The Lung Master Protocol (Lung-MAP, S1400) is a groundbreaking clinical trial designed to advance the efficient development of targeted therapies for squamous cell carcinoma (SCC) of the lung. There ...are no approved targeted therapies specific to advanced lung SCC, although The Cancer Genome Atlas project and similar studies have detected a significant number of somatic gene mutations/amplifications in lung SCC, some of which are targetable by investigational agents. However, the frequency of these changes is low (5%-20%), making recruitment and study conduct challenging in the traditional clinical trial setting. Here, we describe our approach to development of a biomarker-driven phase II/II multisubstudy "Master Protocol," using a common platform (next-generation DNA sequencing) to identify actionable molecular abnormalities, followed by randomization to the relevant targeted therapy versus standard of care.
The FDA's Oncology Center of Excellence's (OCE) launch of Project Optimus signals increased focus on dose optimization approaches in oncology drug development, particularly toward optimization in the ...premarket setting. Although sponsors continue to adapt premarket study designs and approaches to align with FDA's expectations for dose optimization, including consideration of the optimal dosage(s), there are still instances where questions remain at the time of approval about whether the approved doses or schedules are optimal. In these cases, FDA can exercise regulatory flexibility by issuing postmarketing requirements (PMR) and avoid delaying patient access to promising therapies. This landscape analysis demonstrates that over the past decade (2012-2022), FDA frequently used PMRs to answer additional questions about dosing for novel oncology approvals. We found more than half of drugs (78/132, 59.1%) had a dosing PMR and observed a recent increase in PMRs intended to evaluate whether a lower dose could be more optimal. These results suggest there are opportunities to adapt premarket dose optimization strategies and leverage innovative development tools to ensure timely identification of the optimal dose.
The purpose of this study was to evaluate the potential collective opportunities and challenges of transforming real‐world data (RWD) to real‐world evidence for clinical effectiveness by focusing on ...aligning analytic definitions of oncology end points. Patients treated with a qualifying therapy for advanced non‐small cell lung cancer in the frontline setting meeting broad eligibility criteria were included to reflect the real‐world population. Although a trend toward improved outcomes in patients receiving PD‐(L)1 therapy over standard chemotherapy was observed in RWD analyses, the magnitude and consistency of treatment effect was more heterogeneous than previously observed in controlled clinical trials. The study design and analysis process highlighted the identification of pertinent methodological issues and potential innovative approaches that could inform the development of high‐quality RWD studies.
As diagnostic tests become increasingly important for optimizing the use of drugs to treat cancers, the co-development of a targeted therapy and its companion diagnostic test is becoming more ...prevalent and necessary. In July 2011, the US Food and Drug Administration released a draft guidance that gave the agency's formal definition of companion diagnostics and introduced a drug-diagnostic co-development process for gaining regulatory approval. Here, we identify areas of drug-diagnostic co-development that were either not covered by the guidance or that would benefit from increased granularity, including how to determine when clinical studies should be limited to biomarker-positive patients, defining the diagnostically selected patient population in which to use a companion diagnostic, and defining and clinically validating a biomarker signature for assays that use more than one biomarker. We propose potential approaches that sponsors could use to deal with these challenges and provide strategies to help guide the future co-development of drugs and diagnostics.
The Value of Addressing Patient Preferences Allen, Jeff D., PhD; Stewart, Mark D., PhD; Roberts, Samantha A., PhD ...
Value in health,
02/2017, Volume:
20, Issue:
2
Journal Article
Peer reviewed
Open access
Abstract Recent scientific progress is, in some cases, leading to transformative new medicines for diseases that previously had marginal or even no treatment options. This offers great promise for ...people affected by these diseases, but it has also placed stress on the health care system in terms of the growing cost associated with some new interventions. Effort has been taken to create tools to help patients and health care providers assess the value of new medical innovations. These tools may also provide the basis for assessing the price associated with new medical products. Given the growing expenditures in health care, value frameworks present an opportunity to evaluate new therapeutic options in the context of other treatments and potentially lead to a more economically sustainable health care system. In summary, the contribution to meaningful improvements in health outcomes is the primary focus of any assessment of the value of a new intervention. A component of such evaluations, however, should factor in timely access to new products that address an unmet medical need, as well as the magnitude of that beneficial impact. To achieve these goals, value assessment tools should allow for flexibility in clinical end points and trial designs, incorporate patient preferences, and continually evolve as new evidence, practice patterns, and medical progress advance.
Our understanding of the biology of cancer and the application of this knowledge to cancer treatment has greatly outpaced what we know of the biology underlying the symptoms and toxic effects that ...therapies produce. These adverse effects of therapy cause substantial discomfort and distress to patients and their families, limit treatment tolerability and can persist indefinitely in post-treatment survivorship. Despite these concerns, little research effort is targeted at documenting the nature of these effects. Similarly, limited efforts are being made in the drug-development arena to identify or develop treatments that might prevent or reduce toxicities. A panel of clinicians and researchers as well as representatives from advocacy groups, federal agencies and the pharmaceutical industry was convened to identify gaps in cancer treatment toxicity research and to provide direction for future action. With an emphasis on coordinating multidisciplinary efforts, this panel has presented a strategy to increase funding for the field and develop a coherent research agenda.
Helper T cells are critical for protective immunity, CD8 ⁺ T-cell memory, and CD4 ⁺ recall responses, but whether the same or distinct CD4 ⁺ T cells are involved in these responses has not been ...established. Here we describe two CD4 ⁺ T cells, LLO118 and LLO56, specific for an immunodominant Listeria monocytogenes epitope, with dramatically different responses to primary and secondary infection. Comparing in vivo responses, LLO118 T cells proliferate more strongly to primary infection, whereas surprisingly, LLO56 has a superior CD4 ⁺ recall response to secondary infection. LLO118 T cells provide more robust help for CD8 ⁺ T-cell responses to secondary infection than LLO56. We found no detectable differences in antigen sensitivity, but naive LLO118 T cells have much lower levels of CD5 and their T-cell receptor levels are dramatically down-regulated after their strong primary response. Thus, distinct CD4 ⁺ helper T cells are specialized to help either in primary or secondary responses to infection.
Significant advancements have been made in the field of cellular therapy as anti-cancer treatments, with the approval of chimeric antigen receptor (CAR)-T cell therapies and the development of other ...genetically engineered cellular therapies. CAR-T cell therapies have demonstrated remarkable clinical outcomes in various hematological malignancies, establishing their potential to change the current cancer treatment paradigm. Due to the increasing importance of genetically engineered cellular therapies in the oncology treatment landscape, implementing strategies to expedite development and evidence generation for the next generation of cellular therapy products can have a positive impact on patients.
We outline a risk-based methodology and assessment aid for the data extrapolation approach across related genetically engineered cellular therapy products. This systematic data extrapolation approach has applicability beyond CAR-T cells and can influence clinical development strategies for a variety of immune therapies such as T cell receptor (TCR) or genetically engineered and other cell-based therapies (e.g., tumor infiltrating lymphocytes, natural killer cells and macrophages).
By analyzing commonalities in manufacturing processes, clinical trial designs, and regulatory considerations, key learnings were identified. These insights support optimization of the development and regulatory approval of novel cellular therapies.
The field of cellular therapy holds immense promise in safely and effectively treating cancer. The ability to extrapolate data across related products presents opportunities to streamline the development process and accelerate the delivery of novel therapies to patients.
Evolutionary analyses of population translocations (experimental or accidental) have been important in demonstrating speed of evolution because they subject organisms to abrupt environmental changes ...that create an episode of selection. However, the strength of selection in such studies is rarely measured, limiting our understanding of the evolutionary process. This contrasts with long-term, mark–recapture studies of unmanipulated populations that measure selection directly, yet rarely reveal evolutionary change. Here, we present a study of experimental evolution of male colour in Trinidadian guppies where we tracked both evolutionary change and individual-based measures of selection. Guppies were translocated from a predator-rich to a low-predation environment within the same stream system. We used a combination of common garden experiments and monthly sampling of individuals to measure the phenotypic and genetic divergence of male coloration between ancestral and derived fish. Results show rapid evolutionary increases in orange coloration in both populations (1 year or three generations), replicating the results of previous studies. Unlike previous studies, we linked this evolution to an individual-based analysis of selection. By quantifying individual reproductive success and survival, we show, for the first time, that males with more orange and black pigment have higher reproductive success, but males with more black pigment also have higher risk of mortality. The net effect of selection is thus an advantage of orange but not black coloration, as reflected in the evolutionary response. This highlights the importance of considering all components of fitness when understanding the evolution of sexually selected traits in the wild.
To compare management strategies for neonates <2.5 kg with tetralogy of Fallot and symptomatic cyanosis who either undergo staged repair (SR) (initial palliation followed by later complete repair) or ...primary repair (PR).
Consecutive neonates with tetralogy of Fallot and symptomatic cyanosis weighing <2.5 kg at initial intervention and between 2005 and 2017 were retrospectively reviewed from the Congenital Cardiac Research Collaborative. Primary outcome was mortality and secondary outcomes included component (eg, initial palliation, complete repair, or primary repair) and cumulative (SR: initial palliation followed by later complete repair) hospital and intensive care unit lengths of stay, durations of ventilation, inotrope use, cardiopulmonary bypass time, procedural complications, and reintervention. Outcomes were compared with propensity score adjustments with PR as the reference group.
The cohort included 76 SR (initial palliation: 53 surgical and 23 transcatheter) and 44 PR patients. The observed risk of overall mortality was similar between SR and PR groups (15.8% vs 18.2%: P = .735). The adjusted hazard of mortality remained similar between groups overall (hazard ratio, 0.59; 95% confidence interval, 0.26-1.36; P = .214), as well as during short-term (<4 months: hazard ratio, 0.37; 95% confidence interval, 0.13-1.09; P = .071) and midterm (>4 months: hazard ratio, 1.32; 95% confidence interval, 0.30-5.79; P = .717) follow-up. Reintervention in the first 18 months was common in both groups (53.2% vs 48.4%; hazard ratio, 1.69; 95% confidence interval, 0.96-2.28; P = .072). Adjusted procedural complications and neonatal morbidity burden were overall lower in the SR group. Cumulative secondary outcome burdens largely favored the PR group.
In this study comparing SR and PR treatment strategies for neonates with tetralogy of Fallot and symptomatic cyanosis and weight <2.5 kg, mortality and reintervention burden was high and independent of treatment strategy. Other potential advantages were observed with each approach.
One hundred twenty neonates with symptomatic tetralogy of Fallot weighed <2.5 kg at the time either of primary repair, or initial palliation as part of a staged repair strategy. Forty-four patients underwent primary repair, and 76 patients underwent staged palliation. Overall, approximately 17% of patients died at a median follow-up of more than 5 years. The observed mortality was similar in both groups, at 18% in the primary repair group and 16% in the staged repair group. After complete repair, half of the patients in each group had undergone reintervention. The high mortality in this fragile patient population is sobering. Alternative methods, such as randomized trials and prospective registries are necessary to further compare staged and primary repair strategies for symptomatic neonates with tetralogy of Fallot weighing <2.5 kg. Printed with permission from Texas Children's Hospital. Display omitted
PDF
