industry corner: perspectives and controversies

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1 : perspectives and controversies 27: , 2016 doi: /annonc/mdw143 Published online 30 March 2016 Pragmatic randomized clinical s: a proposal to enhance evaluation of new cancer therapies with early signs of exceptional activity The number of regulatory s for oncology new molecular entities has risen rapidly over the past 5 years. This is likely due to our ability to design targeted agents, a consequence of our improved insight into the molecular basis of cancer. As a result, several new drugs have demonstrated exceptional clinical activity in small phase I or phase II s. This has led to the increased use of regulatory mechanisms that allow initial on the basis of these early data and, more recently, the introduction of the breakthrough therapy designation (BTD) in the United States in 2012 and the anticipated piloting of Sakigake in Japan and PRIME in Europe in 2016 [1, 2]. An analysis of oncology regulatory s since 2011 reveals that exceptional activity in phase I or phase II s strongly predicts sustained efficacy in subsequent phase III studies (Table 1). For our proposal, exceptional activity is defined as (i) an objective response rate (ORR) of 50% to a single agent (with relevant response durability and some complete responses) or (ii) a hazard ratio (HR) of 0.5 in an early randomized study (Table 1). Examples of drugs that showed exceptional activity in phase I or phase II s include ceritinib, ibrutinib, and palbociclib, which received BTD and subsequent accelerated in the United States, and crizotinib, which was granted accelerated in the pre-btd era. However, in spite of the exceptional activity leading to accelerated, full regulatory was contingent upon subsequent verification of clinical benefit in confirmatory phase III randomized controlled s (RCTs). Recently, there has been a growing interest in the systematic collection of real-world data to gain further insight into the impact of new drugs as they are introduced into clinical practice. This is exemplified by the new technology platforms CancerLinQ (by the American Society of Clinical Oncology) and Flatiron (by Flatiron Health, a health care information technology company). Furthermore, payers, physicians, and patients increasingly require more data on alternative comparators, specific subgroups, patient-reported outcomes, and long-term toxicities data that may be more appropriately collected in real-world studies than in separate confirmatory s. This reality raises a few questions: (i) When a drug demonstrates exceptional activity and receives accelerated/conditional and/or BTD, are confirmatory phase III RCTs an optimal way to provide additional evidence to patients, physicians, regulators, and payers? (ii) For drugs with exceptional activity, are phase III RCTs necessary to generate additional indications in the same tumor if a different combination partner or a different line of therapy is studied? Intelligent flexibility is required for the of novel targeted drugs. A proposal for Limited Approval of such drugs on the basis of limited initial clinical investigation was recently described in this very journal [3]. We recognize that our proposal described in this article is a substantial departure both from the current expectations of clinicians and from the requirements of regulators. Why change the current paradigm of confirmatory phase III RCTs? (i) Many patients prefer not to enroll in RCTs because of the requirement for additional testing and strict adherence to the protocol. (ii) Only 3% 7% of patients with cancer meet inclusion criteria [4]. Patients with co-morbidities are generally excluded from RCTs; thus populations are typically homogeneous and not representative of patients in the real world. Surveys of cancer RCTs show that participating patients are typically younger than 65 years (71%), female (84%), not African American (93%), and lack socioeconomic diversity [5 7]. Thus, extrapolation from RCTs to the real world is difficult and uncertainty remains about the risks/benefits of interventions in the most commonly treated populations. (iii) Many practices have limited financial and time resources to meet the stringent requirements of RCTs. (iv) Phase III RCT data are frequently supplemented with guidelines to help practitioners with treatment decisions. Guidelines are more comprehensive than just phase III RCT data, are based on different datasets that may not have been collected in a systematic or validated fashion, and are critical to determine treatment pathways and reimbursement. We propose that when novel oncology drugs meet certain criteria, specifically (i) demonstrate exceptional activity in phase I or phase II studies and (ii) have received accelerated/conditional and/or BTD, a prospectively designed pragmatic randomized clinical ( prct), pre-agreed with regulatory authorities, could provide sufficient evidence for verification of clinical benefit leading to full regulatory (Figure 1). Although prcts may be suitable for the assessment of any drug including those with limited activity, our proposal is that prcts be used instead of industry-sponsored pivotal s specifically for drugs with early signs of exceptional activity and a strongly favorable benefit:risk ratio. We also propose that a prct be The Author Published by Oxford University Press on behalf of the European Society for Medical Oncology. All rights reserved. For permissions, please journals.permissions@oup.com.

2 Volume 27 No. 7 July 2016 doi: /annonc/mdw Table 1. New chemical entity therapeutics, approved since January 2011, which demonstrated exceptional activity a in phase I or phase II and their phase III confirmatory results Therapeutic Indication Phase II results Phase III results BTD US in indication tested EU in ORR % (95% CI) b PFS HR (95% CI) OS HR (95% CI) indication tested ORR 50% in single-arm phase I or phase II TAGRISSO (osimertinib) 2L EGFRm NSCLC 57 (50 64) for study 1 Not yet available Yes Accelerated No (1L T790M+) 60 (54 68) for study 2 ODOMZO (sonidegib) Basal cell carcinoma 58 (45 70) c Not applicable No Full Normal ZYKADIA (ceritinib) 2L ALK+ NSCLC 54.6 (47 62) Not yet available Yes Accelerated Conditional IMBRUVICA (ibrutinib) 2L CLL 58.3 (43 72) 0.22 ( ) 0.43 ( ) Yes Accelerated; converted to full Normal IMBRUVICA (ibrutinib) MCL 65.8 (56 75) Not yet available Yes Accelerated Normal GILOTRIF (afatinib) 1L EGFRm ( ) No Full Normal TAFINLAR (dabrafenib) 1L BRAF+ melanoma 59 (48 70) 0.33 ( ) No Full Normal ICLUSIG (ponatinib) Resistant/intolerant CML MCyR: 54 (48 60) Not yet available Pre-BTD Accelerated Normal XALKORI (crizotinib) ALK+ NSCLC 50 (42 59) 0.45 ( ) for 1L Pre-BTD Accelerated; converted to full Conditional 61 (52 70) 0.49 ( ) for 2L ADCETRIS (brentuximab ALCL 86 (77 95) Not yet available Pre-BTD Accelerated Conditional vedotin) ADCETRIS (brentuximab vedotin) Hodgkin s lymphoma 73 (65 83) 0.57 ( ) Pre-BTD Accelerated; converted to full Conditional ZELBORAF (vemurafenib) BRAFm+ melanoma 52 (43 61) for 2L 0.26 ( ) for 1L 0.47 ( ) for 1L Pre-BTD Full Normal PFS HR 0.50 in randomized phase I or II IBRANCE (palbociclib) 1L ER+HER2 MBC PFS HR: 0.49 ( ) 0.42 ( ) Yes Accelerated No Therapeutics shown in bold have confirmatory phase III results verifying exceptional activity observed in phase 1/phase II. a Exceptional activity defined as: (1) ORR 50% observed in a single-arm for a therapeutic used as a single agent; (2) HR 0.50 in a randomized phase II study. b Phase II results are objective response rate (ORR) except where specified. c Data are shown from the 200 mg arm; however, the study was designed as a randomized of 200 mg ODOMZO versus 800 mg ODOMZO. 1L, first-line therapy; 2L, second-line therapy; ALCL, anaplastic large cell lymphoma; ALK, anaplastic lymphoma kinase; BTD, breakthrough therapy designation; CLL, chronic lymphocytic leukemia; CML, chronic myeloid leukemia; EGFR: epidermal growth factor receptor; ER, estrogen receptor; HER, human epidermal growth factor receptor; MCyR, major cytogenetic response; MCL, mantle cell lymphoma; MBC, metastatic breast cancer; NSCLC, non-small-cell lung cancer; OS, overall survival; PFS, progression-free survival.

3 A Phase I Phase II Accelerated Randomized controlled phase III Full B Phase I Phase II Accelerated accepted for subsequent full of a different line of therapy or different combination in the same disease if a phase III RCT leading to the original in that disease was stopped at interim analysis because of exceptional efficacy (Table 2). A historical example is bortezomib, which demonstrated overwhelming efficacy compared with standard therapy, resulting in early stopping of s at interim analysis. prcts would be prospective clinical studies in which patients are randomized to two or more interventions and then treated and followed up according to the investigators usual practice [8, 9]. The Salford Lung Study was the first prct of a prelicensed medication [10, 11]. Table 3 shows the contrasting features between RCTs and prcts. prct studies, agreed with regulatory agencies at the time of accelerated/conditional, would be large enough to address safety questions and provide evidence of clinical benefit/value in the real-world population. With larger patient numbers, pre-agreed safety reporting, and enhanced reporting of post safety events (compared with spontaneous reporting), prcts would provide a reasonable ability to detect rare adverse events that are unlikely to be captured in typical phase III RCTs. Safety data could be collected via electronic health records and follow-up calls. Formal study visits Strict adherence to study protocol; patients assessed during -prescribed visits Homogeneous patient population Does not provide real-world data Pragmatic randomized clinical in real-world setting Full Flexible adherence to study protocol; patients assessed during routine care Heterogeneous patient population Provides real-world data Figure 1. (A) Current paradigm for regulatory of drugs with exceptional efficacy in phase I/phase II; (B) Proposal for regulatory of drugs with exceptional efficacy in phase I/phase II. would only be required at baseline (consent and randomization) and at study end, with interim study visits as per standard practice and phone follow-up as needed. The financial and economic implications of prcts as used for regulatory purposes will have to be assessed on a case-by-case basis. How would prcts address the limitations of phase III RCTs? (i) Even though patients will be randomized in a prct, strict adherence to a protocol including -prescribed visits to the clinic would not be necessary. These flexibilities would allow the assessment of the treatment during patients routine care. (ii) prcts would be representative of real-world patients, regardless of comorbidities, age, race, or income level, and so allow the assessment of effectiveness in largely unselected populations. (iii) prcts would provide real-world data necessary for full regulatory and would also address questions of the new drug s value for reimbursement purposes. Data from electronic health records would provide long-term outcomes including health economics and would be free from interviewer or recall bias; such data could be supplemented by limited additional data gathering Koehler et al. Volume 27 No. 7 July 2016

4 Volume 27 No. 7 July 2016 doi: /annonc/mdw Table 2. Registrational Phase III studies, since January 2011, which were stopped at interim analysis because of exceptional efficacy Therapeutic Indication Phase I or phase II results Phase III results at interim analysis BTD US in ORR % (95% CI) a PFS HR (95% CI) OS HR (95% CI) indication tested OPDIVO (nivolumab) 2L RCC ( ) Yes Full Not yet IBRANCE (palbociclib) + FASLODEX (fulvestrant) 2L Hormone receptorpositive, ( ) Yes Not yet No HER2 MBC OPDIVO (nivolumab) 2L Non-squamous ( ) Yes Full Not yet NSCLC IMBRUVICA (ibrutinib) + TREANDA Refractory CLL ( ) No Not yet Not yet (bendamustine) + RITUXAN (rituximab) KEYTRUDA (pembrolizumab) 1L Melanoma 34 (28 40) 0.58 ( ) 0.69 ( ) Yes Not yet Normal GAZYVA (obinutuzumab) Refractory NHL ( ) No Not yet Not yet OPDIVO (nivolumab) 2L Squamous NSCLC 17.1 ( ) 0.59 ( ) Yes Full Normal TAFINLAR (dabrafenib) + MEKINIST (trametinib) BRAFm+ melanoma 76 (62 86) 0.56 ( ) 0.69 ( ) No Full Normal IMBRUVICA (ibrutinib) 2L CLL 58.3 (43 72) 0.22 ( ) 0.43 ( ) Yes Full Normal XTANDI (enzalutamide) 1L Prostate cancer ( ) No Full Normal XTANDI (enzalutamide) 2L Prostate cancer ( ) Pre-BTD Full Normal ZYDELIG (idelalisib) + RITUXAN (rituximab) Relapsed CLL ( ) Yes Not yet Normal STIVARGA (regorafenib) 2L Colorectal cancer DCR: ( ) Pre-BTD Full Normal ZYTIGA (abiraterone) 1L Prostate cancer ( ) 0.75 ( ) Pre-BTD Full Normal AFINITOR (everolimus) 2L ER+, HER2 MBC 0.43 ( ) Pre-BTD Full Normal EU in indication tested a Phase II results are ORR% except where specified. 1L, first-line therapy; 2L, second-line therapy; BTD, breakthrough therapy designation; CLL, chronic lymphocytic leukemia; DCR, disease control rate; ER, estrogen receptor; HR, hazard ratio; HER, human epidermal growth factor receptor; MBC, metastatic breast cancer; NHL, non-hodgkin lymphoma; NSCLC, non-small-cell lung cancer; ORR, objective response rate; OS, overall survival; PFS, progression-free survival; RCC, renal cell carcinoma.

5 Table 3. Comparison of conventional RCT versus prct Randomized controlled Pragmatic randomized clinical General/strategic Purpose of study Hypothesis testing in well-defined study population; Regulatory Health Technology Assessment/policy decision making; Quality assurance; Reimbursement support; Comparative assessment research Proposed: Regulatory Target stakeholders Regulatory authorities Payers, physicians, patients, guideline committees Proposed: Regulatory authorities Primary objective Impact on clinical practice Efficacy and safety (versus specific comparator) in well-defined study population, aim to equalize non-specific effects Provides initial and subsequent guidance in selected indication; frequently high impact on change in practice Methodological considerations Outcome measures, Objective efficacy parameters/surrogates (ORR, end points PFS, OS); Safety according to NCI CTCAE criteria Effectiveness (benefit/risk) in real-world setting versus standard practice; Determine relative value of a novel treatment in a generalizable population, aim to optimize non-specific effects. Proposed: Efficacy and safety in confirmatory settings High impact on physicians and patients due to a priori real-world study setting Practical impact of therapy on daily life, cost-effectiveness Proposed: Objective efficacy parameters/surrogates (ORR, PFS, OS); Further patient-relevant outcomes (e.g. time-to-subsequent-therapy); Co-primary end points of PRO and efficacy; Safety according to NCI CTCAE criteria Not practical in real-world setting; focus is on external validity Blinding and placebocontrol Desirable; focus is on internal validity Randomization Individual patients are randomized Cluster/Center Level randomization preferred to allow for real-world practice within study centers; Individual patient s randomization possible Patients Homogeneous; careful selection of patients to ensure well-defined study population Heterogeneous; broad inclusion criteria including comorbidities; Physicians judgment as in real-world situations Physicians/Study centers participating Limited number of specialized/well-trained study centers, often organized in study networks Larger number of less specialized study centers, patient referral as in daily routine Proposed: Same centers as for RCT as well as above (training in GCP necessary) Sample size Depends on hypothesis and end point Large sample size to account for heterogeneous population, less precise timing of follow-up, and individual or cluster randomization. Proposed: Size of the study agreed with respect to expected effect on primary end point; Primary end point may be hybrid of efficacy and patient-related outcomes Follow-up Short with clearly defined assessment intervals Study setting may offer more flexible and longer follow-up Adherence Practical considerations Data acquisition Validity and relevance to practice Drug utilization Sponsor involvement in conduct Non-adherence can be a challenge in study conduct and a serious confounder Complex data acquisition, heavy follow-up, queries High internal validity, lower external validity, frequently low relevance/impact on practice. Dosing precisely defined by protocol criteria and adherence rules High, with standardized monitoring and study conduct in each phase of Flexible treatment/diagnostic schedules lower adherence burden; Nonadherence and their causes may be part of the outcomes measured; Measurement of adherence may be part of a High external validity, lower internal; High relevance/impact on practice. Realistic assessment of drug utilization and use of health care resources (costs) Low, sponsor mainly responsible for enabling real-world study setting; Commercial drug supply Proposed: sponsor provides funding for data collection and conduct; Sponsor and regulatory authorities agree a priori any specific safety monitoring criteria beyond GCP, possible added efficacy mandatory monitoring in selected studies Continued 1346 Koehler et al. Volume 27 No. 7 July 2016

6 Table 3. Continued Randomized controlled Pragmatic randomized clinical Costs To be evaluated case by case: Costs are driven by sample size, interventions, diagnostic and follow-up measures, recruitment dynamic, training effort of study centers etc. prct may have higher sample size, longer follow-up, higher recruitment rate, fewer number of specific procedures, most costs covered by routine medical care. prct potentially more efficient in answering reimbursement-relevant questions, i.e. better return-on-investment than (additional) conventional RCT CTCAE, common terminology criteria for adverse events; GCP, good clinical practice; NCI, National Cancer Institute; ORR, objective response rate; OS, overall survival; PFS, progression-free survival; RCT, randomized controlled ; prct, pragmatic randomized clinical s; PRO, patient-reported outcome. Despite their benefits, prcts are not without limitations: (i) specific training of healthcare professionals would be required before recruitment; (ii) end points may be limited by routine clinical care and must be carefully selected for expected precision; (iii) bias is possible because most prcts would be open-label; (iv) independent review, data monitoring, and statistical analysis may be challenging; and (v) treatment switching/sequencing may dilute efficacy end points. The key objectives of prcts would remain enrollment of a sufficiently large population to support the conversion of initial to full regulatory, collection of data with minimal disruption to patient care, and appropriate safety monitoring to meet ethical and regulatory requirements. The sponsor would be expected to consult experts, the FDA/EMA/ Japan PMDA, patient advocacy groups, and payers to select end points and other design features. An important hurdle remains the end point of the prct. Overall survival (OS) would be the simplest measurable outcome, especially in later-stage disease when subsequent therapies would unlikely affect OS. Duration of subsequent progression-free survival [12] or time-to-subsequent treatment could also be end points that could be measured with sufficient precision. Regulatory agencies, payers, and biopharmaceutical companies could work in partnership to prospectively agree to the degree of preliminary efficacy and safety as well as to the type and size of an acceptable prct. If prcts were an alternative to Phase 3 RCTs for drugs with exceptional activity, let us look at an example of how prcts could provide sufficient confirmatory evidence for full or subsequent in the same tumor type. Bortezomib represents a pre-btd era compound that revolutionized the treatment of multiple myeloma (MM). The initial open-label non-randomized phase II (n = 202) in relapsed/refractory MM showed an ORR of 35% with a median duration of 12 months and a median OS of 16 months [13]. At the time of the initial in the United States, two s were ongoing: a phase III study (n = 669) comparing monotherapy bortezomib with dexamethasone in recurrent disease [14] and another (n = 682) comparing bortezomib plus melphalan and prednisone versus melphalan and prednisone in previously untreated patients with MM [15]. Both studies were stopped at the time of pre-specified interim analyses due to exceptional efficacy and led to rapid full for the first-line and refractory conditions. However, data from these studies did not answer the value question in the real-world setting. In retrospect, a prct to support the first-line MM indication could have provided important data on a novel therapeutic in a real-world setting. The example of bortezomib suggests that a meaningful result in one randomized setting (bortezomib versus dexamethasone), in the context of impressive single-agent activity with compelling biological rationale, is likely to be repeated in a different setting (i.e. first-line therapy) and could be tested in a prct. In conclusion, we propose that for oncology drugs that demonstrate exceptional activity in phase I or phase II s and receive accelerated/conditional and/or BTD, and for certain expanded indications, regulatory authorities should consider accepting data from prospectively agreed prcts to grant full regulatory. These real-world prct s would focus more on physicians and patients experience and outcomes, a dataset that is difficult and impractical to obtain in burdensome RCTs. The exceptional activity would be defined as an ORR of 50% for a single agent or an HR of 0.5 in a randomized phase II study. We believe that prcts would offer sufficient precision to assess the efficacy and safety of new treatments and required evidence in situations where the preliminary data are adequately robust, the biological evidence and mechanism of action are strong, and the observed early benefit is convincing. Such an approach for drugs with exceptional efficacy could reshape the future of clinical s, meet the demands for confirmatory studies, accelerate the availability of therapy to patients, and satisfy the demand by patients, physicians, and payers for value-based medical evidence. M. Koehler 1*, E. T. Donnelly 2, D. Kalanovic 3, R. Dagher 4 & M. L. Rothenberg 1 1 Pfizer Oncology, New York; 2 Pfizer Oncology, Cambridge, USA; 3 Pfizer Oncology, Regional Medical Affairs, Berlin, Germany; 4 Pfizer, Worldwide Safety and Regulatory, Groton, USA (* maria.koehler@pfizer.com) acknowledgments The authors thank Robert Glassman (Credit Suisse) for contribution to an early version of the manuscript, Prakash Naik Volume 27 No. 7 July 2016 doi: /annonc/mdw

7 (Pfizer) and Mary Skousen (Pfizer) for their help in analyzing prior s and registrational studies supporting the proposal, and Sashi Nadanaciva (Pfizer) for writing support. funding There is no grant or funding related to this work. disclosure MK, ETD, DK, RD, and MLR are employees of and own stock of Pfizer. references 1. Sherman RE, Li J, Shapley S et al. Expediting drug development the FDA s new breakthrough therapy designation. N Engl J Med 2013; 369: Reflection paper on a proposal to enhance early dialogue to facilitate accelerated assessment of priority medicines (PRIME). Eur Med Agency ema.europa.eu/ema (12 April 2016, date last accessed). 3. Dhingra K. Oncology 2020: a drug development and paradigm. Ann Oncol 2015; 26: Transforming Clinical Research in the United States: Challenges and Opportunities: Workshop Summary. Institute of Medicine (US) Forum on Drug Discovery, Development, and Translation. Washington, DC: National Academies Press, Murthy VH, Krumholz HM, Gross CP. Participation in cancer clinical s: race-, sex-, and age-based disparities. JAMA 2004; 291: Javid SH, Unger JM, Gralow JR et al. A prospective analysis of the influence of older age on physician and patient decision-making when considering enrollment in breast cancer clinical s (SWOG S0316). Oncologist 2012; 17: Unger JM, Gralow JR, Albain KS et al. Patient Income Level and Cancer Clinical Trial Participation: a prospective survey study. JAMA Oncol 2016; 2: Methodology Committee of the Patient-Centered Outcomes Research Institute (PCORI). Methodological standards and patient-centeredness in comparative effectiveness research: the PCORI perspective. JAMA 2012; 307: Jones PB, Barnes TR, Davies L et al. Randomized controlled of the effect on quality of life of second- vs first-generation antipsychotic drugs in schizophrenia: Cost Utility of the Latest Antipsychotic Drugs in Schizophrenia Study (CUtLASS 1). Arch Gen Psychiatry 2006; 63: Bakerly ND, Woodcock A, New JP et al. The Salford Lung Study protocol: a pragmatic, randomised phase III real-world effectiveness in chronic obstructive pulmonary disease. Respir Res 2015; 16: Woodcock A, Bakerly ND, New JP et al. The Salford Lung Study protocol: a pragmatic, randomised phase III real-world effectiveness in asthma. BMC Pulm Med 2015; 15: Engelsberg A. Cross-over-it s a feature, not a bug. Ann Oncol 2015; 26: Richardson PG, Barlogie B, Berenson J et al. A phase 2 study of bortezomib in relapsed, refractory myeloma. N Engl J Med 2003; 348: Richardson PG, Sonneveld P, Schuster MW et al. Bortezomib or high-dose dexamethasone for relapsed multiple myeloma. N Engl J Med 2005; 352: San Miguel JF, Schlag R, Khuageva NK et al. Bortezomib plus melphalan and prednisone for initial treatment of multiple myeloma. N Engl J Med 2008; 359: Koehler et al. Volume 27 No. 7 July 2016