A nested group sequential framework for regional evaluation in global drug development program

Multiregional clinical trials (MRCTs) present great opportunities but also challenges to the trial community. To address the challenges and fully realize the opportunities, a PhRMA MRCT Cross-Functional Key Issue Team (KIT) was formed in 2008. One of the work streams within the KIT particularly focuses on the assessment of consistency of treatment effects across regions. As the main objective of this work stream, this research explores a number of definitions for consistency assessments. We address the issues primarily for superiority trials with continuous endpoints, then extend briefly to noninferiority trials, random effect models, binary endpoints, and survival endpoints. Computations and simulations are used to study the properties of the proposed definitions, particularly the power for showing consistency. To illustrate applications of the methods, we use a trial example with a continuous endpoint. We discuss considerations for trial design as well as for data analysis. The consistency assessment relies heavily on the definition of regions and the number of regions. We recommend working with health authorities to define region in a manner that is sensible from a practical interpretation standpoint and also makes region consistency assessment a feasible undertaking.

Proposal for the revision of guidelines for clinical trials of vaccines to prevent infectious diseases in Japan

In order to encourage innovative medicine to address Chinese unmet medical needs, China has changed its drug regulatory landscape to speed up access to new medicines. In order to understand the fast‐changing landscape and to enable planning of more global drug development programs and study designs in China, we reviewed 15 published clinical pharmacology‐related guidances by the National Medical Products Administration (NMPA), and compared them with reference guidances from the US Food and Drug Administration (FDA), the European Medicines Agency (EMA), or the International Conference on Harmonization (ICH), to understand the similarities and differences, especially any China‐specific requirements, such as ethnic sensitivity analysis. Overall, by reviewing these clinical pharmacology‐related NMPA guidances, it is clear that NMPA guidances are very similar to FDA, EMA, and ICH guidances. There are no relevant differences in the major principles, but some differences in structure, contents, and focus were noted. The NMPA is adapting flexibility statements into newly published guidances. Ethnic sensitivity analysis needs to be implemented early in drug development plans. The NMPA encourages sponsors to conduct early clinical trials in China or include China early in multiregional clinical trials, and to obtain safety, efficacy, and pharmacokinetic data for ethnic sensitivity analysis. Depending on the stage of development, ethnic sensitivity analysis can be conducted using in vitro or literature data, other Asian clinical data, or Chinese clinical data.

Regulatory agencies in different parts of the world may have different requirements for end-points, which significantly affects the design and conduct of registrational multiregional clinical trials (MRCT). In particular, different health authorities may request or require different endpoints as primary or key secondary hypotheses in phase 3 MRCTs. In addition, differences between regions may involve the time point considered primary, patient populations analyzed, study design, or noninferiority margins.No guidance exists on how pharmaceutical companies should handle such regional differences, and harmonized guidance across regions would be useful. Initial steps in any global program should involve attempts to reach consistency in an MRCT. We review scenarios involving different health authority requirements for endpoints and other study design features and recommend approaches to handling differing health authority requirements within a global program, when a consistent global approach is not acceptable ...

To accelerate the drug development process and shorten approval time, the design of multiregional clinical trials (MRCTs) incorporates subjects from many countries/regions around the world under the same protocol. After showing the overall efficacy of a drug in all global regions, one can also simultaneously evaluate the possibility of applying the overall trial results to all regions and subsequently support drug registration in each of them. In this paper, we focus on a specific region and establish a statistical criterion to assess the consistency between the specific region and overall results in an MRCT. More specifically, we treat each region in an MRCT as an independent clinical trial, and each perhaps has different treatment effect. We then construct the empirical prior information for the treatment effect for the specific region on the basis of all of the observed data from other regions. We will conclude similarity between the specific region and all regions if the posterior probability of deriving a positive treatment effect in the specific region is large, say 80%. Numerical examples illustrate applications of the proposed approach in different scenarios.

The landscape of drug development evolves with the globalization of the health industry as an integral part of the economy as well as public health worldwide. It is recognized that there are major advantages of being involved in conducting Multi-Regional Clinical Trials (MRCTs) as a part of it: Increasing drug development efficiency, promoting local or regional clinical research, providing local regulatory authorities a large body of data including their own patients studied under the same standard to evaluate the medical product, benefiting citizen patients to access new drugs around the same times as other nations. For these reasons, participating in various MRCTs globally is a rising trend for China as an emergent country in its biopharmaceutical industry and medical-health policy. China has joined the ICH as a member country in 2017. ICH E-17 contains general principles of MRCTs but lacks specifics. In this article, we highlight pertinent design and analysis issues with MRCTs and discuss current common approaches from the statistical aspects.

Drug development has been globalized, and multi-regional clinical trial (MRCT) for regulatory submission has widely been conducted by many discovery based global pharmaceutical companies with the objective of reducing the time lag of launch in key markets and improve patient access to new and innovative treatments. Sponsors are facing several challenges while conducting multiregional clinical trials. Challenges under the heads statistics, clinical, regulatory operational, and ethics have been discussed. Regulators in different countries such as USA, EU-Japan, and China have issued guidance documents in respect of MRCT's. Lack of harmonization in the design and planning of MRCT is perceived to create a difficult situation to sponsors adversely affecting progressing MRCT in more and more discoveries. International conference on hormonisation (ICH) has initiated the process for having a harmonized guidance document on MRCT. This document is likely to be issued in early 2017.

Delays in the introduction to the Japanese market of drug-eluting stents (DES) developed overseas (i.e., "device lag") decreased sharply between 2004 and 2012. The reduction accompanied a shift in clinical development from a succession pattern (initial product development and approval overseas followed by eventual entrance into the Japanese market) to parallel development (employing multiregional clinical trials (MRCTs)). Although resource-intensive in the short-term, MRCTs are proving to be an effective tool in simultaneous global product development. Creative study designs and the absence of significant ethnic differences in Japanese subjects regarding DES safety and efficacy and the pharmacokinetic behavior of their coating drugs propel this process. More general factors such as medical need and industry incentivization also encourage this shift. Physicians' preference for DES over other percutaneous coronary interventions, the expanding global DES market, and streamlined development and approval prospects each motivate industry to continue investing in DES product development. The efforts of various stakeholders were also integral to overcoming practical obstacles, and contributions by 'Harmonization by Doing' and a premarket collaboration initiative between the USA and Japan were particularly effective. Today, USA/Japan regulatory cooperation is routine, and Japan is now integrated into global medical device development. MRCTs including Japanese subjects, sites, and investigators are now commonplace.

Globalized drug development studies, such as multiregional clinical trials (MRCTs), have attracted much attention due to their ability to expedite drug development and shorten the time lag of drug release. While observing the overall effect of a new drug, the region-specific effects to support drug registration in constituent regions can also be evaluated. Several challenges arise in conducting MRCTs, such as the heterogeneity in the variability of the primary endpoint across regions. However, most of the existing statistical methods assume a common variability, which may not be valid in practice due to differences across regions (eg, diversities in ethnicity or disparities in medical culture/practice). We present a statistical method for the design and evaluation of MRCTs to consider the heterogeneous variability across regions. We assessed the overall sample size requirement and addressed the region-specific sample size determination to establish the consistency of treatment effects between the specific region and the entire group. We demonstrate the proposed approach with numerical examples.

ABSTRACTIn recent years, multi-regional clinical trials (MRCT) that conduct clinical trials simultaneously in Asian Pacific region, Europe, and the United States have become very popular for global pharmaceutical development. The main purpose of multi-regional clinical trials is to shorten the time for pharmaceutical development and regulatory submission, and approval around the world. In practice, however, clinical results observed from some regions (sub-population) may not be consistent with the results from other regions and/or all regions combined (entire population). The inconsistency observed may be due to ethnic differences in different regions, differences in medical practice, time points of assessment, or by random chance due to small sample size for the region. Some regional regulatory agencies require consistency evaluation between local country results and overall results. However, the challenge is there is no detailed guidance on the definition of ‘consistency’ and methodology to evaluate it. Therefore, the questions are: how to evaluate consistency and what statistical methods are appropriate to be used for consistency evaluation? In this article, several statistical tests for consistency (similarity) between clinical results observed from a specific sub-population and the entire population are proposed. These methods are compared through extensive simulation. As most published articles discussed consistency evaluation for superiority situations, we have discussed consistency evaluation for non-inferiority situation in this article through a simulated example concerning consistency in some countries. Recommendations of the statistical methods to be used for consistency evaluation are given. Other aspects that should be considered for consistency evaluation are also provided.

The multi-regional clinical trials (MRCTs) being administered in different regions of the world now play a major role in providing evidence for the efficacy and safety of new drugs amidst the simultaneous global development and worldwide registration of such drugs, in support of the expeditious availability of medical products to patients. However, such trials present considerable challenges as far as quality, design, implementation, analysis, and interpretation are concerned. In this article, we share our observations and lessons learned from the design, implementation, analysis, and interpretation of some MRCTs with case examples. Current Japanese regulatory guidance on MRCTs is introduced along with some suggestions for design, implementation, and interpretation.

Recently, a design was proposed for the Simultaneous Global Drug Development Program (SGDDP) to assess the impact of ethnic factors on the effect of a new treatment for a targeted ethnic (TE) population. It used weighted Z tests to combine the information collected from the TE and non-TE (NTE) subgroups in the SGDDP based on the fundamental assumption on their shared biological commonality. In this article, we mathematically formulated this assumption as the quantitative interaction between treatment effect and subgroup. We used it to more rigorously describe the hypotheses, and showed the unbiasedness of the weighted Z test. Moreover, to study the loss of efficiency from down weighting the NTE information in this SGDDP design, we compared the power of their test with that of the uniformly most powerful (UMP) test, which we showed was also a weighted Z test. We discussed that the choice of weight should balance the maximization of power when the assumption holds and the minimization of bias otherwise.

Venoarterial extracorporeal membrane oxygenation versus off-pump lung transplantation: Interim analysis of a prospective, randomized clinical trial.

End points and outcomes in follicular lymphoma: what should we measure, how, and why?

In this issue of the Journal of Clinical Oncology, Buyse et al evaluate progression-free survival (PFS) as a surrogate end point for overall survival (OS) in advanced colorectal cancer (CRC). They employ a general methodology for validating surrogate end points across multiple trials, as proposed by Buyse et al in 2000. They considered trials where leucovorin-modulated fluorouracil (FU) was compared with either FU without leucovorin or with raltitrexed. In these trials, they were able to show modest correlation between the proportion alive and progression free at 6 months and the proportion alive at 12 months, as well as good correlation when data across all time were considered. More importantly, they showed that the effect of treatment on each of these end points was highly correlated both when data across all time were considered and when the PFS and OS data were censored at 6 and 12 months, respectively. This latter step is an important advance over previous attempts to establish surrogacy. The model relating treatment effects between the PFS and OS end points was validated on a set of three contemporary trials in which leucovorin-modulated FU was compared with regimens that added irinotecan or oxaliplatin. The model was used to predict the treatment effect on OS given the observed treatment effect on PFS. The observed treatment effect on OS for the validation trials fell within the prediction limits for all three trials. The authors conclude that PFS is an acceptable surrogate for OS in advanced CRC and provide a surrogate threshold effect (STE), which is the treatment effect size for PFS which, if exceeded, would rule out equivalence with 95% confidence for the OS end point based on the model’s prediction limits. PFS has now been validated as a surrogate end point for OS in advanced CRC, but OS is not a perfect end point for this disease. In advanced CRC, the goal of therapy in order of desirability of outcome is to eliminate cancer, reduce cancer burden, stabilize cancer, or slow cancer progression. Prolongation of life is secondary to the goal of therapy. As more and better options for secondand third-line therapies in advanced CRC become available, the relevance of OS as the primary end point is increasingly coming into question. Let’s take a moment to compare and contrast the virtues of PFS and OS as potential primary end points for first-line treatment of metastatic CRC. OS is usually defined as time to death from any cause and may be considered a composite end point based on the cause of death where the event is the first of death related to the same cancer, death related to another cancer, death related to treatment, or death resulting from other causes. PFS is a composite end point where the event is the first of progression resulting from increasing size of tumor, progression resulting from formation of a new tumor, death related to the same cancer, death related to another cancer, death related to treatment, or death resulting from other causes. The component events are listed in Table 1 for the PFS and OS end points along with their relationship to the disease process under study or the therapies being studied. Events related to the disease process under study or to treatment toxicity provide important information for comparing potential therapies. Events that are unrelated to the disease process under study or to treatment toxicity are essentially background noise and provide little useful information for comparing potential therapies. We don’t want to ignore these likely irrelevant events, because sometimes treatments have unintended consequences. The underlying rates of these so-called background events should be equivalent on the treatment arms, because they are by definition unrelated to the disease process or treatments. Some desirable attributes for a primary end point in advanced CRC are listed in Table 2. Event status determination is extremely reliable in OS. The difficulties associated with determining