Ten years ago, doctors drilled a hole into John Gotschall's skull, inserted two catheters, and pumped a poison into his brain. Using a child's morphine pump, the team of neurosurgeons pushed diphtheria toxin into Gotschall's temporal parietal lobe over a period of four days. Eight weeks later, they did it again, reusing the same cavity and pumping in a slow stream of tissue-killing fluid.
Gotschall was not well. Shortly before he invited a team of surgeons to experiment with his cerebral tissue, the 44-year-old municipal worker had plowed his car into a snow bank on a Baltimore street. When he woke up at the hospital, doctors told him he'd had a seizure at the wheel. An MRI revealed the cause of that seizure: a tumor deeply embedded in his brain tissue. There are different grades of brain tumor, many of them slow-growing. Gotschall had glioblastula multiforma (GBM), brain cancer in its most aggressive and deadly form, and he likely had only months to live.
Gotschall's physicians initially ordered chemotherapy and radiation, the same weapons with which doctors have fought cancers for decades. Neither worked. After he exhausted the standard options, he started searching for nonstandard ones. His neuro-oncologist pointed him to a group of doctors at Johns Hopkins and a drug in development called TransMID. TransMID had survived Phase I testing, in which researchers evaluate a medication's safety and appropriate dosage, and was then in Phase II, in which researchers begin to evaluate efficacy. Gotschall finally caught a break: He qualified for entrance into the trial. Along with 43 other patients, Gotschall would have a chance at a radical new treatment that might add years to his life.
TransMID is a Trojan horse: The drug attacks the tumor under the pretense of a gift. Tumors feed on iron they absorb from surrounding tissue, and the drug delivers deadly, iron-wrapped diphtheria toxin straight to the site of the disease. The method is meant to be more precise than scooping out the cancerous tissue, a technique that can be as clumsy as its cringe-worthy name, debulking.
The treatment proved immediately effective in the most dramatic way possible. Gotschall's tumor simply vanished. TransMID's newest poster child, he touted the treatment on CBS Morning News. "It is dramatic," Gotschall's neurosurgeon, John Weingart, told CBS. "I mean, there is no question that this is an unbelievable response."
Ten years later, TransMID is still not available to the public. About 18,500 Americans will be diagnosed with GBM this year, and the median patient will survive 14 months. Treatment has not advanced significantly in the last 20 years, so GBM victims will be offered more of the same: chemotherapy, radiation, and when possible, surgery. TransMID entered Phase III tests, meant to confirm efficacy and monitor the drug's side effects, last year. But most currently diagnosed GBM patients probably will never know about the drug, and most of those who do find out about it will not qualify for trials. If TransMID ever does go to market, these patients will be dead by the time it gets there.
For as long as there are lifesaving drugs in development, there will be dying patients undaunted by the dangers of an unapproved treatment. But within the strictures of the current regulatory regime, very few patients--mainly those who, like Gotschall, meet the criteria for clinical trials--are granted the freedom to risk their lives in the face of certain death. Consider the conditions for admission to the TransMID trial. "The tumor has to have grown 25 percent since the patient's last MRI, but it has to be under five centimeters," explains Patrick Rossi, a physician employed by Celtic Pharma, TransMID's manufacturer. "It can't have grown into the ventricles or the brain stem. The patients have to have failed every other treatment: chemo, radiation, stereotopic radio surgery, any kind of oncology agent, grandma's soup, voodoo, you name it."
To terminally ill patients who do not qualify for such trials, and typically cannot receive drugs until they are deemed effective by the Food and Drug Administration (FDA), this obsession with clinical control can appear deadly and cruel. As TransMID trickles through the FDA pipeline, GBM continues to kill thousands of Americans every year. Most patients who don't meet the criteria for admission to clinical trials will not be granted the right to risk their lives with a developmental treatment.
Since the 1960s, when randomized, double-blind clinical trials became a standard requirement for bringing new drugs to market, clinical researchers have confronted the chaos of disease with the trappings of a regimented, uncompromising order. Drug trials are rooted in centralized authority: trial slots are numbered, subjects handpicked, control groups maintained, patients monitored. Maintaining this level of precision requires not only the cooperation of willing test subjects, but the coercion of the general population. To preserve pristine testing conditions, the federal government curtails our freedom of exchange and our right to take risks. Ailing individuals and drug companies are prohibited from trading in unapproved drugs, and terminal patients forbidden to experiment outside a clinician's watch.
This approach to drug testing is rife with serious ethical problems, but the preconditions for meaningful change are mind-boggling. The current clinical trial regime is cemented in place by legal restrictions that prevent patients from waiving their rights to sue and a regulatory regime that resists even incremental change. Alternatives to the standard placebo-controlled, closed clinical trials exist, but guarantees that such trials will lead to a drug's approval do not. A system meant to facilitate innovation in drug development is itself resistant to change.
With billions of dollars on the line, the clinical trial industry has never been more powerful. But in an age of increasing patient autonomy, the walls surrounding the drug testing system are under assault like never before. An organization called the Abigail Alliance for Better Access to Developmental Drugs is suing the FDA, claiming a constitutional right to trade in lifesaving pharmaceuticals. The group wants to crack open the system, to give patients and their doctors the right to choose between taking experimental, often dangerous drugs and dying untreated.
To the dismay of the medical establishment, bioethicists, and many groups representing cancer patients, a federal appeals court has ruled in the alliance's favor. As the case continues to wend its way through the courts, doctors, researchers, and even patients warn that the suit could bring the drug development process to a screeching, lethal halt.
The FDA runs on $1.5 billion a year, while the global clinical trial industry is worth roughly $10 billion. The Abigail Alliance, based in its founder's home in Fredericksburg, Virginia, subsists on $50,000 a year in donations. Its one full-time employee is Frank Burroughs, father of the late, eponymous Abigail.
Burroughs, now in his sixth year of advocacy, has lost many of his most important co-members. After last year's ruling in the alliance's favor, the FDA argued that the group no longer had legal standing to sue it, since none of the patients who had signed the original affidavits were still members. They were all dead.
The alliance launched its assault on the FDA in 2001, right after 21-year-old Abigail Burroughs died while fighting for access to developmental treatment for head and neck cancer. In 2003, Frank Burroughs and his pro bono lawyers at the Washington Legal Foundation, a public-interest litigation group, filed a federal lawsuit in D.C. They maintain that terminal patients have a constitutional right to lifesaving experimental drugs that have passed the first phase of FDA testing--the phase that establishes the safety and tolerability of a treatment. The right to self-preservation through access to experimental drugs, the alliance argues, is a substantive due process right, implicit in the Fifth Amendment principle that no person may be deprived of life, liberty, or property without due process of law. The Supreme Court has used substantive due process reasoning, which is highly controversial among legal scholars, to recognize unenumerated constitutional rights to abortion, to private sexual activity, and to send children to private schools. The Abigail Alliance argues that it also protects the right of terminally ill patients, acting on a doctor's advice, to obtain potentially lifesaving medication when all other alternatives have been exhausted.