Outline and argumentative paper

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

The clinical research industry has implications not only in its bearing on the welfare and

safety of human subjects, but in its staggering multi-billion dollar price tag. One estimate brings

the research and development of one drug to roughly 800 million dollars (Light & Lexchin,

2012). Despite the revenues for the pharmacology industry, the rising cost of animal research

increases the time to market, directly impacting its availability for therapeutic use (Liu & Davis,

2010). The analysis of a single substance can take half a decade to complete preclinical testing

and cost in the millions of dollars. There is a direct impact on the study subjects as well. The

comparison of routine healthcare related expenses to those attributed to clinical research shows a

25% cost increase in the latter. Moreover, clinical trials are not considered in alignment with

medical standard of practice; therefore private insurance companies may not provide

reimbursement for treatments related to participation (Bennett, Stinson, Vogel, Robertson, Leedy,

Obrien & Weiner, 2000). The transition to testing methods such as computer modeling and in

vitro techniques would provide early identification of ineffective products in a more cost-

efficient manner, and address negative public viewpoints relative to the ethical treatment of

animals and general clinical benefit (Lund, Morkbak, Lassen, & Sandoe, 2014).

ANIMALS IN RESEARCH: A CHANGING PERSPECTIVE 8

Trending towards Change

The development of toxicology and genetic engineering assays as alternatives to animal

testing are at the forefront of the scientific community priorities. These validated methods have

shown greater efficacy and safety of the resulting investigational products supporting the merits

of cell-based research. Identification of the need to reduce animal surrogacy, while maintaining

the quality of the research and protecting human subjects has already translated into legislation

that can affect change (Huggins, 2003; Steindler, 2007).

Roadmap for Change

In order to realize expansion beyond traditional methods, we must understand what is

necessary to bridge the gap between scientific theory and practice for cell-based clinical research.

The 3Rs principle (Replacement, Reduction, and Refinement) is one operational model for

collaborative research into alternative approaches to animal testing, as well as advancement in

molecular biology and toxicology (Liebsch, Grune, Seiler, Butzke, Oelgeschläger, Pirow, &

Luch, 2011). The primary goals are to decrease the numbers of animals used in research, replace

many of the procedures with alternative methods, or find ways to minimize the pain and

suffering inflicted during animal testing.

The U.S. National Research Council (NRC) report titled “Toxicity Testing in the

21st Century: A Vision and a Strategy encompasses a comprehensive review of testing methods

supporting the transformation from animal testing to in vitro methods based on human biologic

components” (Basketter, Clewell, Kimber, Rossi, Blaauboer, Burrier, & Hasiwa, 2012).

Furthermore, guidelines for quantitative analysis, epidemiology exploration, micro-dose human

testing and computer modeling have all found a path to regulatory consideration in the last

decade (Mak, Evaniew, & Ghert, 2014).

ANIMALS IN RESEARCH: A CHANGING PERSPECTIVE 9

Proven Success

One of many concerns regarding the implementation of alternative testing is the timeline

for accessibility to these research paradigms. However, there are already many examples of

successful implementation of substitute methodologies.

The Johns Hopkins Center for Alternatives to Animal Testing is dedicated to effecting

change and identifying other avenues for research. Their contribution to the communication,

collaboration, and identification of funding sources has been globally recognized, and their

vision far preceded any recognition of alternative testing as a viable scientific methodology

(Goldberg, 2015).

Barendregt, Van Oortmarssen, Vos, and Murray (2003) discuss the facilitation of the

Dismod and Dismod II computer design to capture the incidence and predominance of disease in

certain populations. This tool for epidemiological measurement does more than offer empirical

observation, but also aids in the prediction of disease remission and mortality rates. Three-

dimensional in vitro models meet today’s challenges of toxicity study, addressing liver failure

triggered by disease or drug intoxication and reshapes how we look at the physiological

principles of absorption and filtration of harmful substances (Soldato, LeCluyse, Griffith &

Rusyn (2013). Finally, the introduction of Phase 0 trials, allowed for safe and efficient

pharmacogenomic evaluation and management of patients suffering from the debilitating

cognitive impairment associated with Alzheimer’s disease (Andrade Nunes, Araujo Viel, &

Sousa Buck, 2013).

ANIMALS IN RESEARCH: A CHANGING PERSPECTIVE 10

Staying the Course: Arguments Against Change

Historically, the last century has been offered many medical innovations all directly

resultant of animal research. Experimentation comprising the removal of a canine pancreas led

to the discovery of insulin for the treatment of diabetes. Opposing arguments to the

discontinuation of animal subjects in clinical research state that more animals are used for human

consumption than for experimentation, and they allude to a “misinterpretation” of animal-human

surrogacy and the impact on disease (Jackson, 1996). Examples of the vaccines derived from

animal research such as smallpox and polio offer robust data related to the benefits of utilizing

cows, mice, and monkeys towards the eradication of these diseases. Paul (2002) believes that

removing animal use from the testing process would drastically limit our knowledge of human

health and physiology, thereby influencing society’s ability to guard against infectious disease

outbreak. For genetic disease study, a selection of scientists consider the accelerated

reproduction rates in mice as beneficial to congenital disease identification in humans. In

regards to the Thalidomide tragedy, many supporters of animal research believe that the failure

to include pregnant animals in the preclinical phase resulted in an incomplete assessment of the

drug. There is widespread appreciation for the benefits to animals as well as their human

counterparts. The deterrence of the spread of rabies, as well as control of feline leukemia and

canine parvovirus all support the continued endorsement by the American Veterinary Medical

Association. While there is a factual foundation for animal use in research, this is not of

question. What remains to be shown is whether limiting our research to one area is the best

choice for determining drug safety and efficacy in humans.

Joni Magnusson� 3/17/2017 11:07 AM Comment [8]: Again, both sides of the issue are considered.

ANIMALS IN RESEARCH: A CHANGING PERSPECTIVE 11

Conclusion

There is substantial evidence supportive of each distinct research methodology. Animal

research has significantly influences many of the medical and veterinary advances of the past

century. These traditional practices, while not always entirely successful have guided our

progress towards understanding diseases such as AIDS, developed successful procedures for

organ transplants, and established vaccine protocols that have advanced our management of

epidemiological diseases. Nonetheless, the advantages of an aggregate approach that utilizes

animal-based testing in conjunction with modern alternatives to testing are profound.

Technological advancements have provided three-dimensional models for predicting the

corrosive properties of a product. Micro-dosing allows for small amounts of a drug to be tested

in humans without the devastating systemic effects. Human genetics and cell-based models

remove the inconsistency related to animal surrogacy and alternative testing methodologies

significantly reduce costs and are an expedient pathway to safe and effective medical treatments

(Knight & Breheny, 2001; Mangipudy, Burkhardt, & Kadambi, 2014).

The only barrier now is in the commitment to regulatory control and funding for these

holistic models. Establishments like The Johns Hopkins Center for Alternatives to Animal

Testing have paved the way, but there is still work to be done in order to foster a global mindset

of standardization instead of practice exception.

Whereas there is equalized debate regarding animal testing and alternative models, the

resulting evidence clearly supports the overwhelming benefits of an integrative approach to

preclinical investigation. As such, we will see a brighter future for the lives of many animals

while also promoting the advancement of clinical research.

Joni Magnusson� 3/17/2017 11:12 AM Comment [9]: The conclusion reiterates the thesis and wraps up and reviews the main points of the essay effectively and therefore flows well from the paper.

Joni Magnusson� 3/17/2017 10:32 AM Comment [10]: Please note that, overall, this paper features effective grammar and punctuation as well as accurate spelling and clear, varied, and complete sentences. The writing, overall, is polished and smooth. Also, the tone is professional and formal, which is appropriate for an argument essay assignment.

ANIMALS IN RESEARCH: A CHANGING PERSPECTIVE 12

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Joni Magnusson� 3/17/2017 11:00 AM Comment [11]: This references page follows APA format effectively. Also, it includes well over the required minimum of 10 reputable sources and the required minimum of five current (published in the last five years) sources.

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