Drug Addiction

, a breast oncologist and bioethicist, is the author of The Ends of Human Life and the creator of the Medical Directive living will form. Virginia waddled down the corridor to an examination room. Her ankles were terribly swollen and her eyes were tinged with yellow. Five years earlier, she had been treated for a very small and early-stage breast cancer. For a while, she was fine--teaching third-graders, living with her husband and four children. Then, at age 56, her cancer came back. She began having difficulty breathing, and a CT scan revealed the cancer had metastasized to her lungs and liver. After a year and a half, the conventional drugs stopped working, but Virginia wanted to fight, and she opted for experimental drugs. The day she came to the office, Virginia had just completed a trial of a second experimental agent, but it had failed to halt the growth of the tumor in her liver.One of the hardest parts of being an oncologist is explaining to a patient that her battle has come to an end. This has been made more difficult by the growing number of experimental drugs and treatments that give dying patients hope. While I began talking to Virginia about palliative care and hospice, all she wanted to know was if there was another experimental drug that she could take. I told her that her liver was not functioning adequately and her performance status--her energy level and the amount of time she spent resting in bed--excluded her from more trials. But, regardless of her eligibility, Virginia still wanted access to experimental drugs. Like many young, desperate patients, Virginia was willing to stake almost anything--hair loss, infections, nerve or lung damage, nausea and vomiting, even a high chance of death--on the unlikely prospect that an unproven drug could extend her life. Recently, the courts decided that such a gamble is the prerogative of terminally ill patients like Virginia. On May 2, the District of Columbia Circuit Court ruled, in a 2-1 decision, that dying patients have a constitutional right to any experimental drug that has passed the safety phase of human testing--Phase I--even while the drug's effectiveness is still unproven and undergoing research. The case, Abigail Alliance v. von Eschenbach (for the FDA), was inspired by a 21-year-old with head and neck cancer named Abigail Burroughs. In 2001, Abigail had exhausted conventional cancer treatments and wanted to get an experimental agent, Erbitux, being developed by ImClone--the biotech company of Martha Stewart fame--or another drug, Iressa, being developed by the pharmaceutical giant AstraZeneca. But, like Virginia, Abigail was too frail to qualify for the research trials. She died just three months after conventional treatments failed. Shortly after her death, her father, Frank Burroughs, started the Abigail Alliance for Better Access to Developmental Drugs, a nonprofit organization, which fights to ensure that cancer patients, no matter how sick and weak, can have their insurance companies buy any experimental drug that has passed safety testing. To this end, the Alliance sued the FDA. But, while the D.C. Circuit Court ruling in favor of the Abigail Alliance might seem like a victory for patients like Virginia, it's not. What cancer patients really need are new drugs that are proven to fight and cure cancer, not access to an array of unproven chemicals that provide false hope. Furthermore, drugs with minimal safety testing could actually increase the suffering of patients dying of cancer. If implemented, the Circuit Court's ruling threatens the very research process that gets drugs tested and quickly delivers safe and effective ones to the most patients. This could force us to relive the types of historic tragedies that shaped federal drug policies in the first place. In the summer of 1937, Harold Cole Watkins, the chief chemist and pharmacist for the S.E. Massengill Company, set out to make a liquid form of sulfanilamide, a popular drug used to treat strep throat. He quickly discovered that sulfanilamide dissolves in diethylene glycol, and, after adding a raspberry flavor to the concoction, the company sent shipments of the new elixir across the country. But, rather than curing patients, the elixir caused severe abdominal pain, vomiting, and convulsions. Within two months, more than 100 people in 15 states, many of them children, had died. The solvent--diethylene glycol--was a form of anti-freeze. For most of our history, drug manufacturers have had minimal oversight. After the Civil War, various patented remedies and cures--what became known as "snake oils"--were developed and sold to unsuspecting people. Many of the so- called treatments of the late eighteenth and early nineteenth centuries made people vomit or explode with diarrhea. But, despite the need, there was little ability to test and regulate these concoctions. Doctors did not know how to design a real research study to see if a drug worked; even the statistical techniques necessary to evaluate a study were only just being developed for farming and had not migrated to health care. Around the turn of the twentieth century, clinical research matured sufficiently to begin early drug-testing, although without today's scientific rigor. In 1906, Congress passed the Wiley Act, which gave the government power to recall drugs that were adulterated or misleadingly labeled. This was an attempt to get "cures" for diabetes and other worthless potions off the market. But the sulfanilamide tragedy created a public furor, and, in response, Congress passed the 1938 Federal Food, Drug, and Cosmetic Act, which required manufacturers to prove that drugs are safe before they can be marketed. It took another tragedy for Congress to increase FDA regulation. In 1960, the Richardson-Merrell pharmaceutical company in Cincinnati submitted an application to the FDA to sell a drug called Kevadon. It was the very first application for Frances Oldham Kelsey, a new medical officer. After reviewing it, she decided that data from early safety trials were inadequate, and she delayed the approval. But other countries did not. European doctors, who had been prescribing the drug to pregnant women under the name Thalidomide, began to report an increase in deformed newborns. By the time the dangers of the drug were understood, thousands of deformed babies had been born. As a result, Congress passed the Kefauver-Harris Amendments, which required proof of efficacy before drugs could be sold. The Thalidomide tragedy reminds us that even the early trials for safety (the Phase I trials) are not--and are not intended to be--foolproof tests of safety. Something safe enough to be subjected to further research does not imply it is safe enough to be sold to patients. Typically, these early Phase I studies are done on 20 to 80 patients. Many side effects, such as the deformities found with Thalidomide, just don't show up in the early-phase studies. Subsequent trials that typically involve hundreds and thousands of patients--though they focus on the efficacy of the new drugs--are also designed to closely monitor safety. The Abigail Alliance approach would eliminate this kind of careful monitoring on larger groups of patients before widespread access becomes available. Instead, unproven drugs would be tested for safety in fewer than 80 people and then could be sold to patients. The benefit of a few desperate patients would come at a steep cost for the rest of us, especially the Virginias and Abigails of tomorrow. It would make it much harder to get people to enroll in research studies and get the data necessary to show whether a drug really was effective or not. Why should people enroll in a randomized, controlled study--where they could be put in the group receiving only conventional treatment--when they could just get their insurance to pay for whatever drug they thought was best? We have had experience with this "expanded access" folly before. In the late '80s and early '90s, there was tremendous excitement about treating metastatic breast cancer with bone-marrow transplants. The procedure was grueling and included risks like organ damage, life-threatening infections, and even death, and there was little scientific evidence it actually worked. But people were convinced it was a cure and persuaded many states to enact laws mandating insurance companies pay for transplants. Large, government-funded, randomized clinical studies were designed to evaluate its effectiveness, but over 20,000 women got transplants outside the trials. It took years to enroll just 1,000 women to complete the research. The results: bone-marrow transplantation was not effective compared with regular chemotherapy. Precious time was wasted due to delayed enrollment. Thousands of women were unnecessarily subjected to bone-marrow transplants--and hundreds died in the process, often in isolation rooms separated from their families. Millions, if not billions, of dollars were spent on a substandard treatment. If, as in the case of bone-marrow transplantation, the Abigail Alliance's "expanded access" delays research, then future patients with cancer will suffer because they will have access to fewer proven treatments. Americans will get access to unproven experimental agents for a few patients at the expense of more, faster research and access to proven treatments for every patient. This is the height of irrationality born of desperation. And it is the major reason why many, if not most, cancer advocacy groups oppose the Abigail Alliance's effort. As the National Breast Cancer Coalition put it: "[A] policy expanding availability of investigational new drugs for individuals outside of clinical trials will weaken the move towards more and better research, expanded clinical trials, and access to care for all Americans." Expanded access would also rob the rest of us who may never need a cancer treatment. Individuals and society in general are struggling to pay the nation's $150 billion-plus drug bill. And that is for medications proven to work. Now add the requirement that insurance companies pay for drugs we don't know work, and you have a formula for financial disaster. Costs would skyrocket as we pay billions through our insurance premiums and Medicare taxes for worthless drugs. Given these problems, why did the D.C. Circuit Court want to go back to the snake-oil days? Citing a physician-assisted suicide case, Washington v. Glucksberg, the Court argued that a "mentally competent, terminally ill adult patient [has a substantive due process right] to access potentially lifesaving post-Phase I investigational new drugs." Essentially this makes access to unproven drugs a fundamental constitutional right, not just an interest that can be weighed against other interests. This sets an almost impossibly high bar for the FDA to overcome to restrict access to these drugs. More important, the Circuit Court seems to have gotten the assisted-suicide cases wrong. Chief Justice William H. Rehnquist made clear in both Cruzan v. Director (the 1990 case about terminating life-sustaining treatments) and Vacco v. Quill (a 1997 assisted-suicide case) that the right is not a right to die but to not have intrusive life-sustaining treatments imposed against one's wishes, based "on well established traditional rights to bodily integrity and freedom from unwanted touching." A right to bodily integrity does not imply a right to demand medical treatments. The Circuit Court majority disingenuously claimed that the right it is recognizing is narrow, applying to terminally ill patients, but a constitutional right such as this cannot be so restricted. What about people suffering from multiple sclerosis, rheumatoid arthritis, congestive heart failure, diabetes, or any number of illnesses? They too would have the constitutional right to demand access to whatever experimental drugs they wanted, especially if there were no proven treatments for their debilitating condition. This is hardly narrow. The court also made an argument from history: "[T]he government has not blocked access to new drugs throughout the greater part of our Nation's history. Only in recent years has the government injected itself into consideration of the effectiveness of new drugs." This is pure historical revisionism. The reason the government failed to limit access to new drugs in the nineteenth century was not based on philosophical or legal objections to such regulation but on limits of science and statistics. Finally, the court all but ignored the fact that the FDA has not been deaf to the concerns of patients like Abigail. For example, in 1987, the FDA established something called a Treatment Investigational New Drug (IND). This has allowed tens of thousands of terminally ill patients to quickly access drugs before they are approved for general sale. The FDA gives Treatment INDs on the condition that the drug has shown some evidence of being effective (not just safe, as the Abigail Alliance would have it) and that giving it to the patient won't inhibit the collection of research data. But the advantage is that the administration of the drug is carefully monitored for safety. Amazingly, the Circuit Court's majority does not even acknowledge the existence of such a process, although, as the dissenting judge makes clear, the majority was well-aware of it. If we're not protecting a dying patient's right to safe and effective drugs, what exactly are we protecting with rulings like Abigail Alliance v. von Eschenbach? What the Circuit Court seeks to preserve on behalf of the terminally ill is hope in a hopeless situation. As every oncologist knows, maintaining a dying patient's hope is essential to their quality of life. But maintaining hope should never be confused with delaying the research studies that could give hope to future patients or administering ever-more ineffective and unproven treatments. Often, giving toxic drugs is just an excuse for appearing to do something--no matter how futile, painful, and ultimately hopeless--rather than offering compassion. Getting Virginia another experimental drug was not going to stop her breast cancer from growing and eventually killing her. I gently explained to her that investing all her energy chasing after another unproven drug was not going to help her and her family. Virginia was disappointed and refused to consider hospice, because she saw it as giving up. Holding her hand, I talked to her about spending time with her husband and daughters and making a videotape for her future grandchildren. We also discussed getting visiting nurses to come to her house. I saw her once more in my office. She was more accepting and found at least some of the activities meaningful. Because of her failing liver, less than three months later, she lapsed into a coma and died with her family present.

By ezekiel j. emanuel