Discussion Post

Healthcare Research

Learning Objectives

By the end of this chapter, you should be able to:

1. Describe how advances in medical research infl uenced the development of the U.S. healthcare system.

2. Explain the structure, process, and function of scientifi c research, including characteris- tics of the diff erent research protocols.

3. Discuss ethical issues in health research.

4. Describe economic factors in research, including costs, funding, and regulation.

5. Discuss the impact of medical research on U.S. healthcare now and in the future.

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Chapter 9

As Chapter 2 describes in depth, modern medicine would not exist without research. It is the foundation for all new drugs, devices, surgical procedures, and health maintenance protocols. Not only does research improve overall health and quality of life, it is a major driver in the U.S. economy. For example, new smart phone-based devices are being developed to allow individuals to monitor basic body functions like blood pressure, blood glucose, weight, blood flow, and oxy- gen. The market for these and similar devices and applications is expected to exceed 100 million units annually by 2016 (Gullo, 2011).

Breakthroughs in research are most often the culmination of hundreds or perhaps thousands of prior endeavors. For instance, basic science discoveries about retroviruses and an enhanced understanding of how the immune system works were necessary before it was possible to identify and develop new treatments for human immunodeficiency virus infection/acquired immunode- ficiency syndrome (HIV/AIDS). Major breakthroughs often result in a paradigm shift (Kuhn, 1962) in thinking about a particular research area.

The history of medical research is rife with failed attempts, false starts, and misdirection, but without such trial and error, vaccines for measles and polio, treatments for AIDS, and statins (a class of drug used to lower cholesterol levels) for atherosclerosis, or insulin for diabetes would not exist. Nor would surgeons be able to perform safe and successful surgical procedures on essentially every part of the human body. Over the past 100 years, medical research has led to an increase in the average life span in the United States, from approximately 47 years to 79 years for women and about 72 years for men:

Back when the United States was founded, life expectancy at birth stood at only about 35 years. It reached 47 years in 1900, jumped to 68 years in 1950, and steadily rose to 76 years in 1991. In 1991, life expectancy was higher for women (79 years) than for men (72 years) (U.S. Census Bureau, 1995, para. 5).

It is not so much that we are living longer—the maximum life span of humans has not changed since the beginning of recorded history. For example, the maximum life expectancy a thousand years ago was approximately 72 years of age, even though fewer individuals managed to survive to this age. But today, more of us make it into older life because more of us are surviving what used to be “killer diseases” in the first few years of life—measles, whooping cough, and similar childhood diseases.

With each new discovery, knowledge of science and medicine increases exponentially. Today humanity is on the frontier of nanomedicine, a method by which microscopic particles deliver targeted treatments that interact directly with cells. Stem cell breakthroughs show promise for growing replacement parts for the body. Further down the road are virtual biopsies and colo- noscopies, bionic organs, and operating rooms so high-tech they could serve as a backdrop for a science fiction movie.

Many research challenges remain, including the growth of antibiotic resistance, worldwide epi- demics of influenza and obesity, and the resurgence of some diseases previously thought to be eradicated, such as measles, tuberculosis, and whooping cough (Gough, 2012). These topics are discussed in more detail in Chapter 12. Advances also bring with them new ethical issues, rising medical costs, and ever increasing government regulation. This chapter discusses some of these challenges as well as the research process and its role in improving healthcare in the United States.

Structure and Function of Research Chapter 9

9.1 The Role of Research in Shaping U.S. Healthcare Chapter 2 discusses some of the major medical breakthroughs of the last century. This chapter

• discusses the role of research in healthcare,

• provides historical background of healthcare research, and

• examines some of the implications for research.

The U.S. government’s attention to public health in the early part of the 20th century produced substantial improvements in the quality of water, milk, food, drugs, medical devices, and sanitation. It led also to lon- ger life spans and better quality of life for the majority of its citizens. The discovery of vaccines, antibiotics, insulin, analgesics (e.g., morphine), and anti-inflammatory drugs (e.g., aspirin) saved millions of lives and improved the quality of life for many more. The research and development needed to advance these new drugs and make them available created an international pharmaceutical industry with two results for healthcare: (1) greater access to safer and more effective drugs, and (2) increased profits for the drug industry. Together, these two events changed the landscape of medical care.

As a result of medical research, surgery has become a scientific discipline capable of performing miracles instead of a “risky art” with bad outcomes. New imaging devices allow the surgeon to see inside the body before operating, and new testing devices allow earlier detection and diagnoses of life threatening diseases. In recent decades, surgery has become less invasive. Today, minimally invasive surgery is replacing open surgery for many conditions, thus limiting trauma, minimiz- ing the extent of immunocompromise (an immune system that has been impaired or weakened by illness), and allowing for a more rapid recovery with better cosmetic results. Such leaps in the sophistication of diagnostic equipment and surgical technique have added additional costs to surgical procedures, however, and at times increased the overall healthcare cost burden.

Telemedicine, the communication of medical, imaging, and health information data over long distances, has been of enormous benefit to individuals living in isolated communities and remote regions and those unable to travel to medical facilities. Telemedicine allows them access to the sophisticated services usually available only in large urban health centers. On the horizon is remote surgery—a combination of robotics, high-speed data connections, and management information systems (Anvari, McKinley, & Stein, 2005).

9.2 Structure and Function of Research The cornerstone of valid, reputable research is the scientific method, which the Oxford English Dictionary defines as “a method or procedure that has characterized natural science since the 17th century, consisting in systematic observation, measurement, and experiment, and the for- mulation, testing, and modification of hypotheses.” This section defines the steps of the research process and provides some examples that help explain this process.

Ossie Leviness/NY Daily News Archive/Getty Images

▲▲ Public health efforts, including widespread use of vaccines, have saved millions of lives since the early 20th century.

Structure and Function of Research Chapter 9

Process of Research

Th e hypothetico-deductive model (Whewell, 1937) of scientifi c research begins with an inquiry, which proceeds from a hypothesis that can be either true or false as determined by a test on observable data. Th is scientifi c approach is shown in Figure 9.1.

In other words, the research process starts with a question. For example, does taking a daily multivitamin prevent cardiovascular disease? To learn more about this topic, researchers gener-

ally begin with a review of the literature. In some cases, they may fi nd inconsistent results from research studies that included diff erent study populations (observational versus experimental) and used diff erent research approaches (prospective versus retrospective) and study lengths. (See the Clinical research section and Figure 9.3 for more information about these research methods.) In addition, they may be unable to fi nd any long-term trials.

Once they decide to pursue a line of inquiry, the researchers pose a hypothesis or objective for the study. It can be either in the form of a null hypothesis, i.e., the fi nding occurred by chance, as

Figure 9.1: Hypothetico–deductive method combined with the general model of scientifi c research in psychology

The research process always starts with a question, which often arises from an informal observation or a practical problem.

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Theory Evaluation

Hypothesis Testing

Theory Construction/

Revision

Hypothesis Derivation

Data analysis

Conclusions Empirical

study

Research question

Informal observations/ practical problems

Research literature

Theory Evaluation

Hypothesis Testing

Theory Construction/

Revision

Hypothesis Derivation

Data analysis

Conclusions Empirical

study

Research question

Informal observations/ practical problems

Research literature

Source: Price, P. C. (2012). Psychology research methods: Core skills and concepts. “Using Theories in Psychological Research,” section 4.3. Retrieved from http://2012books.lardbucket.org/books/psychology-research-methods-core-skills-and-concepts/s08-03-using-theories-in-psychologica.html

Structure and Function of Research Chapter 9

in, there is no relationship between multivitamin consumption and heart disease. Or it can be the alternative; that is, the finding did not occur by chance, as in, there is a relationship between mul- tivitamin consumption and heart disease. The outcome is decided on data with statistical hypoth- esis testing usually assuming a p-value (the estimated probability of rejecting the null hypothesis of a study question when that hypothesis is true) of <0.05 as being statistically significant. That is, the relationship between taking vitamins and a decrease in heart disease is real and significant. In this example, the hypothesis might be that men who take a common daily multivitamin will have fewer cardiovascular events.

Each step of the experiment must now be established and documented. This generally includes, but is not limited to

• how individuals qualify to enter the study, • conditions that would cause an individual to be excluded from participating, • the treatments (brand, dose, frequency, etc.) that will be given, • the data that will be collected, and • how frequently data will be collected and for how long.

It is particularly important that the outcome of the research is defined specifically. The methods that are used to analyze the data must also be defined before the study begins.

Adverse events must be collected and are generally categorized based on severity and possible cause. Many, but not all, clinical trials are double-blind trials, meaning that during the trial itself, neither the subject nor the investigator knows which treatment a particular participant is receiving. At the specified endpoint of the study, the collected data are unblinded and analyzed.

The predictions of the hypothesis (men taking daily multivitamins have fewer cardiovascular events) are compared to the null hypothesis (there is no statistical difference as to number of cardiovascular events between men taking daily multivitamins and men taking a placebo). This comparison is performed to determine which one is better able to explain the data. Finally, the investigator makes a conclusion regarding the findings. For instance: Major cardiovascular events, MI (myocardial infarction), stroke, and CVD (cardiovascular disease) mortality were not reduced in the population of U.S. male physicians taking a daily multivitamin after more than a decade of treatment.

Sharing of study results is as important as the experiment itself. In the published results, the author will attempt to explain the findings and provide a perspective on how the results may affect clinical practice. The author will usually discuss potential limitations of the study and explain why the findings may be flawed.

This example is based on The Physician’s Health II Study, a large (14,641 participants), random- ized, double-blind, placebo-controlled trial that assessed the effect of multivitamin use on car- diovascular events among male physicians in the United States. The investigators found that taking a daily multivitamin did not reduce major cardiovascular events, MI, stroke, and CVD mortality after more than a decade of treatment and follow-up (Sesso et al., 2012).

Types of Research

A broad range of approaches for scientific research are in use. This chapter focuses on those approaches that are associated most often with healthcare research. Primary research can be classified as basic, clinical, or epidemiological.

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Basic research In biology, basic research is fundamental research about how life organisms function. Basic research can be theoretical, which attempts to prove or disprove a theory or hypothesis, or applied, which is basic research conducted on a molecular, genetic, cellular, organ, or whole ani- mal level. Under the basic research umbrella fall physiological studies, which provide a better understanding of how the human body functions. Physiological studies fall into two categories:

• In vitro, or test-tube experiments, use isolated tissue or organs to examine physiological processes, such as the study of cancer treatments on isolated cancer cells.

• In vivo studies are conducted using living organisms in their normal, intact state. An in vivo study might be as simple as measuring blood flow within a human brain while the subject is asleep.

Clinical research Clinical research studies the safety and effectiveness of drugs, devices, biologics, and procedures intended for human use. Clinical research can be either experimental or observational in nature.

• Experimental clinical trials—Assess the safety and efficacy (effectiveness) of a drug, surgi- cal technique, or medical device in healthy volunteers or patients with a specific disease. A new drug usually advances through four pre-marketing phases and two post-marketing phases. Drug discovery studies include in vitro/in vivo efficacy, toxicity, and pharmacoki- netic (how a drug is absorbed and excreted) studies in animals. These preliminary stud- ies are followed by five phases: preclinical and phases 1-4. Figure 9.2 describes the drug approval process.

• Observational studies—When a randomized, controlled study might be impractical or unethical, an observational study may be used in which the participants are observed or certain outcomes are measured without intervention. Such a study might record the incidence of cardiovascular disease in a population taking vitamin E compared with a population not taking vitamin E (drug study). A simple approach can be taken by observ- ing prognostic, diagnostic, or therapeutic outcomes. Although often criticized as inferior to randomized control trials, carefully designed observational studies can provide useful information that is on a par with experimental studies (Concato, 2004).

Epidemiology studies Epidemiology (population) studies entail public health research that identifies risk factors for disease and targets for preventive medicine in a defined population. Epidemiological studies may be experimental or observational. One example of an interventional, experimental epidemiology study was conducted by James Lind in 1747. This study involved administering oranges and lem- ons to one group (treated group) and the typical diet at the time to the other (control group), then determining whether or not scurvy improved.

Observational studies have no intervention. Rather, they follow a group of people who share a common characteristic or experience within a defined period and record the health outcomes of the group. This can be done either prospectively or retrospectively.

• Prospective studies follow the effects of a treatment or risk on the development of a dis- ease or condition. They are considered more definitive than retrospective studies.

• Retrospective studies, also called historic cohort studies (which have a shared event in a similar time period), attempt to link outcomes with exposures by looking back at risks

Structure and Function of Research Chapter 9

or treatments. Retrospective studies are more error prone due to confounding and bias. Established registries and large databases of medical records or claims generally provide the source data for these studies. An example of a retrospective study might be the odds of returning to work among a group of workers with lower back pain who received therapy versus those who did not receive therapy as determined from claim information (“What Researchers Mean,” 2010).

Figure 9.3 compares prospective (a) and retrospective (b) approaches. Retrospective studies may not need institutional review board (IRB) approval if subjects of the study are unidentifi able or the study is exempt under federal regulations. Any prospective study using human subjects requires IRB approval.

Major areas of epidemiological study include:

• Disease etiology (causes and origins) • Outbreak investigation • Disease surveillance and screening • Biomonitoring • Comparisons of treatment eff ects, as in clinical trials, usually in large populations

Th e identifi cation of causal relationships between exposures to harmful agents, such as alcohol, tobacco, biological agents, stress, or chemicals, to outcomes, such as mortality and morbidity, are an important aspect of epidemiology. An early example of using epidemiology to solve pub- lic health problems was employed by Dr. John Snow during the 19th century cholera epidemic. When he noticed higher death rates in two areas supplied by the Southwark Water Company, Dr. Snow used chlorine to clean the water supplied by one pump in the Soho district and used

Figure 9.2: Cycle of the drug approval process

After a drug discovery is made, the research teams complete a pre-clinical trial before they can begin clinical trials.

Sifting through compounds, ~10,000 that are possibly useable for the indication

Choice of candidates narrowed to ~250 compounds

Drug discovery Pre-clinical

Choice of candidates narrowed to ~250 compounds

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Submission of investigational New Drug

Application (NDA)

Safety (PK and PD) clinical trials in 20– 100 healthy volunteers single or multiple dose

Placebo controlled and/ or dose escalation efficacy and safety studies in 100–500 patients with disease under study

Placebo controlled and long-term follow-up efficacy and safety studies in 1,000–5,000 patients with disease under study

Phase I Phase II

Clinical Trials

Phase III

5 years 1.5 years 6 years 2 years 2 years

Placebo controlled and long-term follow-up efficacy and safety studies in 1,000–5,000 patients with disease under study

Submission of investigational New Drug

Application (NDA)

Monitoring drug safety/ efficacy after drug is on market; comparative effectiveness; new indications

Phase IV

Structure and Function of Research Chapter 9

another area as the control. Death rates decreased for individuals using the treated pump, ending the outbreak (Vachon, 2005).

Th e results of epidemiologic research is often used to advocate changes in public behavior such as those associated with smoking, alcohol use, and the consumption of junk food, as well as envi- ronmental issues.

Secondary research studies Secondary research studies re-examine primary studies in the form of a systematic review of the literature. Th ese studies look at the fi ndings for a number of similar studies or a meta-analysis (the use of statistical methods that combine data from a systematic review of individual studies).

Figure 9.3: A comparison of the prospective (a) and retrospective (b) approaches to study design

Prospective study designs aim to monitor effects as they occur in separate groups. Retroactive study designs work backwards to determine differences among those groups already affected.

(a)

(b)

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Direction of data collection

Direction of data collection

Time

Time

Not exposed

Exposed

Exposed

Not exposed

Exposed

Not exposed

Sample of healthy subjects

Yes

Yes

No

Yes

Population

No

No

Exposure Illness

Exposure Illness

Source: Röhrig, B., du Prel, J-B., Wachtlin, D., et al. (2009). Types of Study in Medical Research—Part 3 of a Series on Evaluation of Scientifi c Publications Deutsches Ärzteblatt International, 106(15), 262-8. doi: 10.3238/arztebl.2009.0262

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Subclasses of research studies Other subclasses of studies may use similar protocols to the ones previously defined:

• Behavioral studies are reaction/response studies that test how people and animals behave, interact, and communicate in response to stimulation, natural environmental conditions, and artificial conditions. Behavioral studies are most common in the field of psychology (the science of mind and behavior that pertains exclusively to human beings) or ethology (the scientific study of animal behavior).

The 1961 obedience to authority study conducted by Stanley Milgram is probably the most frequently cited psychological behavioral experiment. To understand the human behaviors that made possible the atrocities of World War II, Milgram told students to obey authority figures who ordered them to apply a series of electrical shocks to other students crying out in pain (subjects did not actually receive shocks, but acted as if they did). Sixty-five percent of those following orders administered lethal-level shocks (Milgram, 1963).

• Prevention studies evaluate ways to prevent specific conditions or diseases, such as the use of a vaccine to prevent the spread of flu virus.

• Public health research is a field of research that makes use of any of the types of research mentioned above plus biology, statistics, and social sciences. Public health research tries to improve the health and well-being of a community from a population-level perspective through surveillance of cases and the promotion of healthy behaviors. An example might be how the distribution of clean needles affects the spread of HIV in a community of intra- venous drug users.

• Genetic studies examine the link between genes and disease or beneficial traits in humans, animals, and plants. Genetic research has opened a number of ethical issues, such as privacy of genetic information, reproductive decision-making, free will versus genetic determinism, and health and environmental concerns. One of the most controversial uses of genetic research is the development of foods derived from genetically modified organ- isms (GMOs) engineered for faster growth, resistance to pathogens, production of extra nutrients, or other beneficial purposes. Most of the concern surrounding GMOs relates to their potential for negative effects on the environment and human health.

• Community-based participatory research (CBPR) is a form of study that engages commu- nity partners as equal participants along with trained public health research partners. The objective is to translate the knowledge gained from research into interventions and poli- cies that improve the health of various groups, especially minority communities and other disadvantaged populations (Viswanathan et al., 2004). These studies examine a variety of community issues, such as cancer screening behavior, alcohol consumption, rates of immunization, and safe-sex behavior.

• Randomized controlled trials (RCT) are studies in which the investigator assigns partici- pants in random sequence to receive either a treatment or a control, and the outcomes are assessed after a defined period of time. Randomized trials are the gold standard for reach- ing conclusions about the safety and effectiveness of interventions.

Understanding the process and varied approaches to research gives some insight into the role it plays in U.S. healthcare. Just as the process of research is bound by certain protocols, researchers themselves are bound by strict codes of ethics, ones that are defined and regulated by governing bodies within the United States, as well as various global entities. The next section of this chapter examines some of the central concerns and implications of ethics in research.

Ethics in Research Chapter 9

9.3 Ethics in Research Apart from the process and scope of research, perhaps no other aspect of the research field com- mands the attention of researchers more than ethical parameters. Without proper oversight and standards, the treatment of living subjects in scientific research offers great potential for abuse and exploitation. As a result, research studies, whether they employ humans or animals, are subject to numerous governmental and nongovernmental regulations. These regulations make clear how human subjects, vulnerable populations, and subjects from developing countries are to be enrolled and treated. An example of such a regulation is the Nuremberg Code of 1947. In addition to regulations, a variety of activist community voices push for control of research design

and direction.

Standards of Care

The Helsinki Declaration requires that research studies provide the “best” care for all patients. Patients entering into a clinical study should expect to receive, at the minimum, the appropriate treatment based on scientific evidence, i.e., the rec- ommended or usual diagnostic and treatment pro- cess for a certain type of patient, illness, or clinical

◀▲The U.S. government officially apologized to the men who were falsely led to believe they were receiv- ing treatment by government doctors during the Tuskegee syphilis experiment. This case highlights the importance of legislation to protect human research.

Doug Mills/Associated Press

U N D E R T H E M I C R O S C O P E

The Nuremberg Code

Following World War II, the Nuremberg Code of 1947 set ethical standards for human experimen- tation. The code outlined 10 points for using humans in research studies, starting with and most importantly, the voluntary consent of the subject. This means that subjects must have the legal capacity to give consent of their free will, with enough information to make an informed deci- sion concerning what they consent to. The endpoints of the experiment should benefit society and be procurable only by this means of study. Previous experiments, possibly in animals, should be performed to establish the foundation and justification for the study. Volunteers should not be subjected to unnecessary physical and mental suffering, injury, or death, while necessary precau- tions should be made to reduce risk and protect the subject against even the remote possibilities of injury, disability, or death. Those conducting the study must be prepared to terminate the experi- ment at any stage if they believe harm will come to the subject.

In the United States, the Office for Human Research Protections (OHRP) provides leadership in the protection of the rights, welfare, and well-being of subjects involved in research conducted or sup- ported by the U.S. Department of Health and Human Services (HHS).

(continued)

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circumstance. Thus in the research environment, the subject can expect to receive the current “standard of care” or a new treatment that is considered to be as good as or better than the stan- dard of care. However, whether to use the best or the usual (community) standard of care is the subject of some debate, in particular for clinical studies being conducted in developing countries. IRBs must be aware of this dilemma and allow investigators to use less than the worldwide best methods in certain situations. These include answering the scientific question posed by the trial

• when the findings of the trial will help address an important health need or provide a ben- efit to the host community, or

• when the subjects or host community will not be made prospectively worse off than they would be in the absence of the trial (Wendler, Emanuel, & Lie, 2004).

Research in Developing Countries

Pharmaceutical companies are increasingly choosing to conduct more of their clinical trials in developing countries like India and Nigeria as opposed to the typical European and North American sites. An outbreak of cerebral spinal meningitis in Nigeria in 1996 prompted Pfizer to send employees to Nigeria to conduct a clinical trial with the antibiotic travaloxacin. Pfizer hoped to provide the country with a life-saving, less painful and costly treatment for men- ingitis, particularly in children. Although Pfizer’s intended purpose was life-saving, a high number of children died or developed disabilities after treatment. This study is cited still today as an example of the nega- tive consequences of clinical testing in a

The OHRP and a series of federal laws and regulations requiring institutional review boards (IRBs) for the protection of subjects in clinical trials were a direct result of abuses during the Tuskegee syphilis experiment. In this study, conducted by the U.S. Public Health Service between 1932 and 1972, researchers knowingly failed to treat patients appropriately, even after penicillin was deter- mined to be an effective cure. Subjects in the study, rural black men, thought they were receiving free healthcare. By the end of the study, which included 399 test subjects, 28 men died of syphilis, 100 died of related complications, 40 infected their wives, and 19 children were born with congeni- tal syphilis (Brunner, 2007).

In 1964, the World Medical Association (WMA) established ethical principles for human experimen- tation known as the Declaration of Helsinki. The fundamental principles of the Declaration are respect for the individual, the right to self-determination, and the right to make informed decisions regarding participation in research, both initially and during the course of the study. The concept of publication ethics was expanded later to include the disclosure of conflicts of interest and the prob- lem of publication bias.

GODONG / BSIP / SuperStock

▲▲ Ethical issues abound in conducting clinical trials in develop- ing countries.

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developing country. Despite this example, collaboration between developing countries and phar- maceutical companies is increasing.

The reasons for the shift of clinical trials to the developing world vary, but an important driv- ing factor is the shortfall of trial enrollments in the United States, Canada, and Western Europe. Other reasons include a desire to help the host country develop effective and affordable interven- tions for an indigenous health problem, or to gain efficiency by researching a condition in a coun- try in which it is more prevalent, such as malaria or dengue fever in Africa. Foreign locations are also sometimes more convenient and less expensive. In some cases, participants can be enrolled more quickly, and regulatory requirements may be less burdensome. However, fewer regula- tory requirements may lead to less protection for individuals enrolled in these clinical studies (National Bioethics Advisory Committee [NBAC], 2001).

Ethical issues and global studies As studies become more global, new ethical considerations arise. Among these are

• the lack of infrastructure to provide appropriate ethical review, • the choice of a suitable control, and • valid, informed consent of the participants.

Recently there has been much discussion about the appropriateness of using a placebo control as opposed to an alternative research design that might better address the health needs of those in the host country. One example is the challenges made in Africa, Asia, and the Caribbean to the use of a placebo as a comparator in clinical trials to test drugs that might reduce perinatal trans- mission of HIV (Resnik, 1998). As mentioned previously, the choice of an appropriate standard of care can also be controversial.

Several studies evaluating the prevention of maternal-to-infant transmission of HIV in develop- ing countries received criticism for not using the standard of care currently being used in the United States. Criticisms included reducing dosages to reduce drug cost, initiating treatment later in the pregnancy so as to coincide with the timing of usual prenatal interventions in the countries where the studies were being conducted, and administering the treatment orally to more closely duplicate local practice versus intravenous treatment.

The most highly criticized aspect of the studies was the use of a placebo. Because the drug being studied was considered the standard of care at the time, placebo control would not have been per- mitted in a developed country. This has created an ethical controversy in international research.

Research challenges in developing countries Critics argue that studies conducted in developing countries should provide the same standard of care as that provided to subjects in the developed countries to avoid unnecessary morbidity and mortality (Lurie & Wolfe, 1997). However, defenders of placebo-controlled studies argue that the standard of care in some developing countries for some diseases (e.g., HIV) is no treatment at all, thus those receiving a placebo would be no worse off, and more participants and faster results would be achieved with placebo-controlled trials.

Another challenging ethical issue in developing countries is the concept of informed consent—an essentially Western ritual that requires comprehension, understanding of the voluntary nature of the study, competence, and sometimes community or family consent. In one South African study, 88% of women felt compelled to participate in a study despite having been told it was

Ethics in Research Chapter 9

voluntary (Karim, Abdool Karim, Coovadia, & Susser, 1998). Their reasons suggest a desire to be compliant with an authority figure and to assure receiving treatment. Study sponsors need to consider each country’s distinctive history, culture, politics, judicial system, and economic situa- tion when planning clinical studies in developing countries (London et al., 1997).

Vulnerable Populations

Specific ethical policies exist for enrolling vulnerable populations, such as pregnant women; human fetuses and neonates (newborns); prisoners; children; the cognitively impaired; students and employees; AIDs patients; or anyone unable to give informed consent. The Code of Federal Regulations (CFR) and the “Common Rule” as set out by the 1979 Belmont Report (National Commission for the Protection of Human Subjects of Biomedical and Behavioral Research, 1979; U.S. Department of Health and Human Services [HHS], n.d.) emphasize the need for cultural, gender, ethnic, and geographical considerations, as well as respect for persons, beneficence, and justice when enrolling vulnerable populations in research studies (Shore, 2006).

Political and Cultural Influences on Medical Research

In 1942 Mary and Albert Lasker created the Lasker Foundation to promote research to fight can- cer, and health activists have been shaping the direction of research ever since. Beginning in the

C A S E

Placebos in International Research

In 1997, a study was conducted in a developing country to find a cheaper, more acceptable treat- ment to lower the rate of maternal-to-infant transmission of HIV. Based on a successful study con- ducted in the United States, the study compared the HIV drug, zidovudine (AZT), with a placebo administered continuously to women as early as the 14th week of pregnancy.

The standard of care in developed countries, the high cost of AZT, and the lack of a healthcare infrastructure to administer the regimen made the treatment difficult to use in developing coun- tries. To make the course of treatment more acceptable and less costly in resource-poor countries, a lower dose was used, treatment was initiated later in pregnancy (women in this country do not traditionally receive early prenatal care), AZT was administered orally rather than intravenously, and newborns did not receive full treatment, if any.

In the United States, the use of a placebo-controlled trial would have been prohibited as it is con- sidered unethical to withhold from women in a research study an effective treatment that they could obtain as part of their routine medical care. It was justified in a developing country because the existing level of care was no care at all. The study did show that a cheaper (lower dose), short- course AZT regimen was significantly better than the placebo. However, the study generated a good deal of ethical discussion.

For more information, see the online article Ethical Issues in International Research–Setting the Stage, available at http://bioethics.georgetown.edu/nbac/clinical/Chap1.html.

Critical Thinking Questions

1. What are some possible arguments for this study? What are some possible arguments against it? 2. Could a different study design have been adopted for this study? If so, what might have been an

alternate design?

Ethics in Research Chapter 9

1980s, activists for breast cancer and AIDs began influencing the direction of funding as well as research. Through public protest and campaigns, activists have exerted a strong influence on the National Institutes of Health (NIH) and the U.S. Food and Drug Administration (FDA), aggres- sively fighting to increase research funding, redirecting funds toward scientists more aligned with their philosophy, guiding policy and setting research agendas, and most significantly, chal- lenging scientific authority (Bix, 1997).

Until the late 1980s, men were often the only participants in health and drug studies. Two medical disasters galvanized the women’s health activists: (1) The Dalkon Shield, a contracep- tive intrauterine device, was linked to miscarriage and pelvic inflammation, and (2) the synthetic estrogen diethylstilbestrol (DES), which was given to women to avoid miscarriage, was linked to cancer.

Following these revelations, women’s health activists pressured the NIH to increase research funding for women’s health issues and applied political pressure to open up research investiga- tions to female subjects. With the 1991 confirmation of Dr. Bernadine Healy as the first woman to head the NIH, women’s health became a new focus of the agency. At about the same time, activists turned their attention to the issue of breast can- cer to the exclusion of lung disease and heart disease, which accounted for more deaths among women than breast cancer. Government funding for breast cancer research jumped from $90 million to $465 million between 1990 and 1995 compared with $90 million for lung cancer.

A similar story played out when activists demanded more money for AIDS research, a faster drug approval process, and more control over the structure of scientific research itself. The FDA instituted accelerated approval for newly discovered anti-AIDS treatments. Activists became more vocal about the

design of research studies, asserting that randomized, placebo-controlled trials unfairly and dan- gerously left some patients with ineffective treatments. Funding for AIDS increased to $800 mil- lion by 1991, representing almost 10% of the NIH budget.

The amount of money poured into a health campaign is one factor that gives it authority and determines the course of research. And the celebrity factor often comes into play as well. Soon celebrity advocates—not scientists—may dictate scientific study (Moreno, 2013). Julia Roberts supports the eradication of Rett syndrome, a serious neurological disorder affecting almost exclu- sively girls. Research for AIDS (Magic Johnson and Elizabeth Taylor), breast cancer (Ann Jillian and Rosie O’Donnell), paralysis (Christopher Reeve, deceased), juvenile diabetes (Mary Tyler Moore), multiple sclerosis (Montel Williams), and Parkinson’s (Michael J. Fox) have all received celebrity support. In addition, Congressional members are not shy about persuading NIH to sup- port research and institutions in their home states. A study published in Science found political influence affected 3% to 7% of the overall NIH allocations (Hegde & Mowery, 2008). Most indi- viduals would agree that a more equitable distribution of both the burdens and the benefits of medical research are needed, but science should not be overwhelmed by political and personal interests.

Dennis Cook/Associated Press

▲▲ Celebrity activism plays an important role in health campaign funding. Julia Roberts advocates for Rett Syndrome suf- ferers and their families.

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Animal Rights Movement

Another check on medical research has been the animal rights movement, which grew out of the English anti-vivisection movement of the 1890s. The American anti-vivisection movement, established in Philadelphia in 1883, focused on inhumane treatment of dogs and cats. It was fol- lowed, however, by the American Humane Association, which became the leading advocate for animal and child protection. Although the original anti-vivisection movement died out in the early part of the 1900s, the writings of animal-rights philosophers Peter Singer and Tom Regan revived it in the 1970s. Singer in particular popularized the concept of “speciesism” as akin to racism and sexism. The philosophy of speciesism encouraged animal rights activists to oppose the use of animals for experimental purposes. Groups like People for the Ethical Treatment of Animals (PETA) and the Animal Liberation Front (ALF) protested outside NIH-funded research facilities, in some instances breaking in to “liberate” research animals. The break-ins became so frequent and damaging that Congress passed the 2006 Animal Enterprise Terrorism Act mak- ing these and similar tactics a crime.

Animal rights groups were successful in getting cosmetics companies to develop alternative methods of testing through vigorous protesting and publication of the results of some animal studies, such as the Draize Test. Cosmetic companies used this test to determine the safety of cosmetics by placing them in the eyes of rabbits. Animal rights groups showed that the test led to eye redness, bleeding, ulcers, and even blindness in these animals, not to mention a great deal of suffering. These groups also persuaded the FDA to replace the LD 50 test (the lethal dose of a toxic substance, which will kill half or more of a group of test animals) with tests using cells (Walls, 2008). Animal activists were also instrumental in imposing regulations, such as the Animal Welfare Act, which established standards for the humane treatment of animals by deal- ers, research facilities, and exhibitors connected with research using federal funds.

Supporters of animal research, meanwhile, point out that the vast majority of animals used in research studies are rodents, including those bred for specific research purposes, and the use of animals in medical research has resulted in many major advances in medicine. Although animal rights leaders argue that computer models can replace the use of animals in research studies, sci- entists claim that computer models can serve only as adjuncts to basic animal research (“Animal Rights,” 2005), and cannot replace them. Former U.S. surgeon general Jocelyn Elders said, “The use of animals in biomedical research and testing has been, and will continue to be, absolutely critical to the progress against AIDS and a wide range of other applications in both humans and animals” (”Animal Rights,” 2005, para. 14).

9.4 Regulation and Finance In spite of ethical controversies, medical research is tightly regulated by an array of agencies, both domestic and international. Some are government-based, others are situated within the scien- tific and healthcare industries. The next section of the chapter looks at some of these regulatory agencies, many of which wield significant influence in the direction of the healthcare system as a whole. Then the chapter examines some of the sources of funding for medical research.

The Role of Regulatory Agencies

Government plays a dominant role in healthcare funding and regulation, and it is an impor- tant influence on the direction of research and development of medical products in response to

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emerging public health threats. In addition, a number of independent bodies exist to regulate the goals, methodologies, outcomes, and reporting of research studies throughout the world.

FDA and EMA The origins of the FDA date back to 1848, but its modern-day regulatory functions began in 1906 with the passage of the Pure Food and Drugs Act, which prohibited interstate commerce in adul- terated and misbranded food and drugs. Although the Act represented the culmination of years

of efforts by the agency, it passed only after the uproar caused by Upton Sinclair’s book, The Jungle, which described appalling con- ditions in the meat packing industry.

Since then, in addition to drugs and foods, the FDA has become involved in the regu- lation of medical devices, cosmetics, vet- erinary products, and the illegal sales of banned substances. The FDA maintains control over the pharmaceutical industry and devices makers by mandating approval of all new drugs and medical devices before marketing. The European Medicines Agency (EMA) is the European equivalent of the FDA and often works with the FDA and other regulatory agencies (e.g., World Health Organization and country-specific regulatory bodies) around the world to assure best practices and to oversee any medicinal products within its sphere of influence.

International Conference on Harmonisation (ICH) As drug development became more complicated and more global, the regulatory authorities and pharmaceutical industry came together to discuss scientific and technical aspects of drug reg- istration. Established in 1990, the International Conference on Harmonisation of Technical Requirements for Registration of Pharmaceuticals for Human Use (ICH) includes groups from Europe, Japan, and the United States. The mission of the ICH is “to make recommenda- tions towards achieving greater harmonization in the interpretation and application of technical guidelines and requirements for pharmaceutical product registration, thereby reducing or obvi- ating duplication of testing carried out during the research and development of new human med- icines” (International Conference on Harmonisation of Technical Requirements for Registration of Pharmaceuticals for Human Use (ICH), n.d.., para. 1).

Several countries have adopted the ICH into law and the FDA uses it as guidance in the form of good clinical practice (GCP) guidelines, which define the standards for the design, conduct, performance, monitoring, auditing, recording, analysis, and reporting of clinical trials or stud- ies and the roles and responsibilities of sponsors, investigators, and study monitors. Compliance with GCP assures protection of the rights, safety, and well-being of human subjects involved in research.

Lee Lorenz / The New Yorker Collection/www.cartoonbank.com

▲▲ “The F.D.A. is nuts about it. ”

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Consolidated Standards of Reporting Trials (CONSORT) Th e Consolidated Standards of Reporting Trials (CONSORT) comprises journal editors, clini- cal trialists, epidemiologists, and methodologists interested in the problems stemming from inadequate reporting of randomized control trials (RCTs). Th e main product of this group, the CONSORT Statement, is an evidence-based, minimum set of recommendations for reporting RCTs. CONSORT off ers a standard way for authors to prepare reports of trial fi ndings, facilitate complete and transparent reporting, and aid critical appraisal and interpretation. Th e statement, fi rst developed in 1993 and updated regularly, consists of a 25-item checklist and fl ow diagram.

Th e checklist outlines how trialists should report trial design, analysis, and interpretation. Th e content to be included for the subsections of the manuscript is also described: Title, Abstract, Introduction, Methods, Results, Discussion, and Other Information.

Th e fl ow diagram outlines how many subjects participated in the trial and how the subjects progress through the trial, starting with enrollment, followed by intervention allocation, follow- up, and analysis. Figure 9.4 shows a sample fl ow diagram of the progress through the phases of a parallel RCT of two intervention groups.

Figure 9.4: RCT fl ow diagram from the CONSORT Statement checklist

The CONSORT statement is comprised of a checklist and a fl ow diagram. The fl ow diagram outlines information about the subjects that participate in a trial.

f09.04_HCA305.ai

Randomized (n = )

Excluded (n = ) • Not meeting inclusion criteria (n = ) • Declined to participate (n = ) • Other reasons (n = )

Allocated to intervention (n = ) • Received intervention allocation (n = ) • Did not receive intervention allocation (give reasons) (n = )

Allocated to intervention (n = ) • Received intervention allocation (n = ) • Did not receive intervention allocation (give reasons) (n = )

Lost to follow-up (give reasons) (n = )

Discontinued intervention (give reasons) (n = )

Lost to follow-up (give reasons) (n = )

Discontinued intervention (give reasons) (n = )

Analyzed (n = ) • Excluded from analysis (give reasons) (n = )

Analyzed (n = ) • Excluded from analysis (give reasons) (n = )

Accessed for eligibility (n = )

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ro ll

m e n

t A

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ca ti

o n

Fo llo

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ys is

Source: The CONSORT Group www.consort-statement.org

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World Medical Association As mentioned previously, medical research can no longer be conducted in a U.S. vacuum if the results are to gain worldwide acceptance. To this end, an international group of physicians came together in 1947 to found the World Medical Association to promote and defend the rights of subjects and patients participating in research studies. Other areas of service include:

• Physician medical education • Human resources planning for healthcare services • Patient safety • Public health policy and projects, such as tobacco control and immunization • Democracy-building for new medical associations, especially in new or developing

democracies • Leadership and career development • Torture of prisoners • Occupational health and safety (World Medical Association [WMA], 2013)

Every clinical trial has an independent group of experts who comprise a Data Monitoring Committee or Data Safety Monitoring Board (DSMB) that monitors progress of the clinical trial and ensures that it is conducted, recorded, and reported in accordance with the study protocol, standard operating procedures (SOPs), good clinical practice (GCP), and other applicable regula- tory requirements. The Committee also periodically reviews unblinded data and has the power to terminate a trial because (a) the treatment arm has demonstrated statistical significant benefits compared with the control, (b) for futility (little evidence of a difference between treatment and control), or (c) for safety issues (Ellenberg, Fleming, & DeMets, 2002).

Institutional review boards (IRBs) Institutional review boards (IRBs) approve and oversee ongoing clinical trials to ensure the pro- tection of the rights, safety, and well-being of human subjects. Institutions that accept research funding from the federal government must have an IRB to review all research involving human subjects (even if a given research project does not involve federal funds). IRBs make sure that all subjects have consented to be in the trial and that study protocols are upheld. IRBs are sometimes called independent ethics committees (IECs) or ethical review boards. For more on IRBs, see http://inside.bard.edu/irb/.

Other measures In March 2004, the FDA launched the Critical Path Initiative (CPI), a project that is intended to improve: the development processes of drug and medical devices; the quality of evidence gener- ated during development; and the outcomes of clinical use of these products. In addition, the Therapeutic Discovery Project Tax Credit included in the Affordable Care Act (ACA) is intended to spur innovation and increase investment for orphan drug development (drugs that treat rare medical conditions), medical devices, and other proven interventions.

In 2001 an Institute of Medicine (IOM) report, Crossing the Quality Chasm, reported that the use of e-prescribing could help reduce medication errors and reduce healthcare expenditures spent on treating adverse drug events (Odukoya & Chui, 2012). After receiving a special push from the HHS, adoption of e-prescribing systems to improve patient quality of care and safety is now federally mandated.

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Economics of Research

Just as the agencies involved in regulating standards of research exert considerable influence on the direction and scope of medical research within healthcare, so do the financial realities of medical research. Perhaps not unsurprisingly, the sources of research funding often have a size- able effect on the nature and direction of research.

In the past, scientists were free to pursue scientific research unfettered by the need to obtain funding. They drew on their personal resources and generally worked without government or other institutional interference. Things are much different today. The cost of research is such that studies are almost always funded by either private or public sources. Public and private finan- cial support of biomedical research follows cycles of plenty and scarcity. Investment in research doubled between 1994 and 2004 when adjusted for inflation (Moses, Dorsey, Matheson, & Thier, 2005). The annual growth rate was 7.8% and the United States spent 5.6% of its total health expen- ditures on biomedical research, more than any other country. Between 2003 and 2007, spending on biomedical research funding increased from $75.5 billion to $101.1 billion, an annual growth of only 3.4%, or 4.5% of U.S. total health expenditures. Blame for the decrease in spending on medical research is attributed to economic instability and upheaval in the world’s financial mar- kets. Funding from all sources is likely to continue to shrink as a result of decreases in endow- ments and increased taxes.

Who funds research? The majority of public and private funding for biomedical research comes from industry (medi- cal device, biotechnology, and pharmaceutical companies), government agencies (state, local, and federal), private foundations (e.g., the Bill and Melinda Gates Foundation), public charities, medi- cal research organizations (e.g., the Howard Hughes Medical Institute), and voluntary health organizations (e.g., American Cancer Society). Table 9.1 shows the top 10 foundations awarding grants for health, which includes medical research, in 2009.

Table 9.1: Top 10 U.S. foundations awarding grants for health*, 2009

Foundation State Total awarded ($) No. of grants

Bill and Melinda Gates Foundation WA 1,717,253,472 424

The Susan Thompson Buffett Foundation NE 294,332,494 147

The Robert Wood Johnson Foundation NJ 278,676,296 670

The California Endowment CA 146,441,151 490

Bloomberg Philanthropies NY 83,026,738 7

The Community Foundation for Greater Atlanta GA 52,205,973 111

Doris Duke Charitable Foundation NY 52,110,800 32

Robert W. Woodruff Foundation, Inc. GA 51,340,068 8

The Starr Foundation NY 50,789,975 25

The California Wellness Foundation CA 47,807,500 271

* Grants for health include: general and rehabilitative health; mental health and crisis intervention; multipurpose services and services associated with specific diseases, disorders, and medical disciplines; and medical research.

Source: Foundation Center, Foundation Stats. Retrieved from http://data.foundationcenter.org/#/fc1000/subject:health/all/ top:foundations/list/2009 and http://taxonomy.foundationcenter.org/subjects

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Cost of research The NIH and industry collectively contributed $90.2 billion to medical research funding in 2007 and $88.8 billion in 2008. Industry (58%) was the largest funder, followed by the NIH (27%). Other significant contributors included state and local governments (5%), private sources (4%), and other federal funding (5%). Table 9.2 shows the funding for biomedical research by source.

Table 9.2: Funding for biomedical research by source, 2003–2008

Source of funding

As reported by

U.S. $ in billions

2003 2004 2005 2006 2007 2008

National Institutes of Health

National Science Foundation

26.0 27.3 27.9 27.7 27.8 27.9

Other federal Calculationa 2.0 3.6 4.0 4.8 5.2 NA

State and local government

National Health expenditure accounts

4.2 4.5 4.6 4.8 5.2 NA

Foundations, charities, and other private funds

National Health expenditure accounts

3.3 3.4 3.7 4.0 4.3 NA

Pharmaceutical firms Pharmaceutical Research and Manufacturers of America

27.1 29.6 31.0 34.0 36.6 38.4

Biotechnology firms Burrill & Company 9.3b 10.5 11.9 12.2 15.3 14.9

Medical device firms U.S. Securities and Exchange commis- sion filings

3.6 4.2 4.8 5.9 6.7 7.6

Total 75.5 83.1 87.9 93.4 101.1 incomplete

Adjusted totalc 92.3 97.9 99.7 101.2 105.6 Incomplete

Adjusted total, National Institutes of Health and industry onlyd

80.7 84.4 85.7 86.5 90.2 88.8

a Estimated as the difference between total federal funding and funding for the National Institutes of Health. b Burrill and Company reports on biotechnology companies that are not members of the Pharmaceutical Research and Manufacturers of America and that were not available in 2003. Linear regression was used to generate an estimate for 2003. c Adjusted for inflation to 2008 dollars by the Biomedical Research and Development Price Index. d Adjusted for inflation to 2008 dollars by the Biomedical Research and Development Price Index. Totals for 2008 reflect funding from the National Institutes of Health, pharmaceutical, biotechnology, and medical device firms.

Support from pharmaceutical, biotechnology, and medical device companies increased by about 25% between 2003 and 2007. However, the number of approvals for new and novel drugs and devices did not increase. Table 9.3 shows the new drugs and devices that were approved by the FDA between 2003 and 2008.

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Table 9.3: New drug and device approvals by U.S. Food and Drug Administration, 2003–2008

Category 2003 2004 2005 2006 2007 2008

New molecular entities 21 31 18 18 16 17

Biologic license applicationsa 5 2 4 2 3

Device pre-market application approvalsb 33 46 32 38 25 25

a The Food and Drug Administration reported biologic license approvals beginning in 2004. b Numbers include instruments, implantables, patient monitoring, diagnostic devices, and in-vitro tests.

Source: Dorsey, E. R., de Roulet, J., Thompson, J. P., Reminick, J. I., Thai, A., White-Stellato, Z., . . . Moses, H. (2010, January 13). Funding of US biomedical research, 2003–2008. Journal of the American Medical Association, 303(2), 137–143. doi:10.1001/jama.2009.1987

The federal stimulus bill, the American Recovery and Reinvestment Act of 2009 (commonly referred to as the Stimulus) injected $10.3 billion into medical research and is directing more money toward health services research and information technology. The ACA added pressure to direct even more funds toward new tools to evaluate the clinical value of new drugs, procedures, and technology. Although biomedical research provides treatments that are more effective, and drives economic development and new commercial products, the rate of increase in funding is slowing. Funding for research at colleges and universities fell behind in the mid-2000s, suggesting that private funding sources, which more often fill in the economic gap for academic research, may be drying up (Boat, 2010). An added burden is the scheduled $2.5 billion reduction in NIH funding due to the Sequestration Transparency Act of 2012.

Funding trends at present tend to favor low-risk, near-term projects, and late-stage clinical trials rather than new drug discovery, which is increasingly being farmed out to small biotech firms. The cost of care and the use of the research dollar are receiving added scrutiny as we face the challenges of an aging population, greater burdens of chronic diseases, an increased sense of obli- gation toward disease in the developing world, and new or refractory (resistant) infections (e.g., 2009 influenza A [H1N1]).

9.5 The Impact of Research on Healthcare The positive impact that medical research has had on healthcare has not come without challenges and controversy. This section touches upon a few of the more controversial topics and discusses where health research may be heading in the future.

Challenges in Medical Research

New and exciting medical advances and challenges are appearing daily that are changing the face of healthcare. Although controversial, the use of stem cells promises to provide new therapies for cancer, heart disease, diabetes, and numerous other life-threatening pathologies. Finding new drugs to replace the drug-resistant strains of common bacteria is constantly challenging and poses significant problems for seriously ill patients. Diseases such as diphtheria and tuberculosis that were once on the almost-eradicated list are re-emerging, and not just in developing coun- tries. In 2012 a total of 9,951 new tuberculosis cases were reported in the United States (“Trends in Tuberculosis,” 2012). As one side of healthcare regresses, advances in gene therapy, imaging, and molecular medicine offer hope that all disease may one day be curable or prevented.

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Stem cells Stem cells are unspecialized cells that are capable of renewing themselves through cell division and have the capacity to develop into many different cell types. In the future, they may serve as an internal repair system for damaged organs or tissue. Although stem-cell research has raised hopes for a range of new therapies, it has done so at the cost of intense ethical debate. There are several sources for stem cells; the best known are embryonic stem cells and adult stem cells.

Most embryonic cells are derived from embryos developed from eggs that have been fertilized in an in-vitro fertilization clinic and then donated for research purposes with the informed con- sent of the donors. Adult stem cells, on the other hand, are cells that have not yet “specialized” (undifferentiated cells). These cells have the ability to self-renew and to differentiate in order to yield some or all of the major specialized cell types of the tissue or organ in which they are found (National Institutes of Health [NIH], 2012b). Adult stem cells are often used without ethical debate for bone marrow transplants, skin stem cell therapies for burns, and limbal stem cells for corneal replacement. Because they are restricted in the types of cells they can become, they are not thought to be as useful as embryonic stem cells. Currently no medically accepted treatments use embryonic stem cells; their importance as a potential therapy lies in their ability to differenti- ate into any human cell type.

Much of the controversy surrounding the use of embryonic stem cells centers on perceived dif- ferences concerning the status of the human embryo. Current technology requires that human embryos be destroyed to obtain their stem cells. Governments are divided on the subject of whether or not to allow the production of embryonic stem cell lines. For example, Finland, Greece, the Netherlands, Sweden, Italy, and the United Kingdom permit the production of embryonic stem cell lines, but Austria, France, Germany, and Ireland do not. In the United States, research with existing cell lines can be publicly funded, while new embryonic stem cells can be generated only if private funding is used. Table 9.4 outlines the two sides of the ongoing stem cell debate.

Table 9.4: Arguments for and against federal funding of embryonic stem cell research

For Against

• Adult stem cells lack the versatility of embryonic cells, making them less likely to lead to breakthrough medical discoveries compared to embryonic stem cells.

• The research is too important to be left to private researchers; researchers are required to share data when their work is federally funded.

• Using frozen human embryos that would otherwise be discarded is ethically acceptable given the potential that stem cells hold.

• Performing research on embryonic stem cells is effectively destroying life, and it should therefore be avoided.

• Twenty years of research has not produced a single approved treatment or human trial using embryonic stem cells.

• The side effects of embryonic stem cell therapy are quite severe: It tends to produce tumors and malignant carcinomas, cause transplant rejection, and form the wrong kinds of cells.

• The necessity of harvesting a woman’s eggs for further embryonic research increases the risks associ- ated with superovulation or high-dose hormone therapies. Risks include cancer, infertility, memory loss, stroke, seizure, and death.

• Embryonic research brings about increased possibili- ties for future commercial exploitation of women (poor women, in particular) to collect their eggs.

Source: U.S. federal stem cell legislation. (2007). The Center for Media and Democracy. Retrieved from http://www.sourcewatch.org/index.php?title=U.S._federal_stem_cell_legislation#_note-39

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New approaches to stem cell research are being investigated that would make it possible to use only one or just a few cells from an embryo, rather than completely destroying the embryo. In addition, pluipotent stem cells—cells that can give rise to any fetal or adult cell type—have been derived from umbilical cord blood. With these advances the debate may subside.

Antibiotic resistance The increasing number of drug-resistant strains of common bacteria is quickly becoming an important public health concern. As this section is being written, news stories are circulating regarding carbapenem-resistant Enterobacteriaceae (CRE), a family of bacteria that are difficult to treat because they have high levels of resistance to antibiotics. Examples of Enterobacteriaceae include Klebsiella species and Escherichia coli, both of which are a normal part of the human gut bacteria. CRE infections most commonly occur among patients whose care requires devices like ventilators, urinary or intravenous (vein) catheters, and patients who are taking long courses of certain antibiotics. Some CRE bacteria have become resistant to most available antibiotics; infec- tion can be deadly.

Other bacteria species (e.g., Staphylococcus aureus, Pseudomonas aeruginosa, Clostridium dif- ficile, Escherichia coli, and Mycobacterium tuberculosis) are also developing drug resistance. Although drug resistance is not a new phenomenon, the widespread use of antibiotics in both human and veterinary medicine has created selective pressure for the resistant bacteria to sur- vive, while the susceptible bacteria die off (D’Costa et al., 2011). Multidrug resistance varieties allow for the spread of resistance between bacterial species (Todar, 2009).

Although the increase in resistance has mostly been attributed to misuse or overuse of antibiot- ics, other contributing factors have been suggested, such as the use of antibiotics in livestock feed and their inclusion in household soaps and other products.

New and more effective anti-bacterial treatments are needed, but the actual number of new drugs is in decline (Donadio, Maffioli, Monciardini, Sosio, & Jabes, 2010). The pharmaceutical industry is reluctant to invest large sums of research and development money to develop drugs that may have little payback. Antibiotic resistance, therefore, poses a significant problem, and physicians fear that they may not have effective treatments for their seriously ill patients in the near future.

New and re-emerging diseases Fifty years ago, specialists in the field looked forward to the eradication of most infectious dis- eases within their lifetime, but as of today, only smallpox has been eliminated. Meanwhile, the World Health Organization has identified polio and measles viruses among the next targets for global eradication. Re-emerging infectious diseases are major health problems that went into decline then re-emerged as major problems again. The World Health Organization has sounded the alarm regarding the re-emergence of diphtheria, cholera, dengue fever, yellow fever, malaria, and tuberculosis.

Prion diseases are a group of rare, fatal brain diseases that affect animals and humans. Among these diseases are Creutzfeldt-Jakob disease (which infects humans), scrapie (sheep), and bovine spongiform encephalopathy, commonly known as “mad cow disease.”

Emerging and re-emerging infectious diseases threaten all countries, not just the developing world. Africa has seen the emergence of Ebola hemorrhagic fever, while Legionella pneumophila was first recognized during a Philadelphia Legionnaires convention in 1976. Schistosomiasis, a vector-borne flat-worm disease re-emerged in Egypt, largely as result of building the Aswan Dam. Table 9.5 provides some examples of emerging infectious diseases.

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Table 9.5: Examples of emerging infectious diseases

Disease Infection Year recognized Contributing factor

Lassa fever Arenaviridae family (virus) 1969 Urbanization and other conditions that favor the rodent host; nosocomial (hospital) transmission

Ebola hemorrhagic fever Filoviridae family (virus) 1977 Unknown natural reservoir; nosocomial transmission

Legionnaire disease Legionella pneumophila (bacterium)

1977 Cooling and plumbing systems

Hemolytic uremic syndrome

Escherichia coli 0157-H7 (bacterium)

1982 Mass food production systems

Lyme borreliosis Borrelia burgdorferi (bacterium)

1982 Conditions favoring the tick vector and deer, such as re-forestation near homes

HIV/AIDS Human immunodeficiency virus

1983 Migration to cities, global travel, transfusions, organ transplants, intravenous drug use, multiple sexual partners

Gastric ulcers Helicobacter pylori (bacterium)

1983 Newly recognized as due to infectious agent

Cholera Vibrio cholerae 0139 1992 Evolution of new strain of bacteria combining increased virulence and long-term survival in the environment

Hantavirus pulmonary syndrome

Bunyaviridae family (virus) 1993 Environmental changes favoring contact with rodent hosts

Pandemic influenza Orthomyxoviridae family (virus)

New viral strains emerge periodically

Pig-duck agriculture (possibly)

Sources: Morse, S. S. (Ed.). (1993). Examining the origins of emerging viruses. In Emerging viruses. New York: Oxford University Press; Morse, S. S. (1995). Factors in the emergence of infectious diseases. Emerging Infectious Diseases, 1(1). [Serial online]. Retrieved from http://www.cdc.gov/ncidod/EID/index.htm; National Institutes of Health (NIH). (2007). Understanding emerging and re-emerging infectious diseases. NIH Curriculum Supplement Series [Internet]. Retrieved from http://www.ncbi.nlm.nih.gov/books/NBK20370/; and Satcher, D. (1995). Emerging infections: Getting ahead of the curve. In Emerging Infectious Diseases, 1(1). [Serial online]. Retrieved from http://www.cdc.gov/ncidod/EID/index.htm

Environmental changes that led to greater contact between humans and insect/animal vectors may be the cause of the emergence of infectious diseases, such as Lyme disease (ticks), hantavirus pulmonary syndrome, and Lassa fever (rodents).

Factors related to the emergence of infectious diseases such as Legionnaires disease (air con- ditioning ducts) and hemolytic uremic syndrome (mass food production) are associated with changing technologies. Table 9.6 lists re-emerging infectious diseases.

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Table 9.6: Re-emerging infectious diseases

Disease Infectious agent Contributing factors

Cryptosporidiosis Cryptosporidium parvum (protozoa) Inadequate control in water supply; international travel; increased use of child-care facilities

Diphtheria Corynebacterium diphtheriae (bacterium)

Interruption of immunization program due to political changes

Malaria Plasmodium species (protozoan) Drug resistance; favorable condi- tions for mosquito vector

Meningitis, necrotizing fascilitis (flesh-eating disease), toxic shock syndrome, and other diseases

Group A Streptococcus (bacterium) Uncertain

Pertussis (whooping cough) Bordetella pertussis (bacterium) Refusal to vaccinate based on fears the vaccine is not safe; other possible factors; decreased vaccine efficacy or waning immunity among vaccinated adults

Rabies Rhabdovirus group (virus) Breakdown in public health measures; changes in land use; travel

Rubeola (measles) Morbillivirus genus (virus) Failure to vaccinate; failure to receive second dose of vaccine

Schistosomiasis Schistosoma species (helminth) Dam construction; ecological changes favoring snail host

Tuberculosis Mycobacterium tuberculosis (bacterium)

Antibiotic-resistant pathogens; immunocompromised popula- tions (malnourished; HIV-infected, poverty-stricken)

Yellow fever Flavivirus group (virus) Insecticide resistance; urbanization; civil strife

Sources: Krause, R. M. (1992). The origin of plagues: Old and new. Science, 257, 1073–1078.; “Measles–United States, 1997.” (1998). Morbidity and Mortality Weekly Report, 47(14), 273–276. Centers for Disease Control and Prevention.; National Institutes of Health (NIH). (2007). Understanding emerging and re-emerging infectious diseases. NIH Curriculum Supplement Series [Internet]. Retrieved from http://www.ncbi.nlm.nih.gov/books/NBK20370/; and “Pertussis vaccination: Use of acellular pertussis vaccines among infants and young children.” (1997). Morbidity and Mortality Weekly Report, 46(RR–7). Centers for Disease Control and Prevention. Retrieved from http://www.cdc.gov/mmwr/PDF/rr/rr4607.pdf

“When the proportion of immune individuals in a population drops below a particular thresh- old, re-introduction of the pathogen into the population leads to a new outbreak of the disease” (Biological Science and Curriculum Studies & Videodiscovery, 1999, p. 3, para. 22). Antibiotic drug resistance has been suggested for the re-emergence of tuberculosis and malaria. The re- emergence of diphtheria and whooping cough (pertussis) is thought to be related to inadequate childhood vaccination. Scientists are working feverishly to understand the life processes of pathogens and their interaction with the host in order to develop new vaccines or new anti- microbial drugs where none exists or where current approaches are inadequate. To disrupt the route of pathogenic transmission, public health measures are being developed to ensure a safe water supply; more effective sewage treatment and disposal; and food safety, animal control, and vaccination programs. The NIH funds research on how the immune system interacts with a host pathogen, identifying where vaccines might be able to prevent disease.

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New Directions

The subject of the future of research is explored in detail in Chapter 12. This chapter concludes by looking briefly at some of the research directions that will likely have the biggest impact on healthcare in the coming years.

Integration of diagnostic imaging and therapy It is now possible to visualize tumor properties (including molecular structure), tissue texture, oxygenation, and tumor blood vessel structure using diagnostic imaging techniques such as mag- netic resonance imaging (MRI). Combining this information with genetic sequencing to identify gene expression has the potential to inform drug therapy selection, surgical/radiological inter- ventions, adjunct therapy, and monitoring. For example, using imaging or DNA sequences to identify cancer patients who will not respond to a particular therapy means these patients will not be subjected to the side effects of an ineffective treatment. With the cost of some new anti- cancer drugs exceeding $100,000 (USD) per patient per year, the ability to select patients who are most likely to respond may also result in a more efficient allocation of healthcare resources and a more personal approach to treatment (Spekowius & Wendler, 2006).

Gene therapy Gene therapy is a process through which a defective gene that is responsible for a disease pro- cess is either replaced with a normal gene or repaired, or the regulation of the abnormal gene is altered. The process usually involves inserting a normal or modified version of the gene into a viral vector, which carries the gene into the targeted tissue.

Like many new therapies, gene therapy had a controversial start: A young patient who received gene therapy for a genetic disorder died 4 days later from multiple organ fail- ures. The FDA has not approved any human gene therapy protocol to date. Experimental studies have had success with treating Gaucher’s disease (a dysfunction in the liver and spleen), phenylketonuria (an amino acid metabolic disorder), and Duchenne muscular dystrophy (an x-linked recessive form of muscular dystrophy).

An experimental approach with curative genes in humans born with the ocular dis- order retinal dystrophy reported restoring partial sight in these patients (Bainbridge et al., 2008). Factors limiting the usefulness of

gene therapy at this point include the short-lived nature of DNA after introduction in the target cell, the risk of rejection due to an immune response, and the difficulty of treating multifacto- rial disorders (relating to inheritance depending on more than one gene and other contributing factors such as lifestyle and environment) with single gene therapy techniques (McBane, 2010).

There are also ethical considerations for gene therapy. For example, who will decide what is nor- mal and what is a disability? Moreover, given gene therapy’s high cost, who will be given access to treatment, and who will pay?

ERMAKOFF / BSIP / SuperStock

▲▲ Gene therapy offers new hope for the prevention and cure of diseases.

The Impact of Research on Healthcare Chapter 9

Nanotechnology Nanotechnology offers the promise of building molecular-scale machines to deliver drugs, repair cells, diagnose diseases, and kill harmful viruses.

Nanotechnology emerged as a concept in 1959 in a lecture (There’s Plenty of Room at the Bottom) by physicist Richard Feynman who proposed the idea of direct manipulation of atoms. It developed into a field in the 1980s with the invention of the scanning tunneling microscope that was used to manipulate individual atoms in 1989. Commercialization of nanoscale- based products soon followed. Some examples include the Silver Nano platform that uses sil- ver nanoparticles as an antibacterial agent, nanoparticle-based transparent sunscreens, and carbon nanotubes for stain-resistant textiles (American Elements, n.d.; Project on Emerging Nanotechnologies, 2013).

Nanoparticles are under development to deliver chemotherapy drugs directly to cancer cells, sparing the healthy cells. Some researchers are pursuing the use of gold nanorods fitted with DNA strands. In another technique, chemotherapy drugs enmeshed in a scaffold of DNA strands and gold nanorods are being used to attack cancer cells. Nanofibers have also been used success- fully to stimulate the production of cartilage in damaged joints. Lenses coated with carbon nano- tubes that convert light from a laser into focused sound waves have been used to blast tumors without harming healthy tissue.

Nanotechnology has also been applied diagnostically. Carbon nanotubes and gold nanoparticles are being used in a sensor that accurately detects oral cancer in less than an hour. Burn dress- ing coated with nanocapsules containing antibiotics shows promise as anti-microbial treatment. Designs are also underway for nanorobots programmed to repair specific diseased cells. Also on the horizon is molecular nanotechnology—the ability to build an object molecule by molecule.

Molecular medicine Molecular medicine entails building molecules that can carry out specific tasks, lock onto spe- cific receptor sites in the body, and defeat specific pathogens.

Coupled with computed tomography, MRI, and positron emission tomography (PET) scanners, molecular medicine can detail the process of the disease at the molecular level (physiologic imag- ing) rather than just identifying the location or shape of the disease (anatomic imaging). Earlier diagnoses will be possible. Imaging the actual disease process will radically alter the way medi- cine is practiced (Schimpff, 2010).

Molecular diagnostics is increasingly essential to disease management and treatment. Genetics determines how a drug is metabolized. Armed with a test to determine an individual’s drug metabolism variability, physicians will be able to use drug treatment protocols tailored to the individual, maximizing the chances of therapeutic success (Market Research.com, 2010).

Before this personalized approach to treatment can occur, however, genetic correlations with spe- cific diseases need to be validated. Clear guidance is also needed from the FDA on genetic tests; also necessary is expanded education regarding molecular diagnostics for physicians, health care workers, and the general public.

Summary and Resources Chapter 9

Summary and Resources Medical research has indisputably had a significant impact on the advancement of U.S. healthcare. Life spans have increased for both healthy and diseased individuals. The structure of research has expanded to include many subdisciplines as our field of knowledge about the functions of the body and the world has expanded. However, the process always starts the same—with a ques- tion. Historical malfeasances such as Nazi experimentation in human subjects and the Tuskegee syphilis experiments have led to ethical checks on the type of research and how it is conducted. Standards established by the Nuremberg Code, the Declaration of Helsinki, the Belmont report and the animal rights movement have established standards for ethical research procedures involving humans as well as animals.

Regulatory agencies such as the U.S. Food and Drug Administration (FDA), the International Conference on Harmonisation (ICH), the Consolidated Standards of Reporting Trials (CONSORT), and the World Health Organization (WHO) provide protocols and standards for conducting research studies. Like the agencies, private and public finance have a major impact on the direction and scope of medical research. Support for medical research is increasing as technology improvements lead to a better quality of life. Technology advancements have enabled doctors to view the mechanical workings of the heart, observe neuronal activation of the brain in real time, replace arthritic blood vessels with artificial vessels, and many more examples, some of which are discussed in Chapter 12.

Half a century ago, contracting pneumonia, cancer, or heart disease constituted a death sentence; now, an array of treatments and cures can prolong the life of those with such health problems. True, breakthroughs have come at a price. The cost for all stages of healthcare—preventive, cura- tive, and palliative medicine—remains extremely high. But the costs of medical advances are arguably justified. Consider that a mere century ago, six to nine women died from pregnancy- related complications for every 1,000 births and 10% of newborns died before they reached one year of age (“Achievements in Public Health,” 1999).

It is reasonably certain that healthcare will be more complicated in the future, but perhaps the healthcare system’s focus will be wellness and prevention, not just treatment. Research may be construed as knowledge that, when coupled with choice, equals power. When added to the right behavioral traits, power increases personal and public health. As Sir William Osler said, “If it were not for the great variability among individuals, Medicine might be a Science, not an Art” (Osler, 1892).

Key Terms

adverse events Any unwanted harmful event that occurs as a result of treatments such as medication or surgery. Also known as a side effect.

Animal Enterprise Terrorism Act A law that prohibits any person from engaging in conduct for the purpose of damaging or interfering with the operations of an animal enterprise. The law amends the Animal Enterprise Protection Act of 1992 and gives the U.S. Department of Justice greater authority to target animal rights activists.

Animal Welfare Act A federal law passed in 1966 that regulates certain animal activities, including commercial dog and cat breeding; buying animals from breeders and selling them to pet stores or other resellers; exhibiting animals (including circuses); and operating a research laboratory that uses live animals.

Summary and Resources Chapter 9

basic research Fundamental research regarding how life organisms function. Basic research can be theoretical, which attempts to prove or disprove a theory or hypothesis, or applied, which is basic research conducted on a molecular, genetic, cellular, organ, or whole animal level.

behavioral studies Systematic analysis and investigation of human and animal behavior through controlled and naturalistic observation and disciplined scientific experimentation. Includes psychology, psychobiology, and the cognitive sciences.

clinical trials Research that generates safety (adverse drug reactions) and efficacy (effective- ness) for health interventions (e.g., drugs, diagnostics, devices, therapy protocols).

CONSORT Statement Evidence-based, minimum set of recommendations for reporting ran- domized controlled trials (RCTs). It offers a standard way for authors to prepare reports of trial findings, facilitating their complete and transparent reporting and aiding their critical appraisal and interpretation.

Declaration of Helsinki A set of ethical principles established in 1964 regarding human experimentation, widely regarded as the cornerstone document of human research ethics.

double-blind A type of experimental procedure in which neither the subjects of the experi- ment nor the persons administering the experiment are aware of which treatment is being received or administered. This procedure guards against both experimenter bias and placebo effects.

Draize Test Widely used cosmetic test that involves applying small amounts of a test sub- stance to the skin or eyes of rabbits to determine harmful effects.

e-prescribing Generating, transmitting, and filling of medical prescriptions electronically to reduce error and improve readability, while maintaining consistent electronic records.

genetically modified organism (GMO) Specific controlled change that is introduced into the DNA of an organism (such as food) to improve its features.

good clinical practice A set of standards established by the International Conference on Harmonisation that defines how clinical trials involving human subjects should be conducted and defines the roles and responsibilities of clinical trial sponsors, clinical research investiga- tors, and monitors.

hypothetico–deductive model A scientific inquiry process whereby a hypothesis is either confirmed or denied by a test on observable data, and then through inference helps predict fur- ther effects that can be verified or disproved by future experiments. The model is attributed to William Whewell’s 1937 work, History of the Inductive Sciences from the Earliest to the Present Times.

institutional review board (IRB) An independent ethics committee or ethical review board designated to approve, monitor, and review medical research in order to protect human subjects from physical or psychological harm. IRBs often conduct a risk–benefit analysis to determine whether or not research should be conducted.

International Conference on Harmonisation of Technical Requirements for Registration of Pharmaceuticals for Human Use (ICH) A body of experts from the pharmaceutical industries of Europe, Japan, and the United States that recommends ways to achieve greater harmonization in the interpretation and application of technical guidelines and requirements

Summary and Resources Chapter 9

for product registration. The goal is to reduce redundancy and to eliminate unnecessary delay in the global development and availability of new medicines, while maintaining safeguards on quality, safety, efficacy, and regulatory obligations.

minimally invasive surgery Surgery involving small incisions, the use of tiny video cameras, and specially designed surgical instruments to perform surgical procedures. Compared with open surgery, this technique leads to less blood loss, reduced post-operative pain, fewer and smaller scars, and a faster recovery.

molecular medicine A field of medicine that entails building molecules that can carry out specific tasks, lock onto specific receptor sites in the body, and defeat specific pathogens.

nanomedicine A method by which microscopic particles deliver targeted treatments that interact directly with cells. Nanomedicine includes medical applications of nanomaterials, nonoelectronic biosensors, and the possible future applications of molecular nanotechnology.

nanotechnology Encompassing nanoscale science, engineering, and technology, nanotech- nology involves imaging, measuring, modeling, and manipulating matter at the nanoscale, or units denoting a factor of 10−9 or one billionth. Nanotechnology offers the promise of build- ing molecular-scale machines to deliver drugs, repair cells, diagnose diseases, and kill harmful viruses.

paradigm shift A significant change in the way one thinks about a set of principles defining a subject; one conceptual world view is replaced by another. An example is the replacement of the miasma theory of disease (the belief that diseases were a result of bad air from rotting organic matter) by the germ theory of disease.

pharmacokinetic The study of the mechanisms of absorption, distribution, changes, and routes of excretion of an administered drug.

physiological studies A type of study that provides a better understanding of how the human body functions. In vitro and in vivo are two types of physiological studies.

prospective studies Observation studies that follow the effects of a treatment or risk on the development of a disease or condition.

retrospective studies An historic cohort study that looks back at events that already have taken place. For example, in medicine, describing a look back at a patient’s medical history or lifestyle.

Tuskegee syphilis experiment Infamous clinical study conducted between 1932 and 1972 by the U.S. Public Health Service to study the natural progression of untreated syphilis in rural black men who thought they were receiving free healthcare from the U.S. government.

unblind To reveal the data from a blinded study.

vector Any agent (person, animal or microorganism) that carries and transmits an infectious pathogen (bacteria, fungi, viruses, or protozoa) into another living organism.

Summary and Resources Chapter 9

Critical Thinking Questions

1. Given what you have read in this chapter concerning ethics, do you feel that the current regulations regarding the use of humans and animals in medical research are sufficient? Why or why not?

2. The federal government exercises considerable power over the medical research process. Do you think there should be more or less government control of research? Why?

3. After reviewing the material in this chapter, speculate about future developments in research. What might be their impact on the healthcare system as a whole?

4. Read the article at http://scopeblog.stanford.edu/2011/11/07/the-economic-benefits-of- publicly-funded-medical-research/. What are some of the indirect economic benefits of pub- licly funded medical research?

5. An indigenous population of Inuit never exposed to tuberculosis (TB) is being considered for testing a new vaccination that has been shown to be fatal to some patients in similar populations unexposed to TB. What ethical considerations are relevant to a decision to test this vaccine in this population?

6. In light of past breakthroughs for cancer treatment, do you think molecular medicine rep- resents a significant breakthrough in the treatment for cancer or is it just another stop on a long road? Explain why or why not.

7. What role do you envision for molecular medicine in personalized medicine?

Suggested Resources

Papers and books

Arias, E. (2007).United States life tables, 2007. National Vital Statistics Reports. http://www.cdc. gov/nchs/data/nvsr/nvsr59/nvsr59_09.pdf

Green, D. (2005). Improving healthcare and laboratory medicine: The past, present, and future of molecular diagnostics. Proc Bayl Univ Med Cent, 18, 125–129. http://www.ncbi.nlm.nih. gov/pmc/articles/PMC1200712/

National Center for Biotechnology Information (NCBI). (2007). Understanding emerging and re-emerging infectious diseases. http://www.ncbi.nlm.nih.gov/books/NBK20370/

Spekowius, G., & Wendler, T. (2006). Advances in healthcare technology: Shaping the future of medical care. The Netherlands: Springer.

Websites

U.S. Department of Health and Human Services. Office for Human Research Protections (OHRP): http://www.hhs.gov/ohrp