Dying for Lifesaving Drugs

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

Kerry Howley from the August/September 2007 issue

(Page 3 of 5)

In its fight against a sclerotic system, the AIDS community had a major advantage: It actually was a community. Organized around civil rights, supported by the political left, noticed by the mainstream media, AIDS patients formed a vocal, recognizable class. "Contrast that with the class of patients who are terminal," says Walker. "There are hundreds of cancers. These people have nothing in common. By the time they're sick, they have no way of connecting to anyone else. They don't have time to go to meetings and lobby the FDA. The only thing they have in common is that the FDA stands in their way. And sometimes they don't even know that."

It's more than a lack of organization that plagues the alliance. Groups representing the victims of deadly diseases are often vocally opposed to its agenda. The American Society of Clinical Oncology submitted an amicus brief in the alliance's pending case-in support of the FDA. In a September 2003 press release, Fran Visco, head of the National Breast Cancer Coalition, announced that a victory for the Abigail Alliance would "undermine scientific research and impede our search for answers that will help everyone." The Leukemia & Lymphoma Society, the National Childhood Cancer Foundation, and the National Patient Advocate Foundation have all voiced their intention to side with the government.

‘Piles of Bodies'
While Burroughs and Walker believe they are tearing down senseless bureaucratic obstacles, their opponents charge that the Abigail Alliance is trying to hijack drug development the world over. Clinical trials have been the primary way the medical establishment obtains information about drug efficacy for the last 50 years. To its detractors, the alliance seems prepared to cripple an ever-evolving body of pharmaceutical research. In the interests of a few patients suffering now, it is willing to cause an untold amount of damage to patients yet to be diagnosed.

Trials conducted in the United States are the most rigorous in the world, consisting of three distinct phases, typically involving thousands of patients. Only 11 percent of drugs that enter clinical trials are ultimately approved, and the numbers are markedly worse for cancer drugs. Anyone who argues for the unencumbered right of patients to take developmental cancer drugs must grapple with the fact that 94 percent of them will not work.

To sift the pharmaceutical gold from this vast bed of chemical silt, drug companies need some type of trial system, and for trials they will need patients. Trials are typically randomized, meaning that some patients will receive the treatment and others will not. If patients could simply obtain the medicines they wanted, they would have little incentive to enter the clinical testing lottery.

"How do you take a rational person and get that person to enroll in a double-blind, randomized clinical trial?" asks Steve Walker. "How do you get people to do that? You give them no other choice. They're not lives worth saving. They're lives worth using. If you can't get into the trial, they can't use your life. They need two piles of bodies."

Mindful of medicine's dependence on test subjects, the alliance isn't asking that all patients get access to development drugs. It's asking that patients already denied admission to trials--patients like Abigail Burroughs and Jennifer McNeillie--be able to buy the drugs they're denied. And even this concession, argue their opponents, would dismantle the clinical trial system.

The amicus brief submitted by the American Society of Clinical Oncology argues that if people who didn't qualify for trials had access to drugs, patients would have an incentive to appear ineligible. Their physicians could easily help them game the system by, say, ordering a round of chemotherapy, which disqualifies patients for many Phase II and Phase III trials.

By that logic, Abigail Burroughs had to be denied treatment to protect the integrity of the clinical trial process. Terminal patients who cannot gain admission to trials still must be prevented from receiving developmental drugs, lest future patients refuse to submit themselves to randomized testing. "They need test subjects," says Walker, "and patients are their only resource." Pull even a single thread, and the whole information-aggregating web unravels.

This conflict has a way of pitting those without any hope of survival against those with some chance at life. Take David Welch, co-founder of the successful software company Telco Exchange. In 2004 doctors found a tumor the size of a lemon in Welch's left frontal and left temporal lobes. The 38-year-old chose to be aggressive, pursuing a treatment so risky that three review boards rejected his request to have the operation performed at their hospitals. The treatment was successful, and Welch, now on his 19th round of chemotherapy to keep the remaining cancerous cells at bay, is unambiguously positive about the operation and his right to risk it.

Welch might seem the typical Abigail Alliance booster, eager to argue for the right to experiment in the face of death, but he is deeply ambivalent. "I medically inherit what has been given to me," he says. "Statistically, I've got a time line of five to six years. The more time I buy, the more time I have for clinical trials to play out. I'm still open to arguments, but I fail to see how we can change the process without breaking it down."

Welch also argues that even if pharmaceutical companies were allowed to sell their drugs prior to approval, they have strong incentive not to do so. Anything that happens to a patient taking a drug in development could later be used to argue against approval, halting manufacture and denying that drug to future patients. And under current FDA regulations, patients cannot waive liability for negligence. Whether they want it or not, patients must have the right to sue, which means they may never be given the chance to take a risk. If the Abigail Alliance wins its case, it will face additional legal battles.

There is a serious argument to be made that the entire clinical trial system is antiquated, that it is time to stop counting piles of bodies and to start using more sophisticated measures of drug efficacy. Biomarkers, substances whose presence in the body indicates a particular disease state, could provide objective evidence on how a drug is working on a particular patient. As such measures improve, the need for placebos may lessen. "Clinical trials are very cumbersome," says Thomas Garvey, a gastroenterologist and former FDA supervisor who has designed thousands of clinical trials. "Although they are not the be all and end all. The science is evolving and getting better."

A March 2005 editorial in The Wall Street Journal advocated scrapping placebo trials for cancer patients altogether, giving everyone access to the drugs, and using advanced statistical methods to measure patient progress versus the typical survival rate for a particular cancer. This is the kind of change the Abigail Alliance hopes for, but more incremental changes are already in play.

In an attempt to increase flexibility and reduce approval times, some pharmaceutical companies have begun to conduct what are known as "adaptive" trials. Standard trials are blinded: The findings remain secret from researchers until each phase of the trial is over, and they are conducted on general populations of patients with similar conditions. Even after a standard trial has ended, it can be difficult to know which patients within a population will respond most positively or suffer the most severe side effects from a particular drug.

Comments

|7.25.07 @ 12:04PM|#

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

thoreau|7.25.07 @ 12:09PM|#

I agree. That was excellent science reporting.

|7.25.07 @ 12:37PM|#

Another feather in Kerry's headdress.

|7.25.07 @ 12:38PM|#

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

|7.25.07 @ 12:50PM|#

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|7.25.07 @ 1:42PM|#

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.

|7.25.07 @ 2:09PM|#

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

|7.25.07 @ 2:26PM|#

see: thalidomide babies

|7.25.07 @ 2:53PM|#

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|7.25.07 @ 3:44PM|#

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|7.25.07 @ 7:31PM|#

What we need is "No Patient Left Behind."

Robert|7.25.07 @ 8:40PM|#

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.

|7.25.07 @ 10:17PM|#

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

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

David Bevan|7.26.07 @ 6:08AM|#

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...

|7.26.07 @ 6:56AM|#

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.

|7.26.07 @ 7:55AM|#

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|7.26.07 @ 10:39AM|#

"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.)

|7.26.07 @ 10:56AM|#

@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.

|7.26.07 @ 12:05PM|#

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.

|7.26.07 @ 12:53PM|#

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|7.30.07 @ 8:03AM|#

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|7.30.07 @ 10:18PM|#

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 .