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Oncology
Original research
Factors affecting the feasibility of post-authorisation RCTs for conditionally authorised anticancer medicines: a multistakeholder perspective from a qualitative focus group study
  1. Christine C van Hattem1,2,
  2. Amos J de Jong1,
  3. Jolien S de Groot2,
  4. Jarno Hoekman3,
  5. K Esther Broekman2,4,
  6. Gabe S Sonke5,6,
  7. Paula B van Hennik2,
  8. Lourens T Bloem1
  1. 1Division of Pharmacoepidemiology and Clinical Pharmacology, Utrecht Institute for Pharmaceutical Sciences, Utrecht University, Utrecht, the Netherlands
  2. 2Medicines Evaluation Board, Utrecht, the Netherlands
  3. 3Innovation Studies, Copernicus Institute of Sustainable Development, Utrecht University, Utrecht, the Netherlands
  4. 4Department of Medical Oncology, University Medical Centre Groningen, Groningen, the Netherlands
  5. 5Department of Medical Oncology, Netherlands Cancer Institute, Amsterdam, the Netherlands
  6. 6Department of Medical Oncology, University of Amsterdam, Amsterdam, the Netherlands
  1. Correspondence to Dr Lourens T Bloem; L.T.Bloem{at}uu.nl

Abstract

Objective The collection of comprehensive data from post-authorisation trials for conditionally authorised anticancer medicines is frequently delayed. This raises questions about the feasibility of post-authorisation randomised controlled trials (RCTs) that aim to address remaining uncertainties. Therefore, this study explored factors that facilitate or impede the feasibility of post-authorisation RCTs from the perspective of stakeholders directly involved in the design, medical-ethical approval, and conduct of these RCTs.

Design We conducted four qualitative focus groups (FGs).

Setting FG discussions focused on the oncology setting in European context.

Participants Twenty-eight European patients, physicians, medical ethicists and pharmaceutical industry representatives participated in the FGs.

Intervention Respondents were informed about the topic and the purpose of the FGs before and at the start of FG discussions. An FG script was used to guide the discussion, which was informed by 14 semi-structured interviews with various stakeholders.

Results We identified factors with the potential to impact feasibility related to trial design, trial conduct, factors external to a trial and post-authorisation interaction with regulators. Factors that may be particularly relevant for the post-authorisation setting include the choice of relevant endpoints and the inclusion of a fair comparator (trial design), strategies to increase patients’ and physicians’ willingness to participate (trial conduct), and external factors relating to a medicine’s commercial availability, the presence of competing medicines and trials and the perceptions about clinical equipoise. Post-authorisation interaction with regulators about how to obtain comprehensive data was deemed necessary in cases where a post-authorisation RCT seems infeasible.

Conclusions Based on the identified factors, our findings suggest that patient recruitment and retention could be assessed more in-depth during regulatory feasibility assessments at the time of granting conditional marketing authorisation and that sponsors and regulators should better inform patients and physicians about the remaining uncertainties for conditionally authorised medicines and the necessity for post-authorisation RCTs. By enhancing the evaluation of trial feasibility, timely completion of post-authorisation RCTs may be facilitated to resolve the remaining uncertainties within a reasonable timeframe.

  • ONCOLOGY
  • Randomized Controlled Trial
  • QUALITATIVE RESEARCH
  • THERAPEUTICS
  • Health policy

Data availability statement

Data are available upon reasonable request. Focus group transcripts were used in this study. Participants did not consent to make the transcripts publicly available. Supporting quotes are available in tables 2-5. Excerpts from anonymised transcripts can be made available upon request. Please contact the corresponding author for more information.

http://creativecommons.org/licenses/by-nc/4.0/

This is an open access article distributed in accordance with the Creative Commons Attribution Non Commercial (CC BY-NC 4.0) license, which permits others to distribute, remix, adapt, build upon this work non-commercially, and license their derivative works on different terms, provided the original work is properly cited, appropriate credit is given, any changes made indicated, and the use is non-commercial. See: http://creativecommons.org/licenses/by-nc/4.0/.

https://doi-org.ezproxy.u-pec.fr/10.1136/bmjopen-2024-084483

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    STRENGTHS AND LIMITATIONS OF THIS STUDY

    • Focus group discussions allowed for the identification of complementary perspectives from patients, physicians, medical ethicists and pharmaceutical industry representatives.

    • The current study focusses on the oncology setting in European context, but our results are expected to be relevant for other geographical regions and therapeutic areas where expedited approval pathways are used.

    • Distinguishing feasibility factors specific to post-authorisation randomised controlled trials (RCTs) for medicines with a conditional marketing authorisation and for post-authorisation RCTs in general is challenging.

    • This study took an exploratory approach: a quantification of the most important impediments to post-authorisation RCTs and defining strategies to optimise feasibility assessments require future research, which should include the perspectives of regulators and health technology assessors.

    Introduction

    For medicines that are authorised on the basis of non-comprehensive data through an expedited pathway—such as the European Medicines Agency’s (EMA) conditional marketing authorisation (CMA) and the US Food and Drug Administration’s (FDA) accelerated approval1–3 (box 1), typically more uncertainties are accepted compared with a standard marketing authorisation. In the European Union, CMAs have increasingly been granted based on single-arm trial (SAT) data as pivotal evidence, particularly for targeted therapies in oncology settings.4–10 Consequently, specific obligations imposed by the EMA to generate additional, comprehensive, evidence typically include randomised controlled trials (RCTs).2 11

    Box 1

    Conditional marketing authorisation and specific obligations

    Since its implementation in 2006, the conditional marketing authorisation (CMA) pathway has been used in the European Union with the intention of accelerating patient access to novel medicines that address an unmet medical need.9 11 As stipulated in European Commission Regulation No 507/2006, the CMA pathway enables authorisation based on non-comprehensive evidence.1

    Medicines eligible for CMA are those that are intended for ‘seriously debilitating diseases or life-threatening diseases’, those that are ‘to be used in emergency situations’, or are an ‘orphan medicinal product’.2 The following additional requirements should be met1 2:

    (i) The benefit-risk balance of the medicine is positive.

    (ii) It is likely that the applicant will be able to provide comprehensive data in a timely manner.

    (iii) An unmet medical need will be fulfilled.

    (iv) The benefits to public health of the immediate availability of the medicine outweigh the risks inherent in the fact that additional data are still required.

    The European Commission can grant the CMA upon a positive opinion from the European Medicines Agency’s Committee for Medicinal Products for Human Use (CHMP).1

    Specific obligations are imposed as legally binding conditions for marketing authorisation. Typically, the obligations concern new or ongoing randomised controlled trials (although other designs could be considered).27 These specific obligations and their submission due dates are stipulated in Annex II of a medicine’s Summary of Product Characteristics.1

    A CMA has a 1-year validity, which is required to be annually renewed.1 To that end, the marketing authorisation holder must submit a report on the fulfilment of the specific obligations.2 Compliance with the specific obligations is then reviewed and assessed by the CHMP. A continued positive benefit-risk balance is critical for maintaining the CMA. Upon fulfilling the specific obligations, the CMA is converted to a standard marketing authorisation with an initial 5-year validity.1 2

    However, the feasibility of conducting RCTs in the post-authorisation setting is considered challenging, complicating evidence generation for regulatory, reimbursement and clinical decision making purposes.12–15 For example, recruitment of trial participants—particularly those who are covered by the authorised indication—may be difficult when the medicine in question is already available to patients.2 16–18 This is recognised in the European public assessment report (EPAR) of olaratumab (CMA for soft tissue sarcoma, which was later retracted based on a negative post-authorisation RCT) and detailed that ‘once a country has approved the medicine, no further patients would likely be included in the study from that region’.19 Additionally, the EPAR for pixantrone (for non-Hodgkin B-cell lymphoma), which was granted CMA based on data from a non-Western European population, detailed that immediate availability on the European market ‘will hamper the clarification of relevant scientific questions such as the benefit in a (Western) European population’.20

    Timely provision of comprehensive data is one of the prerequisites for granting CMA and extension of the due date for providing the additional evidence is only allowed when feasibility issues were not foreseen at the time of granting CMA.2 However, analyses have shown that the submission of post-authorisation data is frequently delayed.21–26 For example, for medicines granted CMA between 2010 and 2016, the majority of changes to specific obligations (34 out of 39) were due date extensions.24 Therefore, it is essential that the feasibility of post-authorisation RCTs is thoroughly assessed by the EMA’s Committee for Medicinal Products for Human Use (CHMP).2

    Regulatory guidelines provide limited guidance as to what feasibility assessments entail, and details of feasibility assessments as performed by the CHMP are rarely described in the EPARs.2 16 27 Consequently, it is not sufficiently clear which factors are relevant for feasibility assessments of post-authorisation RCTs. Therefore, this exploratory study aims to identify factors that facilitate or impede the feasibility of post-authorisation RCTs for anticancer medicines that are conditionally authorised based on non-comprehensive data from SATs from the perspective of those stakeholders involved in the design, medical-ethical approval and conduct of these RCTs.

    Methods

    Study context and design

    To identify factors that, from the perspective of stakeholders, facilitate or impede the feasibility of post-authorisation RCTs for anticancer medicines granted CMA based on SAT data, we performed an exploratory qualitative focus group (FG) study. In light of the CMA requirement to provide comprehensive data in a timely manner,2 feasibility is defined as the expectation to conduct a post-authorisation RCT within a reasonable timeframe.2 28 We focused on the oncology setting as CMAs on the basis of non-randomised SAT data are most frequently granted to anticancer medicines.8 9

    For this study, FG discussions were conducted with each of four stakeholder groups directly involved in the design, medical-ethical approval and conduct of post-authorisation RCTs: (i) patient representatives, (ii) medical ethicists, (iii) physicians (ie, (hemato-)oncologists) and (iv) pharmaceutical industry representatives. These FGs allow for interaction between respondents, fostering the exchange of experiences, ideas and solutions.29

    Focus groups

    Potential respondents were identified through professional organisations, the research team’s network and respondents’ recommendations. Respondents had to be familiar with anticancer medicinal product development or medical oncology and proficient in the Dutch and/or English language. Eligibility was not based on respondents’ seniority or experience with (post-authorisation) clinical research. Respondents were asked to share their own perspectives based on professional experience rather than representing views of their respective organisations.

    Data collection

    From August to October 2022, eligible respondents were invited to participate in FG discussions in October 2022. FGs lasted for approximately 2 hours and were conducted separately with each stakeholder group. After a round of introductions and introducing the purpose of the FG, the respondents were asked to discuss various topics, which were introduced separately by a research team member. The FG script was informed by 14 semi-structured, individual, 1 hour pilot interviews with medical ethicists, physicians and representatives from regulatory authorities, health technology assessment (HTA) organisations, clinical guideline committees, patient advocacy groups and the pharmaceutical industry (online supplemental 1 and 2). The main topics included (i) trial design, (ii) trial conduct and (iii) motivations (online supplemental 3). Data on respondent characteristics were collected through an online questionnaire that was shared prior to the FG.

    Data analysis

    The FG discussions were transcribed verbatim and analysed through thematic analysis using NVivo 12 PRO (QSR International, version 14, Burlington, MA, USA).30 Themes and individual factors were identified both deductively (informed by the topics from the interviews: trial design, trial conduct and motivations) and inductively in an iterative manner. Factors that impede or facilitate the conduct of post-authorisation RCTs were grouped under the themes and visualised in an Ishikawa diagram. The FG transcripts were coded independently by two researchers (CCvH and AJdJ), after which the coding structure was discussed iteratively within the research team. Due to differences in interests and areas of expertise, not all topics were discussed to the same extent across all FGs. Consequently, if no reference is made to a stakeholder group in the results, this should not be understood as a fundamental difference between stakeholders.

    Patient and public involvement

    Through patient organisations and public engagement offices, we were able to involve patient representatives in the conduct of this research. Patient organisations helped recruiting respondents for the FG with patient representatives and one patient representative who helped in the recruitment also critically reviewed the manuscript (see Acknowledgements). We plan to actively disseminate the study findings to patients and the public through social media and plain-language summaries and infographics on the websites of the authors’ affiliated organisations. Herein, we plan to involve patient representatives. The study findings will furthermore be shared at research institutions, regulatory agencies and academic conferences.

    Results

    Respondent characteristics and main themes

    After reaching out to 199 individuals and organisations, 28 respondents agreed to participate, 45 respondents indicated that they were not interested in participating due to time constraints, perceived limited knowledge of the topic, or other reasons, and others did not respond. In total, 28 European respondents participated in one of the FGs: patient representatives (n=5), medical ethicists (n=6), physicians (n=6) and pharmaceutical industry representatives (n=11) (table 1).

    View this table:
    Table 1

    Characteristics of focus group respondents

    Themes

    We identified four main themes from the FG transcripts: trial design, trial conduct, factors external to a trial and post-authorisation interaction with regulators tables 2–5). Under these themes, we grouped the main facilitating and impeding feasibility factors as reported during the FGs as displayed in figure 1.

    Figure 1
    Figure 1

    Ishikawa diagram showing factors that facilitate or impede the feasibility of post-authorisation randomised controlled trials for anticancer medicines that are conditionally authorised, as identified from the focus groups. HTA, health technology assessment; RCT, randomised controlled trial; SAT, single-arm trial.

    View this table:
    Table 2

    Factors regarding trial design that facilitate or impede the feasibility of post-authorisation randomised controlled trials as identified from the focus groups

    View this table:
    Table 3

    Factors regarding trial conduct that facilitate or impede the feasibility of post-authorisation randomised controlled trials as identified from the focus groups

    View this table:
    Table 4

    External factors that facilitate or impede the feasibility of post-authorisation randomised controlled trials as identified from the focus groups

    View this table:
    Table 5

    Factors regarding post-authorisation interaction with regulators that facilitate or impede the feasibility of post-authorisation randomised controlled trials as identified from the focus groups

    Trial design

    Feasibility factors regarding trial design reported by the FG respondents relate to the indication of interest, endpoints, the amount of data to be collected, the use of blinding, the comparator and the enrolment status of a post-authorisation RCT (figure 1, table 2). First, part of the oncology indications concerns rare diseases or specific subpopulations for which it may be difficult to identify patients, as was reiterated in all FGs. This was especially considered true for indications of targeted therapies. Additionally, the lack of standardised manners for collecting biomarker data (eg, molecular diagnostics) was mentioned by physicians to impede patient identification.

    Second, respondents mentioned that there is a trade-off between generating data relatively fast, using surrogate endpoints (eg, progression-free survival), and generating data on clinically relevant endpoints (eg, overall survival and quality of life). Respondents furthermore mentioned that the inclusion of clinically relevant endpoints in a post-authorisation RCT enhances the willingness of patients and investigators to participate in these trials (FG patients, physicians).

    Third, collecting only essential data was deemed a particular facilitating factor in post-authorisation settings, specifically when an RCT aims to include different locally requested endpoints and comparator arms to cater to multiple regulatory bodies (FG industry). In terms of broad inclusion criteria and trial procedures that align with routine care, employing more pragmatic RCT elements was frequently mentioned as facilitating for post-authorisation data generation (FG patients, physicians, industry).

    Fourth, the ‘risk’ of randomisation to the (perceived inferior) control arm instead of a ‘fair’ comparator was discussed in all FGs and was deemed to impede feasibility, especially when a trial is not blinded by design.

    Fifth, early planning of an RCT may result in an ongoing trial at the time of granting CMA with patient recruitment started or even finished before a CMA is granted. This was deemed to enhance feasibility (FG physicians, industry). In general, respondents mentioned that involving various stakeholders in the design of a post-authorisation RCT is key for trials to be meaningful for more stakeholders (FG physicians, patients, industry).

    Trial conduct

    Feasibility factors regarding the conduct of a trial identified from all FG discussions relate to the willingness to participate in a post-authorisation RCT and incentives for pharmaceutical companies to conduct a post-authorisation RCT (figure 1, table 3).

    First, specific to post-authorisation settings, investigators’ willingness to participate was deemed crucial. Industry representatives indicated that it can be difficult to involve clinical investigators for post-authorisation RCTs because of low scientific interest as the medicine is already authorised. Physicians indicated that a clinically relevant research question and enabling patient access to the medicine in question are particularly important for their participation in post-authorisation trials. As further discussed with physicians, the administrative and data collection burden impedes their participation in these trials. Respondents mentioned that investigators’ willingness is generally supported by a physician’s professional responsibility (FG patients, ethicists), financial compensation and the possibility that participation will result in a publication (FG ethicists). Although not specific to post-authorisation RCTs, research capacity and related availability of sufficient resources and research infrastructure in the participating centres were considered pivotal to facilitate trial conduct (FG physicians).

    Second, respondents indicated that patients’ willingness to participate is affected by factors that are more apparent in a post-authorisation setting including the chance for randomisation to the control arm, possible cross-over to the intervention arm and available treatment alternatives (FG patients, ethicists, physicians). General factors that may affect patients’ willingness include access to the medicine in question, altruism, a patient’s relationship with the investigator, the involvement of patient representatives in the trial design, while weighing potential treatment benefits and possible side effects (FG patients, ethicists, physicians). Generally, the burden for patients to participate in a clinical trial was considered impeding, while pragmatic trial elements, such as data collection alongside routine clinical care, were considered facilitating (FG patients, ethicists, physicians). Patients’ awareness and understanding of trial participation options, as well as other methods for informing patients about participation opportunities aside from communication through physicians, were considered important for participant recruitment (FG patients).

    Third, divergent views existed regarding the incentives for pharmaceutical companies to conduct post-authorisation RCTs. Ethicists and physicians indicated that it is not necessarily in a sponsor’s interest to conduct these studies as the benefit-risk balance could become negative. On the other hand, industry representatives mentioned that performing post-authorisation RCTs is not only a regulator-imposed obligation but would also increase the evidence base, which strengthens the conclusion on clinical benefit and aids sponsors in reimbursement negotiations. Additionally, if a post-authorisation RCT is performed in a different line of treatment than the conditionally authorised indication, this could lead to an extension of the indication (FG industry).

    External factors

    Factors external to the post-authorisation trial itself may change over time and affect trial feasibility. External factors that stakeholders reported included competition with other medicines or trials, commercial availability of the medicine and the related (perceived) clinical equipoise (figure 1, table 4).

    Particularly in the post-authorisation setting, competition with other available medicines (particularly those of the same class) and other clinical trials were mentioned as impeding factors for participant recruitment (FG patients, physicians, industry). Additionally, the commercial availability of the medicine—which, in Europe, is dependent on reimbursement decision-making supported by national HTA organisations—was mentioned as impactful on the motivation to participate in a post-authorisation RCT, as the medicine is accessible outside the context of a trial (all FGs). Respondents indicated that post-authorisation RCTs may be conducted in countries where the authorised medicine is not commercially available, which can in turn raise questions on ethics and generalisability (FG ethicists, physicians, industry). In the oncology setting, differences in genetics, pretreatment regimes and standards of care were deemed to influence the generalisability of trial results to clinical practice.

    Furthermore, clinical equipoise (ie, ‘a state of genuine uncertainty on the part of the clinical investigator regarding the comparative therapeutic merits of each arm in a trial’31) and how it is perceived was mentioned as a feasibility factor. Several aspects relate to clinical equipoise, including the expected benefit of the new medicine, the availability of a fair comparator and trial participants’ perceptions. The expected benefit was noted to be determined by the effect size observed in pre-authorisation data (ie, SATs) and the biological rationale (FG physicians), which in turn affect both patients’ and investigators’ motivations to participate. Nonetheless, physicians indicated that they could be more critical when appraising trial outcomes. Additionally, respondents indicated that, particularly for post-authorisation trials with conditionally authorised medicines, therapeutic misconception (ie, the tendency of participants to think that trial participation will benefit them) should be prevented by clarifying the uncertainties related to both the expected benefits and risks (FG patients, ethicists).

    Clinical equipoise further depends on the choice of a ‘fair’ comparator. In general, respondents in all FGs mentioned that randomisation to the best available care, including the best supportive care when treatment options are exhausted, should be considered. A fair comparator further facilitates the evaluation of the new medicine’s added clinical benefit relevant for clinical practice (FG physicians). On the other hand, choosing a fair comparator for post-authorisation RCTs was indicated to be challenging due to the dynamic treatment landscape and varying standards of care across countries (FG industry).

    Although others were hesitant, some ethicists indicated that eligible patients should be empowered to make decisions themselves about participation in case it is difficult to weigh the benefits and risks. Clinical trial applications should not be declined beforehand by ethics committees when uncertainties are difficult to weigh, which could be the case for conditionally authorised medicines.

    Post-authorisation interaction with regulators

    If a post-authorisation RCT is deemed infeasible, further discussion with regulators may be required (figure 1, table 5). For instance, if the medicine is accessible outside the context of a trial, respondents suggested conducting the post-authorisation RCT in an earlier line of treatment (FG ethicists, physicians, industry); this was also suggested to maintain clinical equipoise. For the same reason, treatment optimisation trials (eg, those that investigate a different dose or a shorter treatment period) allow for randomisation in the line(s) of treatment of the authorised indication according to the respondents (FG patients, physicians). Additionally, for generating comprehensive data, alternatives to post-authorisation RCTs were proposed in all FGs, particularly in the context of rare indications. These alternatives included contextualising SAT results with external controls, registry-based studies and studies based on data obtained from drug access protocols, such as the DRUG Access Protocol in the Netherlands (ie, for anticancer medicines that are not yet reimbursed).32 Nonetheless, respondents also reiterated the disadvantages of such alternatives, including potential confounding bias, lack of high-quality databases in which the variables of interest are captured and continuously changing standards of care.

    Discussion

    When CMAs are granted, sponsors are required to address uncertainties in a timely manner through the generation of post-authorisation evidence.2 However, as generation of post-authorisation evidence is frequently delayed, increased understanding and enhancement of the feasibility of post-authorisation RCTs are needed in the context of CMA, particularly for anticancer medicines.2 16 24 27 In the current study, we identified factors that, from the perspective of multiple stakeholders, affect the feasibility of post-authorisation RCTs for conditionally authorised anticancer medicines (figure 2).

    Figure 2
    Figure 2

    Feasibility of post-authorisation randomised controlled trials: a process visualisation

    Feasibility factors specific to the post-authorisation setting

    Some of the feasibility factors we identified are not specific to the post-authorisation setting but relevant for all RCTs, for example, recruitment difficulties due to the chance of randomisation to a control arm or more burdensome treatment, or the logistical, mental and administrative burden of participating in a clinical trial.33–36 However, the choice of comparator and endpoints, the trial population in relation to the one covered by the authorised indication, competition with other trials and medicines and a lack of scientific interest on the part of investigators seem more relevant to the post-authorisation setting.16 17 22 24 37

    As was also mentioned by the respondents, there are two potential situations to consider in relation to a post-authorisation RCT: either (i) the post-authorisation RCT is ongoing at the time of CMA—in which case the sponsor has recruited (most of) the participants of the post-authorisation RCT—or (ii) the post-authorisation RCT is newly initiated, as seen for lapatinib (for breast cancer).38 In the latter situation respondents noted that a lack of reimbursement or reimbursement conditional on trial participation may increase the feasibility of the post-authorisation RCT because the medicine is otherwise not accessible. However, the ethics and feasibility of such approaches remain to be addressed in a broad societal discussion.39

    Our findings suggest that employing more pragmatic trial elements could particularly facilitate trial conduct in the post-authorisation setting. Pragmatic—and decentralised—trial elements may allow for data collection alongside clinical practice and the use of broader eligibility criteria and could be considered when compatible with the post-authorisation evidence requirements. This may alleviate participation and data collection burden while increasing the number of eligible and willing patients, ultimately recruiting a more representative population and therefore answering questions (more) relevant to patients and physicians.40–42 An example is the recently launched Pragmatica-Lung trial for NSCLC in the USA, which applies broad eligibility criteria and aims to alleviate participation burden by collecting only essential data.42

    Additionally, according to the respondents, clinical equipoise is more evident in a post-authorisation RCT in an earlier line of treatment, which supports patients’ and physicians’ willingness to participate. In turn, this may provide evidence for a potential extension of the indication. In practice, post-authorisation RCTs in oncology settings are often performed in an earlier line of treatment. For instance, the indications of amivantamab (for NSCLC) and dostarlimab (for endometrial cancer) as monotherapies were extended based on data from the respective post-authorisation RCTs conducted in an earlier line of treatment and as combination therapies.43–48 However, conducting a trial in a different line of treatment in principle aims to answer a different research question and may thus not allow to resolve the remaining uncertainties.

    Impact of uncertainty on perceived clinical equipoise

    The available evidence and residual uncertainties may affect how clinical equipoise is perceived. Uncertainties associated with CMAs granted based on SATs may be clear to regulators. A recent EMA reflection paper emphasises important biases that may occur when there is a lack of a control arm, randomisation and blinding.49 Our findings, however, highlight that other stakeholders may perceive the evidence and uncertainties differently. Patients, physicians and medical ethicists tended to assume that a new medicine is the preferable treatment option for the respective indication once regulators appraise the benefit-risk profile as positive, even though authorisation is conditional. Similarly, previous studies found that US physicians and patients often overestimated the evidence base and underestimated uncertainties for newly authorised medicines, including those with an accelerated approval.50–52 In turn, our findings suggest that conditional authorisation in combination with high expectations of the medicine may hamper patients’ and physicians’ willingness to participate in a post-authorisation trial. In addition, respondents indicated the need for scrutiny of therapeutic misconception, especially for patients with limited or no alternative treatment options. Overestimation, difficulty understanding or incorrect interpretation of a medicine’s benefits and its risks may compromise patient autonomy.53 Patients and physicians should thus be better informed about the uncertainties that remain for conditionally authorised medicines that are to be addressed by post-authorisation RCTs.54

    To maintain clinical equipoise for post-authorisation RCTs, respondents noted that a fair and active comparator should be included. However, in a fast-changing treatment landscape with high unmet medical needs—such as NSCLC, for which more than 330 medicines are in clinical development55—identifying an appropriate comparator can become increasingly complex due to a lack of both directly comparative data and a clear standard of care.9 To that end, post-authorisation RCTs could involve the use of (adaptive) platform designs that evaluate multiple interventions against one control arm.56 Such trial designs could also facilitate country-specific assessment of added benefit against a locally available relevant treatment.57

    Policy implications

    In light of these considerations, we propose several actions to enhance the feasibility of post-authorisation RCTs. First, (transparency on) feasibility assessments of post-authorisation RCTs should be strengthened. During these assessments, which are conducted as part of the decision to grant CMA, sponsors and regulators should focus their discussion more explicitly on the identified feasibility factors to increase the likelihood that the sponsor will provide comprehensive data in a timely manner. Admittedly, regulators already consider the enrolment status of post-authorisation RCTs, as described in EPARs,2 and many of the factors we identified directly and indirectly affect enrolment and retention. These factors could however be described more explicitly in EPARs. Additionally, projects like the US FDA’s FrontRunner show the commitment of regulators to generate comprehensive evidence through RCTs.58 This project aims to determine if a pragmatic trial design in early lines of oncology treatment indeed enhances the feasibility of RCTs in the post-authorisation setting.58 Furthermore, feasibility assessments and post-authorisation evidence generation should aim to incorporate the evidence needs of HTA organisations and medical societies.15 59 Such discussions may be facilitated through the parallel joint scientific consultations of the EMA and the European Network for Health Technology Assessment (EUnetHTA) 21 consortium and its successors.60 61

    Second, trial feasibility and stakeholders’ motivation to participate may be enhanced when stakeholders are well-informed, for instance, through informed consent procedures, as to how regulators weigh the remaining uncertainties of conditionally authorised medicines and how these will be addressed by the trial. More transparency is needed on why the post-authorisation RCT is imposed as well as its enrolment status, which could for instance be communicated through the informed consent procedures.39 Additionally, involving additional stakeholders in the design of post-authorisation RCTs may enhance willingness to participate. For instance, preference studies can be conducted to elicit patient preferences for addressing uncertainties and trial design features.62

    Third, feasibility of post-authorisation RCTs may be enhanced by providing clearer guidance on what is considered fit-for-purpose evidence generation in specific situations. This includes a clear indication-specific definition of the concept of ‘comprehensive evidence’, the circumstances under which RCTs are considered paramount, and when alternative study designs, such as observational studies, are acceptable.

    Fourth, the reasons of not meeting specific obligations in time24 and when withdrawing a CMA is considered necessary should be further investigated. For example, in Europe, thus far, the CMAs for three anticancer medicines have been withdrawn: olaratumab has been withdrawn by regulators after 3 years, whereas the indications of rucaparib and vandetanib have been restricted (after four and 11 years, respectively) because post-authorisation RCTs could not confirm the positive benefit-risk balance.63–66 In comparison, in the USA, clinical benefits remained unconfirmed for almost half (112 out of 253) the medicines that received accelerated approval until 2021, of which 24 await confirmation after more than 5 years on the market and only 16 have been withdrawn.67 Additionally, potential measures (eg, increased financial penalties or temporary revoking the CMA) to counter such situations should be considered, including an analysis of the legal and policy implications of these measures. Notably, in Japan a type of expedited approval can be granted for a maximum of 7 years, which is automatically withdrawn if the applicant fails to obtain standard approval during that time.68

    The feasibility for generating additional evidence is an important requirement for granting CMA and a lack of feasibility to obtain such data may be reason for regulators not to grant CMA.2 The current use of CMA calls for broader discussion about the balance between accepting uncertainties and expediting patient access; that is, the circumstances under which expedited authorisation may be preferred over delaying patient access although there is substantial uncertainty concerning a medicine’s benefit-risk profile.39 69–71 Specifically, the current use of CMA requires discussion on the criteria that must be met before a CMA is granted and how these criteria will be evaluated, including the definition and level of unmet medical need,72 the level of uncertainty considered acceptable, the observed effect size in pre-authorisation data and the likelihood that the sponsor will be able to provide comprehensive data in a timely manner.1 2 Alternatively, if generating additional evidence is not deemed feasible at all, granting marketing authorisation under exceptional circumstances may be a more appropriate pathway in Europe, as it would explicitly show involved stakeholders (including patients, physicians) that the uncertainties on a medicine’s benefit -risk balance are not deemed resolvable through post-authorisation data generation.1

    Strengths and limitations

    The participation of representatives from various stakeholder groups enabled the identification of feasibility factors for post-authorisation RCTs from complementary perspectives. This study reports respondents’ perspectives on factors that are deemed facilitating or impeding, and the overview of factors may be incomplete. Respondents were experts in their respective roles, allowing for in-depth discussion. Many of the invited respondents considered themselves less equipped for participation because of a limited understanding of the regulatory system, while this might have been representative of their stakeholder group. In addition, only Dutch physicians participated, despite our efforts to include physicians from other European countries as well. Nonetheless, the identified feasibility factors are expected to be relevant for other geographical regions and other therapeutic areas where expedited approval pathways are used. It may, however, be difficult to distinguish between feasibility factors specific to post-authorisation trials for anticancer medicines with a CMA and for post-authorisation RCTs in general. Given the exploratory character of the current study, future studies should aim to quantify the most important impediments to post-authorisation RCTs—from a multistakeholder perspective including regulators and HTA organisations—and identify solutions that could address these. Additionally, strategies to inform patients and physicians about the need for post-authorisation RCTs should be investigated.

    Conclusions

    This study identified factors that impact the feasibility of post-authorisation RCTs relating to trial design and conduct, and factors external to a trial from the perspective of various stakeholders. Considering the exploratory nature of this study, we recommend regulators to involve those factors more explicitly in assessing and describing trial recruitment and retention during the feasibility assessment of a proposed post-authorisation RCT and, with that, the possibility for granting a CMA. Moreover, we recommend sponsors and regulators to better inform patients and physicians about remaining uncertainties of conditionally authorised anticancer medicines to empower them to make well-informed decisions and to potentially improve their willingness to participate in post-authorisation RCTs. In line, trial designs should be tailored to the post-authorisation setting, considering the inclusion of clinically relevant endpoints, and a fair comparator.

    Data availability statement

    Data are available upon reasonable request. Focus group transcripts were used in this study. Participants did not consent to make the transcripts publicly available. Supporting quotes are available in tables 2-5. Excerpts from anonymised transcripts can be made available upon request. Please contact the corresponding author for more information.

    Ethics statements

    Patient consent for publication

    Ethics approval

    This study involves human participants and was approved by the Institutional Review Board of the Division of Pharmacoepidemiology and Clinical Pharmacology of Utrecht University and is registered under number UPF2210. Participants gave informed consent to participate in the study before taking part.

    Acknowledgments

    We would like to thank all interview and focus group respondents who generously shared their time and perspective for this study. Additionally, we would like to thank Professor Toine Egberts (Utrecht University, University Medical Center Utrecht), Professor Pieter de Graeff (Medicines Evaluation Board), Professor Kit Roes (Radboudumc, Medicines Evaluation Board) and Dr Kim Holtzer (Dutch Federation of Cancer Patient Organisations) for their contributions to this study and for critically reviewing the manuscript.

    References

    1. ↵
      1. European Commission
      . Commission regulation (EC) No 507/2006 of 29 March 2006 on the conditional marketing authorisation for medicinal products for human use falling within the scope of regulation (EC) No 726/2004 of the European Parliament and of the Council. Off J Eur Union 2006;92:6–9.
      OpenUrl
    2. ↵
      1. European Medicines Agency
      . Guideline on the scientific application and the practical arrangements necessary to implement commission regulation (ec) no 507/2006 on the conditional marketing authorisation for medicinal products for human use falling withing the scope of regulation (ec) no 726/2004 (ema/chmp/509951/2006,rev.1). 2016.
    3. ↵
      1. U.S. Food and Drug Administration
      . 21 CFR Part 314 subpart H - Accelerated approval of new drugs for serious or life-threatening illnesses.
    4. ↵
      1. Tenhunen O,
      2. Lasch F,
      3. Schiel A, et al
      . Single-Arm Clinical Trials as Pivotal Evidence for Cancer Drug Approval: A Retrospective Cohort Study of Centralized European Marketing Authorizations Between 2010 and 2019. Clin Pharmacol Ther 2020;108:653–60. doi:10.1002/cpt.1965
      OpenUrlPubMed
    5. ↵
      1. Collignon O,
      2. Schritz A,
      3. Spezia R, et al
      . Implementing Historical Controls in Oncology Trials. Oncol 2021;26:e859–62. doi:10.1002/onco.13696
      OpenUrl
    6. ↵
      1. Naci H,
      2. Smalley KR,
      3. Kesselheim AS
      . Characteristics of Preapproval and Postapproval Studies for Drugs Granted Accelerated Approval by the US Food and Drug Administration. JAMA 2017;318:626–36. doi:10.1001/jama.2017.9415
      OpenUrlCrossRefPubMed
    7. ↵
      1. Scott EC,
      2. Baines AC,
      3. Gong Y, et al
      . Trends in the approval of cancer therapies by the FDA in the twenty-first century. Nat Rev Drug Discov 2023;22:625–40. doi:10.1038/s41573-023-00723-4
      OpenUrlPubMed
    8. ↵
      1. Garsen M,
      2. Steenhof M,
      3. Zwiers A
      . A Decade of Marketing Authorization Applications of Anticancer Drugs in the European Union: An Analysis of Procedural Timelines. Ther Innov Regul Sci 2021;55:633–42. doi:10.1007/s43441-021-00260-5
      OpenUrlPubMed
    9. ↵
      1. Bloem LT,
      2. Schelhaas J,
      3. López-Anglada L, et al
      . European Conditional Marketing Authorization in a Rapidly Evolving Treatment Landscape: A Comprehensive Study of Anticancer Medicinal Products in 2006-2020. Clin Pharmacol Ther 2023;114:148–60. doi:10.1002/cpt.2906
      OpenUrlCrossRefPubMed
    10. ↵
      1. Mulder J,
      2. Teerenstra S,
      3. van Hennik PB, et al
      . Single-arm trials supporting the approval of anticancer medicinal products in the European Union: contextualization of trial results and observed clinical benefit. ESMO Open 2023;8:101209. doi:10.1016/j.esmoop.2023.101209
    11. ↵
      1. European Medicines Agency
      . Conditional marketing authorisation. Report on ten years of experience at the European Medicines Agency (EMA/471951/2016). 2017.
    12. ↵
      1. Vreman RA,
      2. Bloem LT,
      3. van Oirschot S, et al
      . The Role of Regulator-Imposed Post-Approval Studies in Health Technology Assessments for Conditionally Approved Drugs. Int J Health Policy Manag 2020;11:642–50. doi:10.34172/ijhpm.2020.198
      OpenUrl
    13. ↵
      1. Trapani D,
      2. Tay-Teo K,
      3. Tesch ME, et al
      . Implications of Oncology Trial Design and Uncertainties in Efficacy-Safety Data on Health Technology Assessments. Curr Oncol 2022;29:5774–91. doi:10.3390/curroncol29080455
      OpenUrlPubMed
    14. ↵
      1. Vreman RA,
      2. Bouvy JC,
      3. Bloem LT, et al
      . Weighing of Evidence by Health Technology Assessment Bodies: Retrospective Study of Reimbursement Recommendations for Conditionally Approved Drugs. Clin Pharmacol Ther 2019;105:684–91. doi:10.1002/cpt.1251
      OpenUrlCrossRefPubMed
    15. ↵
      1. Cherny NI,
      2. Dafni U,
      3. Bogaerts J, et al
      . ESMO-Magnitude of Clinical Benefit Scale version 1.1. Ann Oncol 2017;28:2340–66. doi:10.1093/annonc/mdx310
      OpenUrlCrossRefPubMed
    16. ↵
      1. Cipriani A,
      2. Ioannidis JPA,
      3. Rothwell PM, et al
      . Generating comparative evidence on new drugs and devices after approval. The Lancet 2020;395:998–1010. doi:10.1016/S0140-6736(19)33177-0
      OpenUrl
    17. ↵
      1. McKinley L,
      2. Pressler ML,
      3. Hiatt MA, et al
      . A Sponsor’s View on Postmarketing Regulatory Commitments Involving Human Drug Products. Clin Pharmacol Ther 2022;111:1199–201. doi:10.1002/cpt.2335
      OpenUrlPubMed
    18. ↵
      1. Simon R,
      2. Blumenthal GM,
      3. Rothenberg ML, et al
      . The role of nonrandomized trials in the evaluation of oncology drugs. Clin Pharmacol Ther 2015;97:502–7. doi:10.1002/cpt.86
      OpenUrlPubMed
    19. ↵
      1. European Medicines Agency
      . CHMP Assessment Report for Lartruvo (EMA/CHMP/742133/2016). 2016.
    20. ↵
      1. European Medicines Agency
      . CHMP Assessment Report for Pixuvri (EMA/309145/2012). 2012.
    21. ↵
      1. Davis C,
      2. Naci H,
      3. Gurpinar E, et al
      . Availability of evidence of benefits on overall survival and quality of life of cancer drugs approved by European Medicines Agency: retrospective cohort study of drug approvals 2009-13. BMJ 2017;359:j4530. doi:10.1136/bmj.j4530
    22. ↵
      1. Hoekman J,
      2. Klamer TT,
      3. Mantel-Teeuwisse AK, et al
      . Characteristics and follow-up of postmarketing studies of conditionally authorized medicines in the EU. Br J Clin Pharmacol 2016;82:213–26. doi:10.1111/bcp.12940
      OpenUrlCrossRefPubMed
    23. ↵
      1. Cherla A,
      2. Mossialos E,
      3. Salcher-Konrad M, et al
      . Post-Marketing Requirements for Cancer Drugs Approved by the European Medicines Agency, 2004-2014. Clin Pharmacol Ther 2022;112:846–52. doi:10.1002/cpt.2679
      OpenUrlPubMed
    24. ↵
      1. Bloem LT,
      2. Mantel-Teeuwisse AK,
      3. Leufkens HGM, et al
      . Postauthorization Changes to Specific Obligations of Conditionally Authorized Medicines in the European Union: A Retrospective Cohort Study. Clin Pharmacol Ther 2019;105:426–35. doi:10.1002/cpt.1169
      OpenUrlPubMed
    25. ↵
      1. Deshmukh AD,
      2. Kesselheim AS,
      3. Rome BN
      . Timing of Confirmatory Trials for Drugs Granted Accelerated Approval Based on Surrogate Measures From 2012 to 2021. JAMA Health Forum 2023;4:e230217. doi:10.1001/jamahealthforum.2023.0217
    26. ↵
      1. Banzi R,
      2. Gerardi C,
      3. Bertele’ V, et al
      . Approvals of drugs with uncertain benefit-risk profiles in Europe. Eur J Intern Med 2015;26:572–84. doi:10.1016/j.ejim.2015.08.008
      OpenUrlCrossRefPubMed
    27. ↵
      1. European Medicines Agency
      . Guideline on the evaluation of anticancer medicinal products in man (EMA/CHMP/205/95,Rev.5). 2017.
    28. ↵
      1. Gadke DL,
      2. Kratochwill TR,
      3. Gettinger M
      . Incorporating feasibility protocols in intervention research. J Sch Psychol 2021;84:1–18. doi:10.1016/j.jsp.2020.11.004
      OpenUrlPubMed
    29. ↵
      1. Kitzinger J
      . Qualitative research. Introducing focus groups. BMJ 1995;311:299–302. doi:10.1136/bmj.311.7000.299
      OpenUrlFREE Full Text
    30. ↵
      1. Braun V,
      2. Clarke V
      . Using thematic analysis in psychology. Qual Res Psychol 2006;3:77–101. doi:10.1191/1478088706qp063oa
      OpenUrlCrossRefPubMed
    31. ↵
      1. Freedman B
      . Equipoise and the ethics of clinical research. N Engl J Med 1987;317:141–5. doi:10.1056/NEJM198707163170304
      OpenUrlCrossRefPubMedWeb of Science
    32. ↵
      1. Zeverijn LJ,
      2. van Waalwijk van Doorn-Khosrovani SB,
      3. van Roy A, et al
      . Harmonising patient-access programmes: the Dutch DRUG Access Protocol platform. Lancet Oncol 2022;23:198–201. doi:10.1016/S1470-2045(21)00707-5
      OpenUrlPubMed
    33. ↵
      1. Fogel DB
      . Factors associated with clinical trials that fail and opportunities for improving the likelihood of success: A review. Contemp Clin Trials Commun 2018;11:156–64. doi:10.1016/j.conctc.2018.08.001
      OpenUrlPubMed
    34. ↵
      1. Walters SJ,
      2. Bonacho Dos Anjos Henriques-Cadby I,
      3. Bortolami O, et al
      . Recruitment and retention of participants in randomised controlled trials: a review of trials funded and published by the United Kingdom Health Technology Assessment Programme. BMJ Open 2017;7:e015276. doi:10.1136/bmjopen-2016-015276
    35. ↵
      1. de Groot S,
      2. Rijnsburger AJ,
      3. Versteegh MM, et al
      . Which factors may determine the necessary and feasible type of effectiveness evidence? A mixed methods approach to develop an instrument to help coverage decision-makers. BMJ Open 2015;5:e007241. doi:10.1136/bmjopen-2014-007241
    36. ↵
      1. Coalition for Reducing Bureaucracy in Clinical Trials
      . Coalition for Reducing Bureaucracy in Clinical Trials. Recommendations of the Coalition for Reducing Bureaucracy in Clinical Trials (Version November 2021). 2021.
    37. ↵
      1. Dane A,
      2. Ashraf S,
      3. Timmis J, et al
      . Barriers to patient enrolment in phase III cancer clinical trials: interviews with clinicians and pharmaceutical industry representatives. BMJ Open 2022;12:e055165. doi:10.1136/bmjopen-2021-055165
    38. ↵
      1. European Medicines Agency
      . CHMP Assessment Report for Tyverb (EMEA/302222/2008). 2008.
    39. ↵
      1. Maksimova MV,
      2. van Thiel GJMW,
      3. Tromp Y, et al
      . Balancing ethical norms and duties for the introduction of new medicines through conditional marketing authorization: a research agenda. Front Med (Lausanne) 2024;11:1408553. doi:10.3389/fmed.2024.1408553
    40. ↵
      1. Zuidgeest MGP,
      2. Goetz I,
      3. Groenwold RHH, et al
      . Series: Pragmatic trials and real world evidence: Paper 1. Introduction. J Clin Epidemiol 2017;88:7–13. doi:10.1016/j.jclinepi.2016.12.023
      OpenUrlCrossRefPubMed
    41. ↵
      1. de Jong AJ,
      2. van Rijssel TI,
      3. Zuidgeest MGP, et al
      . Opportunities and Challenges for Decentralized Clinical Trials: European Regulators’ Perspective. Clin Pharmacol Ther 2022;112:344–52. doi:10.1002/cpt.2628
      OpenUrlPubMed
    42. ↵
      1. National Cancer Institute
      . Pragmatica-Lung Cancer Treatment Trial. 2023. Available: https://www.cancer.gov/types/lung/research/pragmatica-lung-cancer-trial
    43. ↵
      1. European Medicines Agency
      . CHMP Assessment Report for Rybrevant (EMA/629045/2021). 2021.
    44. ↵
      1. European Medicines Agency
      . CHMP Assessment Report for Rybrevant - Type II Variation (EMA/CHMP/111303/2024). 2024.
    45. ↵
      1. Zhou C,
      2. Tang K-J,
      3. Cho BC, et al
      . Amivantamab plus Chemotherapy in NSCLC with EGFR Exon 20 Insertions. N Engl J Med 2023;389:2039–51. doi:10.1056/NEJMoa2306441
      OpenUrlPubMed
    46. ↵
      1. European Medicines Agency
      . CHMP Assessment Report for Jemperli (EMA/176464/2021). 2021.
    47. ↵
      1. European Medicines Agency
      . CHMP Assessment Report for Jemperli - Type II Variation (EMA/483641/2023). 2023.
    48. ↵
      1. Mirza MR,
      2. Chase DM,
      3. Slomovitz BM, et al
      . Dostarlimab for Primary Advanced or Recurrent Endometrial Cancer. N Engl J Med 2023;388:2145–58. doi:10.1056/NEJMoa2216334
      OpenUrlPubMed
    49. ↵
      1. European Medicines Agency
      . Reflection paper on establishing efficacy based on single-arm trials submitted as pivotal evidence in a marketing authorisation (EMA/CHMP/564424/2021). 2023.
    50. ↵
      1. Kesselheim AS,
      2. Woloshin S,
      3. Lu Z, et al
      . Physicians’ Perspectives on FDA Approval Standards and Off-label Drug Marketing. JAMA Intern Med 2019;179:707–9. doi:10.1001/jamainternmed.2018.8121
      OpenUrlPubMed
    51. ↵
      1. Kesselheim AS,
      2. Woloshin S,
      3. Eddings W, et al
      . Physicians’ Knowledge About FDA Approval Standards and Perceptions of the “Breakthrough Therapy” Designation. JAMA 2016;315:1516–8. doi:10.1001/jama.2015.16984
      OpenUrlCrossRefPubMed
    52. ↵
      1. Schwartz LM,
      2. Woloshin S
      . Communicating Uncertainties About Prescription Drugs to the Public. Arch Intern Med 2011;171:1463. doi:10.1001/archinternmed.2011.396
      OpenUrlCrossRefPubMedWeb of Science
    53. ↵
      1. Sandman L,
      2. Liliemark J
      . From evidence-based to hope-based medicine? Ethical aspects on conditional market authorization of and early access to new cancer drugs. Semin Cancer Biol 2017;45:58–63. doi:10.1016/j.semcancer.2017.05.009
      OpenUrlPubMed
    54. ↵
      1. Davis C,
      2. Wagner AK,
      3. Salcher-Konrad M, et al
      . Communication of anticancer drug benefits and related uncertainties to patients and clinicians: document analysis of regulated information on prescription drugs in Europe. BMJ 2023;380:e073711. doi:10.1136/bmj-2022-073711
    55. ↵
      1. Nawaz K,
      2. Webster RM
      . The non-small-cell lung cancer drug market. Nat Rev Drug Discov 2023;22:264–5. doi:10.1038/d41573-023-00017-9
      OpenUrlCrossRefPubMed
    56. ↵
      1. Wieseler B,
      2. Neyt M,
      3. Kaiser T, et al
      . Replacing RCTs with real world data for regulatory decision making: a self-fulfilling prophecy? BMJ 2023;380:e073100. doi:10.1136/bmj-2022-073100
    57. ↵
      1. Tafuri G,
      2. Lucas I,
      3. Estevão S, et al
      . The impact of parallel regulatory–health technology assessment scientific advice on clinical development. Assessing the uptake of regulatory and health technology assessment recommendations. Brit J Clinical Pharma 2018;84:1013–9. doi:10.1111/bcp.13524
      OpenUrl
    58. ↵
      1. U.S. Food and Drug Administration
      . Project FrontRunner. 2023. Available: https://www.fda.gov/about-fda/oncology-center-excellence/project-frontrunner
    59. ↵
      1. Gyawali B,
      2. de Vries EGE,
      3. Dafni U, et al
      . Biases in study design, implementation, and data analysis that distort the appraisal of clinical benefit and ESMO-Magnitude of Clinical Benefit Scale (ESMO-MCBS) scoring. ESMO Open 2021;6:100117. doi:10.1016/j.esmoop.2021.100117
    60. ↵
      Directorate-General for Health and Food Safety. Regulation (EU) 2021/2282 of the European Parliament and of the Council of 15 December 2021 on health technology assessment and amending Directive 2011/24/EU. Off J Eur Union L 2021;458:1–32.
      OpenUrl
    61. ↵
      1. European Medicines Agency & Gemeinsamer Bundesausschuss
      . Guidance on parallel EMA/HTA body (HTAb) scientific advice for the interim period (EMA/250551/2023). 2023.
    62. ↵
      1. Thomas C,
      2. Mulnick S,
      3. Krucien N, et al
      . How do study design features and participant characteristics influence willingness to participate in clinical trials? Results from a choice experiment. BMC Med Res Methodol 2022;22:323. doi:10.1186/s12874-022-01803-6
    63. ↵
      1. Herold R,
      2. Camarero J,
      3. Melchiorri D
      . Revocation of the conditional marketing authorisation of a cancer medicine: The olaratumab experience. Eur J Cancer 2019;123:25–7. doi:10.1016/j.ejca.2019.09.020
      OpenUrlPubMed
    64. ↵
      1. European Medicines Agency
      . CHMP Assessment Report for Rubraca (EMA/674344/2022). 2022.
    65. ↵
      1. European Medicines Agency
      . CHMP Assessment Report for Lartruvo - Article 20 Referral (EMA/254126/2019). 2019.
    66. ↵
      1. European Medicines Agency
      . CHMP Assessment Report for Caprelsa - Type II Variation (EMA/CHMP/30610/2023). 2022.
    67. ↵
      1. Mahase E
      . FDA allows drugs without proven clinical benefit to languish for years on accelerated pathway. BMJ 2021;1898. doi:10.1136/bmj.n1898
    68. ↵
      1. Jokura Y,
      2. Yano K,
      3. Yamato M
      . Comparison of the new Japanese legislation for expedited approval of regenerative medicine products with the existing systems in the USA and European Union. J Tissue Eng Regen Med 2018;12:e1056–62. doi:10.1002/term.2428
      OpenUrlPubMed
    69. ↵
      1. Eichler H-G,
      2. Pignatti F,
      3. Flamion B, et al
      . Balancing early market access to new drugs with the need for benefit/risk data: a mounting dilemma. Nat Rev Drug Discov 2008;7:818–26. doi:10.1038/nrd2664
      OpenUrlCrossRefPubMedWeb of Science
    70. ↵
      1. Eichler H-G,
      2. Barker R,
      3. Bedlington N, et al
      . The evolution of adaptiveness: balancing speed and evidence. Nat Rev Drug Discov 2018;17:845–6. doi:10.1038/nrd.2018.90
      OpenUrlPubMed
    71. ↵
      1. Fashoyin-Aje LA,
      2. Mehta GU,
      3. Beaver JA, et al
      . The On- and Off-Ramps of Oncology Accelerated Approval. N Engl J Med 2022;387:1439–42. doi:10.1056/NEJMp2208954
      OpenUrlPubMed
    72. ↵
      1. Vreman RA,
      2. Heikkinen I,
      3. Schuurman A, et al
      . Unmet Medical Need: An Introduction to Definitions and Stakeholder Perceptions. V Health 2019;22:1275–82. doi:10.1016/j.jval.2019.07.007
      OpenUrl

    Supplementary materials

    • Supplementary Data

      This web only file has been produced by the BMJ Publishing Group from an electronic file supplied by the author(s) and has not been edited for content.

    Footnotes

    • CCvH and AJdJ are joint first authors.

    • Presented at Preliminary findings of this study were presented at the International Society for Pharmacoepidemiology 2023 Mid-Year Meeting and at the Cancer Medicines Forum led by the EMA and the European Organisation for Research and Treatment of Cancer.

    • Contributors CCvH, AJdJ, JSdG, JH, KEB, GSS, PBvH and LTB wrote the manuscript and designed the research. CCvH, AJdJ, JSdG and LTB conducted the interviews and focus groups. CCvH and AJdJ analysed the data. LTB acts as the guarantor .

    • Funding We received funding from the Dutch Cancer Society (KWF Kankerbestrijding) to conduct this study (grant number 9086).

    • Disclaimer The views expressed in this article are the personal views of the authors and may not be understood or quoted as being made on behalf of or reflecting the position of the agencies or organisations with which the authors are affiliated, or one of their committees or working parties.

    • Competing interests GSS reports he received institutional research support from Agendia, AstraZeneca, Merck, Novartis, Roche, Seagen, and consulting fees from Biovica and Seagen, all outside the scope of this study. PBvH reports she worked for the Medicines Evaluation Board during the conduct of this study and that she transitioned to ProPharma during the finalisation of this study. The other authors report no conflicts of interest in relation to this study.

    • Patient and public involvement Patients and/or the public were involved in the design, conduct, reporting or dissemination plans of this research. Refer to the Methods section for further details.

    • Provenance and peer review Not commissioned; externally peer reviewed.

    • Supplemental material This content has been supplied by the author(s). It has not been vetted by BMJ Publishing Group Limited (BMJ) and may not have been peer-reviewed. Any opinions or recommendations discussed are solely those of the author(s) and are not endorsed by BMJ. BMJ disclaims all liability and responsibility arising from any reliance placed on the content. Where the content includes any translated material, BMJ does not warrant the accuracy and reliability of the translations (including but not limited to local regulations, clinical guidelines, terminology, drug names and drug dosages), and is not responsible for any error and/or omissions arising from translation and adaptation or otherwise.