 to 2.25) | <0.001 |
| Phase 2 trial data | 1.18 (0.85 to 1.64) | 0.31 |
| Facilitated approval | 1.46 (1.13 to 1.92) | 0.006 |
| Surrogate endpoint | 1.25 (0.93 to 1.59) | 0.13 |
| Drugs within the haematology therapeutic area | 1.20 (0.85 to 1.69) | 0.29 |
| Supplemental indication | 0.8 (0.35 to 1.82) | 0.59 |
HRs and 95% CIs were estimated using multivariable Cox regression. Reference categories were defined as follows: therapeutic area: other therapeutic fields, which were included in the analyses; application types and clinical trial phase were each analysed using separate binary indicators for each category, with the reference group defined as all other categories; approval type: standard approval; primary endpoint: clinical endpoint.
Statistically significant variables in the multivariable analysis were oncologic drugs (HR 1.71 (95% CI 1.31 to 2.25), p<0.01), applications approved following multiple review cycles (HR 1.42 (95% CI 1.14 to 2.58), p=0.024) and facilitated approval pathways (HR 1.46 (95% CI 1.13 to 1.92), p=0.006).
Discussion
Leveraging a reference regulatory authority’s assessment process offers efficiency benefits by streamlining the process and benefiting from trusted expertise. Regulatory authorities worldwide are increasingly adopting reliance pathways to enhance efficiency in their assessment processes.17–19 Since January 2021, the Medicines and Healthcare products Regulatory Agency has implemented a reliance pathway for Marketing Authorizations for approvals granted by the European Commission (EC) through the centralised procedure, for a period of 3 years.17 Since the beginning of 2024, the agency has expanded the reliance to another six reference regulatory authorities. This approach facilitates approval, allowing faster access to new medicinal products.18 19 However, such processes require careful consideration due to potential gaps between the two regulatory landscapes, including discrepancies in policies, unique target populations, broader regulatory environments and sometimes a more thorough examination during reliance pathway applications is warranted. This study aimed to characterise variables associated with a higher rate of MPM modifications, which may require closer regulatory attention, when assessing applications, especially when done in a reliance registration pathway.
We found that, in our cohort applications within the oncology therapeutic area, applications approved based on early phase clinical trial data, facilitated approval pathways and approval based on a surrogate endpoint were statistically associated with higher rates of MPM Safety modifications. By focusing on these predictive factors, regulators can identify characteristics warranting closer scrutiny, and ultimately achieve the intended benefits of streamlined authorisation while mitigating potential risks.
The rate of drug applications approved following multiple review cycles (17.8%) indicates that clinical safety and efficacy data are open to different interpretations and considerations.8 A critical review of drug applications has also been described in different regulatory authorities’ publications. Dorr et al compared drug approvals made by Swissmedic to those made by the FDA and EMA. The authors presented the divergent regulatory interpretations and decision-making between these agencies.20 Our findings align with this perspective, indicating that such differences exist also in the postmarketing phase and underscore that reliance pathways should account for the specific clinical interpretations and regulatory landscapes.
We found that among drug applications approved following multiple review cycles, in which reservations regarding efficacy and/or safety were raised and additional data were requested, the rate of MPM modifications was higher compared with drug applications approved following a single review cycle (68.7% vs 53.1%, respectively, p=0.01). While these univariate analyses provide a descriptive overview of the risk, the multivariable analysis further confirmed that applications approved following multiple review cycles remain relevant predictive factors for MPM modifications, after accounting for other application characteristics.
The duration of time for the first PM major modification by EMA and/or FDA for applications approved following multiple review cycles was significantly shorter as compared with applications approved following a single review cycle (14.6 vs 27.6 months, respectively, p=0.01).
Multiple review cycles were more often performed in applications of oncological drugs and those based on surrogate endpoints. Previous studies described surrogate endpoints for approval as variables associated with MPM Modifications.21–23 Drug approval based on limited data is associated with more PM safety-related label modification.24–27 Emerson et al found that using surrogate endpoints as the basis of facilitated oncological drug approval was associated with saving 11–19 months compared with the duration using overall survival as the endpoint for approval.28 Alongside the benefits of allowing rapid access to breakthrough therapies for the patient population, there are potential limitations of expedited approval pathways, particularly those relying on surrogate endpoints. Some studies have indicated that certain surrogate endpoints may not always accurately predict clinical benefit.29 A systematic review found that most surrogate endpoints in oncology have a low or modest correlation with survival outcomes.30
During the study period, the 21st Century Cures Act was signed into law on 13 December 2016, to help accelerate medical product development and bring new innovations to patients who need them faster and more efficiently.31 According to the publication of Gloy et al, facilitated approval pathways increased over time; from 73% to 92% for priority review, and breakthrough therapy designation increased after its introduction in 2012 to 52%.32 EMA launched the PRIME (Priority medicines) in 2016, to optimise development plans and speed up evaluation of unmet medicines.33 We acknowledge that these shifts may have led to a higher proportion of medicinal products entering the market, however we have taken this into account while addressing factors as independent variables.
As facilitated approvals gain prominence, the potential value of maintaining an independent local drug evaluation remains important to ensure optimal alignment with specific population needs and healthcare systems.
Study limitations
This study describes the data from the Israel Ministry of Health, a single agency. The trial focused on the two leading reference regulatory authorities, FDA and EMA, that maintain a publicly available online database, excluding drug applications authorised by other regulatory agencies. PM modifications from the FDA and EMA were pulled together into a single database. The pathways for submission, evaluation and approval of PM modifications by EMA and FDA are different, potentially leading to different outcomes. Furthermore, as an observational study, the identified associations do not imply direct causality. Although we used a multivariable Cox model to adjust for key factors, residual confounding cannot be excluded. Additionally, the use of automated p value screening and backward elimination for variable selection has several limitations. While this data-driven approach can be useful for identifying initial associations in exploratory analyses, it focuses primarily on statistical associations with the outcome. Consequently, it may be less optimal for confounder control compared with prespecified causal models and may exclude variables that are not statistically significant but are theoretically relevant or potentially result in overadjustment. Furthermore, we cannot exclude the risk of confounding bias, thus our findings should be interpreted with caution. Not all approved applications were included due to predefined exclusion criteria intended to avoid confounders. We believe there is no concern regarding external validity, as these applications constitute only a minor part of all submitted applications. Finally, we did not stratify according to the type of data completion required by the ACDR (efficacy and/or safety data). Such data would have shed more light on the characteristics of applications that undergo major safety postmarketing variations.
Conclusions
Reliance pathways offer a valuable tool for regulatory bodies, leveraging trusted expertise and streamlining the marketing authorisation process. However, careful consideration of potential discrepancies between regulatory environments is crucial. This study uniquely identifies independent variables statistically associated with higher rates of MPM modification, such as multiple review cycles, applications within the oncology therapeutic area and facilitated approval pathways. While these findings should be interpreted as associations rather than causal determinants, they highlight the importance of scrutinising factors like policy differences, target population characteristics and broader regulatory landscapes. By focusing on these variables, regulators can strengthen the reliance pathway assessment process, ensuring a balance between efficiency and robust risk mitigation to safeguard public health. The Israel MOH has implemented a revised framework for evaluating applications, aiming to facilitate the process of granting access to effective and safe drugs. Additional research is warranted to assess the effectiveness of the procedure and to further validate these findings.
Footnotes
Prepublication history for this paper is available online. To view these files, please visit the journal online (https://doi.org/10.1136/bmjopen-2025-104073).
Patient consent for publication: Not applicable.
Provenance and peer review: Not commissioned; externally peer-reviewed.
Patient and public involvement: Patients and/or the public were not involved in the design, or conduct, or reporting, or dissemination plans of this research.
Data availability statement
Data are available in a public, open access repository. Data may be obtained from a third party and are not publicly available.
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