Page 367 - Withrow and MacEwen's Small Animal Clinical Oncology, 6th Edition

CHAPTER 18 Clinical Trials and Developmental Therapeutics 345

bedside) and effectiveness research as type II (bedside to curbside) of this approach, and are focused on providing advances for both
research. Generally, an RCT that determines efficacy occurs under humans and dogs to combat metastatic progression in the MRD
ideal conditions whereas long-term effectiveness studies, which
setting.
VetBooks.ir can be prospective or, on occasion, either meta-analyses or retro- Veterinary Registration Trials
spective, define the overall effect of a drug. Also important to con-
sider are the pharmacoeconomics of a drug, wherein a cost/benefit Veterinary drug development follows the same critical regulatory
analysis weighs factors such as actual cost of medication, number steps described earlier but oversight is provided by the FDA–CVM
or lives saved, minimization or exacerbation of hospital stays or and, in the case of biologics, by the US Department of Agriculture
doctor visits, and QOL measures, and computes their individual (USDA). Before 2007 with the conditional approval of ONCEPT
and societal expense. Once these outcome measures are studied (Canine Melanoma Vaccine, DNA, Boehringer-Ingelheim), all
and calculated, then comparisons between agents, new and old, cancer drugs used in veterinary medicine were originally devel-
can be made. 55–57 oped for humans and not approved for use in animals. Cancer
chemotherapeutics are used in an “extralabel” manner as allowed
Regulatory Oversight by the Animal Medicinal Drug Use Clarification Act of 1994.
The FDA is the regulatory body of the US government that over- Significant gains have occurred recently in veterinary oncology
sees the activities of the drug and pharmaceutical industry. The product development with full approval of toceranib phosphate
FDA provides oversight for drug development primarily through (Palladia, Zoetis), masitinib (Masivet, AB Science), and ONCEPT
written guidance, which describes rules and requirements for (Boehringer-Ingelheim). Palladia and Masivet are both receptor
quality control and conduct. FDA guidance include oversight of TKIs and are approved for treatment of recurrent or inoperable
drug standards, including chemistry, manufacturing, and control grade II or III mast cell tumors with or without regional lymph
(CMC); preclinical animal toxicology; documentary requirements node involvement. 20,47,48,62 Palladia was developed by SUGEN
for investigational new drug (INDs) and new drug applications as SU11654, a sister compound to SU11248 later approved for
63
(NDAs); and ethics of clinical trials. In 1997 the FDA moved human patients as Sutent. ONCEPT is a xenogeneic tyrosinase
beyond its traditional approval paradigm by creating the FDA DNA vaccine indicated for dogs with stage II or stage III oral
Modernization Act. It necessitates PK bridging studies for new canine melanoma. 64,65 Registration trials for these agents involved
58
populations (e.g., pediatric PK studies) and allows for one ade- safety and efficacy assessments in multicenter clinical trials under
quate and well-controlled clinical investigation by “confirmatory GCP conditions.
evidence” comprising PK or PK/PD data to lead to drug approval.
This emphasizes the importance of exposure and mechanism stud- Consortia
ies to more accurately determine the safety and effectiveness of One of the most exciting achievements in veterinary oncology
novel drugs, especially targeted agents or ones evaluated in special since 2008 has been the development of successful and collabora-
populations. 59 tive consortia that are purposed to perform multicenter clinical
FDA drug development is a multistep process that defines trials and prospective tumor biospecimen repository collections.
interaction between the FDA, the drug sponsor, and their dis- Consortium infrastructures allow larger scale clinical trials and
covery and clinical teams with a shared goal of FDA approval. It provide the voice for collective advocacy in veterinary and com-
involves a preclinical testing phase (IND requirements for CMC, parative oncology.
animal testing, design of phase I clinical studies), IND evalua-
tion, and NDA review, and marketing. FDA is attempting to Comparative Oncology Trials Consortium
improve and expedite the process of drug development through The COTC is an active network of 24 academic comparative
a number of initiatives. The most innovative are the Critical Path oncology centers (https://ccrod.cancer.gov/confluence/display/
Initiative (2004), end-of-phase 2a (EOP2a) meeting (2004), and CCRCOPWeb/Comparative+Oncology+Trials+Consortium),
model-based drug development (2005) (physiologically based PK centrally managed by the National Institutes of Health–NCI’s
[PBPK], 2009). In January 2017, the FDA formed the Oncol- Comparative Oncology Program that functions to design and
60
ogy Center of Excellence (OCE), which leverages the combined execute clinical trials in dogs with cancer to assess novel thera-
skills of regulatory scientists and reviewers with expertise in drugs, pies. 66,67 The goal of this effort is to answer biologic questions
biologics, and devices. This initiative will help expedite the devel- geared to inform the development path of these agents for use in
opment of oncology and hematology medical products and sup- human cancer patients. COTC trials are pharmacokinetically and
port an integrated approach in the clinical evaluation of such pharmacodynamically rich, with the product of this work directly
agents for treatment of cancer. In addition, the FDA is working to integrated into the design of current human early and late phase
implement provisions of the Cancer Moonshot initiative and 21st clinical trials. They are focused to answer mechanistic questions
Century Cures Act through the formation of the OCE, and has and define dose–toxicity and dose–response relationships. They
recently published a perspective on oncology drug development can be designed to compare varying schedules and routes of drug
that explores concepts geared toward an approach that could pro- administration, validate target biology, model clinical standard
vide earlier access to highly effective therapeutic drugs, thus com- operating procedures (SOPs), and assess biomarkers. In addition,
plementing existing expedited programs such as breakthrough within this effort, the COTC PD Core was created. The COTC
designation and accelerated approval. The OCE also supports PD Core is a virtual laboratory of assays and services, including
61
the use of common control trials, which share a common con- pathology, immunohistochemistry, immunocytochemistry, flow
trol arm, involve multiple different drugs for the same indication, cytometry, genomics, proteomics, cell culture, PK, and cell biol-
68
and may involve different companies and/or sponsors. The Mor- ogy designed to support COTC clinical trial biologic endpoints.
ris Animal Foundation’s Osteosarcoma Project trials, currently As of 2018, the COTC has completed 13 clinical trials and has
underway through the National Cancer Institute (NCI) Com- been successful in promoting the utility of comparative oncology
parative Oncology Trials Consortium (COTC), are emblematic modeling within the drug development community.