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30.06.17
Submission of comments on Concept paper on the need to revise Condition Specific guidance, Appendix 4 to the guideline on the evaluation of anticancer medicinal products in man EMA/CHMP/102314/2017
Comments from:
Name of organisation or individual: Janssen R&DEFPIA Sandra Rodrigues (sandra.rodrigues@efpia.eu)
Please note that these comments and the identity of the sender will be published unless a specific justified objection is received.
When completed, this form should be sent to the European Medicines Agency electronically, in Word format (not PDF).
General comments
Stakeholder number
(To be completed by the Agency)General comment (if any)Outcome (if applicable)
(To be completed by the Agency)General comment
EFPIA members welcome the initiative of this important concept paper and appreciate the opportunity to comment in view of a draft updated Appendix 4 of the anticancer guideline including minimal residual disease (MRD) as a clinical endpoint in multiple myeloma (MM) clinical studies. EFPIA members look forward to the opportunity to input further on the development of European guidance on the use of MRD as a regulatory endpoint.
Despite recent advances in therapies, MM patients are still in high unmet medical need. As more effective treatments become available, it is crucial to develop and use endpoints for early licensure endpoints such as MRD that are predictive of long term outcome. Early endpoints (and expedited mechanism of registration) are required to demonstrate superior efficacy and make safe and effective therapies available to patients with MM earlier. In this context, the implementation of MRD will participate in bringing effective drugs to patients in a timely manner.
Points to consider: Circumstances under which full approval or early conditional) approval may be granted and large body of evidence already available
Multiple studies and 2 meta-analyses have demonstrated that achievement and maintenance ofMRD negativity was associated with improved clinical outcomes for MM patients in distinct settings, as assessed by multiple methods (MFC/NGF, qASO-PCR, NGS) and different depths (10-4 to 10-6) of MRD negativity(Landgren, 2016a; Munshi, 2017; Rawstron, 2013; Rawstron, 2015) Recently. data on MRD assessment in MM have been reviewed in the literature by several groups ADDIN EN.CITE ADDIN EN.CITE.DATA ( HYPERLINK \l "_ENREF_1" \o "Anderson, 2017 #3" Anderson, 2017; HYPERLINK \l "_ENREF_7" \o "Landgren, 2016 #41" Landgren, 2016a; HYPERLINK \l "_ENREF_8" \o "Landgren, 2017 #5" Landgren, 2017; HYPERLINK \l "_ENREF_9" \o "Landgren, 2016 #66" Landgren, 2016b; HYPERLINK \l "_ENREF_20" \o "Sherrod, 2016 #63" Sherrod, 2016) and support the use of MRD negativity as an endpoint in MM.
NDMM Transplant Eligible and Transplant Non-eligible
A recent meta-analysis included data from 21 studies (15 with quantitative synthesis), which included data from studies in the NDMM setting, including both TE and TNE patients ADDIN EN.CITE ADDIN EN.CITE.DATA ( HYPERLINK \l "_ENREF_12" \o "Munshi, 2017 #20" Munshi, 2017).
A recent pooled analysis of 3 studies of TE and TNE patients indicated that achievement of MRD negativity at 9 months after initiation of treatment (ie, after induction plus transplant in TEpatients or after 9 cycles of therapy in TNE patients) significantly improved PFS and OScompared with patients who remained MRD positive (median PFS = 63 months, p < 0.001; median OS not reached, p<0.001) ADDIN EN.CITE ADDIN EN.CITE.DATA ( HYPERLINK \l "_ENREF_6" \o "Lahuerta, 2017 #1" Lahuerta, 2017)
NDMM Transplant Eligible
Five studies included in the meta-analysis by Munshi et al ADDIN EN.CITE ADDIN EN.CITE.DATA ( HYPERLINK \l "_ENREF_12" \o "Munshi, 2017 #20" Munshi, 2017) evaluated MRD status before and aftertransplant ADDIN EN.CITE ADDIN EN.CITE.DATA ( HYPERLINK \l "_ENREF_4" \o "Korthals, 2012 #121" Korthals, 2012; HYPERLINK \l "_ENREF_5" \o "Korthals, 2013 #108" Korthals, 2013; HYPERLINK \l "_ENREF_10" \o "Ludwig, 2013 #112" Ludwig, 2013; HYPERLINK \l "_ENREF_16" \o "Rawstron, 2013 #105" Rawstron, 2013; HYPERLINK \l "_ENREF_18" \o "Roussel, 2014 #90" Roussel, 2014), and all indicated that transplant increased the proportion of MRD-negative patients. Two of these studies indicated that maintenance therapy increased the proportion of patients who achieved and maintained MRD negativity ADDIN EN.CITE ADDIN EN.CITE.DATA ( HYPERLINK \l "_ENREF_16" \o "Rawstron, 2013 #105" Rawstron, 2013; HYPERLINK \l "_ENREF_18" \o "Roussel, 2014 #90" Roussel, 2014).
NDMM Transplant Non-eligible
Two of the prospective studies described above also included a cohort of TNE patients. Similar to the data in TE patients, TNE patients who achieved MRD negativity experienced clinical benefits ADDIN EN.CITE ADDIN EN.CITE.DATA ( HYPERLINK \l "_ENREF_13" \o "Paiva, 2008 #137" Paiva, 2008; HYPERLINK \l "_ENREF_16" \o "Rawstron, 2013 #105" Rawstron, 2013). In 1 analysis, median PFS was not reached for MRDnegative patients versus 35 months for MRD-positive patients. In the second study, median PFS was 34months for MRD-negative patients versus 14 months for those who remained MRD positive after induction therapy. In both studies, MRD negativity was associated with a trend toward improved OS.
RRMM
Data from several studies of recently approved agents/regimens demonstrated impressive clinical benefits with deep responses and long PFS and OS. Initial MRD data from two Phase 3 RRMM clinical trials represent the first randomized, controlled, prospective evaluation of MRD in this setting ADDIN EN.CITE ADDIN EN.CITE.DATA ( HYPERLINK \l "_ENREF_2" \o "Avet-Loiseau, 2016 #47" Avet-Loiseau, 2016). Data from the POLLUX ADDIN EN.CITE ADDIN EN.CITE.DATA ( HYPERLINK \l "_ENREF_3" \o "Dimopoulos, 2016 #176" Dimopoulos, 2016) and CASTOR ADDIN EN.CITE ADDIN EN.CITE.DATA ( HYPERLINK \l "_ENREF_15" \o "Palumbo, 2016 #177" Palumbo, 2016) trials indicated significantly higher rates of MRD negativity at 10-4, 10-5, and 10-6 ADDIN EN.CITE ADDIN EN.CITE.DATA ( HYPERLINK \l "_ENREF_2" \o "Avet-Loiseau, 2016 #47" Avet-Loiseau, 2016). Patients who achieved MRD negativity at 10-5 had fewer PFS events compared to patients who were MRD positive.
All those recent publications and others based on meta-analysis and robust data allow for certainty on the use of MRD negativity for decision making.
MRD used as primary-endpoint for full registration
In reference to the Anticancer Guideline (EMA/CHMP/205/95/Rev.4) stating:
where induction is followed by consolidation and/or maintenance therapy, confounding effects of therapies administered after the end of experimental therapy may make endpoints other than PFS or EFS more appropriate. This means that CR (and CR + PR, if specifically justified) after end of experimental therapy could be an acceptable primary endpoint when further therapy is scheduled. In these cases, the possible influence of the experimental compound on the activity of consolidation therapy should always be addressed and outcomes with respect to CR should be supported by EFS or PFS data;
And considering that newer treatment regimens have resulted in high overall response rates (ORRs) and deepening of responses as measured by higher complete response (CR) rates ADDIN EN.CITE Landgren20175(Landgren, 2017)5517Landgren, O.Iskander, K.Myeloma Service, Division of Hematology Oncology, Department of Medicine, Memorial Sloan-Kettering Cancer Center, New York, NY, USA.
Department of Clinical Development, Amgen, Thousand Oaks, CA, USA.Modern multiple myeloma therapy: deep, sustained treatment response and good clinical outcomesJ Intern MedJournal of internal medicineJ Intern MedJournal of internal medicineJ Intern MedJournal of internal medicine365-38228142017/02/17Mrdcombination therapymultiple myelomaresponsesurvival2017Apr0954-68202820526210.1111/joim.12590NLMeng( HYPERLINK \l "_ENREF_8" \o "Landgren, 2017 #5" Landgren, 2017) MRD negativity as a primary endpoint (supported by EFS or PFS) would then demonstrate a robust response measurement to allow registration in the setting of frontline treatment.
In this context, considerations should be given on the totality of the safety and efficacy data available for the drug in development to support early approval of an indication based on MRD (see below specific comment 2 on the text) and associated acceptable conditions. Points to consider: Magnitude of absolute MRD negativity improvement expected to translate into meaningful improvement in clinical outcomes (OS, PFS):
MRD negativity rates and the association with long-term outcomes may vary by MM subtype (including molecular sub-types to be further defined), it is possible that the magnitude of MRD improvement that would translate into meaningful improvements in long-term outcomes may vary by sub-type ADDIN EN.CITE ADDIN EN.CITE.DATA ( HYPERLINK \l "_ENREF_14" \o "Paiva, 2012 #178" Paiva, 2012). Similarly, variability could be observed between newly diagnosed (1L) MM transplant eligible, ineligible ADDIN EN.CITE ADDIN EN.CITE.DATA ( HYPERLINK \l "_ENREF_7" \o "Landgren, 2016 #41" Landgren, 2016a; HYPERLINK \l "_ENREF_12" \o "Munshi, 2017 #20" Munshi, 2017) and/or relapsed/refractory (R/R) MM ADDIN EN.CITE San-Miguel2016179(San-Miguel, 2016)17917917San-Miguel, J. F.Einsele, H.Moreau, P.Clinica Universidad de Navarra, CIMA, IDISNA, Pamplona, Spain. sanmiguel@unav.es.
Medizinische Klinik und Poliklinik II, University of Wurzburg, Wurzburg, Germany.
University Hospital of Nantes, Nantes, France.The Role of Panobinostat Plus Bortezomib and Dexamethasone in Treating Relapsed or Relapsed and Refractory Multiple Myeloma: A European PerspectiveAdv TherAdvances in therapyAdv TherAdvances in therapyAdv TherAdvances in therapy1896-192033112016/10/28Multiple myelomaOncologyPanobinostatRelapsedRelapsed and refractory2016Nov0741-238x27677481PMC508377310.1007/s12325-016-0413-7NLMeng( HYPERLINK \l "_ENREF_19" \o "San-Miguel, 2016 #179" San-Miguel, 2016). It would be helpful that the guideline describe the situations under which there is flexibility to observe smaller treatment effects on MRD still supporting licensure.
Points to consider: Recommendations on robust and reproducible laboratory methods for MRD measurements:
Appropriately validated and calibrated diagnostic methods which are globally acceptable are needed to measure MRD to ensure uniform and robust evaluation in pivotal clinical trials. Criteria to ensure quality and reproducibility of the testing within and across trials would be desirable and clarification on criteria for the acceptability of those methods would be valued. However the field is evolving and EFPIA members do not support the recommendation of any particular method at this point and wish to retain flexibility in order to be able to adapt the most appropriate method to the indication and setting and in order to maximize the number of MRD-evaluable patients and avoid a high rate of missing data. Points to consider: timing of MRD assessment
Whether timepoints at which MRD status is assessed could be adapted depending on line of therapy or treatment regimens under evaluation (e.g. with or without stem cell transplantation, drug treatment of fixed duration or until progression, etc).
Whether a single assessment is acceptable or if repeated measurements would be required (durable MRD); and if so, at what time interval.
Points to consider: definition of MRD negative status
Whether the IMWG-recommended cut off of 1 malignant cell within 10-5 nucleated bone marrow cells should always be used, or if alternative cut offs could be considered (e.g. 10-6, 10-4) depending on the assay performance, patient population, expected rate of MRD negative status between treatment arms, or other considerations. Ultimately these thresholds must be driven by clinical evidence. Will the agency provide guidance regarding MRD assessment in high risk populations, where achievement of MRD negativity is not very common and may not be maintained for very long.
Whether the MRD status should be measured by collecting and analysing bone marrow aspirate from all patients, regardless of conventional response assessment, or only tested in patients achieving a Complete Response (CR).
In this specific situation, could the guideline clarify how to define the status of a patient who is MRD negative as measured by a validated and high quality assay, yet has not (yet) achieved CR by conventional assessments. For example, due to the 4-week half-life of immunoglobulin proteins, patients with a negative MRD measurement may still be positive for M protein by immunofixation electrophoresis and thus defined conventionally as very good partial response (VGPR). Guidance on the appropriate resolution of these conflicting results would be helpful.
Points to consider Further guidance on statistical considerations for using MRD as an endpoint in clinical trials:
Guidance on statistical considerations for calculating and comparing MRD negativity rate between different arms of the same trial would be welcome (e.g. intent-to-treat population vs. response-evaluable population).
Rawstron reported a significant improvement in OS for each log depletion in MRD level ADDIN EN.CITE ADDIN EN.CITE.DATA ( HYPERLINK \l "_ENREF_17" \o "Rawstron, 2015 #76" Rawstron, 2015). It would be helpful to provide recommendations on when MRD as a continuous measure could be used as an intermediate endpoint for early licensure.
The Estimand framework ADDIN EN.CITE Mehrotra2016180(Mehrotra, 2016)18018017Mehrotra, D. V.Hemmings, R. J.Russek-Cohen, E.Merck Research Laboratories, North Wales, PA, USA devan_mehrotra@merck.com.
Medicines and Healthcare Products Regulatory Agency, London, UK.
U.S. Food and Drug Administration, Silver Spring, MD, USA.Seeking harmony: estimands and sensitivity analyses for confirmatory clinical trialsClin TrialsClinical trials (London, England)Clin TrialsClinical trials (London, England)Clin TrialsClinical trials (London, England)456-81342016/02/26DropoutsInternational Conference on Harmonization E9estimandmissing datasensitivity analysistrial planning2016Aug1740-77452690854510.1177/1740774516633115NLMeng( HYPERLINK \l "_ENREF_11" \o "Mehrotra, 2016 #180" Mehrotra, 2016) provides a useful way to describe the scientific question under investigation and the endpoints to evaluate that question (including handling of missing data); and a draft addendum to ICH E9 R1 (including Estimand framework) is expected to be released for public consultation in 2017. It would be helpful if the future guideline for the use of MRD in MM encouraged Sponsors to implement the Estimand framework in the proposed multiple myeloma trials using MRD as a registrational endpoint.Additional points to be considered
It would be desirable that the guideline not be overly prescriptive or restrictive in relation to the overall development programme i.e. the Sponsor should have the flexibility to design the programme according to the specifics of their own molecule (e.g. use of MRD across lines or different combination therapies).
MRD has been recognised as an important endpoint in various haematological malignancies. It could be of value to provide considerations on the use of MRD in the different haematological malignancies
In the interest of all stakeholders the question of harmonization between FDA and EMA guidelines deserves attention.
Input from Health Technology Assessment bodies will be key to ensure patient access to medicine, in particular in the case of early licensure approval.
Specific comments on text
Line number(s) of the relevant text
(e.g. Lines 20-23)Stakeholder number
(To be completed by the Agency)Comment and rationale; proposed changes
(If changes to the wording are suggested, they should be highlighted using 'track changes')Outcome
(To be completed by the Agency)2 Problem statement
Thus there is a need to reflect on the utility of MRD in the development of medicinal products for treatment of multiple Myeloma as primary intermediate efficacy endpointPutting together "primary" and "intermediate" is confusing and somewhat contradictory. This should be clarified if "intermediate" refers to an endpoint for development decision point (for example in phase I or phase II), or to an endpoint which could be used for conditional approval in advanced settings.
Section 3. Discussion
If a good correlation is demonstrated, superiority in MRD negativity, if sufficiently large, should be given special consideration as a potential intermediate endpoint for early licensure with confirmatory follow-up with PFS as outcome measure.
Proposed change (if any):
Comment #1:
The use of the term intermediate endpoint could lead to misunderstanding. Would this support conditional approval for a first MAA and approval with post approval commitments for a new indication? Clarifications would be welcome in the final guideline.
Comment #2:
It would be helpful if the guideline could provide more details as to what sufficiently large means in terms of MRD difference and how the applicants can define if the difference is sufficient for early approval.
Comment #3:
Three meta analyses recently published have shown a strong and positive correlation between MRD negativity and long term outcome including PFS and OS. It is acknowledged that a high correlation between MRD and PFS is needed to formally validate MRD as a primary endpoint in MM. However, the guideline should acknowledge that a general correlation may also be sufficient for registration in specific situations (e.g. if the magnitude of the effect as well as the totality of the data supports a positive risk benefit profile).
Comment #4:
The concept paper refers to confirmatory follow-up with PFS. Depending on the treatment and/or line of therapy, the long term outcome of interest may be different from PFS (e.g. OS) and some flexibility in the wording would be good.
Comment #5:
It is mentioned in the Concept Paper that patient factor and treatment factor should be considered. Please indicate how EMA proposes to separate the patient factor from the treatment factor.
Please add more rows if needed.
ADDIN EN.REFLIST References
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Korthals M, Sehnke N, Kronenwett R, Bruns I, Mau J, Zohren F, et al. The level of minimal residual disease in the bone marrow of patients with multiple myeloma before high-dose therapy and autologous blood stem cell transplantation is an independent predictive parameter. Biology of blood and marrow transplantation : journal of the American Society for Blood and Marrow Transplantation. Mar;18(3):423-31.e3.
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