What Does It Mean To Say A Pricey Drug Works?
10 CommentsBy Ed Silverman // July 5th, 2008 // 7:22 pm
That’s one of a series of questions asked - yet again - about Genentech’s Avastin, which is approved for treating advanced lung, colon or breast cancer by cutting a tumor’s blood supply. The med is widely used, despite a price tag of up to $100,000 a year. Studies, however, show Avastin prolongs life by only a few months and may not be as effective as once thought.
Nonetheless, many patients and docs say the drug can improve the quality of life, The New York Times writes in revisting the issue, while adding such effects can be hard to document. Meanwhile, many patients with other cancers are taking the drug, even in cases where there is no compelling evidence that it can help, the paper adds. This, of course, generates more sales.
Avastin also has serious, if infrequent, side effects, some of which can be lethal, the paper points out. “I still use Avastin routinely, but it’s sobering,” Leonard Saltz, a colon cancer specialist at Memorial Sloan-Kettering Cancer Center in New York, tells the Times, referring to newer data. “It’s not a slam dunk and, in fact, the incremental benefit may be more modest than we want to admit.”
So, the Times asks, what does it mean to say an expensive drug works? Is slowing the growth of tumors enough if life is not significantly prolonged or improved? How much evidence must there be before billions of dollars are spent on a drug? Who decides? When, if ever, should cost come into the equation? As the paper notes, former Merck ceo Roy Vagelos worries high prices will raise concerns about whether the drugs are worth it, leading to a backlash like price controls or restrictions.
Some patient advocates are also troubled, the paper writes. “It’s absolutely critical that we start having a public discussion,” Barbara Brenner, executive director of Breast Cancer Action, an advocacy group, tells the Times. “I think of Avastin as a model that is showing us where the problem is.”
The story goes on to recount the dilemma docs face in weighing patient benefits and high costs that insurers are increasingly passing on to patients, as well as the debate over the FDA decision last February to approve Avastin for advanced breast cancer, even though a key clinical trial found the drug significantly slowed the progression of cancer but didn’t significantly extend life. Genentech and Roche defend their pricing by noting $2.25 billion has spent on Avastin, although GoozNews aptly notes the drugmakers more than recouped their investment thanks to the pricing.
Dan
Market is over 60 billion a year for biopharmaceuticals, with annual growth between 10 and 20 percent. I’m unsure if the benefit is really there.
Paul G
If it works, it works.
One can take this question very far:
- Does a doctor’s appointment work?
- Does an MRI scan save lives?
- Does billions of dollars spend in homeopathy and herbals make any difference?
- etc. etc. etc.
Seems to work for a lot of people and, in the overall scheme of things, this does not seem to be a big part of the overall budget. Either as a society we cover these things based on evidence or we tell people they don’t deserve the chance.
There is so much waste. Including doctors and clinics making huge profits on administering these “buy and bill” drugs
Dan
Furthermore, such innovative treatments still require cancer patients to continue chemotherapy, so the drugs are a supplement, in a way, to a cancer patient’s treatment. Co-pays for such patients may be thousands of dollars a month. The TNF/VGEF concept is validated, but the results are just not there when considering price and value.
Nathan
Thanks for the link, Ed. Your article is just the tip of the iceberg. The Times article is both heartbreaking and exciting. I thought the quote by a doctor on the last page summed up the dilima quite nicely:
“Dr. Winer says that when he is not sitting in front of a patient, he thinks about whether drugs like Avastin are worth it to society. But when facing a seriously ill patient, who, based on clinical trial results, might benefit — even if only a little — from Avastin along with chemotherapy, he has to think about his patient’s needs. “I can’t say, ‘Let’s not use Avastin; it’s a very expensive drug and I am worried about the cost to society,’”
Also, it’s worth pointing out a quote in the middle of the story relevant to the issue of efficacy: “Dr. Kathy Albain… polled colleagues and patients and found overwhelming support for approving drugs based on delaying tumor progression. It would be ideal to show that a drug also prolongs life, but that may not be realistic, she said. The reason is that when a woman’s cancer progresses, doctors change the drugs they use, hoping to slow the cancer. That dilutes any impact of the first drug — in this case Avastin. “
Nathan
Something else interesting: In the original trial in 2004 (using Avestin plus a chemo treatment), the median survival was increased from 15 months to 20 months (~5 months). In the trial in 2007 (using Avestin plus a different chemo treatment), the median survival was increased from 19 months to 20.5 months (~1.5 months). What’s the difference here? The difference isn’t in the Avestin group — the difference is in the CONTROL GROUP. In other words, the standard of care for cancer has increased, while the Avestin benefit has remained constant. In it’s time, Avestin did a great job. But as other chemo treatments have improved, the benefit of Avestin may not be as great as it once was.
Bob Freeman
Excellent point, Nathan–You’ve raised a point that deserves far more attention; viz., the control group involving standard care is not a static comparator, especially in cancer.
Dan
Ed,
Great article brought to our attention on this in the NYT. 9 pages long. Very thorough. Life extension with Avastin with many cancers is poor- a matter of months, possibly. Still have to take the drug with chemotherapy.
Worth reading, this NYT article,
Dan
Paul G
I wonder if anyone in reading this blog faced with the unfortunate prospect of being diagnosed with colon cancer would choose to forgo Avastin if given the choice.
Based on what I read and understand, I would not.
Vince
The benefit to cancer patients really appears to be minimal. It certainly will work as a profit generator.
Gregory D. Pawelski
What may limit the effectiveness of Avastin is that there are multiple ways by which tumors can evolve that are independent of VEGF and independent of angiogenesis. Tumors can acquire a blood supply by three different mechanisms: angiogenesis; co-option of existing blood vessels; and vasculogenic mimicry. All must be inhibited to consistently starve tumors of oxygen.
Instead of growing new blood vessels, tumor cells can just grow along existing blood vessels. This process, called co-option, cannot be stopped with drugs that inhibit new blood vessel formation. Some types of cancers form channels that carry blood, but are not actual blood vessels. Drugs that target new blood vessel formation also cannot stop this process, called vasculogeneic mimicry. The realization is that starving tumors by shutting off their blood flow requires that all three mechanisms be addressed.
It could be vastly more important to measure the net effect of all processes (systems) instead of just individual molecular targets (like VEGF). The cell is a system, an integrated, interacting network of genes, proteins and other cellular constituents that produce functions. You need to analyze the systems’ response to drug treatments, not just one or a few targets or pathways.
There are many pathways to the altered cellular (forest) function, hence all the different “trees” which correlate in different situations. Improvement can be made by measuring what happens at the end (the effects on the forest), rather than the status of the indiviudal trees.
VEGF-targeted drugs are poorly-predicted by measuring the preferred target VEGFR. They can be well-predicted by measuring the effect of the drug on the function of live cells.
Many of these fine drugs (and Avastin is a miracle drug for the few) cry out for validated clinical biomarkers as pharmacodynamic endpoints and with the ability to measure multiple parameters in cellular screens to help set dosage and select people likely to respond. Many molecular diagnostics approved often have been mostly or totally ineffective at identifying clinical responders to various therapies.
If you find one or more implicated proteins in a patient’s tumor cells, how do you know if they are functional (is the encoded protein actually produced)? If the protein is produced, is it functional? If the protein is functional, how is it interacting with other functional proteins in the cell?
All cells exist in a state of dynamic tension in which several internal and external forces work with and against each other. Just detecting an amplified or deleted gene won’t tell you anything about protein interactions. Are you sure that you’ve identified every single protein that might influence sensitivity or resistance to a certain class of drug?
Assuming you resolve all of the preceeding issues, you’ll never be able to distinguish between susceptibility of the cell to different drugs in the same class. Nor can you tell anything about susceptibility to drug combinations. And what about external facts such as drug uptake into the cell? You’re not going to accomplish this using genetic tests.
Improving cancer patient diagnosis and treatment through a combination of cellular and gene-based testing will offer predictive insight into the nature of an individual’s particular cancer and enable oncologists to prescribe treatment more in keeping with the heterogeneity of the disease. The biologies are very different and the response to given drugs is very different.
The major obstacle in controlling cancer drug prices is the widespread inappropriate use of anti-cancer drugs. As the increasing numbers and types of anti-cancer drugs are developed, oncologists become more and more likely to misuse them in their practice. There is seldom a “standard” therapy which has been proven to be superior to any other therapy. What may work for one, may not work for another.