Biomedical Engineering Reference
In-Depth Information
Chapter 19
Safety and Efficacy Evaluation Using
Nonhuman Primates
Donna J. Clemons
*
, Vince Meador
y
, Gerhard F. Weinbauer
z
and G. Alex Wakefield
x
*
Abbott Laboratories, Comparative Medicine, Abbott Park, IL,
y
Anatomic and Clinical Pathology, Integrated Science and Innovation, Covance
Laboratories Inc., Madison, WI,
z
Developmental and Reproductive Toxicology, Covance Laboratories GmbH, Mu¨nster, Germany,
x
Veterinary Services,
Covance Laboratories Inc., Greenfield, IN
Chapter Outline
History and Regulation of Primate Testing
493
Diabetes 500
Antivirals 500
Administration-distribution-metabolism-excretion Models 501
Cardiovascular Models
Overview
493
Scientific Approach
495
Historical Perspective for Drug Development Animal
Usage
502
495
Central Nervous System Models
502
Species Needs for Drug Development
495
Developmental and Reproductive Toxicology (DART)
503
Species Selection
496
Bone Toxicity
505
Preclinical Safety Package
498
Efficacy Studies in the Nonhuman Primate
506
Parameters in Studies
498
Comparison to Use of More Common Species
506
Nonhuman Primate Models of Safety Assessment
498
Use of Normal Animals or Models of Disease
506
Immunogencity
498
Conclusions
507
Toxicities with Small and Large Molecules
499
References
507
HISTORY AND REGULATION OF
PRIMATE TESTING
Overview
Nonhuman primates are used in three main areas in drug
development: (1) research models on disease mechanisms;
(2) efficacy evaluation; and (3) toxicity (safety) evaluation.
Disease mechanisms and drug efficacy studies are done at
the discretion of the organization developing the drug,
which are mostly pharmaceutical companies, often referred
to by third parties as the “sponsor” of the drug. Data from
these studies is used to make decisions on selection of drugs
for development, advancing the drug to clinical trials, and/
or market approval. Regulatory agencies govern develop-
ment of the drug from the time it is decided by the orga-
nization to conduct
and to determine if the compound exhibits pharmacological
activity that justifies commercial development. When
a product is identified as a viable candidate, the sponsor
then focuses on collecting the data and information
necessary to establish that the product will not expose
humans to unreasonable risks when used in limited, early-
stage clinical studies. With limited information regarding
novel compounds and test articles at this stage of devel-
opment, the safety of laboratory staff must be a high
priority. Stringent processes, including biosafety
committee review, must be in place to analyze the risks and
provide the protections necessary for individuals working
with potentially hazardous materials. Biosafety practices
and programs related to working with nonhuman primates
are discussed more thoroughly in Chapter 18.
In general, the intent of regulatory oversight is similar
among major countries (e.g. USA, Japan) or regions
(e.g. Europe); however, approaches to regulatory over-
sight will vary. The approaches, guidelines, expectations,
and regulatory organizations are reviewed in depth and
clinical
trials
through market
application or approval and beyond.
During a new drug's early preclinical development, the
sponsor's (compound owner) primary goal is to determine
if the product is reasonably safe for humans in clinical trials
