Applied Sciences

Running head: ANIMALS IN RESEARCH: A CHANGING PERSPECTIVE 1

Animals in Research: A Changing Perspective

Allison E. Mentzos

November 25, 2016

HSCI 2112W – Writing in the Health Sciences

The George Washington University

Author Note

This paper is submitted on November 25, 2016 to Professor Magnusson in satisfaction of

HSCI 2212W Writing in the Health Sciences. I, Allison E. Mentzos, affirm that I have

completed this assignment in accordance with the GW Code of Academic Integrity.

Joni Magnusson� 3/17/2017 10:29 AM Comment [1]: This title page follows APA format effectively. It includes a running head in the proper format for APA style. All required details are included on the title page.

ANIMALS IN RESEARCH: A CHANGING PERSPECTIVE 2

Animals in Research: A Changing Perspective

Historically animals have served an integral role in the development of investigational

products and devices. However, a lot of controversy surrounds whether the continued

involvement of animals as research subjects is cruel, ethical, reliable, or even necessary. There

are various regulations in place for the humane treatment of laboratory animals such as the

provision of veterinary care, proper shelter and access to food and clean water (OLAW, 2016;

U.S. Department of Agriculture, 2014). Nonetheless, many testing protocols often involve

painful, stressful or invasive procedures, physical restraint, and even purposeful exposure to

lethal chemicals or disease (Novak, 2014). Current evidence indicates that animals do not

provide appropriate surrogates to human subjects. With new advances in technology, translation

of mathematical models, ground-breaking use of human tissue and cell cultures in research, and

combined research methodologies will provide more compassionate alternatives to traditional

methods of testing. There is already the framework in place to minimize use, reduce suffering

and possibly replace animals in research (Ferdowsian & Beck, 2011; Singh, 2012). The time is

now to support advocacy for these unwilling clinical research participants by moving forward

with an integrative clinical trial design.

A Historical Viewpoint

Bhatt (2010) illustrates the investigative benefits associated with the inception of clinical

trials, referencing biblical origins as early as the Old Testament by measuring the consumption

of certain foods and wine on the physical appearance of the young men (Daniel 1:8-16, King

James Bible). The very first exampled documented as a clinical trial is based on the improvised

field medicine by Ambroise Pare, a Frenchman and military surgeon in the early 1500s (Bhatt,

2010). The moral and governing principles for conducting clinical research for the protection of

Joni Magnusson� 3/17/2017 11:02 AM Comment [2]: This early section of the paper works to provide background information related to the issue under investigation and assist the reader with understanding relevant details surrounding the topic. The author gives the history of the issue and points readers toward the argument that will be made in the paper. Joni Magnusson� 3/17/2017 11:01 AM Comment [3]: Early on, the paper identifies a current controversy related to the problem selected for analysis.

Joni Magnusson� 3/17/2017 10:42 AM Comment [4]: The sentences highlighted here successfully and clearly identify the paper’s topic or thesis idea, which meets the assignment criteria of being a specific problem. The sentences also provide insight into how the paper will be organized and serve as a roadmap for readers.

ANIMALS IN RESEARCH: A CHANGING PERSPECTIVE 3

human subjects evolved as the response to forced participation, repeated abuse, inhumane

treatment, catastrophic side-effects and the deaths of many during the first half of the 20th

century (Bhatt, 2010; US Department of Health and Human Services, 2013). The resultant

regulations set forth by the FDA, are in direct compliance with Good Clinical Practice (GCP)

and The International Conference on Harmonisation of Technical Requirements for Registration

of Pharmaceuticals for Human Use (ICH). These encompass the legal and ethical guidelines for

all clinical research activities ensuring that clinical trials run efficiently, effectively, with the

safeguard of data integrity, and most importantly protection of human subjects (Brody, 2016).

Clinical Trials Overview

The structure for transitioning disease modifying therapeutics from inception to public

use involves the utilization of multiple single-phase studies. Each phase focuses on specific

goals of identifying drug safety and potential efficacy (Liu & Davis, 2010; Portney & Watkins,

2015). Each clinical trial is managed based on a protocol designed by the sponsor outlining the

purpose of the study, how the research will be conducted, the parameter for inclusion or

exclusion in the research, and the guidelines for data collection (FDA, 2016). The use of

randomization, comparative groups, and blinding helps researchers maintain an unbiased

interpretation of the research and provides a diverse study population more closely representative

of the identified need for each therapeutic (Rosenberger & Lachin, 2015).

Preclinical Phase

Before testing ever includes the use of human participants, preclinical studies are

conducted to ascertain the pharmacokinetic and pharmacodynamic properties of the drug (FDA,

2016; Liu & Davis, 2010; Portney & Watkins, 2015). This nonclinical phase of drug

development originates during the initial syntheses and focuses on the mechanism of action in

Joni Magnusson� 3/17/2017 11:04 AM Comment [5]: The headings included in this paper help the reader track the logical progression of the paper and enable the author to organize thoughts effectively around certain sub-topics of the overall topic.

ANIMALS IN RESEARCH: A CHANGING PERSPECTIVE 4

animals (in vivo) or through in-vitro testing using test tubes and cell cultures. In addition to the

valuable contribution to our understanding of the impact the investigational product has on the

body, this stage evaluates how the body utilizes, distributes and excretes the drug (FDA, 2015).

The Moral Dilemma

In order to effectively conduct preclinical studies via traditional means, animals are

exposed to the substances or conditions under investigation. Unfortunately, scientific progress

ultimately comes at the detriment of the animal, resulting in pain, fear, anxiety, and even

starvation to meet research endpoints (Beauchamp, Ferdowsian, & Gluck, 2014). Invasive

procedures or surgery, exposure to corrosive substances, electronic shock, and escalating drug

dosing of toxic substances are just a small representation of the downside to animal

experimentation. Primates that have evolved mental, emotional and social characteristics show

particular vulnerability to the psychosocial ramifications of captivity. As many of these animals

are bred in captivity, they know only these abhorrent conditions, and the majority of animals that

do not succumb to their injuries are often euthanized at the end of a study (Hubrecht, 2014).

Human Subject Trials

Clinical trial testing that focuses on the safety and efficacy of investigative drugs and

devices in human subjects can be interventional as well as observational and are typically

divided into three phases. The earlier phases of these trials begin with FDO, or “first dose

observation” and provides evidence of the impact of these therapeutics on healthy participants.

The latter stages involve long-term surveillance, capturing clinical data as well as patient-

reported outcomes such as drug preference, ability to perform activities of daily living, side-

effects, and mental outlook (Centerwatch, n.d.; Mahan, 2014; Tourneau, 2009).

Joni Magnusson� 3/17/2017 11:06 AM Comment [6]: Here the author begins to move beyond summary of the literature in order to critically analyze and synthesize the information related to the selected issue. The author also discusses contrasting viewpoints, considering both sides of the debate on animal testing methods.

Joni Magnusson� 3/17/2017 11:03 AM Comment [7]: This is an example of a correctly formatted, APA style parenthetical citation.

ANIMALS IN RESEARCH: A CHANGING PERSPECTIVE 5

Animal Surrogacy in Testing

Traditional testing has always relied on the assumption that there are direct parallels

between animals and humans in regards to determining chemical sensitivities, drug toxicity and

responsiveness to treatment (Lindhagen, Vig Hgarnaa, Friberg, Latini & Larson, 2004).

Conversely, there are many physiological and disease mechanism considerations when

evaluating representative animal models. Often variability in animal strains, environmental

influences, and response patterns to environmental stimulus are overlooked (Claassen, 2013).

With the realization of computer-based models, cell-based, genetic and non-evasive testing,

modern technologies are now showing us that the most accurate models for human testing are

humans themselves (Martić-Kehl, Schibli, & Schubiger, 2012; Woo & Jusko, 2007).

Species Comparison

The fundamental differences between humans and their animal surrogates directly impact

the authentic translation of data derived from cross-species studies. While studies have shown

some similarities in representative rodent models for specific disease processes, they are often

poor models for evaluation of the total physiological impact of illness (Mak, Evaniew, & Gerk,

2014). The comparisons of anatomy, biochemical variables, and physiology in larger species

show us time and time again that introduction to these compounds in animal subjects elicit very

different response patterns than humans (Claassen, 2013; Pound & Bracken, 2014). These

dissimilarities also occur within the same species. Where an investigational product may prove

beneficial to some, genetic anomalies or even death may occur in others. For one particular

study measuring teratogenicity within various strains of rats, rabbits, canines, felines and

primates, adverse effects were not consistently induced, even after massive exposure to the toxic

substances (Shanks, Greek, & Greek, 2009).

ANIMALS IN RESEARCH: A CHANGING PERSPECTIVE 6

An Illustrative Look

There are many references to harmful side-effects and even death of humans after

products have progressed to human testing. In the late 1950’s, extensive animal testing failed to

predict the tens of thousands of birth defects and fetal deaths resulting from the antiemetic drug

Thalidomide, which was prescribed to pregnant women. Marketed under the brand name

Contergan, initially for the relief of insomnia and anxiety, an Australian pediatrician soon

discovered the off-label effectiveness on morning sickness and the drug gained global

recognition (Kallen, 2016). In 1997, fenfluramine/phentermine – better known as Fen-Phen –

was withdrawn from the market after life-threatening pulmonary hypertension and cardiac-

valvular problems manifested in individuals looking for treatment alternatives for obesity

(Mundy, 2010). There were over 50,000 lawsuits and legal damages in the tens of billions

resulting in strict regulatory guidelines for the development and use of future weight loss

products. Two years later, Merck Pharmaceuticals failed to show the correlation between the

NSAID Vioxx and its propensity towards gastrointestinal toxicity, heart attack, and stroke,

resulting in over 27,000 deaths and culminating the largest global drug recall in history

(Mandal & Parija, 2013; Matthews, 2008).

Statistical Analysis

Since the 1990s, the cost of clinical research has doubled, while the success rate has

steadily declined (Hay, Thomas, Craighead, Economides, & Rosenthal, 2014). Less than ten

percent of all drugs succeed towards FDA approval. Examination of post-study data cites figures

as high as 92% for the failure of medicines in human trials despite their success

in preclinical animal testing (Akhthar, 2015). Hundreds of drugs, developed to treat stroke,

while successful in earlier testing phases, failed to provide adequate results in humans. In the

ANIMALS IN RESEARCH: A CHANGING PERSPECTIVE 7

effort to manage the sudden outbreak of the AIDS virus, scientists became optimistic in the

numbers of primates responding positively to investigative vaccines, again to discover their

ineffectiveness in humans. So as to statistically improve the outcome of preclinical testing, we

must develop predictive models that close the gap between nonclinical and clinical stages

(Akhthar, 2015; U.S. Department of Health and Human Services, 2006).

Cost-Benefit Analysis

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