Clinical, Pathological, and Ethical Considerations for the Conduct of Clinical Trials in Dogs with Naturally Occurring Cancer: A Comparative Approach to Accelerate Translational Drug Development

Abstract The role of comparative oncology in translational research is receiving increasing attention from drug developers and the greater biomedical research community. Pet dogs with spontaneous cancer are important and underutilized translational models, owing to dogs’ large size and relative outbreeding, combined with their high incidence of certain tumor histotypes with significant biological, genetic, and histological similarities to their human tumor counterparts. Dogs with spontaneous tumors naturally develop therapy resistance and spontaneous metastasis, all in the context of an intact immune system. These fundamental features of cancer biology are often lacking in induced or genetically engineered preclinical tumor models and likely contribute to their poor predictive value and the associated overall high failure rate in oncology drug development. Thus, the conduct of clinical trials in pet dogs with naturally occurring cancer represents a viable surrogate and valuable intermediary step that should be increasingly incorporated into the cancer drug discovery and development pipeline. The development of molecular-targeted therapies has resulted in an expanded role of the pathologist in human oncology trials, and similarly the expertise of veterinary pathologists will be increasingly valuable to all phases of comparative oncology trial design and conduct. In this review, we provide a framework of clinical, ethical, and pathology-focused considerations for the increasing integration of translational research investigations in dogs with spontaneous cancer as a means to accelerate clinical cancer discovery and drug development.

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

American Society of Clinical Oncology Educational Book ◽

10.1200/edbk_242229 ◽

2019 ◽

pp. 374-387 ◽

Cited By ~ 3

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.

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

Journal of Clinical Oncology ◽

10.1200/jco.2017.35.15_suppl.2543 ◽

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.

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Role of the US Food and Drug Administration in Cancer Drug Development

Principles of Anticancer Drug Development ◽

10.1007/978-1-4419-7358-0_12 ◽

2010 ◽

pp. 305-332

Author(s):

Ann T. Farrell ◽

Ramzi N. Dagher ◽

Richard Pazdur

Keyword(s):

Drug Development ◽

Drug Administration ◽

Food And Drug Administration ◽

Cancer Drug ◽

The Us

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Childhood extracranial neoplasms: the role of imaging in drug development and clinical trials

Pediatric Radiology ◽

10.1007/s00247-015-3342-8 ◽

2015 ◽

Vol 45 (11) ◽

pp. 1600-1615 ◽

Cited By ~ 3

Author(s):

Lucy A. Fowkes ◽

Dow-Mu Koh ◽

David J. Collins ◽

Neil P. Jerome ◽

David MacVicar ◽

...

Keyword(s):

Clinical Trials ◽

Drug Development

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Barriers to phase I clinical trial protocol IRB approval at KCI

Journal of Clinical Oncology ◽

10.1200/jco.2007.25.18_suppl.9080 ◽

2007 ◽

Vol 25 (18_suppl) ◽

pp. 9080-9080

Author(s):

D. Wang ◽

E. Heath ◽

A. Powell ◽

T. Chaperon ◽

F. LaGrone ◽

...

Keyword(s):

Clinical Trials ◽

Drug Development ◽

Phase I ◽

Median Time ◽

Ethical Issues ◽

Phase 1 ◽

Cancer Drug ◽

Final Approval ◽

Standard Language ◽

Molecular Therapeutics

9080 Phase I oncology clinical trials are critical in the oncology drug development process. To protect human subjects, every phase 1 protocol must be approved by an institutional review board (IRB) to assure safety before patient accrual. As the volume and complexity of phase 1 trials have increased, the amount of time spent on IRB protocol reviews have also increased for various reasons. Objectives: 1) Determine the average time spent on protocol approval by IRB at KCI/WSU; 2) Identify potential issues raised by IRB resulting in approval delays; 3) Identify the redundancies for which “standard language” implementation could facilitate future IRB applications thereby expediting approval. Methods: 96 Phase 1 research IRB applications at KCI/WSU between 8/1/2005 and 10/31/2006 were reviewed. These applications were stratified based on submission (new protocol versus amendment) and IRB approval (tabled, provisional or approved) status. Concerns frequently brought up by the IRB were identified. Results: The average and median time spent from initial submission to final approval of all 96 applications were 41.4 days and 43 days, respectively. Forty eight of 96 applications (50%) were provisionally approved from the initial review. Average and median time of obtaining final approval were 52.5 days and 52 days. Nine of 96 (9.4%) protocols were tabled with their average approval 83 days. The most common concerns raised by IRB were risks/benefit issues. These concerns were an even greater approval barrier when protocols involved specialized technologies of molecular therapeutics or complicated study designs. Regulatory policy changes issued by oversight organizations also required “real-time” updates into protocols and consent form amendments. Areas of “standard language” for future IRB applications are being compiled and will be discussed upon presentation. Conclusion: Phase 1 clinical trials are essential to anti-cancer drug development. The complicated ethical issues and science warrant an ongoing constructive collaboration of both parties. Identification of commonalities that delay IRB approval will lead to more expeditious IRB approval not only at our institution, but could also benefit other institutions. No significant financial relationships to disclose.

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