Dying for Lifesaving Drugs

Will desperate patients destroy the pharmaceutical system that produces tomorrow's treatments?

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.

Resurrection and Insurrection
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.

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  • ||

    Read this in the print version. It was a thoughtful piece that didn't gloss over the complexities of the situation. Very nice.

  • thoreau||

    I agree. That was excellent science reporting.

  • ||

    Another feather in Kerry's headdress.

  • ||

    I read the print version over the weekend. The reporting is solid and Howley's observations are thought-provoking.

  • ||

    As someone who works in the biotech industry (but thankfully, no longer works with life-saving drugs; it's very depressing), I'd like to highlight a point that was mentioned in the article, but perhaps not as strongly as many others. The double-blind clinical test methodology is in place because for non-life-threatening situations (the vast majority of clinical trials,) it is simply the best. It provides the most, highest quality data in the shortest period of time with far fewer ethical complications than those situations where people's lives are on the line. So that explains WHY that system is in place. Now as to why that model is then draped over a situation as different as life-threatening diseases, there comes a legitimate argument over what is or is not life-threatening. There is no magical line in the sand that can be drawn that will satisfy all (or most) people as "now it's okay, now it isn't." And I think we can all agree that a case-by-case basis is ripe for abuse.

    And as an aside, I would like to mention that in clinical volumes (especially in phase 2), drug manufacturing costs are often very high. So even if drug companies were allowed to make their drugs available to patients that were not part of their trials, small companies (or low-profit divisions at large companies) would still have little financial incentive to do so.

    An excellent article, Ms. Howley, including a realistic discussion of many of the tradeoffs in what is an emotionally trying field. Very well done.

  • thoreau||

    I don't think that a freer market for medicine would necessarily mean the end of controlled studies for medicines. It might mean the end of placebo-controlled studies for life-threatening illnesses, but studies controlled with a previously tested drug could still go on. And people could be persuaded to participate if the treatment (new or old) was offered free.

    As to why anybody would take a chance of going for the old treatment, there's only an incentive to spurn the old treatment if you actually know that the new one is better. If you're not yet sure about that, then taking the old one that's known to work in some fraction of cases is no worse of a gamble than taking the new one that might be better or might be worse.

    Not everybody would go for that bet, but I suspect a lot of people would. Especially if both treatments were free. So controlled studies (with willing volunteers, private funds, yadda yadda) could continue while other people opt to pay for experimental treatments outside a controlled study.

  • ||

    It seems to me that an unspoken component in this whole issue is power. Who has power and who gets to yield that power. Doctors, the FDA, and the Pharmas have power while patients are merely the inputs to maintaining that power (yes a bit extreme and cynical, but like I said this is a component of this debate that is rarely discussed.)

    Regards,
    TDL

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  • ||

    Good story, enjoyed it quite a bit.

    Also, I have a friend who just saw SICKO a few days ago, and he won't shut up about how "eye opening" it was.

    I showed him my new issue of Reason, specifically the aforementioned article, and he hasn't said a word about SICKO since.

  • Russ 2000||

    And people could be persuaded to participate if the treatment (new or old) was offered free.

    Free isn't enough. Some trials require relocation and giving up one's occupation. Even if the medical care is free and living expenses are covered, the price is still high. My late brother-in-law had to make the decision - relocate for a period of time and give up his income for the unknown odds of tacking on a few more years to his life OR work as hard as he could in the time he had remaining so that his kids would have their college tuition covered.

  • LarryA||

    What we need is "No Patient Left Behind."

  • Robert||

    It was pointed out to me years ago what eventually strikes anyone in this field: that there is no ethical way to test treatments on humans in almost any circumstances. If you have enough reason to be testing A vs. B, it's because you suspect one is better than the other, in which case your judgement should be to use the one you think is better, no matter how uncertain you are, rather than to test them.

  • ||

    Add me to the list-- "Well done!"

    Almost tempts me to pay for this rag... :o)

  • David Bevan||

    No Robert, that won't do...ethics must have a comparative dimension, because ethics consists of choices between different acts. Given that treatment of disease with effective drugs is ethical, testing them properly on humans to see if they are effective is more ethical than not testing them.

    As for 'suspecting' one drug to be better than another (or placebo) and therefore sidestepping the whole clinical trial project, that raises the spectre of ten thousand doctors all giving different treatments according to their own subjective, ignorant, unreliable or predjudiced thinking, or medical dogma - in other words, the way it was pre 1900 when most medicine was utterly ineffective.

    New drug X may be better and safer than old drug Y, but may also be dangerous and worse. Try thinking of randomised studies as tests of whether new drugs are worse...

  • ||

    I used to believe that double blind controlled trials were the end all, final word in good science. Doulbe blind trials are very useful, but as examples from Vioxx to Avandia demonstrate, burrowing down into data gives one inescapable conclusion: we are unique - - each drug is a lifesaver and each drug is a killer - it doesn't do you (an individual) much good to know what the "average" response is.

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    Again, rather than debating the ultimate regulatory or scientific testing framework, I believe the thrust of the article was that individuals have the right to do with their lives what they choose. In the sense that patients have a "right to the drugs," I disagree. I would agree that they have a right to risk their lives to see if a drug will work for them, and the drug producer has the right to decide whether or not to include them. As usual, the 9000 pound Government gorilla does not need to be in the room.

    Our medical establishment, like our government, assumes that because they are smart, we all must be dumb and incapable of even understanding what is going on, and certainly not allowed to make any decisions for ourselves. This arrogance and elitism pervades both fields, and like most situations, only free exchange of ideas, goods, and money will solve the problem.

  • Robert||

    "Given that treatment of disease with effective drugs is ethical, testing them properly on humans to see if they are effective is more ethical than not testing them."

    Not on the individual test subject, at least not with normal doctor-patient ethics.

    "As for 'suspecting' one drug to be better than another (or placebo) and therefore sidestepping the whole clinical trial project, that raises the spectre of ten thousand doctors all giving different treatments according to their own subjective, ignorant, unreliable or predjudiced thinking, or medical dogma - in other words, the way it was pre 1900 when most medicine was utterly ineffective."

    Of course. But it still couldn't, and can't, be done ethically. (And don't exaggerate -- medicine wasn't utterly ineffective in 1900.)

    This is not my invention. All medical ethicists can explain it. Normal medical ethics has to be suspended during testing.

    There's no way around this by pretending that below a certain level of certainty, there is only ignorance regarding A vs. B. They won't even let you test on humans unless you give them good reason to believe a particular one of those (the new one) is better than the other. (The other may be doing nothing, or may be an existing rx.)

  • ||

    @Legate Damar

    I'd like to highlight a point that was mentioned in the article, but perhaps not as strongly as many others. The double-blind clinical test methodology is in place because for non-life-threatening situations (the vast majority of clinical trials,) it is simply the best. It provides the most, highest quality data in the shortest period of time with far fewer ethical complications than those situations where people's lives are on the line.

    I agree. It's easy enough to paint a sympathetic portrait of an Abigail Burroughs, who dies from being denied what could possibly be a life-saving drug. What you don't see is what I believe economists call an "opportunity cost" - the people who would die due to insufficient data because the trials didn't occur.

    I understand the libertarian dilemma - the government is essentially deciding who will live and who will die "for the greater good". Nobody likes the idea of the government arbitrarily gambling with people's lives.

    The problem is, in this case it's actually placing some pretty good bets with a high return. Occasional Thalidomide disasters notwithstanding, on balance the smart money says the data collected by the trials has saved more lives than if the trials hadn't occurred.

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    When the femist revolution was at its height, its proponents kept saying things like "Our bodies -- ourselves." A woman's right to an aborton was advanced in terms of bodily autonomy. Eloquent arguments were advanced in support of the notion that one had an absolute right to do whatever one wished with one's body, so long as it did not directly harm others.

    Where are those exponents when right-to-treatment issues arise? If one has a right to remove an unwanted growth from one's womb, surely one has a right to remove an unwanted growth from one's brain by whatever means necessary.

    My guess is that many, if not most, of the proponents of "Our-bodies, ourselves" ideology were, or have become "nanny-staters," and would, if anything, support the FDA's right to control access to life-saving drugs in the name of the greater pulic good. But it is difficult for me to draw a distinction between a government whose laws prevent one from exercising control over one's reproductive organs and laws which prevent one from exercising control over one's tumors.

  • ||

    I'd like to highlight a point that was mentioned in the article, but perhaps not as strongly as many others. The double-blind clinical test methodology is in place because for NON-life-threatening situations (the vast majority of clinical trials,) it is simply the best. It provides the most, highest quality data in the shortest period of time with far fewer ethical complications than those situations WHERE PEOPLE'S LIVES are on the line.
    I also thought the L Damar comments were good, but what I took from them is that the rationale for clinical trials when your dealing with terminal illness is not so overwhelming. The fact remains that medical progress only happens with experimentation. Anything that hinders increasing the number of patients treated diminishes the amount of data generated to evaluate the drug.
    However, the more substantial reason of non-availability of these drugs is cost. But if the firm's investors believe that the drug works, and makes it avaliable so patients can afford it, and a patient with no alternative is willing to take the risk, it would benefit society to increase treatments with these new therapies.

  • Ben||

    We should be able to give up our right to sue in any limited or unlimited context we choose. Period. Or any other right. Formally. In light of our being found competent, perhaps, but no more than that.

    When the feds tell us we can't do something, it had better be in a sentence that says "to this other entity over here" or else it is pure and utter coercion.

    The government often makes the case that it is protecting us from ourselves. I do not solicit such protection and if I only could, I would opt out. This is because I am quite certain that I any threat I would pose to myself will be balanced by potential benefits I am looking for, and that any risk I face I can evaluate with a clear mind.

    Having said that, I am forced to observe that no one seems to be able to protect me from the government; furthermore, no one even seems to be interested. In today's society, the maxim seems to be that "the quest to deliver good to the many justifies utterly destroying the liberties of the individual, and if convenient, the individual as well."

    In its terminator-like campaign to give everyone what is "good for them", the government has destroyed a thing I once held very dear: hope.

  • Bob Armstrong||

    The idea that the FDA has any life or death power over individual choices is offensive .

    The arguments for government restricted testing versus open market based evaluation are bogus . Just as with Amazon or YouTube consumer ratings and commentary , both effective and dangerous products would be perhaps more quickly recognized and as data accumulates it can be mined for the statistics of efficacy , etc . It didn't take double blind studies to determine the dangers of smoking . Nor would it for any proposed nostrum , no coercion necessary .

    As my old professor Donald T Campbell used to stress , life is unavoidably experimental .

    Restricting freedom just slows it down .

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