Introduction

A new oncology product can only be marketed in the EU after the European Commission grants a marketing authorisation. This authorisation is based on the favourable opinion from EMA's CHMP following a rigorous scientific evaluation. However, following the scientific evaluation a new product may also be refused by CHMP. This happens in the event any outstanding issues remain with major objections raised by CHMP, that are not resolved during the final stage of the procedure for a new marketing authorisation application (MAA), or a variation to an existing marketing authorisation to extend the indication (Type II variation). In order to resolve these issues, an OE may be requested by the CHMP or even by the applicant and can be held more than once during the same procedure. Therefore, an OE is regarded as an ultimate opportunity for applicants to explain their position and present their arguments to the CHMP in case there are still major objections. It is important that applicants preparing for an OE bear in mind that only clarification of the aspects relating to the outstanding issues is allowed [1,2,3].

At any stage during MAA or Type II variation application review, the CHMP can request the involvement of a Scientific Advisory Group (SAG), composed of independent European experts, where the applicant may be given the opportunity to present data supporting the application and addressing the specific questions addressed by the CHMP to the SAG [4]. This consultation can also be triggered by the applicant in case of a re-examination procedure. SAG provides a non-binding advice to CHMP on specific scientific matters but does not address the benefit-risk balance which is under the CHMP remit. The Inter-Committee SAG for Oncology (hereinafter referred to as the SAG-O) is the group dealing with oncology aspects. CHMP will ultimately adopt a final opinion and a summary of the SAG written answers will be published in the European public assessment report (EPAR) [5].

The applicant also has the option to apply for a re-examination procedure after a CHMP Opinion has been adopted for a MAA or Type II variation application within 15 days of receipt of the opinion (after which, if the applicant does not appeal, the opinion shall be considered as final).

An overview of the human medicines regulatory approval process depicting the different phases from pre-submission (with Scientific Advice (SA)) up to marketing authorisation granted by the European Commission is provided in Fig. 1.

Fig. 1
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Overview of the human medicines regulatory approval process

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After the initial Marketing Authorisation is granted, the applicant can extend the authorised indication(s) by submitting a major variation of Type II for a new or modified therapeutic indication for which a “90-day timetable” applies.

In summary, an OE is an important event during procedures for a MAA or Type II variation application to extend the indication. Extensive preparation is required by the applicant and the regulators for this meeting with CHMP as it may well be the key moment in the approval process. Considering the importance of OEs for the availability of new oncology treatments, the objectives of the present study were aiming to investigate how many procedures having an OE resulted in a regulatory approval for oncology products in the EU and to understand the factors associated with a positive or negative outcome.

Methods

Procedures for new MAAs and Type II variations to an existing marketing authorisation to extend the indication for oncology products with at least one OE, and a final outcome taking place in a period of 4 years (31 January 2016 to 31 January 2020) in which many new oncology products were assessed and approved, were included in the analysis.

Procedures of interest were identified using publicly available CHMP agendas/meeting minutes where outcome of the oral explanation is explicitly given. A positive outcome was defined as a positive opinion by the CHMP. A negative outcome was defined as a negative opinion by the CHMP or withdrawal of the application by the applicant prior to CHMP opinion.

The publicly available EPARs of the initial MAA or Type II variation to extend the indication on the EMA website were used to obtain public information of the selected oncology procedures and their final outcome. In case of withdrawal by the applicant after the first stage of the assessment, the publicly available withdrawal assessment report was consulted. From the EPARs, general information was extracted (type of product, active substance, and therapeutic indication (proposed and approved), key milestones (OE, SAG-O, re-examination procedure, CHMP opinion, CHMP opinion date or withdrawal date)).

The EPARs were also used to confirm if a CHMP SA had been given during any of the MAA/Type II procedures, but compliance with the given SA was not assessed, and to identify whether divergent opinions were expressed by CHMP members when a positive opinion was ultimately adopted. Data entry was checked by a second person and corrected in case of a data entry error.

Results

For the period from 31 January 2016 up to 31 January 2020, an average overall number of 150 oncology procedures had a final review outcome by EMA based on the summaries of opinions that EMA has posted on approvals, negative opinions, withdrawals for initial MAAs and for the extensions of indications. An OE occurred in about 20% of procedures (n = 28/150) for oncology products during the review period. These 28 procedures selected for the analysis included a total of 22 products with different mechanisms of action. The products can be divided into 5 main categories as shown in Table 1.

Table 1 List of oncology products by mechanism of action
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Table 2 MAA/Type II procedures resulting in a restricted indication
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These 22 products, assessed in 28 procedures, could be divided into 19 new MAAs and 9 Type II variations, which had at least one OE, with or without any SAG-O meeting, as detailed in Supporting Information Table S1.

In total, 44 meetings were held for these selected oncology products, consisting of 32 OE and 12 SAG-O meetings. Analysing the distribution of these meetings over this 4-year period (Fig. 2), there was a high number of OE/SAG-O meetings seen in 2017, 2018, 2019 and overall, a more limited number of SAG-O consultations compared to OE meetings.

Fig. 2
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OE and SAG-O meetings between 31 January 2016 up and 31 January 2020

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Procedures with a Positive Outcome

Out of the 28 procedures, the majority, 61% (n = 17/28), resulted in a positive opinion for 12 MAA (atezolizumab, durvalumab, cemiplimab, gilteritinib, larotrectinib, lorlatinib, neratinib, trastuzumab, polatuzumab vedotin, abemaciclib, rucaparib, padeliporfin) and 5 Type II (nivolumab in 2L Non-Small Cell Lung Carcinoma (NSCLC), melanoma, Renal Cell Carcinoma (RCC)), pembrolizumab in 2L Head and Neck Squamous Cell Carcinoma (HNSCC), blinatumomab in leukaemia).

Although a positive opinion was adopted for these 17 procedures, only half of the procedures ended with a unanimous vote by CHMP namely for 5 MAA (durvalumab, cemiplimab, abemaciclib, gliterinib, larotrectinib) and 3 Type II (nivolumab CheckMate-057 (NSCLC), pembrolizumab KEYNOTE-040 (2L HNSCC), blinatumomab (leukaemia)), while the other half of these positive procedures concluded with divergent opinions expressed by some CHMP members divided as 7 MAA (atezolizumab, rucaparib, padeliporfin, trastuzumab, lorlatinib, neratinib, polatuzumab vedotin) and 2 Type II (nivolumab CheckMate-067 in melanoma and CheckMate-214 in RCC).

Furthermore, it should be noted that among those procedures with a positive outcome, 41% (n = 7/17) were approved with a restricted indication (5 MAA and 2 Type II) as summarised in Table 2.

Procedures with a Negative Outcome

Out of the 28 procedures, 39% (n = 11/28) resulted in a negative outcome (i.e. withdrawal or refusal) including 7 MAA (quizartinib, mAB for IL-1α, vosaroxin, etirinotecan pegol, enasidenib, plitidepsin, doxorubicin HCL) and 4 Type II (nivolumab in gastric cancer and 1L NSCLC, pembrolizumab in 1L NSCLC and oesophageal cancer). The main reasons for a negative outcome for these procedures were reviewed and have been summarised in Table 3.

Table 3 Reasons for negative outcome (negative CHMP Opinion or withdrawal)
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Re-examination Procedure

Furthermore, a re-examination was requested in half of the procedures where a negative opinion was initially adopted by CHMP (n = 7/14). This resulted in a negative outcome for 4 MAA (57%) namely etirinotecan pegol, mAB for IL-1α, plitidepsin and doxorubicin HCL and a positive outcome for 2 Type II and 1 MAA (43%) namely blinatumomab (leukaemia), nivolumab (1L RCC) and neratinib.

SAG-O Consultation

As indicated earlier, CHMP can request involvement of the SAG-O and consultation can also be triggered by the applicant in case of re-examination procedure. For the 28 procedures with at least one OE, SAG-O was also consulted in 45% of procedures (n = 12/28). Among those 12 procedures: 66% resulted in a positive outcome (n = 8/12–5 MAA/3 Type II) and 34% resulted in a negative outcome (n = 4/12–4 MAA) as summarised in Fig. 3 below.

Fig. 3
figure 3

MAA/Type II procedures with SAG-O consultation

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The final CHMP outcome was fully aligned with SAG-O advice in these 12 procedures. Notably, all 3 Type II variations that had an OE and a SAG-O meeting ended positively and 3 out of the 4 MAAs with a positive outcome were conditional MAs based on less comprehensive data than normally required, which means that the applicant should be able to provide the comprehensive clinical data in the future.

Impact of SA Consultation

Finally, among the 28 identified procedures with an OE, the proportion of the MAA/Type II that had received SA was 79%. Obtaining a SA was mainly pursued for new MAA compared to Type II (18 vs 4) and interestingly may be associated with a slightly better outcome (63% vs 50%) as shown in Fig. 4 below.

Fig. 4
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Outcome of MAA/Type II procedures with or without any SA

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Discussion

It was decided to retrospectively evaluate 19 MAA and 9 Type II variations (28 procedures) for oncology treatments which had at least one OE and which final outcome took place between 31 January 2016 up to 31 January 2020 with the aim of better understanding how many procedures having an OE, with or without any SAG-O meeting, resulted in a regulatory approval for oncology products in the EU. In addition, another objective was to evaluate if obtaining a Scientific Advice by the CHMP impacted the MAA/Type II outcome for those procedures having at least one OE.

The results of this analysis suggest that the majority of procedures having an OE, with or without any SAG-O meeting, led to MAA/Type II variation approvals in the Centralised Procedure. The MAA/Type II approval rate of close to 61% for the studied oncology products is a good indicator that this type of agency interaction is an important opportunity for the applicant to have a last chance to defend their position and provide clarifications in front of the CHMP, and to resolve any outstanding major objections at the final stage of the procedure. Other research suggests that larger companies may have more opportunities to experience such meetings at high stake than SMEs and may be better positioned by having more resources to prepare for these highly demanding meetings and engage with external experts to increase their chance for a positive outcome and patient access to new treatments [6]. Interestingly, it is noted that for nearly half of the procedures which concluded positively, there was no unanimous vote with 2 to 8 CHMP members expressing divergent opinions.

In addition, it was also observed that a successful outcome may be contingent upon willingness of the applicant to restrict the indication. As no additional data can be presented by the applicant during an OE, labelling can be considered as a key driver for a successful outcome. This suggests that the applicants should be prepared for potential labelling scenarios to be ready at the time of the OE meeting, especially noting the rate of successful procedures which led to a restricted indication (41%).

It has also been found that the final CHMP outcome was fully aligned with SAG-O advice when requested for some procedures and SAG-O consultation during re-examination procedure could sometimes reverse the initially adopted CHMP negative opinion. It is assumed that SAG-O involvement would be generally expected if there is a new mode of action or innovative treatment for a specific indication.

When comparing the outcome for MAAs and Type II respectively, the analysis showed that a higher number of OEs was reported for MAAs (19 vs 9), which makes sense as this is the first procedure for a product with a potentially new mechanism of action. In addition, slightly more procedures for MAA ended positively compared to those for Type II [n = 12/19 (63%) vs n = 5/9 (55%)]. Here it is important to note that for a new MAA a conditional approval is a valid option, whereas this is not an option for Type II, which might raise the bar to be successful for this type of procedure. However, Post-Authorisation Measures may still be requested for Type II variations.

Although based on a limited number of products and compliance with SA could not be assessed, the MAA/Type II success rate (63%) of procedures that received a SA when compared to procedures that did not receive any SA (50%), suggests that companies who intend to use the Centralised Procedure would benefit from engaging in a dialogue with EMA regarding their development programme via the SA procedure. This is in line with previous researches which show that complying with SA increases the chances of receiving marketing authorisation but it does not guarantee it [7, 8].

A limitation of the analysis was that the selection of the 28 procedures which had at least one OE was based on the review of agenda/minutes of the CHMP meetings and EPARs published by the EMA, which may not accurately reflect the total number of OE/SAG-O meetings that were actually held during this 4-year period. These data are therefore dependent on the information summarised and published by the EMA. In addition, because the numbers are low, it is challenging to do statistical assessments with any confidence; as such, this analysis is only considered as descriptive.

Conclusion

In conclusion, this descriptive analysis indicates that an OE is an important agency meeting for applicants which in the majority of cases may have helped to overcome major objections, resulting in a regulatory approval for oncology products in the EU. The successful outcome for those procedures may be contingent upon willingness to restrict the indication. In addition, obtaining SA by the CHMP early in development and at major transition points is recommended to increase MAA/Type II success rate.

Further research is needed to confirm the current conclusion, considering future procedures in which oncology procedures with an OE are available. In addition, a comparative analysis with other therapeutic areas evaluating how often procedures with this type of meeting led to an approval could be performed. It is important that continuous research efforts are pursued in this area of importance to better understand the impact of the different measures offered by the regulatory system in the EU.