Adaptive designs were primarily used but inadequately reported in early phase drug trials.

BACKGROUND: Faced with the high cost and limited efficiency of classical randomized controlled trials, researchers are increasingly applying adaptive designs to speed up the development of new drugs. However, the application of adaptive design to drug randomized controlled trials (RCTs) and whether the reporting is adequate are unclear. Thus, this study aimed to summarize the epidemiological characteristics of the relevant trials and assess their reporting quality by the Adaptive designs CONSORT Extension (ACE) checklist. METHODS: We searched MEDLINE, EMBASE, Cochrane Central Register of Controlled Trials (CENTRAL) and ClinicalTrials.gov from inception to January 2020. We included drug RCTs that explicitly claimed to be adaptive trials or used any type of adaptative design. We extracted the epidemiological characteristics of included studies to summarize their adaptive design application. We assessed the reporting quality of the trials by Adaptive designs CONSORT Extension (ACE) checklist. Univariable and multivariable linear regression models were used to the association of four prespecified factors with the quality of reporting. RESULTS: Our survey included 108 adaptive trials. We found that adaptive design has been increasingly applied over the years, and was commonly used in phase II trials (n = 45, 41.7%). The primary reasons for using adaptive design were to speed the trial and facilitate decision-making (n = 24, 22.2%), maximize the benefit of participants (n = 21, 19.4%), and reduce the total sample size (n = 15, 13.9%). Group sequential design (n = 63, 58.3%) was the most frequently applied method, followed by adaptive randomization design (n = 26, 24.1%), and adaptive dose-finding design (n = 24, 22.2%). The proportion of adherence to the ACE checklist of 26 topics ranged from 7.4 to 99.1%, with eight topics being adequately reported (i.e., level of adherence ≥ 80%), and eight others being poorly reported (i.e., level of adherence ≤ 30%). In addition, among the seven items specific for adaptive trials, three were poorly reported: accessibility to statistical analysis plan (n = 8, 7.4%), measures for confidentiality (n = 14, 13.0%), and assessments of similarity between interim stages (n = 25, 23.1%). The mean score of the ACE checklist was 13.9 (standard deviation [SD], 3.5) out of 26. According to our multivariable regression analysis, later published trials (estimated ß = 0.14, p < 0.01) and the multicenter trials (estimated ß = 2.22, p < 0.01) were associated with better reporting. CONCLUSION: Adaptive design has shown an increasing use over the years, and was primarily applied to early phase drug trials. However, the reporting quality of adaptive trials is suboptimal, and substantial efforts are needed to improve the reporting.

The quality of clinical trials in neuroendocrine tumours; have we learnt from our mistakes? An evaluation of phase II and phase III clinical trials.

The quality and reporting of neuroendocrine tumour (NET) clinical trials has previously been found to be heterogeneous impairing trial interpretability. We aimed to perform an updated review of the quality of phase II/III clinical trials in NET to assess if trial design and reporting have improved since 2011. We performed a PubMed search for phase II/III trials evaluating systemic anticancer therapies or liver-directed therapies published between 2011 and 2018. Data collected comprised administrative data, study population characteristics, endpoints, reporting and statistical design parameters, and results. Sixty studies were included (5218 patients): 50 phase II and 10 phase III trials. Study populations were heterogeneous: 52% of trials allowed tumours from various primary sites, 28% allowed both well- and poorly-differentiated tumour morphology or did not specify, and 57% did not report proliferative indices and/or tumour grade in ≥80% of the study population. Only 36% of trials mandated radiological disease progression on participant enrolment using a validated measure. Statistical design and primary endpoint were clearly defined in 67% and 88% of trials, respectively. Toxicity (88%), radiological response rate (85%) and progression-free survival/time to progression (82%) were well reported in a majority of trials, but health-related quality of life was included in the minority. Of the randomised trials (n = 11), study populations were more homogeneous and study design was more often clearly defined; however, only 45% mandated radiological progression at baseline as measured per Response Evaluation Criteria In Solid Tumours, and reporting of health-related quality of life (55%) remained suboptimal. The design and reporting of NET clinical trials, predominantly of single-arm phase II trials, remains suboptimal and has not considerably improved over time despite the growth in our knowledge of the biology and unique characteristics of NETs. Higher quality is seen in randomised trials, although certain design and reporting elements remain inadequate in some studies. We must prioritise the design and conduct of NET clinical trials to effectively inform future research and guide practice change.

A Study of Regulatory Challenges of Pediatric Oncology Phase I/II Trial Submissions and Guidance on Protocol Development.

The purpose of this study was to identify key deficiencies in pediatric oncology early phase clinical trial protocols in Germany and to provide guidance for efficient trial protocol development. A systematic review of the response letters of German competent authorities (CAs) and Ethics Committees to phase I/II pediatric oncology trial submissions in the period from 2014 to 2019 was performed. Documents were requested from all five Society for Paediatric Oncology and Haematology in Germany (GPOH) phase I/II trial networks plus all nine German Innovative Therapies for Children with Consortium Cancer (ITCC) centers. A blinded dataset containing aggregated data from 33 studies was analyzed for validation. All deficiencies were reviewed, listed, and weighted using a structured matrix according to frequency, category, significance, and feasibility. In total, documents of 17 trials from 6 different sites were collected. Two hundred fifty deficiencies identified by the CAs were identified and categorized into eight categories. "Toxicity and safety" was the most prominent category (27.6%), followed by "Manufacturing and Import" (18%). The majority of deficiencies were categorized as minor and potential measures as easy to address, but an important group of major and difficult to implement deficiencies was also identified. The blinded validation dataset confirmed these findings. The majority of the EC deficiencies could be resolved by changing the wording in the patient-facing documents. In conclusion, this study was able to detect a pattern of key deficiencies. Most of the shortcomings can be anticipated by minor changes in the protocol and increased awareness can prevent time-consuming revisions, withdrawals, or even rejections. A corresponding guideline describing key regulatory aspects is provided.

Fragility index of trials supporting approval of anti-cancer drugs in common solid tumours.

BACKGROUND: The Fragility Indexquantifies the reliability of positive trials by estimating the number of events, which would change statistically significant results to non-significant results. METHODS: We identified randomized trials supporting drug approvals by the US FDA between 2009 and 2019 in lung, breast, prostate, and colon cancers and in melanoma. We reconstructed survival tablesand calculated the number of events, which would result in a non-significant result for the primary endpoint. The FI was then compared to the number of patients in each trial who withdrew consent or were lost to follow-up. Regression analyses were used to explore associations between RCT characteristics and FI and trials in which FI was lower or equal to number of participants who withdrew consent or were lost to follow-up. RESULTS: Among 81 RCTs, the median FI was 28. The median number of patients who withdrew consent or were lost to follow up was 27. FI was equal or lower than the number of patients who withdrew consent or were lost to follow-up in 47 trials (58%). There was a modest increase in FI over time (p = 0.02). Trials with overall survival as the primary endpoint (p = 0.006) and those in the palliative setting (p < 0.001) had lower FI. There was no association with trial sample size or duration of follow-up. FINDINGS: Statistical significance of RCTs in common solid tumours can be reversed often with a small number of additional events. Post-approval RCTs or real-world data analyses should be performed to ensure results of registration trials are robust.

Systematic review of phase-I/II trials enrolling refractory and recurrent Ewing sarcoma: Actual knowledge and future directions to optimize the research.

BACKGROUND: Optimal Phase-II design to evaluate new therapies in refractory/relapsed Ewing sarcomas (ES) remains imperfectly defined. OBJECTIVES: Recurrent/refractory ES phase-I/II trials analysis to improve trials design. METHODS: Comprehensive review of therapeutic trials registered on five databases (who.int/trialsearch, clinicaltrials.gov, clinicaltrialsregister.eu, e-cancer.fr, and umin.ac.jp) and/or published in PubMed/ASCO/ESMO websites, between 2005 and 2018, using the criterion: (Ewing sarcoma OR bone sarcoma OR sarcoma) AND (Phase-I or Phase-II). RESULTS: The 146 trials identified (77 phase-I/II, 67 phase-II, and 2 phase-II/III) tested targeted (34%), chemo- (23%), immune therapies (19%), or combined therapies (24%). Twenty-three trials were ES specific and 48 had a specific ES stratum. Usually multicentric (88%), few trials were international (30%). Inclusion criteria cover the recurrent ES age range for only 12% of trials and allowed only accrual of measurable diseases (RECIST criteria). Single-arm design was the most frequent (88%) testing mainly single drugs (61%), only 5% were randomized. Primary efficacy outcome was response rate (RR=CR+PR; Complete+Partial response) (n = 116/146; 79%), rarely progression-free or overall survival (16% PFS and 3% OS). H0 and H1 hypotheses were variable (3%-25% and 20%-50%, respectively). The 62 published trials enrolled 827 ES patients. RR was poor (10%; 15 CR=1.7%, 68 PR=8.3%). Stable disease was the best response for 186 patients (25%). Median PFS/OS was of 1.9 (range 1.3-14.7) and 7.6 months (5-30), respectively. Eleven (18%) published trials were considered positive, with median RR/PFS/OS of 15% (7%-30%), 4.5 (1.3-10), and 16.6 months (6.9-30), respectively. CONCLUSION: This review supports the need to develop the international randomized phase-II trials across all age ranges with PFS as primary endpoint.

Landscape of phase 1 clinical trials for minors with cancer in the United States.

OBJECTIVES: Understanding trends in characteristics of early phase trials that allow minors with cancer to participate may inform additional efforts to improve cancer drug development for young people. METHODS: We accessed data for oncology phase 1 or phase 1/2 trials in the United States from ClinicalTrials.gov with lower age bound for eligibility <18 years. Descriptive statistics were calculated and trends over time evaluated using logistic and multinomial logistic regression. RESULTS: Six hundred twelve trials met inclusion criteria. Sixty-five percent of trials were for older adults that also allowed minors, while 9% were exclusively for patients ≤18 years of age. Eighty-three percent of trials included at least one novel agent, while 17% studied only conventional therapies. Fifty-eight percent of trials studied treatments not yet Food and Drug Administration (FDA) approved (48% if exclusively for patients ≤18 years). Fifteen percent of trials for which dose-escalation method could be determined, utilized a model-based design. Eighteen percent of all trials were industry sponsored (48% if exclusively for patients ≤18 years). Forty-nine percent of all trials were multicenter (69% if exclusively for patients ≤18 years). There was an increase in trials exclusively focused on patients with central nervous system (CNS) tumors over the study period (P ≤ .02). No other temporal trends were seen. The median times from first-in-adult to first-in-pediatric for monotherapy and combination trials were 5.7 and 3.3 years, respectively. CONCLUSION: The paucity of clear temporal trends highlights the need for innovation in early drug development for young people. Our analysis serves as a benchmark against which to evaluate initiatives to improve pediatric cancer drug development.

Selection bias for treatments with positive Phase 2 results.

In drug development, treatments are most often selected at Phase 2 for further development when an initial trial of a new treatment produces a result that is considered positive. This selection due to a positive result means, however, that an estimator of the treatment effect, which does not take account of the selection is likely to over-estimate the true treatment effect (ie, will be biased). This bias can be large and researchers may face a disappointingly lower estimated treatment effect in further trials. In this paper, we review a number of methods that have been proposed to correct for this bias and introduce three new methods. We present results from applying the various methods to two examples and consider extensions of the examples. We assess the methods with respect to bias of estimation of the treatment effect and compare the probabilities that a bias-corrected treatment effect estimate will exceed a decision threshold. Following previous work, we also compare average power for the situation where a Phase 3 trial is launched given that the bias-corrected observed Phase 2 treatment effect exceeds a launch threshold. Finally, we discuss our findings and potential application of the bias correction methods.

TOP: Time-to-Event Bayesian Optimal Phase II Trial Design for Cancer Immunotherapy.

BACKGROUND: Immunotherapies have revolutionized cancer treatment. Unlike chemotherapies, immune agents often take longer to show benefit, and the complex and unique mechanism of action of these agents renders the use of multiple endpoints more appropriate in some trials. These new features of immunotherapy make conventional phase II trial designs, which assume a single binary endpoint that is quickly ascertainable, inefficient and dysfunctional. METHODS: We propose a flexible and efficient time-to-event Bayesian optimal phase II (TOP) design. The TOP design is efficient in that it allows real-time "go/no-go" interim decision making in the presence of late-onset responses by using all available data and maximizes statistical power for detecting effective treatments. TOP is flexible in the number of interim looks and capable of handling simple and complicated endpoints under a unified framework. We conduct simulation studies to evaluate the operating characteristics of the TOP design. RESULTS: In the considered trial settings, compared to some existing Bayesian designs, the TOP design shortens the trial duration by 4-10 months and improves the power to detect effective treatment up to 90%, with well-controlled type I errors. CONCLUSIONS: The TOP design is transparent and easy to implement, as its decision rules can be tabulated and included in the protocol prior to the conduct of the trial. The TOP design provides a flexible, efficient, and easy-to-implement method to accelerate and improve the development of immunotherapies.

Improving Study Conduct and Data Quality in Clinical Trials of Chronic Pain Treatments: IMMPACT Recommendations.

The estimated probability of progressing from phase 3 analgesic clinical trials to regulatory approval is approximately 57%, suggesting that a considerable number of treatments with phase 2 trial results deemed sufficiently successful to progress to phase 3 do not yield positive phase 3 results. Deficiencies in the quality of clinical trial conduct could account for some of this failure. An Initiative on Methods, Measurement, and Pain Assessment in Clinical Trials meeting was convened to identify potential areas for improvement in trial conduct in order to improve assay sensitivity (ie, ability of trials to detect a true treatment effect). We present recommendations based on presentations and discussions at the meeting, literature reviews, and iterative revisions of this article. The recommendations relate to the following areas: 1) study design (ie, to promote feasibility), 2) site selection and staff training, 3) participant selection and training, 4) treatment adherence, 5) data collection, and 6) data and study monitoring. Implementation of these recommendations may improve the quality of clinical trial data and thus the validity and assay sensitivity of clinical trials. Future research regarding the effects of these strategies will help identify the most efficient use of resources for conducting high quality clinical trials. PERSPECTIVE: Every effort should be made to optimize the quality of clinical trial data. This manuscript discusses considerations to improve conduct of pain clinical trials based on research in multiple medical fields and the expert consensus of pain researchers and stakeholders from academia, regulatory agencies, and industry.

Comparison of treatment effect from randomised controlled phase II trials and subsequent phase III trials using identical regimens in the same treatment setting.

PURPOSE: We aimed to determine whether treatment effect size differed between randomised controlled phase II trials and subsequent phase III trials and examine potential predictor of positive phase III trials. METHODS: We searched MEDLINE for randomised controlled phase II studies published from January 2006 to December 2015. Matched phase III trials that investigated same intervention in the same setting of the same cancer were identified through Web of Science, ClinicalTrials.gov and conference proceedings. For each pair of phase II and phase III trials, we extracted hazard ratios (HRs) with 95% confidence intervals (CIs) for both overall survival (OS) and progression-free survival (PFS) and evaluated the differences by ratio of HRs (rHRs): the HR for phase II trial to that for phase III trial. A summary rHR was obtained through a random-effect meta-analysis. Univariable analyses were conducted to identify predictors of positive phase III trials. RESULTS: We identified 57 pairs of phase II and phase III trials. Compared with phase III trials, treatment effect sizes of PFS were, on average, 26% larger in phase II trials (rHR = 0.74, P < 0.001, 95% CI: 0.68-0.80). Treatment effect sizes of OS were 27% greater in phase II trials than in phase III trials (rHR = 0.73, P < 0.001, 95% CI: 0.66-0.79). Fifteen (26.3%) phase III trials were positive, and the only predictor of positive phase III trials was positive phase II trials CONCLUSION: Treatment effects in randomised controlled phase II trials were greater than those in matched phase III trials. Caution must be taken when interpreting promising results from randomised controlled phase II trials.

Enrolling study personnel in Ebola vaccine trials: from guidelines to practice in a non-epidemic context.

BACKGROUND: Enrolling participants in clinical trials can be challenging, especially with respect to prophylactic vaccine trials. The vaccination of study personnel in Ebola vaccine trials during the 2014-2016 epidemic played a crucial role in inspiring trust and facilitating volunteer enrollment. We evaluated the ethical and methodological considerations as they applied to an ongoing phase 2 randomized prophylactic Ebola vaccine trial that enrolled healthy volunteers in Guinea, Liberia, Sierra Leone, and Mali in a non-epidemic context. METHODS: On the assumption that the personnel on site involved in executing the protocol, as well as community mobilizers (not involved in the on-site procedures), might also volunteer to enter the trial, we considered both ethical and methodological considerations to set clear rules that can be shared a priori with these persons. We reviewed the scientific and gray literature to identify relevant references and then conducted an analysis of the ethical and methodological considerations. RESULTS: There are currently no regulations preventing a clinical investigator or site staff from participating in a trial. However, the enrollment of personnel raises the risk of undue influence and challenges the basic ethical principle of voluntary participation. The confidentiality of personal medical information, such as HIV test results, may also be difficult to ensure among personnel. There is a risk of disruption of trial operations due to the potential absence of the personnel for their commitment as trial participants, and there is also a potential for introducing differential behavior of on-site staff as they obtain access to accumulating information during the trial (e.g., the incidence of adverse events). Blinding could be jeopardized, given knowledge of product-specific adverse event profiles and the proximity to unblinded site staff. These aspects were considered more relevant for on-site staff than for community mobilizers, who have limited contact with site staff. CONCLUSION: In a non-epidemic context, ethical and methodological considerations limit the collective benefit of enrolling site staff in a vaccine trial. These considerations do not apply to community mobilizers, whose potential enrollment should be considered as long as they meet the inclusion criteria and they are not exposed to any form of coercion.

A Review of Perspectives on the Use of Randomization in Phase II Oncology Trials.

Historically, phase II oncology trials assessed a treatment's efficacy by examining its tumor response rate in a single-arm trial. Then, approximately 25 years ago, certain statistical and pharmacological considerations ignited a debate around whether randomized designs should be used instead. Here, based on an extensive literature review, we review the arguments on either side of this debate. In particular, we describe the numerous factors that relate to the reliance of single-arm trials on historical control data and detail the trial scenarios in which there was general agreement on preferential utilization of single-arm or randomized design frameworks, such as the use of single-arm designs when investigating treatments for rare cancers. We then summarize the latest figures on phase II oncology trial design, contrasting current design choices against historical recommendations on best practice. Ultimately, we find several ways in which the design of recently completed phase II trials does not appear to align with said recommendations. For example, despite advice to the contrary, only 66.2% of the assessed trials that employed progression-free survival as a primary or coprimary outcome used a randomized comparative design. In addition, we identify that just 28.2% of the considered randomized comparative trials came to a positive conclusion as opposed to 72.7% of the single-arm trials. We conclude by describing a selection of important issues influencing contemporary design, framing this discourse in light of current trends in phase II, such as the increased use of biomarkers and recent interest in novel adaptive designs.

Cumulative Toxicity in Targeted Therapies: What to Expect at the Recommended Phase II Dose.

BACKGROUND: In the era of molecularly targeted agents (MTAs), it is recommended to account for toxicity over several cycles to identify the recommended phase II dose (RP2D). We investigated the relationship between the risk of toxicity at cycle 1 and the cumulative incidence of toxicity over subsequent cycles in trials of single MTAs. METHODS: On individual patient data from 26 phase I clinical trials of single MTAs provided by the National Cancer Institute, we estimated the probability of first-severe toxicity per treatment cycle as well as the cumulative incidence at, below, and above the maximum tolerated dose (MTD). Toxicity was further subclassified into nonhematologic and hematologic. A prediction table was developed to estimate the cumulative incidence up to six cycles based on the toxicity rate observed in the first cycle. RESULTS: Overall, 942 patients were included. For patients treated at the MTD, the probability of first-severe toxicity decreased from 24.8% (95% prediction interval [PI] = 20.3% to 32.9%) to 2.2% (95% PI = 0.1% to 7.7%) from cycle 1 to 6, whereas the cumulative incidence of toxicity reached 51.7% (95% PI = 40.5% to 66.3%) after six cycles. Toxicity rates ranging from 20.0% to 30.0% in the first cycle were associated with 46.8% (95% PI = 39.5% to 54.2%) and 65.8% (95% PI = 57.7% to 73.1%) cumulative incidence after six cycles. CONCLUSION: This study examined the risk of severe toxicity over time of single MTAs. The cumulative incidence of toxicity at the MTD was higher than the usually accepted toxicity targets, challenging the definition of the RP2D of MTAs. The prediction table may help calibrate the target rate at the RP2D.

Use of Both Qualitative and Quantitative Methods to Estimate Meaningful Change Thresholds for Key Endpoints in Pediatric Asthma Trials.

INTRODUCTION: Diary-derived symptom score and rescue medication use endpoints, such as symptom-free days (SFDs) and rescue medication-free days (RFD), are frequently used as clinical trial endpoints. Estimates of meaningful change for SFDs and RFDs have not been generated in pediatric populations. This research aimed to generate evidence supporting estimates of the individual within-patient changes that constitute an important or meaningful change in SFDs, RFDs, and updated estimates on the Childhood Asthma Control Test (C-ACT) in pediatric asthma populations aged 5-11 years. METHODS: Semistructured, qualitative interviews were conducted with children (ages 8-11 years) who had asthma and parents/caregivers of children (4-11 years) with asthma. Before the interview (4-9 days) participants were asked to complete a morning and evening diary. RESULTS: On average, parent/caregiver estimates of the difference in SFDs between a "very bad" and a "little bad" week for their children's asthma were largely concordant with the values reported by their children (differences of 1.8 and 1.4 SFDs, respectively). Both parents/caregivers and children were able to articulate what a meaningful level of change would be on the C-ACT at the item level. This qualitative study generated C-ACT item-level meaningful change estimates in the region of 1-3 category change, which potentially suggests that, if scaled up to represent C-ACT total score, this would lead to change estimates of 7-15 points. CONCLUSIONS: Our findings suggest that both children with asthma and parents/caregivers can quantitatively estimate and to some extent qualitatively articulate meaningful change in SFDs and RFDs.

Challenges and Lessons From Conducting A Paediatric Clinical Trial in Sub-Saharan Africa: The Case of the Praziquantel Oral Dispersible Tablets Phase II Study in Côte d'Ivoire.

The importance of implementing paediatric clinical trials for neglected tropical diseases (NTDs) in compliance with the Good Clinical Practices of the International Conference of Harmonisation (ICH-GCP) and other applicable regulatory and ethics guidelines is increasingly being recognised as an essential pathway to provide safe and effective medicines for millions of untreated children living in sub-Saharan Africa (SSA). This paper describes the learnings and challenges faced by the Pediatric Praziquantel Consortium team during the implementation of an industry-sponsored Phase II clinical study in pre-school-aged children infected with schistosomiasis, conducted in remote rural settings in Côte d'Ivoire. The importance of close interactions with the ethics committee, the regulatory and administrative authorities and the rural communities are highlighted. The difficulties faced included obtaining a valid informed consent from the child's parent or guardian, the collection of blood samples from children during the study while respecting cultural beliefs as well as the weak medical research infrastructure. The paper illustrates how a public-private collaborative partnership can promote capacity-building and high-quality NTD paediatric clinical research in SSA.

Innovation in oncology clinical trial design.

Progress in and better understanding of cancer biology causes a shift in cancer drug development: away from the evaluation of drugs in large tumour histology defined patient populations towards targeted agents in increasingly heterogeneous molecularly defined subpopulations. This requires novel approaches in clinical trial design by academia and industry, and development of new assessment tools by regulatory authorities. Pharmaceutical industry is developing new targeted agents generating many clinical studies, including target combinations. This requires improved operational efficiency by development of innovative trial designs, strategies for early-stage decision making and early selection of candidate drugs with a high likelihood of success. In addition, patient awareness and ethical considerations necessitate that agents will be rapidly available to patients. Regulatory Authorities such as the European Medicine Agency and national agencies recognise that these changes require a different attitude towards benefit-risk analysis for drug approval. The gold standard of randomised confirmatory Phase III trials is not always ethical or feasible when developing drugs for treatment of small cancer populations. Alternative strategies comprise accelerated approval via conditional marketing approval, which can be granted in the EU based on small non-randomised Phase II trials. The paper describes innovative trial designs with their pros and cons and efforts of pharmaceutical industry and regulatory authorities to deal with the paradigm shift. Furthermore, all stakeholders should continue to share their experiences and discuss problems in order to understand the position and concerns of the other stakeholders to learn from each other and to progress the field of novel oncology clinical trial design.

Current Landscape of Late-Phase Clinical Trials for Alzheimer's Disease: Comparing Regional Variation Between Subjects in Japan and North America.

INTRODUCTION: Over the last few decades, numerous late-phase multi-regional clinical trials have been conducted to develop a novel treatment for Alzheimer's disease (AD), with no effective results. OBJECTIVE: To inform the design and interpretation of future clinical trials, the aim of this study was first to examine the current landscape of late-phase clinical trials to determine key study design characteristics, and then assess the regional variation between Japan and North America for the most utilized clinical efficacy endpoint in the most targeted stage of the disease. METHODS: The study design and the mechanism of action of the interventional drugs tested in the late-phase clinical trials initiated in the last 5 years (2014-2018) were assessed based on the records in ClinicalTrials.gov database. The regional variation of the most utilized clinical efficacy endpoint in the most targeted population was assessed using data from two similarly designed observational studies conducted in Japan (Japanese Alzheimer's Disease Neuroimaging Initiative, J-ADNI) and North America (Alzheimer's Disease Neuroimaging Initiative, ADNI). For the most utilized clinical efficacy endpoint, the change from baseline (CFB) at Month 6, Year 1 and Year 2 was estimated using the growth curve model with a random intercept and slope, including gender as a fixed factor and age, apolipoprotein E ε4 genotype and years of education as covariates. RESULTS: Of 48 Phase III trials that were initiated during the study period, 25 were disease-modifying treatment trials in which individuals with early AD were the most studied (56%) and Clinical Dementia Rating-Sum of Boxes (CDR-SB) was the most frequently utilized primary clinical efficacy endpoint (64%). The baseline characteristics of the early AD population between J-ADNI and ADNI were generally comparable, except for years of education. When comparing CDR-SB in early AD, J-ADNI had generally better baseline scores and the overall progression was similar (CFB at Year 2, ADNI 2.7 and J-ADNI 2.3, p = 0.190), despite slower progression in functional domains (CFB at Year 2, ADNI 1.4 and J-ADNI 1.0, p = 0.031). CONCLUSION: Over the years, the target population has shifted toward early stage of the disease, wherein the clinical progression is slower and difficult to measure. Moreover, our results suggest that regional variation could have an impact on functional measurements due to cultural differences in pivotal clinical trials. Therefore, caution should be exercised according to the characteristics of the endpoint used.

Reassessing the Role of Surrogate End Points in Drug Development for Heart Failure.

With few notable exceptions, drug development for heart failure (HF) has become progressively more challenging, and there remain no definitively proven therapies for patients with acute HF or HF with preserved ejection fraction. Inspection of temporal trends suggests an increasing rate of disagreement between early-phase and phase III trial end points. Preliminary results from phase II HF trials are frequently promising, but increasingly followed by disappointing phase III results. Given this potential disconnect, it is reasonable to carefully re-evaluate the purpose, design, and execution of phase II HF trials, with particular attention directed toward the surrogate end points commonly used by these studies. In this review, we offer a critical reappraisal of the role of phase II HF trials and surrogate end points, highlighting challenges in their use and interpretation, lessons learned from past experiences, and specific strengths and weaknesses of various surrogate outcomes. We conclude by proposing a series of approaches that should be considered for the goal of optimizing the efficiency of HF drug development. This review is based on discussions between scientists, clinical trialists, industry and government sponsors, and regulators that took place at the Cardiovascular Clinical Trialists Forum in Washington, DC, on December 2, 2016.