Emerging Medical Technologies: PDF

1 Emerging medical technologies: high stakes science and the need for technology assessment In the past century, advances in medical technol- ogy have yielded enormous improvements in human health. For example, our scientific understanding of the immune response and the resulting development of vac...

1 Emerging medical technologies: high stakes science and the need for technology assessment In the past century, advances in medical technol- ogy have yielded enormous improvements in human health. For example, our scientific understanding of the immune response and the resulting development of vaccines has vastly reduced the incidence of many infectious diseases. Smallpox has killed more people throughout history than perhaps any other infectious disease. Yet, in 1980, the World Health Organization announced that smallpox had been eradicated world- wide through a program of vaccination (Figure 1.1). Despite these advances, many medical technologies are available to only a small segment of the world’s popu- lation that can afford them. Today, emerging technologies have the potential to transform the future of healthcare, offering the potential to diagnose and prevent disease before it strikes, to treat disease in a targeted manner, and to utilize cells and genes for patient-specific therapies. For example, gene therapy offers the promise to cure fatal genetic diseases such as cystic fibrosis and to reprogram a patient’s immune system to more effectively fight HIV/AIDS, the leading cause of death in sub-Saharan Africa. Sequencing the genome of M. tuberculosis has pointed to new molecular targets for more effective drugs to Figure 1.1. The development of the smallpox vaccine and the treat tuberculosis. Small silicon chips containing every subsequent eradication of the disease is an example of a powerful gene in the human genome may soon be used to detect medical technology. CDC/ World Health Organization; Stanley O. cancer at the earliest and most curable stages and to Foster. 2 Biomedical Engineering for Global Health individually tailor therapeutic agents for each patient. which can significantly impact world health. Through- Tissue engineering holds the promise to create artificial out the book, we present and apply tools to system- organs, overcoming problems with the limited supply atically evaluate these new medical technologies. The of donor organs. Novel, biologically active materials book is organized to address four central questions. may be used to coat blood vessels within the heart to prevent heart attacks, one of the leading causes of death in the United States. Four central questions addressed (1) What are the major human health problems worldwide and how do these differ throughout Medical technology the world? The use of novel technologies to develop new (2) Who pays to solve problems in healthcare and drugs, biologics, or medical devices designed to how does this vary throughout the world? diagnose, treat or prevent disease. (3) How can we use technology to solve world Bioengineering health problems? The application of engineering design to develop (4) How do new technologies move from the new medical technologies. laboratory to the bedside? Biotechnology The use of living systems to make or improve new (1) What are the major health products, frequently targeted toward improving problems worldwide? human health. Global mortality data show a significant gap in health status between developed and developing countries. What is needed to bring these new technologies from Leading causes of death in the developed world include the research laboratory to your physician’s office in cancer, ischemic heart disease, and stroke. In the devel- a safe and affordable way? As a society, how should oping world, infectious diseases like tuberculosis and we invest our limited financial and human resources to malaria are far more prevalent owing to widespread develop new medical technologies? Can new technolo- poverty, poor infrastructure, and a lack of healthcare gies reduce global disparities in health or will they sim- resources. A child born today in one of the least devel- ply widen the gap in health status between developing oped countries is more than 1000 times more likely and developed countries? In this textbook, we examine to die of measles, an easily preventable and curable how bioengineers integrate advances in the physical, disease, than one born in an industrialized country. information and life sciences to develop new medical Worldwide, more than 31 million adults and 2.0 million technologies. To be effective, new healthcare technolo- children are living with HIV/AIDS, most in developing gies must provide a better means of preventing, detect- countries. Over the next decade, noncommunicable dis- ing or treating disease. At the same time, technologies eases such as diabetes and heart disease are expected to must also be affordable to those who need them. The overtake infectious diseases and malnutrition as lead- goal of bioengineering is to harness science to solve ing causes of death in developing countries. The frac- health problems in the face of such constraints. Our tion of the global burden of disease linked to lifestyle study of bioengineering for world health is organized to and behavior choices, currently 20–25%, is expected to first understand both global health needs and resource increase throughout the world – for example, by 2020 limitations – as we will see, the healthcare problems and tobacco is expected to kill more people than any single economic constraints vary dramatically throughout the disease, even HIV/AIDS. Understanding how health world. With this beginning, we profile new technolo- needs differ throughout the world and how these needs gies emerging from biotechnology and bioengineering are projected to change in the coming years is the first  Emerging medical technologies 3 Table 1.1. Average health care expenditures per capita of selected UN Millenium Development Goals WHO nations. Some 80% of the world’s population live in Country Avg. Health Care Expenditure per developing countries. In 2000, 189 countries capita, 2001 (US$) committed to a broad set of goals to meet the needs Liberia $1 of the world’s poorest citizens. The goals include India $24 the following. China $49 Eradicate extreme poverty and hunger ! Halve the proportion of people whose income is Colombia $105 Mexico $370 less than one dollar a day by 2015. ! Halve the proportion of people who suffer from Portugal $982 hunger by 2015. Israel $1641 Switzerland $3779 ! Eliminate gender disparity in primary and Achieve universal primary education United States $4887 secondary education in all levels of education by 2015. step to enable the development of new technologies to address these needs. ! Reduce the under-five mortality rate by two thirds Reduce child mortality by 2015. (2) Who pays to solve problems in healthcare? ! Reduce the maternal mortality ratio by 75% by Improve maternal health Despite recent advances, many medical technologies are available only to a small segment of the world’s pop- 2015. ulation. As a result, standards of medical care differ ! Halt and begin to reverse the spread of HIV/AIDS Combat HIV/AIDS, malaria and other diseases radically between the developed and developing world. Average annual healthcare expenditures in high income by 2015. ! Halt and begin to reverse the incidence of malaria countries are more than $1800 per person, compared to only $16 per person in the world’s least developed and other major diseases by 2015. countries (Table 1.1). Even in high income countries, the cost of new medical technologies is of great con- ! Halve the proportion of people without Ensure environmental sustainability cern. Over the past two decades, healthcare spending has risen dramatically in the United States and through- sustainable access to safe drinking water and out the industrialized world, and this rise is expected to sanitation by 2015. continue through the next decade. In the USA, health- Develop a global partnership for development care costs now account for one seventh of the nation’s expenditures. The increasing use of new, expensive The Millenium Country Profiles technologies, an aging population, and increased admin- (http://unstats.un.org/unsd/mi/mi.asp) provide a istrative costs all contribute to the overall rise in health- source of data to compare economic and health care spending. As we will see later, increasing health status of countries and to monitor progress toward expenditures does not always improve health status. As these goals. health spending grows beyond a minimum value, there is a decreasing rate of return on investment, with fewer years of life gained per dollar invested. In order to achieve the promise of new technologies worldwide, 4 Biomedical Engineering for Global Health Major areas of bioengineering Tissue engineering and regenerative medicine The use of engineering design principles to regenerate natural tissues and create new tissues using biological cells and three dimensional scaffolds of biomaterials. Molecular and cellular engineering Engineering approaches to modify properties of molecules and cells to solve biotechnological and medical problems. Computational bioengineering Use of computational tools to analyze large biological data sets such as in genomics or proteomics; computational models to predict structure and behavior of large biological molecules and to guide design of new drugs. Biomedical imaging Design of imaging systems (e.g. ultrasound), image analysis tools, and contrast agents to record anatomic structure or physiologic function. Biomaterials The engineering design of materials compatible with biological organisms that can be used to make implants, prostheses, and surgical instruments that do not provoke immune rejection. Drug delivery Design of materials and systems to achieve controlled release of drugs in physiologic systems. Biomechanics The study of mechanical forces in living systems and the use of engineering design to create prosthetic devices and tools for rehabilitation. Biosensors Engineering design of systems to identify and quantify biological substances. Advances in microelectronics have aided in developing miniature, implantable biosensors. Biosystems engineering Modeling complex, interacting networks of biological systems within cells and organisms to understand physiology and disease and suggest therapeutic strategies to modify behavior. our society must develop and evaluate technologies in resonance imaging, radiation therapy, and vaccines are a cost-conscious manner. all examples of health-related technologies that have become widespread within the past century. The heart– (3) How can bioengineering solve global lung bypass machine, pacemakers and other technolo- health problems? gies have revolutionized the treatment of heart disease, Technology development begins with scientific knowl- reducing cardiovascular mortality by half over the past edge; in health issues this often means an understand- 50 years. In this book, we will consider how new tech- ing of a disease and its effects on the body. Bioengi- nologies can be used to diagnose, treat, and ultimately neers build on this scientific knowledge to create new prevent the three leading causes of death throughout technologies that solve healthcare problems. Magnetic the world: infectious disease, cancer, and heart disease.  Emerging medical technologies 5 As we will see later, the development of new healthcare Answers to these four questions are complex and technologies must take into account the societal and interrelated. We begin our journey to understand how economic context in which they will be used and their bioengineering can be used to improve world health potential status as a priority or a luxury at a given time. by examining a case study of the development of a For example, development of a totally implantable artifi- new technology – the use of high dose chemotherapy cial heart may provide a solution to the problem of end- and bone marrow transplant to treat advanced breast stage heart failure in developed countries, but owing cancer. This case study illustrates the difficult personal to differences in infrastructure and resources is unlikely and social issues that can arise as new technologies are to be a practical solution in many developing coun- developed and tested, and will introduce many of the tries. To help illustrate these challenges, throughout this issues that we will examine in more detail throughout book, we will profile the experiences of several under- the text. We conclude our case study with a look at how graduate students who carried out internships in sub- the process of healthcare technology assessment can be Saharan Africa as a part of a course in Bioengineering systematically used to address these complex and sen- and World Health. Their experiences highlight both the sitive issues in a scientifically sound manner. opportunities and challenges of developing new tech- nologies to improve world health. Case study: breast cancer and bone marrow transplant (4) How do new technologies move from the Breast cancer is both a devastating and a common dis- laboratory bench to the patient’s bedside? ease. If you are female and live in the United States, New medical technologies developed in research labo- you have a one-in-eight (12.5%) chance of develop- ratories must be subjected to a rigorous testing proce- ing breast cancer sometime in your life. When dure to ensure that they are both safe and effective. In detected early, there are many effective treatments for many cases, this involves carrying out experiments with breast cancer. However, few effective treatments exist human subjects. How can we ensure that these exper- for the disease in its later stages. Less than 20% of iments are carried out in an ethical way? How can we women are alive five years after the detection of Stage balance the desire to bring promising new treatments IV metastatic breast cancer, the most advanced form to patients who need them as soon as possible against of the disease. In the 1980s a promising new therapy the risk of harming patients by allowing them access was developed for women with metastatic breast can- to therapies that haven’t been sufficiently tested? As cer: high dose chemotherapy followed by bone marrow healthcare consumers we are often faced with conflict- transplant (HDCT+BMT). ing media reports of the safety of new medical technolo- Small, early clinical trials of this technique were very gies. In order to make choices about our own healthcare, promising. The effectiveness of a new cancer treat- it is necessary to understand how medical research is ment is initially measured by the fraction of patients funded and how new drugs and medical devices are who experience a complete or total response follow- regulated. ing treatment. In the 1980s, a number of small stud- ies showed a substantial increase in the number of Learn more about breast cancer patients with metastatic breast cancer who responded Breast Cancer Facts and Figures 2005–2006. to this new therapy compared to historical experi- (Atlanta, GA: American Cancer Society, Inc.; 2005). ence for patients treated with standard chemother- apy. Although these results were exciting, they were http://www.cancer.org/downloads/STT/ viewed with caution until the patients could be fol- CAFF2005BrF.pdf lowed for a longer period of time. Many patients who initially respond to therapy may relapse; thus long term 6 Biomedical Engineering for Global Health Beyond Traditional Borders: Reports from Student Interns Kim Bennett accompanied Dr. Ellie Click across Malawi conducting intensive training at hospitals as part of a pilot project for the use of bloodspot PCR for infant HIV diagnosis. Dave Dallas and Tessa Elliott assisted in the design and implementation of World Food Program food distribution system at a pediatric AIDS clinic in Mbabane. Lindsay Zwiener and Rachel Solnick pilot-tested software that generates pictorial medication guides, which were developed as their Bioengineering & World Health course projects. They assessed whether these guides help caregivers in Botswana in the proper dosing and timing of anti-retroviral (ARV) medications, promoting adherence to ARV therapy. Christina Lagos and Sophie Kim rolled out their Bioengineering & World Health course project in the SOS Village in Maseru. The project was an after-school activities club to promote interest in science and health education with a focus on HIV/AIDS. They also implemented a Reach Out and Read program at a pediatric AIDS clinic. The course in Bioengineering & World Health was developed and offered at The University of Texas at Austin and at Rice University. Through a new initiative called Beyond Traditional Borders, made possible by a grant to Rice University from the Howard Hughes Medical Institute through the Undergraduate Science Education Program, students at Rice University can travel to Africa for a summer and implement the projects they developed as part of this course. The inaugural class of interns kept a blog describing their experiences. Throughout the book, we include excerpts from the blog to provide a student’s view of how bioengineering can improve world health. You can find more student blogs at: www.owlsbeyondborders.rice.edu  Emerging medical technologies 7 Departure: June 8th, 2007 Christina Lesotho Coming from a close family, I have been doing a lot of explaining about my goals and purpose for this trip and doing my best to calm the fears of my family. I know that they simply want me to be safe and are con- cerned about me while I am gone, and I am used to the ways of overprotective Greek relatives. In the end, I think I have convinced them that this will be the experience of a lifetime and that I have been looking forward to something like this since I began college. I was getting ready to record something in my personal journal last night and found that the last sentence I wrote the last time I made an entry had to do with Africa. From my last weeks in Washington, D.C., working on health policy in Africa, I expressed a desire to go and experience the challenges and situations first hand. “I want to go to Africa... why not me?”, that is what I had written as I wondered why it always seemed so far-fetched or impossible that I would one day be able to visit. And now it’s quickly approaching, and I feel so fortunate and excited for this opportunity. I am prepared for some of the best and worst emotions I have ever experienced and am ready to fully immerse myself in the work I am about to do in Lesotho. I feel almost guilty for having somehow cheated during this pre-departure period... I have been looking at tons of Google images of Maseru, Lesotho, and the surrounding area, and I feel like I have some sort of unfair advantage as I travel. When I was younger and did not use or have access to the Internet as much, traveling to a new place was always so much more of a mystery and I always envisioned my destination so differently than it turned out to be. I know that a bunch of Google images and travel sites will not do Lesotho justice, but I still feel like I have done away with at least a bit of the mystery of travel. Maybe I won’t do that next time. I am looking forward to spending the next few days in Johannesburg with a family-friend who grew up there. I will be there until the 12th when I will be meeting up with Sophie at the airport to head to Maseru. It will be nice to leave the hot and humid start of summer here in Florida and find the cold beginnings of winter in southern Africa! survival rates are often used as a better metric to deter- was little clinical evidence to show that it was superior mine the effectiveness of a new cancer therapy. The to standard therapy. The story of what happened three year survival rate measures the number of patients as this technology was developed and tested illustrates still alive three years after beginning cancer therapy. In how political pressures can overwhelm science, leading the early 1990s, a small study indicated that women to substantially increased medical costs and dramati- with high risk breast cancer treated with HDCT+BMT cally reduced quality of life for patients. had a 72% three year survival rate, dramatically higher than the historical experience for women treated Breast cancer in the USA with standard dose chemotherapy, which was only After skin cancer, breast cancer is the most common 38–52%. cancer among women, and accounts for almost one of These studies offered new hope to women who faced every three cancers diagnosed in women in the United high risk or metastatic breast cancer. HDCT+BMT is States. In 2005, more than 40,000 American women a grueling treatment that has been described by Dr. are expected to die of breast cancer; only lung cancer Jerome Groopman as “an experience beyond our ordi- causes more cancer deaths in women. An estimated nary imaginings – the ordeal of chemotherapy taken to 211,240 new cases of breast cancer occurred in the a near-lethal extreme.” In desperation, more than USA in 2005, and there are over 2.3 million women 41 000 American women with advanced breast cancer living in the USA who have been diagnosed with breast endured HDCT+BMT in the 1990s, even though there cancer. 8 Biomedical Engineering for Global Health Figure 1.2. Female breast cancer incidence rates by race and ethnicity in the United States as reported by SEER. The rates are age adjusted to the 2000 USA standard population. Figure 1.3. Female breast cancer death rates by race and ethnicity in the United States as reported by SEER. The rates are adjusted to the 2000 USA standard population.  Emerging medical technologies 9 Female breast cancer incidence rates have risen in the USA from 1973 to 1998, as reported by the NCI Surveillance, Epidemiology and End Results (SEER) Pro- gram (Figure 1.2). Incidence rates have increased owing Tonsil to a combination of changes in reproductive patterns (delayed childbearing, having fewer children) and bet- ter early detection with mammography. Female breast Thymus Gland cancer death rates in the USA during the same period have decreased (Figure 1.3), primarily owing to bet- ter early detection of more treatable cancers and to improvements in breast cancer treatments. Figure 1.4 shows an illustration of the female breast. Spleen After childbirth, milk is produced in glandular tissue in the breast, leading to milk ducts. This glandular tis- sue is where most breast cancers develop. When cancer Lymph Nodes cells are confined to these ducts, and have not spread to surrounding fatty tissue, the disease is called Stage 0, and is completely curable with surgical excision. Lesions which have spread to the surrounding fatty tissue but Lymphatic Vessels Chest wall Pectoralis muscles Lobules Nipple Figure 1.5. Lymphatic system. Source: SEER Training Modules, surface Lymphoma. US National Cancer Institute. 2009. http://training.seer.cancer.gov/ Areola duct are less than 2 cm in diameter are referred to as Stage I lesions, and also have excellent prognosis, with a 100% five year survival rate. A series of lymphatic vessels, leading to lymph nodes under the armpit (axillary lymph Fatty tissue nodes), drain breast tissue (Figure 1.5). Breast can- cer cells can migrate from the initial lesion and enter Skin these lymphatic vessels, providing a way for breast can- cer cells to spread to other distant organ sites (metasta- Figure 1.4. The human female breast. Source: SEER Training size). If the cancer has spread to one–three lymph nodes Modules, Breast Cancer. US National Cancer Institute. 2009. close to the breast but not to distant sites, it is referred http://training.seer.cancer.gov/ to as a Stage II lesion, and the five year survival rate is in 10 Biomedical Engineering for Global Health Table 1.2. Breast cancer staging. cells cannot repair damage caused by chemotherapy Stage Definition 5 yr drugs so they die. survival Rapidly dividing normal cells may also be affected Stage 0 Cancer cells are located within a duct 100% by chemotherapy drugs, but they can repair this dam- and have not invaded the surrounding age. Because chemotherapy drugs affect rapidly dividing fatty breast tissue normal cells, they give rise to many undesirable side Stage I The tumor is 2 cm or less in diameter 100% effects. The cells which line the gastrointestinal tract and has not spread to lymph nodes or distant sites. divide rapidly; thus chemotherapy can lead to nausea, Stage II The cancer has spread to 1–3 lymph 81–92% vomiting, mouth sores and loss of appetite. Cells in the nodes close to the breast but not to hair follicles divide rapidly and chemotherapy can lead distant sites to hair loss. Rapidly dividing cells in the bone mar- Stage III The cancer has spread to 4–9 lymph 54–67% row which produce oxygen carrying red blood cells, (High risk) nodes close to the breast but not to infection fighting white blood cells, and platelets impor- distant sites tant in blood clotting are also affected by chemotherapy Stage IV Cancer has spread to distant organs 20% (Metastatic) such as bone, liver or lung or to lymph drugs. Chemotherapy patients are thus at high risk for nodes far from the breast. infection, bleeding and fatigue. While these side effects Reprinted by permission of the American Cancer Society, Inc. from are temporary, chemotherapy can also produce perma- www.cancer.org. All rights reserved. nent side effects such as premature menopause and infertility. the range 81–92%. Stage III breast cancers involve more than four nodes, and because the five year survival rates High dose chemotherapy are so low (54–67%) are referred to as “high-risk breast Because chemotherapy can damage both cancer cells cancers.” In metastatic breast cancer (Stage IV), the dis- and rapidly dividing, but crucial, normal cells, can- ease has spread from the lymphatics to other organ sites cer treatment must strike a balance between com- far from the breast, such as the brain. The five year sur- pletely destroying all cancer cells while causing vival rate for metastatic breast cancer is only 20%. The minimal damage to normal cells. In the 1980s a stages of breast cancer and the prognosis for each stage number of dose comparison studies of chemotherapy are summarized in Table 1.2. to treat metastatic breast cancer showed that a higher dosage of chemotherapy was associated with a higher Treatments for breast cancer response rate. Scientists and clinicians hypothesized There are many treatments for breast cancer. Treatment that metastatic breast cancer could be treated more for most early cancers involves some form of surgery effectively with higher doses of chemotherapy. Unfor- to remove the cancer cells. If the lesion is small, only tunately, such high doses completely destroy the bone a portion of tissue may be removed (lumpectomy), marrow, leaving patients with no way to continue to or the entire breast may be removed (mastectomy). produce the cells of the blood system and the immune Larger tumors may be treated using chemotherapy. system, which are necessary for life. In some cases, chemotherapy may be used to shrink Our blood consists of four components: plasma, red larger tumors so that they can be removed surgically; in blood cells, white blood cells, and platelets. Plasma others it may be used following surgery to reduce risk of carries nutrients and hormones throughout the body. recurrence. In chemotherapy, drugs which are toxic to Red blood cells deliver oxygen throughout the body, cancer cells are given intravenously or by mouth. These while white blood cells are necessary to fight infec- drugs travel through the bloodstream, reaching cancer tions. Platelets are necessary for blood clotting following cells throughout the body. Chemotherapeutic drugs injury. Throughout our lives, our blood cells are con- interfere with ability of cells to divide; many cancer tinually renewed within the bone marrow. The source  Emerging medical technologies 11 Figure 1.6. Red and white blood cells are derived from cells of the bone marrow. of all these cells is the pluripotent hematopoeitic stem (PBSCs) which are found in the blood. In a transplant, cell which can give rise to all the types of blood cells these stem cells are isolated from the blood in a pro- (Figure 1.6). Laboratory experiments in mice show that cess known as apheresis. The patient is given medica- a single stem cell can yield the half-trillion blood cells tion to increase the number of stem cells in the blood- of an entire mouse. Clinicians theorized that if the stream. Next, blood is removed from the body through bone marrow was completely destroyed in high dose a central venous catheter and passes through a machine chemotherapy, a bone marrow transplant could be done that removes the stem cells (Figure 1.7). The blood is to restore these hematopoeitic stem cells; in fact such then returned to the patient and the collected stem cells bone marrow transplants had proven very successful in are stored for future transplantation. The entire process the treatment of cancers of the bone marrow. takes 10–12 hours, and yields enough stem cells to fill one syringe. The initial attempts to transplant bone marrow took Learn more about bone marrow place in Cooperstown, NY during the 1950s. The transplants effects of the atom bomb used at the end of World War In his article, “Bone marrow transplant: a healing II sparked a tremendous interest in identifying ways hell,” Dr. Jerome Groopman describes the to restore bone marrow. One reason that the bomb’s experience of two patients who undergo bone radiation was so deadly was because it destroyed the marrow transplants. bone marrow cells of its victims, leading to hemor- J. Groopman. Bone marrow transplant: a healing rhage (uncontrolled bleeding) and the inability to fight hell. The New Yorker (19 October 1998), pp. 34–39. off infection. At the time physicians could successfully transfuse oxygen carrying red blood cells from compat- ible donor to needy recipient. Bone marrow transplants However, bone marrow cells could not be transfused. Stem cells are found in high concentration in the bone Invariably, the recipient’s body identified them as for- marrow, and can be harvested for transplantation in a eign invaders and destroyed them. painful procedure. More recently, stem cells transplants One researcher who was especially interested in the have been carried out using peripheral blood stem cells bone marrow transplant problem was Don Thomas. 12 Biomedical Engineering for Global Health Apheresis technology Most stem cells are found in the bone marrow, but some, called peripheral blood stem cells, can be found in the blood. It is typically much more difficult to harvest bone marrow than cells in peripheral blood – harvesting bone marrow requires hospitalization and general anesthesia. Typically, the concentration of stem cells in the peripheral blood is very low, so patients are given growth factors to increase the concentration of peripheral blood stem cells for several days prior to harvesting stem cells. During apheresis, blood is removed from a large vein in the arm and sent to a machine which contains a centrifuge to separate white blood cells. Anticoagulants must be added to the blood to prevent it from clotting. The centrifuge spins the entering blood, and the resulting centrifugal force separates the various components of blood – plasma, red blood cells and white blood cells – based on differences in their density. The red blood cells are pushed to the outside of the centrifuge, while plasma remains near the center of the rotor. A layer of white blood cells called buffy coat separates the plasma and red blood cells. This layer contains the peripheral blood stem cells and is separated. The remaining blood is returned through a tube to the patient’s other arm. A successful transplant requires collection of a large number of peripheral blood stem cells – approximately five million stem cells per kilogram of body weight are required. Thus, we must quantify the number of peripheral blood stem cells harvested during apheresis to determine whether a sufficient number have been collected. When viewed through a standard microscope the stem cells can’t be differentiated from other white blood cells. However, stem cells express a protein called CD34 on their membrane. The fraction of CD34 positive cells can be quantified by labeling the cells with a fluorescent dye linked to a molecule that binds to CD34 and using a special machine called a flow cytometer to count the number of CD34 positive cells. Over 20 liters of blood must be processed (the entire blood volume must be treated four times) to collect sufficient cells for later transplant, and apheresis is typically performed over several days. These cells are then treated with cryopreservatives and frozen to be injected into the patient following the high dose chemotherapy procedure [13, 14]. Thomas treated patients with cancer of the bone mar- eign invaders and the patient’s own cells. The histo- row (leukemia) with chemotherapy. He believed that compatibility markers explained the failure of previous providing new, healthy bone marrow cells was essential transplant attempts and held the key to future success. to curing leukemia. He tested various transplant tech- When not properly matched, the patient’s immune sys- niques in dogs initially, and then in patients with late tem would reject transplanted cells. Proper matching of stage leukemia. In early trials, every patient who under- histocompatibility markers between donor and recipi- went transplantation died. “Things were pretty grim”, ent led to successful results in dogs. With this advance, Thomas later remarked. After four years of unsuc- Thomas resumed human trials, which led to successful cessful transplantations attempts, he stopped human treatment for leukemia. Thomas (Figure 1.8) received trials. the Nobel Prize in 1990 for his important work in this Eight years later, Thomas identified protein mark- area. ers on the surface of white blood cells. These his- Today bone marrow transplantation is a successful tocompatibility markers are unique to each individual treatment for leukemia. In the past 40 years the five and are found on the surface of nearly every cell in the year survival rate for leukemia has more than tripled, body, but are particularly numerous on the surface of from 14% in 1960–63 to 49% in 1995–2002. How- white blood cells. Histocompatibility markers enable a ever, it is still a gruelingly difficult treatment. Dr. Jerome patient’s immune system to differentiate between for- Groopman describes the experiences of two patients  Emerging medical technologies 13 diagnosed with leukemia. She received a bone marrow transplant, and recounts her experience in Groopman’s article. “It was a complete nightmare. For days, I’d be on all fours and just retch and retch. I looked like a lobster, and thought I had bugs crawling on me. I’d hit myself and scream. I was in that sterile bubble, and for- got what skin against skin felt like. That was lost. I just wanted to hold on to my mom or dad, like a two-year- old, and I couldn’t. I had terrible diarrhea, a blistering rash all over my body, and jaundice. I was the color of an egg yolk.” A new technology for advanced breast cancer, HDCT+BMT With the success of bone marrow transplant for leukemia, clinicians hypothesized that extremely high dose chemotherapy could be used to treat metastatic breast cancer if followed by a bone marrow transplant. In this case, the patient’s own stem cells could be har- vested prior to the chemotherapy and then reinfused Figure 1.7. An apheresis machine. Copyright Caridian BCT, Inc. following treatment, thus insuring a perfect histocom- 2009. Used with permission. patibility match. Compared to standard chemotherapy, this procedure was initially very expensive (>$140,000) who received bone marrow transplants in his article, and initial trials had very high treatment associated mor- “Bone marrow transplant: a healing hell.” Courtney tality (death) rates, in the range 7–22% [16, 17]. Despite Stevens was a high school sophomore when she was the extreme expense and side effects, the combination Figure 1.8. Don Thomas and his wife and partner in research, Dottie, with childhood leukemia survivors. Used with permission from ⃝ c Jim Linna. 14 Biomedical Engineering for Global Health of HDCT+BMT offered some of the only promise for the there was a strong public demand for HDCT+BMT, even treatment of metastatic breast cancer. An early study in the absence of good clinical evidence to indicate that it showed that the three year survival rates of women with worked. high risk breast cancer treated with HDCT+BMT were 40% higher than those of women who had not partici- Public reaction to new hope pated in the trial and had received standard chemother- In 1991, the television show 60 Minutes aired a piece apy. While this study offered hope for the new treat- decrying the company Aetna’s decision to deny insur- ment, it was criticized for several reasons. It was a small ance coverage for HDCT+BMT to treat breast cancer study, involving only 85 patients, and did not randomly. At the same time, Nelene Fox, a 38 year old mother assign women to receive either the new therapy or the of three who was diagnosed with advanced breast can- standard therapy. It also only included women whose cer, sued her insurance company. The company, disease initially responded to standard chemotherapy HealthNet, refused to pay for HDCT+BMT for Fox, even and who therefore might be expected to do better than though it had recently paid for a relative of its CEO to those whose disease was not responsive to standard receive the same treatment. Mrs. Fox and her family treatment. sued HealthNet for failure to provide coverage. In the meantime the family raised more than $210 000 so she could receive HDCT+BMT. Mrs. Fox died of breast can- Learn more about HDCT+BMT cer before a verdict was reached; her family argued that Drs. Michelle Mello and Troyen Brennan provide a the delay in receiving the treatment contributed to her more complete account of the early controversy death. The family was awarded $89M, then the largest surrounding the use of HDCT+BMT to treat breast jury verdict ever against an HMO. The case received cancer. widespread publicity, and in 1993 the Massachusetts M. M. Mello and T. A. Brennan. The controversy legislature mandated that insurers provide coverage for over high-dose chemotherapy with autologous bone HDCT+BMT for advanced breast cancer. In 1994, insur- marrow transplant for breast cancer. Health Affairs, ers approved coverage for 77% of breast cancer patient 20:5 (2001), 101–17. requests for HDCT+BMT as part of clinical trial par- ticipation. However, approval was highly arbitrary, In order to gain more evidence, several larger clini- even for similar patients covered by the same insurer. cal trials were initiated in which women with advanced Nine of 12 large insurers surveyed indicated that the breast cancer were to be randomly selected to receive threat of litigation was a major factor in their decision either standard chemotherapy or HDCT+BMT. Clini- to provide coverage. cians planned to compare the percentage of patients In 1995, the results of a small, short randomized who were still alive (survival rates) three and five years trial of 90 patients in South Africa was reported by following therapy in both arms of the trial as well as the the lead physician, Dr. Werner Bezwoda. Dr. Bez- percentage of patients whose cancer had not recurred woda’s study showed that, on average, women who (disease-free survival rates). received HDCT+BMT for metastatic breast cancer sur- Such randomized clinical trials are considered to be vived twice as long without a relapse than women the most important kind of clinical evidence to indicate who received standard chemotherapy. By this time, whether a new therapy is better, the same, or worse more than 80% of American physicians believed that than a standard therapy. Typically, in the absence of women with metastatic breast cancer should be treated such evidence, a therapy is considered to be experi- with HDCT+BMT, and these results seemingly sup- mental and most insurance companies in the USA will ported that conclusion. During the 1990s, more not pay for it. Because there are so few effective treat- than 41,000 patients underwent HDCT+BMT for breast ments available for advanced breast cancer however, cancer despite a paucity of clinical evidence regarding  Emerging medical technologies 15 Breast cancer in developing Learn more about insurance coverage for countries HDCT+BMT More than 1.2 million people worldwide were The Aetna insurance company will only pay for diagnosed with breast cancer in 2005. Women in HDCT+BMT as part of a controlled clinical trial developed countries have access to imaging sponsored by the Food and Drug Administration or technologies such as mammography and ultrasound the National Cancer Institute. This article explains to aid in early detection and to advances in their rationale. hormonal treatments and chemotherapy. However, Breast cancer: high dose chemotherapy with women in developing countries frequently do not autologous sterm cell support. Clinical Policy have access to these lifesaving technologies. Bulletins (Aetna Inc, 7 October 2005). Maria Saloniki is a 60 year old mother of ten http://www.aetna.com/cpb/data/CPBA0507.html. living in the United Republic of Tanzania. This image of her (below) is used courtesy of WHO/ Chris de Bode. When she was 57 she experienced effectiveness. In fact, it was so difficult to recruit fever, a swollen armpit and pain. Over three years, patients to randomized phase III clinical trials (because she visited local healers, various clinic doctors, and women were afraid they would be randomly selected to even traveled to Nairobi, Kenya to seek treatment. receive the standard therapy) that the trials took more She was prescribed herbal ointments, antibiotics, than twice as long to complete than planned. and told that nothing could be done for her In 1999, at the meeting of the American Society of condition. Finally, three years after her initial Clinical Oncology, the results of five randomized clinical symptoms she traveled to Dar es Salaam, where a trials were reported. Sadly and surprisingly, four of the biopsy showed that she had breast cancer and she studies showed no survival benefit with HDCT+BMT; began chemotherapy. some showed it took a little longer for cancer to return. Her husband has had to borrow a large sum to Figures 1.9a and 1.9b compare the survival and dis- finance her care, and can’t afford both the cost of ease free survival rates over time in women receiving the treatment and bus fare to come and visit her either HDCT+BMT or standard therapy in one of the tri-. als; no meaningful differences were noted in either case. Only one South African study, again from Dr. Bezwoda, showed a survival benefit. In his study, women with high-risk breast cancer had an 83% chance of five year survival if they received HDCT+BMT, compared to only a 65% chance of five year survival with stan- dard chemotherapy. The average disease free survival time was 100 months for women receiving HDCT+BMT, versus only 47.5 months average disease free survival for those receiving standard chemotherapy. The poor results of the four negative HDCT+BMT trials were widely reported in the media. Public reaction was again strong. Prior to the neg- ative trial results, in 1996–98, Anthem Insurance saw the number of women requesting HDCT+BMT for breast cancer increase. In 1999, prior to the trial results, the company expanded indications for which 16 Biomedical Engineering for Global Health (a) Scientific misconduct Scientists could not understand why one trial showed improved survival with HDCT+BMT, while four other trials showed no benefit. A team of scientists was sent to audit the results of the South African trial (Figure 1.10). Unfortunately, the audit team could not find records for many of the patients supposedly enrolled in the study. They found that the study showed little evidence of randomization, and that many patients whose records could be found did not meet the eligibility criteria for the (b) trial. They also found that the trial had not been properly approved by the Institutional Review Board at Dr. Bezwoda’s university, which is required to approve all research involving human subjects in advance. The university conducted a formal ethics inquiry, and Dr. Bezwoda admitted to a “serious breach of scientific honesty and integrity.” The university fired Dr. Bezwoda, and many of his publications were formally retracted from the journal in which they had been published. Figure 1.9. Disease free survival (a) and survival (b) rates over time in women receiving either HDCT+BMT or standard therapy from a Where are we now? randomized clinical trial. Copyright ⃝ c 2003 Massachusetts Scientists continued to follow the patients enrolled in Medical Society. All rights reserved. the five randomized clinical trials originally reported in 1999 (Table 1.3). Even with longer follow up, it appears that there is no survival benefit to HDCT+BMT Learn more about public reaction at either three years or five years following treatment as Denise Grady covered the announcement of these compared to standard chemotherapy. There is a small results for the New York Times. but significant increase in disease free survival at three D. Grady. Doubts raised on a breast cancer years with HDCT+BMT, but this advantage disappears procedure. New York Times (16 April 1999). at five years. Serious side effects are more common with Joanne Silberner covered the announcement of HDCT+BMT compared to standard therapy, but most these results for National Public Radio. are reversible. Patients report that quality of life is lower J. Silberner. Breast cancer. Radio program, at six months following treatment with HDCT+BMT, National Public Radio (16 April 1999). but similar to that of standard chemotherapy one year http://www.npr.org/templates/story/ following treatment. The costs of HDCT+BMT have story.php?storyId=1049404. been reduced to about $60,000, which is still nearly two times that of standard chemotherapy. they would approve HDCT+BMT. After the trial results Most physicians and insurance companies now agree were reported in 1999, they received only four requests that HDCT+BMT should not be used to treat high risk for such coverage, despite the expanded coverage. Most breast cancer outside of a randomized clinical trial. insurance companies now cover HDCT+BMT for breast Research in this area continues, to identify if longer cancer only as part of an FDA or NCI sponsored clinical follow up (7–10 years) will show advantages of high trial. dose therapy, or to determine if there are sub-groups of  Emerging medical technologies 17 Table 1.3. Results of five randomized clinical trials of HDCT+BMT for breast cancer [21, 28–30]. Study # Randomized % survival Disease free survival patients Stadtmauer 184 32% 3 year BMT 9.6 months BMT Metastatic 38% 3 year control 9.0 months control Lotz 61 29.8% 5 year BMT 9% disease free at 5 yrs BMT Metastatic 18.5% 5 year control 9% disease free at 5 yrs control Peters 783 79% 3 year BMT 71% disease free at 3 yrs BMT High Risk 79% 3 year control 64% disease free at 3 yrs control Rodenhuis 885 75% 5 year BMT 65% disease free at 5 yrs BMT High Risk 73% 5 year control 59% disease free at 5 yrs control p = 0.09∗ Tallman 511 58% 6 year BMT 49% disease free at 6 yrs BMT High Risk 62% 6 year control 47% disease free at 6 yrs control Figure 1.10. The results of Dr. Bezwoda’s controversial trial. women who benefit from high dose therapy (for exam- media, the courtroom or the laboratory? In an age ple those whose tumors are negative for certain genetic where high-technology treatments are one of the most markers or who have 10 or more axillary lymph nodes powerful drivers of healthcare costs, these are crucial which show cancer cells). New technologies to com- questions. pletely rid the transplanted stem cells of any rogue can- cer cells may also reduce recurrence rates in women Healthcare technology assessment treated with HDCT+BMT. However, all of these theo- Professors Frazier and Mosteller, experts in health pol- ries must be subject to rigorous testing if they ever are icy and management, have stated, “If we are to have to become methods of standard treatment. good medical care, we need to know what works, and this cannot be known without systematic technology Lessons learned assessment. The intuitions of physicians and the guesses The example of HDCT+BMT to treat breast cancer of biologists are not adequate guides to the best treat- illustrates the dangers of allowing political pressures ments.” How then do we assess new technologies to overwhelm scientific evidence. What is the proper objectively, avoiding political pressures that can lead forum to resolve such controversies? Should it be the us to waste precious healthcare resources and subject 18 Biomedical Engineering for Global Health thousands of patients to punishing, but ineffective, Homework treatments? 1. Advanced breast cancer has a high mortality. Initial clinical trials indicated that high dose chemotherapy followed by a bone marrow transplant could reduce Healthcare technology assessment the mortality rate by as much as 40%. The systematic process of evaluating the safety, a. Why did physicians and scientists believe that short term and long term efficacy, acceptability and higher doses of chemotherapy would be more cost effectiveness of a new medical technology. effective than standard therapy for advanced breast cancer? Answering these questions is increasingly important b. Why is it necessary to give patients a bone in a world where early studies of new medical advances marrow transplant following high dose can receive substantial publicity in the popular press chemotherapy? What will happen if they do not before randomized clinical trials are completed. A recent receive a bone marrow transplant? study published in the Journal of the American Medical c. In the context of this example, discuss how Association compared conclusions presented in highly political pressures overwhelmed scientific cited articles in major general clinical journals to those evidence. How could this be avoided in the of subsequent studies with larger sample size or bet- future? ter controlled design. Results showed that nearly 1/3 d. Find a news report describing a new health of highly cited studies were later contradicted and that technology published in the last year. In your this was most likely for nonrandomized studies. opinion, does this news report provide balanced As we examine these important issues in this book, discussion of the potential promise and the we will build a toolkit to help us answer politically potential limitations of this technology? sensitive questions about how to use limited resources 2. The Pew Global Attitudes Project is a worldwide in a deliberate and unbiased manner. Technology survey of public opinion. In 2002, more than 38,000 assessment will be an important part of our toolkit, and people in 44 countries were asked to assess the it is the subject of Chapter 2. quality of their own lives, their level of optimism about their lives in the next five years, and to rank problems faced by themselves and their countries. Bioengineering and Global Health Project In this exercise, you are asked to review the results Project overview of this survey and to prepare several graphs Design a new technology to solve a health problem, summarizing the results. present a mock prototype of the new technology to Pew World Attitudes Website: http://people-press. a design review committee, and design a clinical org/reports/display.php3?ReportID=165 trial to test the new technology. Pew World Attitudes Report: Throughout this text, you will use the http://people-press.org/reports/pdf/165.pdf engineering design method to design a new solution You will examine results in countries profiled in to an important health problem. You will identify an Unit 2: the United States, Canada, China, India important health problem, and carry out research to and Angola. For parts a–e, please construct understand the scope of the problem and limitations graphs, for part f provide a discussion which of current health technologies. You will follow the supports your findings. engineering method to design a new solution which a. What fraction of people surveyed in each country meets the constraints you identify. You will create a expressed satisfaction with their own lives? physical prototype of your design and will present it b. What fraction of people surveyed in each country to the class as part of a design review exercise. report that they are unable to afford food?  Emerging medical technologies 19 c. What fraction of people in each country cite the (1992–2003) and SEER 9 Regs Public-Use, Nov 2005 following as a very big problem in their country? Sub (1973–2003), National Cancer Institute, DCCPS, Poor drinking water Surveillance Research Program, Cancer Statistics Branch, released April 2006, based on the November Crime 2005 submission. AIDS and disease Surveillance, Epidemiology, and End Results (SEER) d. What fraction of people in each country believe Program (www.seer.cancer.gov) SEER∗ Stat Database: that the following is the greatest danger facing Mortality – All COD, Public-Use With State, Total U.S. the world today? for Expanded Races/Hispanics (1990–2003) and All Nuclear weapons COD, Public-Use With State, Total U.S. (1969–2003), National Cancer Institute, DCCPS, Surveillance AIDS and other infectious diseases Research Program, Cancer Statistics Branch, released e. What fraction of people surveyed in each country April 2006. Underlying mortality data provided by are optimistic that their lives will improve in the NCHS (www.cdc.gov/nchs). next five years? Silverthorn DU. Human Physiology: An Integrated f. Compare general agreement on questions 4 and 5 Approach. 2nd edn. Upper Saddle River, NJ: Prentice throughout countries in Africa and Europe. Hall; 2001. American Cancer Society. Detailed Guide: Breast Cancer: How is Breast Cancer Staged? Sep 18 2006 [cited 2007]. References Available from: http://www.cancer.org/docroot/CRI/ Health in the Millenium Development Goals: Millenium content/CRI 2 4 3X How is breast cancer staged Development Goals, Targets and Indicators Related to 5.asp Health. World Health Organization; 2004. Walker F, Roethke SK, Martin G. An overview of the Glossary of Globalization, Trade and Health Terms: rationale, process, and nursing implications of Health Transition. World Health Organization; 2007. peripheral blood stem cell transplantation. Cancer Beaglehole R, Irwin A, Prentice T. The World Health Nursing. 1994 Oct 10; 17(2): 141–8. Report 2004: Changing History. Geneva, Switzerland: Hansson M, Svensson A, Engervall P. Autologous The World Health Organization; 2004. peripheral blood stem cells: collection and Coulter SL, Cecil B. Assessing the Value of Health Care processing. Medical Oncology. 1996 Jun; 13(2): 71–9. in Tennessee. Chattanooga: Blue Cross Blue Shield of Leukemia, Lymphoma, Myeloma, Facts and Statistics Tennessee; 2003. 2006–2007. White Plains, NY: Leukemia and Breast Cancer Facts and Figures 2005–2006. Atlanta, GA: Lymphoma Society; 2007. American Cancer Society, Inc.; 2005. http://www. White K. Notebook: bone marrow transplant for breast cancer.org/downloads/STT/CAFF2005BrF.pdf cancer is questioned on basis of incomplete data. Peters WP, Ross M, Vredenburgh JJ, Meisenberg B, Journal of Women’s Health and Gender-Based Medicine. Marks L, Winer E, et al. High-dose chemotherapy and 1999; 8(5): 577–82. autologous bone marrow support as consolidation after Brockstein BE, Williams SF. High-dose chemotherapy standard-dose adjuvant therapy for high-risk primary with autologous stem cell rescue for breast cancer: breast cancer. Journal Of Clinical Oncology: Official yesterday, today, and tomorrow. Stem Cells. 1996; 14: Journal Of The American Society Of Clinical Oncology. 79–89. 1993 June; 11(6): 1132–43. Abegunde D, Beaglehole R, Durivage S, Epping-Jordan Groopman J. Bone marrow transplant: a healing hell. J, Mathers C, Shengelia B, et al. Preventing Chronic The New Yorker. 1998 October 19: 34–9. Diseases: A Vital Investment. Geneva, Switzerland: Mello MM, Brennan TA. The controversy over World Health Organization; 2005. high-dose chemotherapy with autologous bone marrow Aetna. Breast cancer: high-dose chemotherapy with transplant for breast cancer. Health Affairs (Project autologous stem cell support. Clinical Policy Bulletins Hope). 2001 Sep–Oct; 20(5): 101–17. 2005 October 5 [available from: Surveillance, Epidemiology, and End Results (SEER) http://www.aetna.com/cpb/data/CPBA0507.html]. Program (www.seer.cancer.gov) SEER∗ Stat Database: Bezwoda WR, Seymour L, Dansey RD. High-dose Incidence – SEER 13 Regs Public-Use, Nov 2005 Sub chemotherapy with hematopoietic rescue as primary 20 Biomedical Engineering for Global Health treatment for metastatic breast cancer: a randomized Horton R. After Bezwoda. Lancet. 2000 Mar 18; trial. Journal Of Clinical Oncology: Official Journal Of 355(9208): 942–3. The American Society Of Clinical Oncology. 1995 Oct; Rodenhuis S, Bontenbal M, Beex LV, Wagstaff J, Richel 13(10): 2483–9. DJ, Nooij MA, et al. High-dose chemotherapy with Tallman MS, Gray R, Robert NJ, LeMaistre CF, Osborne hematopoietic stem-cell rescue for high-risk breast CK, Vaughan WP, et al. Conventional adjuvant cancer. The New England Journal Of Medicine. 2003 Jul chemotherapy with or without high-dose chemotherapy 3; 349(1): 7–16. and autologous stem-cell transplantation in high-risk Stadtmauer EA, O’Neill A, Goldstein LJ, Crilley PA, breast cancer. The New England Journal Of Medicine. Mangan KF, Ingle JN, et al. Conventional-dose 2003 Jul 3; 349(1): 17–26. chemotherapy compared with high-dose Bezwoda WR. Randomised, controlled trial of high dose chemotherapy plus autologous hematopoietic stem-cell chemotherapy versus standard dose chemotherapy for transplantation for metastatic breast cancer. high risk, surgically treated, primary breast cancer. Philadelphia Bone Marrow Transplant Group. The New Proceedings of the American Society of Clinical Oncology. England Journal of Medicine. 2000 Apr 13; 342(15): 1999; 18: 2a. 1069–76. Grady D. Doubts raised on a breast cancer procedure. Antman KH. Randomized trials of high dose New York Times. 1999 April 16; Sect. A1. chemotherapy for breast cancer. Biochimica Et Silberner J. Morning Show: breast cancer. National Biophysica Acta. 2001 Mar 21; 1471(3): M89–98. Public Radio. 1999 April 16. http://www.npr.org/ Frazier HS, Mosteller F. Medicine Worth Paying For: templates/story/story.php?storyId=1049404. Assessing Medical Innovations. Cambridge, Mass.: Anthem. Insurance payments for bone marrow Harvard University Press; 1995. transplantation in metastatic breast cancer. The New Ioannidis JP. Contradicted and initially stronger effects England Journal of Medicine. 2000 April 13; 342(15): in highly cited clinical research. JAMA: The Journal Of 1138–9. The American Medical Association. 2005 Jul 13; 294(2): New audit uncovers scientific misconduct in 1995 South 218–28. African study on metastatic breast cancer. American Face to Face with Chronic Desease: Maria’s Story: Society of Clinical Oncology. 2001 April 26. Fighting Cancer. World Health Organization, 2005.  2 Bioengineering and technology assessment In Chapter 1, we examined the development and intro- The case study of HDCT+BMT for advanced breast duction of a new technology that initially appeared as cancer underscores the need for a systematic method if it could provide new hope to women with advanced to guide the development and introduction of new tech- breast cancer. Small clinical trials showed that women nologies. In Chapter 1, we saw how the interplay of des- with high risk or metastatic breast cancer treated with perate patients seeking the best treatment, early media high dose chemotherapy and bone marrow transplant publicity and a scientist who falsified data all combined (HDCT+BMT) had substantially better response rates to slow the progress of medical science. In the end, and survival compared to historical experience with many patients unnecessarily underwent an expensive standard chemotherapy. These early promising results and highly toxic therapy. How can we prevent this from were widely publicized, and even though the therapy happening with future technologies? In this chapter, had serious side effects, it was used to treat thousands we will consider the methodology of technology assess- of women. Usually, before a new technology is adopted, ment, which provides a systematic set of tools to deter- randomized clinical trials are conducted to compare the mine the performance of a new technology and to assess performance of the new technology to that of exist- the impact of using the technology both for individual ing technologies. In such randomized clinical trials, patients and for society as a whole. When used properly, patients are randomly selected to receive either the cur- technology assessment can help ensure that new med- rent standard therapy or the new therapy; outcomes ical technologies are introduced on the basis of sound such as response rate, survival and side effects are scientific evidence and not simply on the opinions of then compared for the two groups of patients. However, physicians and scientists, or the hopes of patients. because patient demand was so high for HDCT+BMT, As a prelude to technology assessment, we consider randomized clinical trials took much longer to com- the steps involved in bringing a new technology from plete than planned. Ultimately, randomized clinical tri- the laboratory bench to the patient’s bedside. Figure als showed that HDCT+BMT did not improve survival 2.1 shows a roadmap of this process. Bioengineers build for most patients. The promising results of early tri- on the scientific understanding of a disease to design als were misleading due to a combination of factors, new healthcare technologies. New technologies must including their small size, selection bias and scientific be rigorously tested to determine whether they are safe misconduct. and effective. This testing process can include preclini- 22 Biomedical Engineering for Global Health (b) (c) (a) (d) (e) (f) (g) Figure 2.1. A roadmap of the healthcare technology development process. Technology assessment spans the entire range of development activities. Parts (b), (e) and (f), source: Wikimedia. Part (c), source: Jupiter Images. Part (d), source: NCI/Lindia Bartlett. Part (g), source: NCI/Michael Anderson. cal testing in cell or animal models, as well as testing in The Littenberg method of technology human subjects. These tests must be carried out in an assessment ethical manner. In addition, an important consideration Benjamin Littenberg proposed a model of technology in the adoption of new technologies is whether they are assessment that is particularly useful for new technolo- cost effective. The process of health technology assess- gies. The Littenberg method asks five questions ment spans all the steps in the healthcare technology regarding a new medical technology. development process, from lab to patient. ! Biologic plausibility: does our current understanding Learn more about the Littenberg method of the biology of the disease in question support the use of the technology? ! Technical feasibility: can we safely and reliably deliver The Littenberg method of technology assessment is defined in this article and used to analyze screening the new technology to the target patients? ! Clinical Trials: do the results of randomized clinical tests for hypercholesterolemia. Littenberg, B. Technology assessment in medicine. Academic Medicine, 67(7), 424–428. trials comparing the new technology to current stan- dards of care show a benefit?  Bioengineering and technology assessment 23 ! Patient outcomes: are patients better off for having used the new technology? ! Societal outcomes: what are the costs and ethical implications of the technology? It is useful to consider our case study of HDCT+BMT in the context of the Littenberg model to see whether the technology was assessed appropriately at each level and whether that assessment supports the use of the technology. Biologic plausibility: many scientific studies sup- ported the promise of HDCT+BMT. In particular, as the dose of chemotherapeutic agent was increased to treat women with breast cancer, response rates increased. Based on these data, physicians believed patients with advanced breast cancer would benefit from doses of chemotherapy so high that it would destroy bone mar- row. Technical feasibility: mortality rates were initially quite high for breast cancer patients treated with HDCT+BMT, despite the advances in leukemia treat- ments showing that bone marrow transplantation could be safely performed. However, as more women were Figure 2.2. Multiple clinical trials have proven mammography to be treated and regimens were refined, mortality rates effective for screening for breast cancer in women. CDC. dropped substantially, improving technical feasibility. Thus initially HDCT+BMT was supported by both bio- apy; later trials examined survival. In assessing patient logic plausibility and technological feasibility, the first outcomes it is important to consider both short term two criteria of Littenberg’s method. outcomes (e.g. response rates) and long term outcomes Clinical trials: there were many small, clinical trials (e.g. survival) as well as quality of life issues. Clearly, carried out to assess the effectiveness of HDCT+BMT; patients treated with HDCT+BMT experienced a quality however, these trials were not randomized clinical tri- of life that was initially lower because of the side effects als. As we will see later, a randomized clinical trial is the of the treatment. In the end, randomized trials showed strongest source of scientific evidence to assess whether that survival rates were not substantially higher than a new technology is effective compared to current stan- those for standard treatment. dards of care (Figure 2.2). The tragedy of HDCT+BMT Societal outcomes: was society better off for hav- was the delay of completing randomized clinical trials, ing used HDCT+BMT? The new technology was sub- due to political and media pressures and scientific mis- stantially more expensive than standard chemother- conduct. By the time clinical trial results seriously ques- apy while adding no additional survival benefit. If tioning the benefit of HDCT+BMT compared to stan- HDCT+BMT had showed clinical benefit compared to dard chemotherapy were available, many women had standard therapy, then society would have to consider already undergone the treatment. the difficult question of whether the increased benefit is Patient outcomes: were women better off in the long worth the additional cost. term for having been treated with HDCT+BMT? The Thus, HDCT+BMT was not supported by the final early clinical trials assessed only response rates to ther- three criteria of the Littenberg method, a conclusion 24 Biomedical Engineering for Global Health Challenges of anti-retroviral drugs: June 13, 2007 Rachel Botswana As we will see in Chapter 4, patients who are HIV positive are treated with drugs called anti-retrovirals or ARVs. Often, patients must follow complex regimes of drugs. The situation is further complicated for HIV positive children, because drug companies currently do not make ARVs in pediatric doses. So often parents must split pills in half to ensure their children receive the correct dosage. Patients must adhere closely to the schedule of taking their ARVs or HIV can develop resistance to the drugs. This is a major challenge in treating HIV/AIDS today. I was thinking of different ways to help AIDS patients and I thought that a seven-day AM/PM pillbox would be useful. (I have used them, and I remember my grandmother used them for her multitude of pills.) Then at the beginning or end of every week, the patient or the caretaker can put all the pills (and half pills) in the proper compartments. Although this unfortunately excludes all the people who need to take syrups, I was talking with one of the patients who came in for a guide yesterday about adherence and she said it would help. She has a son in his teenage years and, while she gives him the pills most of the days, sometimes he goes out to play football (soccer) with his friends and forgets to take the pills with him. When I asked about how he would feel carrying around a pill box, and if he was comfortable taking it around his friends, she said that he didn’t mind and that some of his friends were on ARVs as well. I am getting a mixed view on exactly how prevalent or entrenched the stigma for AIDS really is. Driving down from Choebe this weekend, even in the smaller towns there were billboards about AIDS encouraging testing, a large ad for condoms, and a free condom box at the passport immigration. I also saw the first abstinence billboard, which seemed almost to contradict the “get tested” billboard on the opposite side of it. that puts the effectiveness of the technology in serious or treatments as well as systems that aid in the delivery doubt. Clearly, HDCT+BMT technology was not ade- of healthcare. The technology can address any com- quately assessed before entering widespread use, a fail- ponent along the healthcare continuum: prevention, ure that led to many women receiving a painful treat- screening, diagnosis, treatment, or rehabilitation. In ment that offered fewer benefits than initially believed. this text you will see examples of technologies ranging from simple childhood vaccinations to prevent disease Important vocabulary of technology to complex total artificial hearts to treat end stage heart assessment disease. While the complexity of the technology can dif- In the rest of this chapter, we will outline in more detail fer dramatically, the process of healthcare technology the methods of technology assessment. They will guide assessment is the same. our thinking as we examine new technologies through- The ultimate goal of health technology assessment is out the rest of the text. We begin with definitions of to inform decision making, whether it is done from the some important terms. Technology does not necessar- perspective of an individual patient or from the larger ily involve sophisticated or expensive James Bond like perspective of society. The underlying questions which gadgetry or devices. Healthcare technology can be any health technology assessment needs to address include intervention to promote health, including specific tests the following.  Bioengineering and technology assessment 25 Prevention: health interventions designed to Examples of benefits and costs of prostate prevent a patient from developing disease. cancer screening Screening: a test given to members of a defined Monitoring the level of prostate specific antigen population, not necessarily at risk for a disease, (PSA) is frequently used to screen older men to to identify those individuals who are most likely determine if they are likely to have prostate cancer. to be helped by further tests to diagnose the Invasive diagnostic testing is performed to disease. determine whether men with elevated PSA levels Diagnosis: the identification of disease through have prostate cancer requiring therapy. signs, symptoms, imaging, bloodwork, cultures, Intended benefits: screening can identify men cytologic sampling, or biopsy. with prostate cancer at an early stage, when it Treatment: a health intervention to cure disease or is still curable. to reduce symptoms of disease. Intended costs: the cost of a PSA exam is less Rehabilitation: the process of restoring skills lost to than $100. illness or injury. Unintended costs: because prostate cancer grows slowly, the new test can identify men with prostate cancer that will never cause any ! What is the clinical impact of the intervention? symptoms. These men undergo further ! What is the cost of the intervention? invasive, painful testing and treatment which ! What is the clinical impact of the intervention may be unnecessary. weighed against its cost? In order to answer these questions, it is necessary to evaluate the safety, effectiveness, cost effectiveness, and. Let’s imagine that our screening test is somewhat the social, ethical, and legal impacts of a technology. invasive and patients perceive it to be much more In this evaluation, we must consider both the direct and uncomfortable than the previous screening test. As a indirect consequences of using a health technology. result, some patients who would have been screened Direct consequences of a health technology are the with the old test now avoid cancer screening altogether, intended benefits and costs. For example, if we because of fear or embarrassment. In this case, the intro- develop a new, more accurate cancer screening test, the duction of a new and more accurate test can actually intended benefits