Novel Therapies Unavailable to Most Patients
Currently, drugs showing efficacy in clinical trials are completely unavailable to seriously ill patients who don’t qualify for trials. The drugs often can’t even be obtained on a compassionate use basis. But getting into clinical trials, no matter how ill you are, could be compared to winning a lottery because the odds of being selected can be almost as slim. This is due to the vast number of restrictive participant requirements imposed by the FDA, some of which demand that seriously ill patients with little time to waste first try—and fail—one or more other available treatments.
With no compassionate use program, Abigail’s and Jennifer’s only hope was to get into a clinical trial. In Abigail’s case, Erbitux® was found to be effective in early trials against the type of cancer cell she had, one shared by both colon and head and neck cancer, among others. Cancer, however, is characterized in trials not by its cellular properties, but by the initial tumor site. So later trials were conducted according to where the cancer is located rather than the type of cancer cell—in this case, for colon cancer only. This restriction was the primary reason Abigail was kept out of the Erbitux® trials—though she had the right type of cancer cells, her cancer was in the wrong place. Economics also played a part, as the drug company would have had to spend twice as much money to put Erbitux® on two separate approval paths.
“Increasingly narrow trial participant restrictions—and more of them—leave most terminally ill people out of clinical trials, including Jennifer McNellie. Many of the restrictions are put in place purely for statistical reasons,” says Walker. Of the patients who do qualify, only a few will be given the chance for a longer life. A Phase III clinical trial for a lung cancer drug, for example, might enroll only 700 patients, yet more than 150,000 die from lung cancer every year. Even worse, only half of those in trials will actually get the potentially life-saving drug because the FDA usually requires that 50% of trial patients—for statistical reasons—receive a sugar pill placebo. Seriously ill patients don’t know if they’re taking a new drug that could save them, or an empty placebo equal to a death sentence.
Clinical Trials Ruled by Statistics, Not Compassion
“The clinical trial system is run by statistics—a branch of applied mathematics,” notes Steve Walker. “It’s caused millions of people to die sooner than they should have and it’s all because of the FDA’s single-minded focus on statistics as the only tool to use. In any other field of science, this is sacrilege. Statisticians are a support specialty. But in clinical research, it’s considered sacrilege to question statistics. And statistics in no way reflect the reality of disease.”
Specifically, the statistic so desired by the FDA is the probability value, or p-value—the mathematical probability that the data are the result of random chance. (Data with a low p-value of less than or equal to 0.05 are considered to be “statistically significant.” A p-value of 0.05, for example, means there is a 1 in 20 probability that the data result from random chance.)
What many people don’t realize is that the current drug approval system bases the decision to approve or not approve a new drug on average results. The way this drug approval process is designed, statistical analysis evaluates the probability that a drug will have a predefined desired outcome, such as a 50% reduction in tumor size and/or number, based upon an average result.
If a new cancer drug produced a dramatic improvement in 15% of the patients with a deadly form of cancer, yet the average of all patients achieving 50% reduction in tumor size failed to achieve statistical significance, this drug would be unlikely to be approved under today’s outmoded system. But if the same drug did not produce a dramatic improvement in any patient, yet achieved statistical significance based upon an average response rate, the drug would be more likely to be approved in the current system.
Although the FDA is slowly and begrudgingly moving towards using active comparators rather than placebo in many studies, many drug approval studies in serious disease states like cancer still use placebo as a comparison. This raises significant ethical issues—why should a patient with deadly life-threatening cancer participate in a study when there is a high likelihood of receiving placebo for treatment?
Says Burroughs: “Essentially, they want people to die so they can see how many die. And that’s the cruelty of all this. Cancer trials aren’t like trials for toenail fungus cream. People’s lives are at stake here.”
The formal drug approval process needs to balance compassion with statistical analysis. The FDA’s continued insistence on using placebo instead of active comparators of approved drugs raises significant ethical questions, since the lives of seriously ill patients are at stake.
Kianna Karnes: Another Victim of the FDA’s Delay
The Alliance’s face of the placebo trials issue was Kianna Karnes, a 44-year-old mother of four and grandmother of one whose kidney cancer had spread throughout her body. By early 2005, she had little hope left, except for two developmental drugs that had shown efficacy against her type of cancer for several years, but were still unapproved.
Despite desperate pleas from Karnes’ family, supporters, and the Abigail Alliance, the FDA refused to hasten approval of the drugs. Astoundingly, the agency instead created new testing requirements that effectively shackled the drugs’ manufacturers and prevented them from giving Karnes the drugs on a compassionate basis. The requirements demanded that a sugar pill placebo be given to dying patients, all in the name of obtaining survival data.
“The public should be totally outraged,” Walker says. “Statistics has turned the FDA clinical trial system into a barbaric, almost criminal pursuit of p-values. It has nothing to do with the responsible and ethical practice of medicine.”
Media coverage of Karnes’ plight was intense. The Wall Street Journal was blistering in its condemnation of the FDA, accusing the agency of having a “placebo fetish” and editorializing on March 24, 2005: “The problem here is the FDA’s unethical—and let us stress, unscientific—placebo-controlled trials, in which a subset of study patients are knowingly denied the new treatment and in some cases denied access to any active treatment at all. This may be moral with an antihistamine; it’s certainly not with treatments for a terminal disease. What’s more, it’s entirely unnecessary. We already know what happens to most cancer patients who don’t get treated. They die.”1
And so did Kianna Karnes, one day after the editorial was published. But the cruelest twist of all had occurred when the FDA, red-faced from the Journal’s op-ed piece, had relented and told Karnes’ family it would approve the drugs’ use on an emergency basis—much too little, far too late. In announcing Karnes’ death days later, the Journal again took the FDA to the woodshed, calling its oncology division “incorrigible” and stating: “... it’s time for Congressional action mandating that the agency use 21st-century science and statistical methods to get these therapies to patients sooner. More specifically, drug approvals could be based on large trials open to all comers and analyzed with so-called Bayesian statistics [which incorporate prior knowledge and accumulated experience into probability calculations], as already happens in the FDA’s medical device division. (Yes, the agency at least recognizes that studies involving, say, ‘placebo’ defibrillators would be beyond the pale.)”2
It’s not that the FDA doesn’t know how to fix the broken system of cancer drug approval. The problem seems to be that it simply won’t. The FDA is a stagnant agency existing in a constant state of institutional worry, says Burroughs. While the Abigail Alliance talks about the issues, the FDA talks about the status quo.“The resistance to change is so powerful. People want to hold on to the status quo,” Burroughs says. “They say, ‘This is how we’ve always done things.’ They’re concerned about how to handle the PR if someone dies during early access use. We are not trying to dismantle the clinical trial process—all we want to do is improve it.”
The solutions proposed by the Abigail Alliance would indeed improve the process by modernizing the methods used to fit the current state of science, while relegating the use of statistics to its proper secondary role in the process. The Abigail Alliance has taken a hard stance in its fight against the FDA. Its first major effort, a 2003 white paper plan titled Tier 1 Initial Approval, became the basis for the legislative action. It described a three-tier approval process in which Tier 1 would allow early approval and provide developmental drugs to those abandoned by the current system. The Tier 1 white paper was presented to then-FDA commissioner Mark McClellan in person. The FDA’s response was a letter to the Alliance that essentially said the agency would continue to do business as usual.
The Alliance then filed a Citizen Petition with the FDA in June 2003. To this day, they’ve received no response. Undeterred, the next step was a lawsuit filed on July 28, 2003 against McClellan and Tommy Thompson, then-Secretary of the Department of Health and Human Services (the FDA is an operational division of DHHS). The lawsuit seeks to stop the FDA from enforcing a policy that “violates the constitutional privacy and liberty rights of terminally ill patients, including numerous Abigail Alliance members, and their constitutional guarantee against deprivation of life without due process.” The suit was dismissed in District Court in 2004, but the Alliance appealed and last May won the first round in Appellate Court, says Burroughs.
“The case was heard before a panel of three judges and we won in a two-to-one decision. The lawsuit was reinstated. But the FDA appealed and has requested that the US Appellate Court of DC re-hear the case en banc, meaning before all ten judges.”
Legal watchers say the court is pretty evenly divided and they believe the appeal could go either way. But the Alliance is optimistic—when oral arguments were presented, observers say a third of the judges were hard on the Alliance, but a third were hard on the FDA, and the remainder were simply quiet. A decision is expected literally any day now.
Says Burroughs: “We hope and pray that the patients win. One way or another, this will likely end up in the US Supreme Court, as the FDA will probably appeal if they lose, and if we lose, we’ll definitely appeal. My guess is the Supreme Court will hear the case, as this is a landmark issue, and an important issue.”
The Alliance believes that at its core, this is a major civil rights issue. While the FDA trembles at the word “risk,” terminally ill patients can view the risks of taking developmental drugs as the only option they have left. The FDA greatly amplifies concerns about safety, and minimizes and contests evidence of efficacy, says Walker. “It’s a risk-averse stance that the FDA routinely takes on all drug development and approval programs, and they use statistics to do it.”
It’s also a privacy issue in that the decision to take an investigational drug and the unknown risks associated with it should be the private decision of a patient in consultation with their doctor. The FDA shouldn’t make the decision for others, a fundamental reason why the Alliance’s fight can be viewed as patient and doctor versus paternalistic FDA.
Says Burroughs: “One of our strengths is that we get the facts out there. We get a lot of good press, and when our issues are in the media, it resonates with the public. People understand that these are important issues. In poll after poll, we find that the public is willing to take risks, and the last time I checked this was a democracy, but that’s not what we’re seeing. The FDA currently decides what the risk-benefit is, and they’re sorry you have a terminal illness, but they don’t want you having any side effects.”
Hope for the Future
The best evidence of the Alliance’s effectiveness is that every drug they’ve pushed for has been approved. “Every drug for cancer and other serious life-threatening illnesses that the Abigail Alliance has pushed for earlier access to in our six year history is now approved by the FDA,” Burroughs says. “Many lives could have been saved or extended, if there had been earlier access to these drugs.”