Chemotalk Newsletter

Chemotalk Newsletter, Vol. 65: September 1, 2013

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This month's contents are articles I couldn't include last month, but couldn't discard because they're either too interesting, or too important. See what you think:

THE GAP IN MEDICAL TESTING

Some diagnostic tests have escaped regulation to ensure they are safe and effective

An alarming number of diagnostic medical tests have never been tested for safety and accuracy. That's because the federal government has a two-tier system for regulating such tests. If a diagnostic test is made by a traditional device manufacturer, the Food and Drug Administration reviews its safety and effectiveness before approving it for marketing. However, if a test is developed by a clinical laboratory for use at its own facilities, it can be sold without a premarket review.

That bifurcated approach made sense in years past when a medical center might develop a diagnostic test for its own doctors and patients. But the landscape has changed with the advent of ore sophisticated tests and the rapid expansion of commercial laboratory companies. Experts are unsure about how well these so-called laboratory-developed tests, or L.D.T.'s, perform in identifying diseases.

There have clearly been problems with some of the tests. Dr. Margaret Hamburg, commissioner of the F.D.A., reminded a meeting of oncologists last month about the case of a simple blood test to detect OVARIAN CANCER at an early stage when it might be curable. The test was put on the market in 2008, but it was quickly found to be flawed and withdrawn four months later.

The F.D.A. has always had the authority to regulate laboratory developed tests but chose not to do when tests were used locally. Now that commercial testing companies with laboratories scattered around the country have become major players, the agency has prepared a draft guidance document on how the tests developed by clinical laboratories should be regulated.

The document is stalled somewhere within the administration, possibly at the Office of Management and Budget, a frequent graveyard for regulatory initiatives. The Cancer Leadership Council, an advocacy group, warned the O.M.B. last November that "cancer patients have I recent years suffered harm from L.D.T.'s that did not provide the accurate and meaningful information that was promised." Regulations are long overdue; the raft guidelines should be quickly released for public comment.

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On the same topic:

DO CLINICAL TRIALS WORK?

By Clifton Leaf

Every spring, some 30,000 oncologists, medical researchers and marketers gather in an American city to showcase the latest advances in CANCER treatment.

But at the annual meeting of the American Society of Clinical Oncology in June of this year, much of the buzz surrounded a study that was anything but a breakthrough. To a packe and whisper-quiet room at the McCormick Place convention center in Chicago, Mark R. Gilbert, a professor of neuro-oncology at the University of Texas M.D. Anderson Cancer Center in Houston, presented the results of a clinical trial testing the drug Avastin in patients newly diagnosed with GLIOBLASTOMA MULTIFORME, an aggressive brain cancer. Inn two earlier, smaller studies of patients with recurrent brain cancers, tumors shrank and the disease seemed to stall for several months, when patients were given the rug, an antibody that targets the blood supply of these fast-growing masses of cancer cells.

But to the surprise of many, r. Gilbert's study found no difference in survival between those who were given Avastin and those who were given a placebo.

Disappointing though its outcome was, the study represented a victory for science over guesswork, of hard data over hunches. As far as clinical trials went, Dr. Gilbert's study was the gold standard. The earlier studies had each been "single-arm," in the lingo of clinical trials, meaning there had been no comparison group. In Dr. Gilbert's study, more than 500 brain cancer patients were randomly assigned to two evenly balanced groups: an intervention arm (those who got Avastin along wth a standard treatment) and a control arm (those who got the latter and a placebo). What's more, the study was "double-blind" -- neither the patients nor the doctors knew who was in which group until after the results had been assessed.

The centerpiece of the country's drug-testing system -- the randomized, controlled trial -- had worked.

Except in one respect: doctors had no more clarity after the trial about how to treat brain cancer patients than they had before. Some patients did do better on the drug, and indeed, doctors an patients insist that some who take Avastin significantly beat the average. Bt the trial was unable to discover these "responders" along the way, much less examine what might have accounted for the difference. (Dr. Gilbert is working to figure that out now.)

Indeed, even after some 400 completed clinical trials in various cancers, it's not clear why Avastin works (or doesn't work) in any single patient. "Despite looking at hundreds of potential predictive biomarkers, we do not currently have a way to predict who is most likely to respond to Avastin a who is not," says a spokesperson for Genentech, a division of the Swiss pharmaceutical giant Roche, which makes the drug.

That we could be this uncertain about any medicine with $6 billion in annual global sales -- and after 10 years of human trials involving tens of thousands of patients -- is remarkable in itself. An yet this is the norm, not the exception. We are just as confused about a host of other long-tested therapies: neuroprotective drugs for stroke, erythropoiesis-stimulating agents for anemia, the antiviral drug Tamiflu -- and, as recent headlines have shown rosiglitazone (Avandia) for diabetes, a controversy that has now embroiled a related class of molecules Which brings us to perhaps a more fundamental question, one that few people really want to ask: do clinical trials even work? Or are the diseases of individuals so particular that testing experimental medicines in broad groups is doomed to create more frustration than knowledge?

Researchers are coming to understan just how individualized huma physiology and human pathology really are. On a genetic level, the tumors in one person with PANCREATIC CANCER almost surely won't be identical to those of any other Even in a more widespread condition like high cholesterol, the variability between individuals can be great meaning that any two patients may have starkly different reactions to a drug.

That's one reason that, despite the rigorous monitoring of clinical trials, 16 novel medicines were withdrawn from the market from 2000 through 2010, a figure equal to 6% of the total approved during the period. The pharmacogenomics of each of us -- the way our genes influence our response to drugs -- is unique.

Human drug trials are typically divide into three phases. In the first, researchers evaluate the safety of a new experimental compound in a small number of people, determining the best way to deliver it and the optimal dosage. In Phase 2, investigators give the rug to a larger number of patients, continuing to monitor its safety a they assess whether the agent works.

"Works" in this stage is broadly defined. Seeing that the drug has any positive effect at all -- say, that it decreases the level of a blood marker associated with a disease -- is often enough to move a drug to Phase 3. Even so, most experimental drugs fail before they get to Phase 3.

The few that make it to Phase 3 are then tested for safety and efficacy in hundreds or thousands of patients This time, the outcomes for those taking the new drug are typically compared head-to-head with outcomes for those getting a placebo or the standard-of-care therapy Generally, the Food ad Drug Administration requires that two "adequate and well-controlled" trials confirm that a drug is safe and effective before it approves it for sale, though the bar can be lower in the case of medicines aimed at life-threatening conditions.

Rigorous statistical tests are done to make sure that the drug's demonstrated benefit is genuine, not the result of chance But chance turns out to be a hard thing to rule out. When the measured effects are small -- as they are in the vast majority of clinical trials -- mere chance is often the difference between whether a drug is deemed to work or not, says John P. A. Ioannidis, a professor of medicine at Stanford.

In a famous 2005 paper published in The Journal of the American Medical Association, Dr. Ioannidis, a authority on statistical analysis, examined nearly four dozen high-profile trials that found a specific medical intervention to be effective. Of the 26 randomized, controlled studies that were followed up by larger trials (examining the same therapy in a bigger pool of patients), the initial finding was wholly contradicted in tree cases (12%). And inn another 6 cases (23%), the later trials found the beefit to be less than half of what was first reported.

It wasn't the therapy that changed in each case, but rather the sample size. And Dr. Ioannidis believes that if more rigorous, follow-up studies were actually done, the refutation rate would be higher.

Donald A. Berry, a professor of biostatistics at M.D. Anderson, agrees. He, too can rattle off dozens of examples of this evaporation effect ad has made a sport, he says, of predicting it. The failures of the last 20 or so Phase 3 trials testing drugs for Alzheimer's disease, he says, could have been predicted based on the lackluster results from Phase 2. Still, the payoff for a successful Phase 3 trial can be so enormous that drug makers will often roll the dice -- not on the prospect that the therapy will suddenly work, but on the chance that a trial will suggest that it does.

At a round-table discussion a few years ago, focused on the high failure rate for Alzheimer's drugs, Dr. Berry was amazed to hear one drug company researcher admit to such thinking out loud. The researcher said that when he and his team designed the Phase 3 trial, he thought the drug would probably fail But if they could get an approval for a drug for Alzheimer's disease, it would be "a huge success."

"What he was saying," marvels Dr. Berry, "was, 'We're playing the lottery.'"

The fact that the pharmaceutical companies sponsor and run the bulk of investigative drug trials brings what Dr. Ioannidis calls "a constellation of biases" to the process. Too often he says, trials are against "a straw-man comparator" like a placebo rather than a competing drug. So the studies don't really help us understand which treatments for a disease work best.

But a more fundamental challenge has to do with the nature of clinical trials themselves. "When you do any kind of trial, you're really trying to answer a question about truth in the universe," says Hal Barron, the chief medical officer ad head of global development at Roche and Genentech. "And, of course, we can't know that. So we try to design an experiment on a subpopulation of the world that we thin is generalizable to the overall universe" -- that is, to the patients who will use the drug.

That's a very hard thing to pull off. The rules that govern study enrollment end up creating trial populations that invariably are much younger, have fewer health complications ad have be4en exposed to far less medical treatment than those who are likely to use the drug.

Roughly 53% of new cancer diagnoses, for example, are in people 65 or older, but this age group accounts for just 33% of participants in cancer drug trials.

Even if clinical researchers could match the demographics of study populations to those of the likely users of these medicines, no group of trial volunteers could ever match the extraordinary biological diversity of the drugs' eventual consumers.

Drug makers are well aware of the challenge. "Listen, it's not lost on anybody that about 95% of drugs that enter clinical testing fail to ever get approved," says Dr. Barron. "It's not hard to imagine that at least some of those might have failed because they work very, very well in a small group. We can't continue to have failures due to a lack of appreciation of this heterogeneity in diseases."

So what's the solution? For subtypes of diseases that are already known, it may be feasible to design small clinical trials and enroll only those who have the appropriate genetic or molecular signature. That's what Genentech did I developing the breast cancer drug Herceptin, which homes in on tumor cells that have an abundance of a protein called HER2.

And that's the strategy the company says it's pursuing now. Sixty percent of the new drugs in the works at Genentech/Roche are being developed with a companion diagnostic test to identify the patients who are most likely to benefit.

But given the dismal success rate for drug development, this piecemeal approach is bound to be slow and arduous. Rather than try to fit patients, a handful at a time, into the decades-old clinical-trials framework, we'd be far better off changing the trials themselves.

In fact, a breast cancer trial called I-SPY 2, already under way may be a good model to follow. The aim of the trial sponsored by the Biomarkers Consortium, a partnership that includes the Foundation for the National Institutes of Health, the F.D.A., and others, is to figure out whether neoadjuvant therapy for breast cancer -- administering drugs before a tumor is surgically removed** -- reduces recurrence of the disease, and if so, which drugs work best.

As with the Herceptin model, patients are being matched with experimental medicines that are designed to target a particular molecular subtype of breast cancer. But unlike in other trials, I-SPY 2 investigators, including Dr. Berry, are testing up to a dozen drugs from multiple companies, phasing out those that don't appear to be working and subbing in other, without stopping the study.

Part of the novelty lies in a statistically technique called Bayesian analysis that lets doctors quickly glean information about which therapies work best. There's no certainty I the assessment, but doctors get to learn during the process and then incorporate the knowledge into the ongoing trial.

Mark Gilert, for his part, would even settle for something simpler in his next glioblastoma study. His definition of a successful clinical trial? "At the end of the day, he says, "regardless of the result, you've learned something."

(** On a personal note, I was given adjuvant therapy before surgery, indicating that my wonderful surgeon and amazing oncologist already knew, at least 8 years ago, that adjuvant therapy was an effective course of treatment for patients like me. Coincidentally, I'm starting my 9th year, cancer-free.)

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BLACK WOMEN'S POORER FATE IN BREAST CANCER CASES IS TIED TO LATER DIAGNOSES

By Tara Parker-Pope

BREAST CANCER survival is, over all, three years shorter for black women compared with white women, mostly because their cancer is often more advanced when they first seek medical care, new research shows.

While cancer researchers have known for two decades that black women with breast cancer tend to fare worse than white women, questions remain about the reasons behind the black-white divide. The new report, from researchers at the University of Pennsylvania, begins to untangle some of the issues by using a analytic method to filter the influence of demographics, treatment differences and variations in tumor characteristics, among other things.

The findings, published in The Journal of the American Medical Association, suggest that while a significant number of black women still get inferior cancer care, the larger problem appears to be that black women get less health care over all, and that screening ad early detection campaigns may have failed to reach black communities.

Using data from Medicare patients traced in the Surveillance, Epidemiology ad End Results database, the researchers analyzed 107,273 breast cancer cases, which included 7,375 black women. The larger number of cases involving white women allowed researchers to fin nearly perfectly matched controls against which to compare the outcomes of black women with breast cancer.

The findings were striking. Over all, white women with breast cancer lived three years longer than black women. Of the women studied, nearly 70% of white women lived at least five years after diagnosis, while 56% of black women were still alive five years later.

The difference is not explained by more aggressive cancers among black women. Instead, the researchers found a troubling pattern in which black women were less likely to receive a diagnosis when their cancer was at an early stage and most curable**. In addition, a significant number of black women also receive lower-quality cancer care after diagnosis, although those differences do not explain the survival gap.

"Something is going wrong," said Dr. Jeffrey H. Silber, a professor at the University of Pennsylvania and the director of the Center for Outcomes Research at the Children's Hospital of Philadelphia, which studies disparities in health care. "These are huge differences. We are getting there too late. That's why we are seeing these differences in survival."

The data show that black patients are twice as likely to never receive treatment The records of 12.6% of black patients did not show evidence of treatment, compared with 5.9% of whites.

Black patients were also more likely to have at least a three-month delay in receiving treatment. Among black and white women with similar tumors, 5.8% of black women had not started treatment after three months, compared with just 2.5% of whites.

One notable finding of the report is that while the introduction of new treatments has improved the outcome for both white and black breast cancer patients since 1991, those improvements have not narrowed the survival gap between the two groups.

But solving disparities in cancer care would not immediately have a major effect on overall survival for black women, the study showed. If black women began receiving exactly the same quality and level of breast cancer treatment as white women, that would lengthen their lives by two to three months, the study showed.

However, two additional years of life could be gained among black women if their breast cancers were detected earlier and if their health were better over all, as is the case with white women with breast cancer. Among the black women studied, 20% received a diagnosis of Stage 111 or IV disease, when the cancer is far less likely to be cured. Among the white women, only 11.4% had late-stage disease.

One reason may be that the black women studied were less likely to seek medical care for any reason.

Although all the patients in the analysis had Medicare coverage, blacks were significantly less likely than white women to have seen a primary care doctor in the 6 to 18 months before diagnosis, and they had far lower rates of cholesterol and COLON CANCER screening. Black women also had far lower rates of breast cancer screening -- 23.5% had been screened 6 to 18 months before diagnosis, compared with 35.7% of white women. "These patients have insurance," Dr. Silber said. "We need to improve screening for these women and improve their relationships with a primary care provider."

In an accompanying editorial, the authors, who included Dr. Jeanne S. Mandelblatt of the Cancer Prevention and Control Program at Georgetown University's Lombardi Cancer Center, wrote that the report may still understate the effect of lower-quality cancer care for black women.

"Ratings of patient-physician communication and trust have been related to black women's, but not white women's, patterns of CHEMOTHERAPY use," the authors wrote. These findings further reinforce the idea that black women may have different cancer care experiences than white women.

 

** By using the word "cured", the author of this, and many such articles give readers the false impression that a cure for this disease actually exists. It does not exist. There is no cure for cancer.

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CANCER CENTERS RACING TO MAP PATIENTS GENES

By Anemona Hartocollis

Electric fans growl like airplanes taking off and banks of green lights wink in a basement at Mount Sinai's medical school, where a new $3 million super-computer makes quick work of huge amounts of genetic and other biological information.

Just a couple of miles away, a competitor, Weill Cornell Medical College and New York-Presbyterian Hospital/Weill Cornell hospital are building a $650 million research tower. Across the street is a newly complete $550 million research tower housing labs for another competitor, Memorial Sloan-Kettering Cancer Center.

Major academic medical centers in New York and around the country are spending and recruiting heavily in what has become an arms race within the war on CANCER. The investments are based on the belief that the medical establishment is moving toward the routine sequencing of every patient's genome in the quest for "precision medicine," a course for prevention and treatment based on the special, even unique characteristics of the patient's genes.

Among other projects, Harvard Medical School has its Center for Biomedical Informatics, which among a broad array of approaches uses mathematical modeling to predict when genetic information could lead to more effective treatment. Phoenix Children's Hospital opened the Ronald A. Matricaria Institute of Molecular Medicine in December, recruiting researchers from Los Angeles and Baltimore and planning to sequence the genomes of 30% of their childhood cancer patients in their search for better therapies.

Johns Hopkins, with its focus on public health wants to develop a "systematic genomic sequencing program" over the next two years that will combine genomic analysis with a patient's environmental exposure, family history and other factors to support preventive medicine, said Scott Zeger, vice provost of research.

"There will be a moment in time when whole genome sequencing becomes ubiquitous throughout health care," said Peter Tonellato, director of the Harvard personalize medicine lab and a clinical investigator inn pathology at Beth Israel Deconess Medical Center in Boston. "Let's say we figure out all the individuals who might have a cancer, and we can predict that with a relatively high level of accuracy. Then presumably we can take steps to avoid those, let's say, decades of treatment."

Sequencing an entire genome correctly costs in the neighborhood of $5,000 to $10,000, not including the interpretation of the information. It is usually not reimbursed by insurance, which is more likely to cover tests for genetic mutations that are known to be responsive to drugs. The treatments themselves, which are sometimes covered, typically cost several times that.

Even optimists warn that medicine is a long way from deriving useful information fro routine sequencing, raising questions about the social worth of all this investment at a time of intense fiscal pressure on the health care system.

"What's the real health benefit?" said Dr Robert C. Green, a Harvard professor and a medical geneticist at Brigham ad Woman's Hospital in Boston. "If you're a little bit cynical, you say, well, none, it's foolish."

Dr Green is part of a federally sponsored research project that is looking at the economic and medical impact of whole genome sequencing. "One of the most prominent downsides is you start chasing risks for a whole lot of disease you'll never have, and generate a lot of cost for little benefits," he said.

He was not ready to dismiss the efforts of Mount Sinai and others, though. "The other side of the question is, what was there to look up on the Internet when the first person got a personal computer? Very little."

The race entails large sums spent not only on construction and technology but also recruitment, salaries and incentives for scientists like Weill-Cornell's Dr. Lewis Cantley, who was lured from Harvard, or Eric E. Schadt, plucked from the biotech world to head the Mount Sinai Institute for Genomics and Multiscale Biology.

New York-Presbyterian/Weill Cornell announced a new Institute for Precision Medicine, headed by a PROSTATE CANCER expert, in January. (The newly fashionable term "precision medicine" is an updated version of another genomics buzzword, "personalized medicine") "I am not in this for competition," said Dr. Laurie Glimcher, dean of Weill Cornell Medical College. "I consider it collaboration, and I thin we all have the same goal in mind, which is to cure disease."

As Weill Cornell was courting Dr Cantley, Memorial was pursuing another Harvard eminence, Dr. Jose Baselga, to be its physician in chief. "It's a small world," Dr Baselga, a BREAST CANCER specialist, said, recalling that he and Dr Cantley had exchanged notes on what each was being offered.

Memorial sequenced 16,000 tumors last year, mainly in LUNG CANCER patients, Dr. Baselga said. In addition to the research building just completed on East 68th Street, a new outpatient building on East 74th Street, to be finished in 2018, will have whole floors dedicated to early-phase clinical trials.

The promise of whole genome sequencing can be seen in trials like one for BLADDER CANCER at Memorial, where the effects of a drug normally used for breast cancer were disappointing in all but one of about 40 patients, whose tumor went away, Dr Baselga said. Investigators sequenced the patient's whole genome. "The patient had a mutation in one gee that was right on the same pathway as the therapy," Dr. Baselga said. "And that explains why this worked."

At Mount Sinai, Dr Schadt, 48, an all-around risk aficionado who rides a BMW S 1000 RR Superbike, says he will use the mathematical principles of weather and markets forecasting to assess the risk of disease, and, given a disease, determine the subtype and best drugs to use.

Mount Sinai has collected what it calls an electronic "biobank" of information on 24,000 patients, who have agreed to participate in DNA sequencing and research over their lifetimes.

Some of that information will be fed into the supercomputer, which is named Minerva, after the Roman goddess of wisdom. Data storage alone is a challenge: one genome is 300 gigabytes of raw data per patient sample. Minerva's supervisor is Patricia Kovatch, 44, a computer engineer who led the team that build Kraken, the world's third fastest computer, in 2009, while working for the University of Tennessee at Oak Ridge National Laboratory.

So much hiring has been going on surrounding personalized medicine at Mount Sinai, she said, that "it feels lie a start-up."

At this point scientists have only an imperfect understanding of how snippets of genetic material can determine a patient's chances of getting many diseases, especially more common ones. And patients are often reluctant to enroll in clinical trials of drugs still in development. But by setting up the right infrastructure -- collecting and sequencing patient DNA, identifying patients who could benefit from a particular drug and aggressively recruiting patients for trials -- the academic medical centers hope to play a bigger role in the development of new drugs which could lead to lucrative patent royalties.

"The pharmaceutical companies need the expertise of academic medical centers, they need our patient groups to participate," said Dr. Dennis Charney dean of the Icahn School of Medicine at Mount Sinai.

Those groups could include patients like Kieran P. Holohan, a 45-year-old lawyer who received a diagnosis of ACUTE MYELOID LEUKEMIA in 2009. After his chemotherapy and the disease's remission, his original doctor pushed him to have a bone-marrow transplant to prolong the remission. A friend fro his rugby club, a geneticist, told him that "this has a lot to do with chromosomes," he recalled and sent him to a doctor at Weill Cornell, Gail J. Roboz.

A relatively new laboratory test found that Mr. Holohan's leukemia had a mutation that meant that his chances of survival would not necessarily improve with the risky transplant. So he opted for more chemotherapy, ad his cancer is still in remission.

"They didn't go with a suit off the rack," he said. "This was bespoke medicine."

His doctor is more cautious. "Unfortunately, cancer is cured three times a day in the media," she said. But that does not mean that there might not be truly customized treatments for cancer 10 years down the line, she said.

Dr James M. Crawford, chair of pathology at Hofstra North Shore-LIJ School of Medicine, said his institution, a competitor in some ways with the Manhattan medical centers, was "quite literally on the fence" about whether to join the race or to "let more data emerge before we decide we are going to commit more resources to this."

"What is the ultimate utility of this personalized medicine?" he said. "As a medical profession but also as a society we have not answered this question to our satisfaction."

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Until next month ..

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And if you have any thoughts of how this newsletter could be improved, please email me directly, at Elaine@elainejesmer.com.

Elaine Jesmer

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