Drug Development in the Era of Personalized Oncology: From Population-Based Trials to Enrichment and Prescreening Strategies

2012 ◽  
pp. 168-172
Author(s):  
Rodrigo Dienstmann ◽  
Jordi Rodon ◽  
Josep Tabernero
Keyword(s):  
Clinical Trials ◽  
Drug Development ◽  
Large Scale ◽  
Human Genetics ◽  
Tumor Biology ◽  
Drug Approval ◽  
Population Based ◽  
Tumor Subtypes ◽  
Recent Success ◽  
Personalized Oncology

Overview: Recent advances in tumor biology and human genetics along with the development of drugs for specific targets hold promise for an era of personalized oncology treatment. Routine use of modern technologies, such as large-scale genome sequencing, will help to unravel the specific biology of each tumor. Adding a rigorous genomic view could determine key genetic events, critical dependencies, and stratification of patients in early clinical trials. Integrating biomarker development into the early testing of novel agents might provide clinically relevant therapeutic opportunities for patients with advanced-stage cancer and also accelerate the drug-approval process. After recent success stories of therapies targeting driver molecular aberrations in genetically defined tumor subtypes, innovative clinical trials based on a strong biologic hypothesis are expected to bring further excitement to the field. In this article, we describe a new trend in biomarker-driven early drug development using enrichment and prescreening strategies. Technical and logistical obstacles that may hinder progress of this approach will be discussed, along with ethical and economic concerns.

Voluntary patient registries

2020 ◽  
pp. 545-550
Author(s):  
Jeff Greenberg ◽  
Sheetal Patel
Keyword(s):  
Rheumatoid Arthritis ◽  
Clinical Trials ◽  
Large Scale ◽  
Standard Of Care ◽  
Population Based ◽  
Patient Registries ◽  
Research Findings ◽  
Comparative Safety ◽  
Approved Drugs ◽  
Shed Light

With the number of approved drugs now available for the treatment of rheumatoid arthritis, there is an ever-increasing need for real-world, objective data to shed light on the comparative effectiveness and comparative safety of newly approved drugs versus other standard of care older medications. This chapter will provide an overview of voluntary rheumatoid arthritis (RA) registries that currently recruit patients and actively publish research findings. It will also highlight some of the key clinical insights derived from these voluntary registries. Voluntary registries have their own strengths and limitations compared to population-based registries. Unlike pharmaceutical sponsored clinical trials, the majority of these voluntary registries do not exclude patients based on comorbidities. Additionally, clinical trials are not always feasible on a large scale and have limited duration. Observational registries do not typically have these limitations.

Molecular Profiling in Drug Development: Paving a Way Forward

2020 ◽  
pp. e309-e318
Author(s):  
Suzanne F. Jones ◽  
Andrew J. McKenzie
Keyword(s):  
Clinical Trials ◽  
Drug Development ◽  
Molecular Mechanisms ◽  
Target Identification ◽  
Tumor Biology ◽  
Chemotherapeutic Agents ◽  
Driver Mutations ◽  
Tumor Evolution ◽  
Screening Techniques ◽  
Molecular Oncology

As researchers learn more about tumor biology and the molecular mechanisms involved in tumorigenesis, metastasis, and tumor evolution, clinical trials are growing more complex and patient selection for clinical trials is becoming more specific. Rather than exploit certain phenotypic characteristics of tumor cells (e.g., rapid cell division and uncontrolled cell growth), pharmaceuticals targeting the genotypic causes of tumorigenesis are emerging. The sequencing of the human genome, advances in chemical techniques, and increased efficiency in drug target identification have changed the way drugs are developed. Now, more precise drugs targeting specific mutations within individual genes are being used to treat narrow patient populations harboring these specific driver mutations, often with greater efficacy and lower toxicity than traditional chemotherapeutic agents. This precision in drug development relies not only on the ability to design exquisitely specific pharmaceuticals but also to identify (with the same level of precision) the patients who are most likely to respond to those therapies. Robust screening techniques and adequate molecular oncology education are required to match the appropriate patient to precision therapies, and these same screening techniques provide the data necessary to advance to the next generation of drug development.

scholarly journals N-of-1 Trials in Pediatric Oncology: From a Population-Based Approach to Personalized Medicine—A Review

Cancers ◽  
2021 ◽  
Vol 13 (21) ◽  
pp. 5428
Author(s):  
Michal Kyr ◽  
Adam Svobodnik ◽  
Radka Stepanova ◽  
Renata Hejnova
Keyword(s):  
Personalized Medicine ◽  
Pediatric Oncology ◽  
Large Scale ◽  
Population Based ◽  
Modern Medicine ◽  
New Drugs ◽  
Small Samples ◽  
Personalized Oncology ◽  
New Treatments ◽  
Analytical Approaches

Pediatric oncology is a critical area where the more efficient development of new treatments is urgently needed. The speed of approval of new drugs is still limited by regulatory requirements and a lack of innovative designs appropriate for trials in children. Childhood cancers meet the criteria of rare diseases. Personalized medicine brings it even closer to the horizon of individual cases. Thus, not all the traditional research tools, such as large-scale RCTs, are always suitable or even applicable, mainly due to limited sample sizes. Small samples and traditional versus subject-specific evidence are both distinctive issues in personalized pediatric oncology. Modern analytical approaches and adaptations of the paradigms of evidence are warranted. We have reviewed innovative trial designs and analytical methods developed for small populations, together with individualized approaches, given their applicability to pediatric oncology. We discuss traditional population-based and individualized perspectives of inferences and evidence, and explain the possibilities of using various methods in pediatric personalized oncology. We find that specific derivatives of the original N-of-1 trial design adapted for pediatric personalized oncology may represent an optimal analytical tool for this area of medicine. We conclude that no particular N-of-1 strategy can provide a solution. Rather, a whole range of approaches is needed to satisfy the new inferential and analytical paradigms of modern medicine. We reveal a new view of cancer as continuum model and discuss the “evidence puzzle”.

scholarly journals Surrogate endpoints for early-stage breast cancer: a review of the state of the art, controversies, and future prospects

2021 ◽  
Vol 13 ◽  
pp. 175883592110595
Author(s):  
María Gion ◽  
José Manuel Pérez-García ◽  
Antonio Llombart-Cussac ◽  
Miguel Sampayo-Cordero ◽  
Javier Cortés ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Clinical Trials ◽  
Drug Development ◽  
Hormone Receptor ◽  
Early Stage ◽  
Drug Approval ◽  
Cancer Drug ◽  
Surrogate Endpoints ◽  
Long Term Outcomes

Drug approval for early-stage breast cancer (EBC) has been historically granted in the context of registration trials based on adequate outcomes such as disease-free survival and overall survival. Improvements in long-term outcomes have made it more difficult to demonstrate the clinical benefit of a new cancer drug in large, randomized, comparative clinical trials. Therefore, the use of surrogate endpoints rather than traditional measures allows for cancer drug trials to proceed with smaller sample sizes and shorter follow-up periods, which reduces drug development time. Among surrogate endpoints for breast cancer, the increase in pathological complete response (pCR) rates was considered appropriate for accelerated drug approval. The association between pCR and long-term outcomes was strongest in patients with aggressive tumor subtypes, such as triple-negative and human epidermal growth factor receptor 2 (HER2)-positive/hormone receptor-negative breast cancers. Whereas in hormone receptor-positive/HER2-negative EBC, the most accepted surrogate markers for endocrine therapy–based trials include changes in Ki67 and the preoperative endocrine prognostic index. Beyond the classic endpoints, further prognostic tools are required to provide EBC patients with individualized and effective therapies, and the neoadjuvant setting provides an excellent platform for drug development and biomarker discovery. Nowadays, the availability of multigene signatures is offering a standardized quantitative and reproducible tool to potentiate the efficacy of standard treatment for high-risk patients and develop de-escalated treatments for patients at lower risk of relapse. In this article, we first evaluate the surrogacies used for long-term outcomes and the underlying evidence supporting the use of each surrogate endpoint for the accelerated or regular drug approval process in EBC. Next, we provide an overview of the most recent studies and innovative strategies in a (neo)adjuvant setting as a platform to accelerate new drug approval. Finally, we highlight some clinical trials aimed at tailoring systemic treatment of EBC using prognosis-related factors or early biomarkers of drug sensitivity or resistance.

scholarly journals Using phase II data for the analysis of phase III studies: An application in rare diseases

2017 ◽  
Vol 14 (3) ◽  
pp. 277-285 ◽  
Author(s):  
Simon Wandel ◽  
Beat Neuenschwander ◽  
Christian Röver ◽  
Tim Friede
Keyword(s):  
Drug Development ◽  
Phase Ii ◽  
Interim Analysis ◽  
Large Scale ◽  
Drug Approval ◽  
Phase Iii ◽  
Orphan Diseases ◽  
Operating Characteristics ◽  
Phase Iii Study ◽  
Phase Iii Studies

Background: Clinical research and drug development in orphan diseases are challenging, since large-scale randomized studies are difficult to conduct. Formally synthesizing the evidence is therefore of great value, yet this is rarely done in the drug-approval process. Phase III designs that make better use of phase II data can facilitate drug development in orphan diseases. Methods: A Bayesian meta-analytic approach is used to inform the phase III study with phase II data. It is particularly attractive, since uncertainty of between-trial heterogeneity can be dealt with probabilistically, which is critical if the number of studies is small. Furthermore, it allows quantifying and discounting the phase II data through the predictive distribution relevant for phase III. A phase III design is proposed which uses the phase II data and considers approval based on a phase III interim analysis. The design is illustrated with a non-inferiority case study from a Food and Drug Administration approval in herpetic keratitis (an orphan disease). Design operating characteristics are compared to those of a traditional design, which ignores the phase II data. Results: An analysis of the phase II data reveals good but insufficient evidence for non-inferiority, highlighting the need for a phase III study. For the phase III study supported by phase II data, the interim analysis is based on half of the patients. For this design, the meta-analytic interim results are conclusive and would justify approval. In contrast, based on the phase III data only, interim results are inconclusive and require further evidence. Conclusion: To accelerate drug development for orphan diseases, innovative study designs and appropriate methodology are needed. Taking advantage of randomized phase II data when analyzing phase III studies looks promising because the evidence from phase II supports informed decision-making. The implementation of the Bayesian design is straightforward with public software such as R.

Patient-Centered Cancer Drug Development: Clinical Trials, Regulatory Approval, and Value Assessment

2019 ◽  
pp. 374-387 ◽  
Author(s):  
Bishal Gyawali ◽  
Thomas J. Hwang ◽  
Kerstin Noelle Vokinger ◽  
Christopher M. Booth ◽  
Eitan Amir ◽  
...  
Keyword(s):  
Clinical Trials ◽  
Drug Development ◽  
Cancer Biology ◽  
Drug Approval ◽  
The United States ◽  
Rapid Expansion ◽  
Cancer Drug ◽  
Trial Participation ◽  
Value Assessment ◽  
The Impact

Historically, patient experience, including symptomatic toxicities, physical function, and disease-related symptoms during treatment or their perspectives on clinical trials, has played a secondary role in cancer drug development. Regulatory criteria for drug approval require that drugs are safe and effective, and almost all drug approvals have been based only on efficacy endpoints rather than on quality-of-life (QoL) assessments. In contrast to Europe, information regarding the impact of drugs on patients’ QoL is rarely included in oncology drug labeling in the United States. Until recently, patient input and preferences have not been incorporated into the design and conduct of clinical trials. In recent years, a more in-depth understanding of cancer biology, as well as regulatory changes focused on expediting cancer drug development and approval, has allowed earlier access to novel therapeutic agents. Understanding the implications of these expedited programs is important for oncologists and patients, given the rapid expansion of these programs. In this article, we provide an overview of the role of QoL in the regulatory drug–approval process, key issues regarding trial participation from the patient perspective, and the implications of key expedited approval programs that are increasingly being used by regulatory bodies for cancer care.

Changes in numbers of randomized (RCT) versus non-randomized (NRCT) clinical trials from 2004-2016: Evidence of shifting cancer drug development pathway.

2017 ◽  
Vol 35 (15_suppl) ◽  
pp. 2543-2543
Author(s):  
Laura Vidal Boixader ◽  
Kelly Kevelin Curtis ◽  
Jim Wahl ◽  
Nicholas Kenny ◽  
Keren Rachel Moss
Keyword(s):  
Clinical Trials ◽  
Drug Development ◽  
Cancer Biology ◽  
Drug Approval ◽  
Cancer Drug ◽  
Phase 2 ◽  
The Past ◽  
Anti Cancer ◽  
High Antitumor Activity ◽  
Drug Approval Process

2543 Background: Trials using randomized designs have been conducted for decades to demonstrate efficacy of novel anti-cancer drugs (NACD). Recently, several NACD have shown high antitumor activity in early phase studies, prompting suggestions that NRCT could expedite drug development. We sought to determine what changes have occurred in numbers of NACD RCT vs NRCT conducted from 2004-2016. Methods: We reviewed a database of NACD clinical trials conducted by INC (excluding phase I and I/II trials) and classified them by RCT vs NRCT, grouped by year (≤ 2010 or > 2010). We queried Citeline Trialtrove database for industry sponsored, phase 2 trials (P2T) initiated from 2006-2016 and examined numbers of RCT vs NRCT by year.A more detailed analysis of non-small cell lung cancer (NSCLC) clinical trials based on drug type category - Immunooncology (IO) vs. all other mechanims of action (NIO) was performed. Results: 190 INC-conducted trials were reviewed. 58 trials (31%) were performed ≤ 2010 and 132 trials (69%) > 2010. Over this period, NRCT (n = 107, 56%) outnumbered RCT (n = 83, 44%). Whereas RCT outnumbered NRCT from 2004-2010 (74% vs 52%), after 2010, NRCT outnumbered RCT (58% vs 42%). Citeline Trialtrove search revealed 4776 industry sponsored P2T initiated from 2006-2016. The total number of P2T started annually was highest in 2007 (n = 621), decreasing to a low of 375 in 2016. The proportion of phase 2 RCT demonstrated an increase from 27% (n = 166) in 2006 to a peak plateau of 37-39% from 2011-2014, followed by a drop to 33% in 2015 and 29% in 2016. Among IO studies, RCT declined in 2015-6 vs. previous years, and a decreased for all NACD in 2016 vs. previous years also was noted. For studies in NSCLC, declines in RCT were evident from 2015-6 vs. previous years ( 45% in 2007-14 vs. 25% in 2015-6). Conclusions: Our data indicate a trend toward fewer trials of NACD using randomized designs and more studies using non-randomized designs, with overall fewer P2T initiated in the past year. This change reflects shifts in NACD development pathways, related to a better understanding of cancer biology, drive to develop personalized treatment and a more flexible regulatory drug approval process.

scholarly journals Genomic profiling of NETs: a comprehensive analysis of the RADIANT trials

2019 ◽  
Vol 26 (4) ◽  
pp. 391-403 ◽  
Author(s):  
James Yao ◽  
Abhishek Garg ◽  
David Chen ◽  
Jaume Capdevila ◽  
Paul Engstrom ◽  
...  
Keyword(s):  
Clinical Trials ◽  
Large Scale ◽  
Neuron Specific Enolase ◽  
Tumor Grade ◽  
Specific Pattern ◽  
Genomic Profiling ◽  
Prognostic Information ◽  
Chromosomal Alterations ◽  
Tumor Subtypes ◽  
Pancreatic Net

Neuroendocrine tumors (NETs) have historically been subcategorized according to histologic features and the site of anatomic origin. Here, we characterize the genomic alterations in patients enrolled in three phase 3 clinical trials of NET of different anatomic origins and assess the potential correlation with clinical outcomes. Whole-exome and targeted panel sequencing was used to characterize 225 NET samples collected in the RADIANT series of clinical trials. Genomic profiling of NET was analyzed along with nongenomic biomarker data on the tumor grade and circulating chromogranin A (CgA) and neuron-specific enolase (NSE) levels from these patients enrolled in clinical trials. Our results highlight recurrent large-scale chromosomal alterations as a common theme among NET. Although the specific pattern of chromosomal alterations differed between tumor subtypes, the evidence for generalized chromosomal instability (CIN) was observed across all primary sites of NET. In pancreatic NET, although the P value was not significant, higher CIN suggests a trend toward longer survival (HR, 0.55, P = 0.077), whereas in the gastrointestinal NET, lower CIN was associated with longer survival (HR, 0.44, P = 0.0006). Our multivariate analyses demonstrated that when combined with other clinical data among patients with progressive advanced NETs, chromosomal level alteration adds important prognostic information. Large-scale CIN is a common feature of NET, and specific patterns of chromosomal gain and loss appeared to have independent prognostic value in NET subtypes. However, whether CIN in general has clinical significance in NET requires validation in larger patient cohort and warrants further mechanistic studies.

Ongoing randomized clinical trials for the treatment of thrombosis in the antiphospholipid syndrome

2001 ◽  
Vol 21 (02) ◽  
pp. 77-81 ◽  
Author(s):  
G. Finazzi
Keyword(s):  
Clinical Trials ◽  
Large Scale ◽  
Low Dose ◽  
Randomized Clinical Trials ◽  
Oral Anticoagulants ◽  
Collaborative Study ◽  
Clinical Problem ◽  
Vascular Events ◽  
Dose Oral ◽  
Adverse Pregnancy

SummaryThrombotic events are a major clinical problem for patients with antiphospholipid antibodies (APA). However, current recommendations for their prevention and treatment are still based on retrospective studies. Data from large scale, prospective clinical trials are required to ultimately identify the optimal management of these patients. To date, at least four randomized studies are underway. The WAPS and PAPRE clinical trials are aimed to establish the correct duration and intensity of oral anticoagulation in APA patients with major arterial or venous thrombosis. The WARSS-APASS is a collaborative study to evaluate the efficacy and safety of aspirin or low-dose oral anticoagulants in preventing the recurrence of ischemic stroke. The recently announced UK Trial compares low-dose aspirin with or without low-intensity anticoagulation for the primary prevention of vascular events in APA-positive patients with SLE or adverse pregnancy history, but still thrombosis-free. It is hoped that the results of these trials will be available soon since clinicians urgently need more powerful data to treat their patients with the APA syndrome.

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