Case 6 Risky Business Treating the Potential for Diseases

Is it appropriate to treat people for diseases that they don't yet have?

Suppose one of your parents or one of your siblings suffers from a condition that "runs in families"- diabetes, schizophrenia, hypertrophic cardiomyopathy, behavioral problems. You've seen the toll that the condition has taken on the affected person and on your whole family. You are offered the chance to be in a clinical trial to see if early treatment will stave off the disease in you. Do you take a chance and agree to a treatment for a disease that may or may not eventually come your way?

Suppose you live in an area where an infectious disease is paralyzing people and killing them. Would you volunteer to be one of the first to try a new vaccine?

Here are three studies in which subjects participated in clinical trials directed at treating or preventing their "potential" diseases.

Polio Vaccine Trials

The "Polio Pioneers" were 1.8 million first, second, and third graders in the United States who participated in a massive clinical trial to test the effectiveneses of a polio vaccine in 195

Some kids received three injections of the newly developed Salk vaccine against polio. Others got placebo injections. Kids in a third group were merely observed. Each child got a button and a certificate when the program ended.

Polio was terrorizing the country. In 1952, close to 58,000 people in the United States contracted the disease, and more than 21,000 of them had lasting paralyses. The numbers of victims rose after World War II, and some speculated that soldiers who had been stationed in Southern Europe and Northern Africa carried the virus back to the States with them.

In 1957, the first year in which the Salk vaccine was widely used, only 5000 people contracted polio. In 1960, a second vaccine-the Sabin vaccine-was introduced, and it eventually became the standard polio vaccine. The numbers of victims continued to drop. In 1991, one boy in Peru contracted polio. He is the last documented person to contract polio in the Western Hemisphere.

Salk and Sabin approached vaccine development differently. Each vaccine contains the three "types" of polio viruses-I, II, and III. But Salk's vaccine is given in three shots, each containing a preparation of killed viruses of just one of the three polio types. These are followed by "booster" shots, which boost the immune responses to all three. Sabin's vaccine contains all three types of viruses mixed together, still alive, but in weakened-attenuated-states. People swallow the Sabin vaccine, so it is easier to take.

The Sabin vaccine, with its live viruses, carries greater risks and greater benefits than the Salk vaccine. The risks, which pertain to any live vaccine, are that the live, attenuated viruses might revert to their virulent forms and cause disease. In addition, the viruses can spread, infecting not just the person who was vaccinated but also persons who come into contact with the vaccinated individual ("contact polio"). The Sabin vaccine is classified and licensed as "unavoidably unsafe"; it is risky but it is also beneficial to society.

In 1994, an international committee certified that polio no longer existed in the wild in the Western Hemisphere. Today, in the United States, the risk of contracting polio from a virus naturally is about equal to the risk of contracting the disease from the Sabin vaccine.

The 1954 polio vaccine trials were conducted before informed consent was mandatory for clinical trials in the United States. In fact, parents were eager for their children to participate, to be Polio Pioneers, because they saw the devastating effects that polio produced.

The campaign against polio was both grassroots and governmental. Franklin D. Roosevelt contracted polio in 1921 and, although he mostly hid his own illness, he held a series of Presidential Birthday Balls to raise money to support research on polio: "To dance so that others may walk." Radio personalities-Eddie Cantor, The Lone Ranger-carried the campaign into American homes in the 1940s by asking their audiences to send in just a dime to the White House. The day after their appeals, the White House received 30,000 envelopes instead of the usual 5000. The next day, 50,000 letters poured in and, by the third day, 150,000. Then the campaign moved into movie theaters, where ushers would go up and down the aisles with a hat collecting coins after the audience watched film shorts of movie stars appealing for donations. Late in the 1940s, the campaign was taken up by mothers-the Mothers' March of Dimes-and this continues today.

Polio remains a problem outside the Western Hemisphere. In 1988, more than 35,000 people throughout the world contracted the disease, and the World Health Assembly adopted the goal of eradicating the disease globally by the year 2000. They didn't meet that goal by the turn of the century, but they are getting close.

Many countries have instituted National Immunization Days, during which, on one or two days a year, all children of a certain age are vaccinated. In 1995, for example, 121 million children in India were vaccinated in one day, and some 51 countries immunized approximately half of the world's children. In El Salvador and other countries, wars have been halted-these are called "days of tranquility"-for a few days so that children can receive immunizations. In fact, the Peruvian boy who had the last known naturally occurring polio infection was not fully protected, because the local clinic where he was receiving his shots had been destroyed by guerrilla fighters.

The United States's vaccination program continues, because polio will remain a threat in this country as long as the virus exists somewhere in the world. For many people in poor countries, though, polio is just one threat to life and wellbeing, and it may not even be the most serious threat. Should policymakers in industrialized countries impose on poorer countries their plans for global eradication of polio when malaria, diarrhea, malnutrition, and other diseases exact a much greater toll on life-both its quality and length-than does polio?

Behavior

One hundred boys in New York, ranging in age from six to ten, participated in three research projects to find out whether the levels of the brain chemical serotonin could be correlated with aggressive behavior.

The boys were chosen for the study not because they had shown aggressive behavior but because their brothers had. Each boy had an older brother who was in jail or a mother who was considered by the researchers to be doing a poor job rearing her sons.

The studies took place in a hospital. Each boy received a single dose of the drug fenfluramine, which increases serotonin levels. Then, the boy had to stay in the hospital bed for 5 hours, during which time numerous blood samples were taken. He could not eat for 17 hours. At the end of the study, each family received a gift certificate for $125 to spend at a local toy store.

Supporters of the study said that aggressive behavior is a growing problem and that finding the causes of aggression and stopping aggression are crucial for any society that expects to continue functioning.

But, opponents found the study to be greatly flawed. First, none of the boys had actually shown aggressive behavior; each was in the study because his brother or mother was aggressive or objectionable. Second, all came from poor families; 44% were African American, 56% were Hispanic, and none were white. Had they been discriminated against? The researchers claimed that the mix of children in their study was representative of the community in which the study was done. Third, the boys endured hunger, pain, discomfort, and inconvenience and yet would not receive any direct benefit from the study. Fourth, the drug is one component of fen-phen, which was recalled as a diet pill in 1997, because it seemed to cause heart valve defects. Was this drug too dangerous for children? Should these boys have been made to be "their brothers' keepers?"

Hypertrophic Cardiomyopathy

Cardiologist Lameh Fananapazir, M.D. observed that his adult patients with the heart disease hypertrophic cardiomyopathy (HCM) felt better and had fewer symptoms-dizziness, and an inability to catch their breath-after they received pacemakers. He wondered if pacemakers might also help children: Could a pacemaker alleviate symptoms in a child who was already showing evidence of HCM? Could a pacemaker actually prevent HCM in healthy but at-risk children by stimulating and perhaps regulating their heartbeats early in life?

Without treatment, the downhill course of the disease involved worsening dizziness and breathing difficulties that soon were unremitting, irregular beating of the heart because the walls had thickened and blood flow was slowed, and eventual death from stroke or heart failure.

Fananapazir recruited a number of children from families in which adults had HCM and implanted pacemakers in the children's chests. In some families, every child, with or without symptoms of HCM, received a pacemaker. The implant procedure is quite invasive, and pacemakers are "usually too dangerous to remove [because] up to 27 inches of wires [are] threaded through the patient's veins."

Almost immediately, children who received pacemakers and who had been debilitated by HCM experienced nearly miraculous improvements. One girl who had been confined to a wheelchair began rollerblading.

But, as time passed, problems developed, and many were serious. Children who had been perfectly healthy when they got their pacemakers began experiencing uncontrolled racing of their hearts. An 8-year old who had been a star basketball player on her elementary school team said her pain was so intense that you "might as well just go ahead and kill me." Another girl, who had lived a relatively healthy life using medication to control HCM, collapsed and died on the school playground after telling a friend that she felt dizzy.

Around the time that the experiments in children began going bad, new data showed that the pacemaker-associated improvements in adults were only short term. After two years, most of the adults were feeling as uncomfortable as they had been before their pacemakers were implanted.

Fananapazir's work came under fire. He was accused of using scare tactics and exaggerating the risk of death from HCM in order to increase the enrollment of children in his studies. He was accused of inadequately informing subjects of the risks and benefits of alternative treatments for HCM. He was accused of being untruthful about the success rate of pacemakers. And he was suspected of having a financial conflict: pacemaker manufacturers paid him to speak at universities and hospitals, and they donated many thousands of dollars to fund his research. The sales of pacemakers doubled, largely as a result of publicity about Fananapazir's work.

Then, in February 2000, a study published in the New England Journal of Medicine supported Fananapazir's contention that implanted pacemakers could save the lives of people with HCM.

Included References

Science 1997, January 3; 275:40-4
Harry Hull, Pax Polio.
Time 1995, October 30; 8
Christine Gorman, When the Vaccine Causes the Polio.
Nature 1998, April 23; 392(6678): 74
Meredith Wadman, Row Erupts Over Child Aggression Study.
Nature 1998 June 18; 393(6686):610, Meredith Wadman, Review Board Head Defends FenFluramine Tests.
Wall Street Journal 1996 June 12; p. A1, A10, Moss.

Additional Resources

Polio

American J. Public Health 1997 June, 87(6):922-925.
American J. Public Health 1997 June, 87(6):913-916.
Patenting the Sun: Polio and the Salk Vaccine, Jane S. Smith, William Morrow and Company, Inc. NY, 1990.
Behavior
Institutional Review Boards: A System In Jeopardy. United States Congress. House Committee on Government Reform and Oversight. Committee on Human Resources. Washington, DC: Government Printing Office, 199
179 p. [Hearing on June 11, 1998; Serial No. 105-166] Testimony and discussion about fenfluramine studies.
New York Times 1998, April 15, B3, Hilts.
HCM
Washington Post 2000, February 10, A2.
Circulation 1994 December 90(6):2731-2742.
Pacing Clinical Electrophysiology 1997 February; 20(Part 2): 478-501.
New England Journal of Medicine 2000 February 10, 365-373.
General
Video: Winding Your Way Through DNA. Video about genetic inheritance and genetic predisposition to disease. Pyramid Media, Santa Monica, CA http://www.pyramidmedia.com.

Aims

Students should understand the following:

Difference between frank disease and potential for disease
Physical effects of polio
How vaccines protect against infectious diseases
Mass immunization programs
Controls in the polio program were both placebos and observed controls
Global health versus local priorities
Effects of grassroots activities that bring about political and social change
Role of Roosevelt and his friends in supporting polio research
Structure of the human heart
Actions of the heart's natural pacemaker
Function and implantation of artificial pacemakers
Informed consent
Purpose of clinical trials
Hypertrophic cardiomyopathy
Brain chemistry involved in behavior
Dangers inherent in using medical experiments to address social problems
Opportunities to coerce children and their parents to participate in clinical trials
Problems associated with prophylactic experimental treatments

Topics for Discussion/Written Assessment

Does benefit to the society-at-large from the Sabin vaccine outweigh the risks of possible disease in a small number of individuals who will get the disease from the vaccine?
How much influence should donors of money have in how local health agencies deliver health care?
A small number of individuals who receive Sabin polio vaccines (one per 11.5 million doses) actually develop polio. And, some cases of "contact polio" develop in individuals who come into contact with those who were immunized. Who should be liable for their disease: the vaccine manufacturer or the U.S. Government, which insists on immunization of all children? Support your choice.
The same factors that make the Sabin vaccine more effective than the Salk vaccine are responsible for making the Sabin vaccine more dangerous. What are these factors?
People who did not die of polio in the 1940s but were paralyzed by it would call themselves "polios." What psychological effects might such complete identification with a disease have on an individual? What social factors make it unlikely that today people would want to be called by the name of their disease?
The mass immunization trial included both placebo controls and children who were just observed. What was the reasoning behind using these two groups of controls? Why did some people argue that the children in the placebo group should get a vaccine (if the vaccine worked) sooner than the observed controls?
Should policy makers in industrialized countries impose plans for global eradication of polio on poor countries? If yes, what responsibilities should they assume to help with the vaccinations and with improving health services generally in those countries? If no, why not?
HCM is inherited and its incidence is 1/500 people (500,000 Americans). Ten percent of those with HCM are at high risk of sudden death. Is this a large enough number to justify giving pacemakers to all people with HCM? Why?
What theories account for criminal behavior? What sorts of experiments have been directed at understanding criminal behavior? What progress has been made toward finding a genetic basis for aggression? What are the concerns and criticisms about such research?
How does the criminal justice system punish and/or rehabilitate those who break the law?
Should participants in behavioral research receive the same protections provided to participants in medical research? What protections should each group be guaranteed?
What ethical concerns arise in research into criminal behavior? How are these concerns similar to or different from those associated with research on physical diseases and conditions? How are these concerns heightened by a study that only involves persons from minority groups?

Extension Questions for Further Investigation

Compare National Immunization Programs in rich and poor countries. How effective have they been in reducing the numbers of people who contract polio? How are the mass immunizations carried out?
What systems are in place in the United States to compensate individuals who develop polio as a result of getting the vaccine?
In some communities in the United States, the Rotary Club has raised money to donate to the National Immunization Program. Find out if your local Club has been involved in this outreach project and exactly what they have done.
FDR developed polio when he was a young man. He hid his paralysis as much as he could. What has changed or not changed since his time with respect to the public's acceptance of disabilities in public figures?
When the stock market crashed in 1939, the country was said to be "paralyzed," "stricken," "having trouble getting back on its feet," "crippled." These metaphors fit with the image of FDR, who was a living example of someone who rose above his own paralysis. Research the role that FDR's personal situation had in making him the right person to bring the United States out of its difficult situation.
Today polio is not a major problem in the United States. The numbers of new cases each year are small. Roughly the same number of people acquire polio from viruses in the wild as contract the disease from the vaccine. But in many poor countries polio continues to harm children, injuring them for life. And, because the virus can be transmitted from one infected person to others, the West is eager to eradicate the disease globally. To what extent should the West dictate to other countries what they should do about polio? Consider in your answer that, in some countries, polio is a minor problem compared to other infections (malaria), chronic conditions (diarrhea), and malnutrition.
How high a priority is eradication of polio in countries of Africa and Asia? Choose one country to study. Find out what diseases are endemic there, what the expenditures for health care are per person per year, and where the eradication of polio stands on the country's healthcare priority list.
The first major polio epidemic in the United States took place in 1916. Between then and the 1950s, major epidemics broke out in many cities and states-Topeka, Los Angeles, Chicago, Tulsa, New York City, New Jersey, Annapolis, Middletown CT. Find out what happened at one of these locations and how the health care community responded.
Many victims of polio spent years breathing with the help of iron lungs. How did these work? Find out what life was like in an iron lung.
What is known about the inheritance of HCM? What is known about the inheritance of behavioral problems? What is the difference between the two? What other diseases and conditions are (or are thought to be) inherited in the same way?
Was there evidence that the doctors who did the aggression study with fenfluramine were singled out or held to a different standard from other researchers? Children have received fenfluramine in other studies that evaluated the drug's effects on behavior and brain chemistry. Do you think that people were concerned because the drug was being used to study aggression (rather than some other behavior) and because all the subjects were from minority populations? Is the drug more suspect now than before, because it has been linked to heart problems when used in combination with other drugs to treat obesity?
Schizophrenia is a devastating psychological condition that affects 2.5 million Americans. Researchers are evaluating whether powerful antipsychotic drugs might halt the disease in people who have the potential to develop it. What factors might people consider as they weigh whether to take strong psychotropic drugs? How can risks and benefits of the drug versus the risks of getting the disease be assessed?
In September 1999, Jesse Gelsinger died in a gene therapy trial at the University of Pennsylvania. Gelsinger had a condition called ornithine transcarbamylase deficiency. He was able to control the symptoms with a low-protein diet and medications (he took 32 pills a day). At the time of the trial, he was reasonably healthy. He was eager to participate in a trial that might help others in the future. Gelsinger tried to enter the study when he was 17, but he was made to wait until he could give consent on his own (age 18). After Gelsinger died, information concerning the study was released. Find out how the study was conducted. What was wrong with the study? Who might have benefited financially, professionally, and medically?
Under what circumstances should experimental research be carried out on individuals who show no symptoms or disease or whose symptoms can be controlled with diet, exercise, medications, and other "standard" treatments?
How are results of experimental studies reviewed? When and how do results of successful studies become standard forms of therapy?
What is the purpose of peer review? Why is peer review important? Can mistakes occur in a system that includes many levels of review?

Topics for Teacher Preparation

Roles of placebo controls and observed controls
Social and political factors that affected polio research
Differences between frank disease and disease potential
Trials in the days before informed consent
General attitudes about disease in the 1940s and 1950s
How vaccines induce immunity
Differences in Salk and Sabin vaccines
Role of industrialized countries in global eradication of polio
Responsibilities of industrialized nations to poor nations
Structure and function of the human heart
The heart's electrical conduction system and the heart's natural pacemaker
Hypertrophic cardiomyopathy
Clinical trials and subject selection
Informed consent
Genetic predisposition to disease and actual risk of disease
Aggressive behavior and brain chemistry