## MATH and Tumors

Well, not really math, but MATH, for mutant-allele tumor heterogeneity. So not math per se, but a measurement. Allow me to explain.

The measurement known as MATH was created by researchers at Massachusetts General Hospital as a way to quantify the degree of heterogeneity of a particular tumor. What is tumor heterogeneity? The thinking goes like this: Multiple genetic mutations are thought to be responsible for the transformation of normal cells into cancerous cells. As cancerous cells continue to evolve, so to speak, the malignant cells become increasingly different, both from their ancestor and from each other. As a rough analogy, it’s like identical twins having their own families. The first cousins are more different from each other than are their parents, and they are more different from each other than from their parents. With second cousins, the differences are even more dramatic. Now picture all those siblings and cousins as cells inside a tumor, and that is (very roughly) the concept of tumor heterogeneity.

And here is the important thing about tumor heterogeneity, at least where treatment is concerned. In general, the more heterogeneous the tumor, the harder it is to treat, or so the thinking goes.

Edmund Mroz and colleagues, who created the MATH measurement, wanted to test out that thinking. Is a high degree of intratumor genetic heterogeneity connected to worse outcomes? Mroz et al conducted a study of patients with head and neck squamous cell carcinoma to see if they could use their MATH measurement to gauge how well patients would do after treatment.

The study, just published in Cancer, indicates that yes, the MATH score of a patient’s tumor is significantly associated with both tumor progression and adverse treatment outcomes.

Here’s a little more about how these researchers arrived at their conclusion. First, Mroz and colleagues obtained clinical, pathological, and outcome data for 74 patients with head and neck cancer. These patients had also had next-generation sequencing data obtained. All patients agreed to provide tumor tissue for the study.

The researchers calculated a MATH value for each tumor sample. How that is done is complicated and I don’t think my paraphrasing could do it justice, so I’ll quote from the report, for the actual math-inclined:

“The MATH value for each tumor was based on the distribution of mutant-allele fractions among tumor-specific mutated loci, calculated as the percentage ratio of the width (median absolute deviation [MAD] scaled by a constant factor so that the expected MAD of a sample from a normal distribution equals the standard deviation [SD]) to the center (median) of its distribution:

Basically, each tumor got measured for genetic heterogeneity, and that heterogeneity was reflected in a numerical score. In this study, the scores ranged from 19 to 55, with a mean of 34, an SD of 10, and a median of 32.

So with those numbers, you can immediately begin to wonder: did patients with a score in the high range fare worse than patients with a score in the low range?

Yes, sadly, they did. “…higher MATH was found to be strongly associated with shorter overall survival,” the study reports. And also: “Each additional unit of MATH was associated with a 4.7% increased hazard of death.”

Interestingly, higher MATH scores were also associated with factors already known to put patients at higher risk for worse outcomes, for example being negative for human papillomavirus, having a TP53 mutation, or having perineural invasion.

The researchers conclude that their work provides evidence for the connection between high genetic heterogeneity and shorter survival.

However, MATH scores were not associated with the N stage of a cancer (in terms of TNM classification, using for staging cancer by measuring the size of a tumor, the number of tumors, and whether or not the cancer has metastasized), or with TNM stage in general. Thus MATH could be used in the clinic as its own prognostic score, the authors note.

There is more to understand about this work. For example, the authors state that the mutation rate of tumors was not associated with MATH or with outcome. So mutations alone are not enough to increase heterogeneity. What other factor could be promoting the progression and survival of genetically distinct cancer cell progeny? Also, will patients increasingly obtain next-generation sequencing of their tumors as part of treatment? If so, how can that information be used to help them?

## Drug Patents Don’t Ensure Innovation

Opinions and perspectives on the Indian Supreme Court’s rejection of Novartis’s patent application for Gleevec/Glivec are plentiful, both in support and against the decision. In the wake of the decision, many words are being typed about how the patent system is necessary to guarantee medical advancement, and also how patents, when extended beyond their original timeline, keep drug costs high and out of reach for many people, especially in poorer countries.

The following is my take on the matter, or at least one of my takes. Having just written a book telling the story behind the creation of Gleevec, this subject is one I’ve been musing about for quite a while. This post ran as an op-ed in the April 15, 2013, edition of the San Francisco Chronicle.

* * *

The Indian Supreme Court denied the pharmaceutical company Novartis a patent for its cancer drug Gleevec on April 1. Hailed by some as a victory for ensuring widespread access to lifesaving medications, the decision is derided by the pharmaceutical industry as counteractive to the discovery of new medicines. Both positions are based on an incomplete view of what promotes innovation.

Without a patent, Novartis could not have brought Gleevec, a breakthrough drug for a rare cancer, to market. The drug will save countless lives, and has transformed the future of cancer treatment. The drug is also a blockbuster. Between 2001 and 2011, worldwide sales of Gleevec totaled more than \$27.8 billion.

Novartis patented Gleevec in 1993, and then an improved formulation in 1995. India does not recognize patents issued before 1995, and the court asserts that the latter formulation is too similar to the original to warrant its own protection. Whether or not Novartis’ patent application in India is legally warranted is a technical matter wrapped in layers of government acts and amendments. The drug is patented in 38 countries but has never had such protection in India.

The consequences of the court decision are mixed. Advocates for the poor applaud the court’s verdict: Everyone, regardless of their economic status, will be able to afford generic Gleevec, whereas the wholesale cost of the brand-name version is about \$77,000 for a year’s supply (and an individual may take the drug for decades).

Novartis says the decision “discourages innovative drug discovery essential to advancing medical science for patients.” But that position ignores the design of the patent system.

Patent expiration is as essential to medical progress as the patent itself. Known as the patent cliff, the moment of expiration – usually 15 to 20 years after issuance – abruptly ends nearly all sales of a patented drug (the U.S. patent of Gleevec expires in 2015). Without new products, the expiration of a blockbuster drug’s patent would put a company under. That fear is a great spur of innovation.

India’s approach isn’t necessarily better. Generics are a \$10 billion-per-year industry for the country, with no investment made in new drugs and no incentive to do so.

China is trying a new tack, which may be the best compromise. Taunting the industry with the world’s third-largest market, the Chinese government is insisting on price concessions for brand-name drugs. Last year, Novartis agreed to give three free doses of Gleevec for every one purchased by the government. The drug is still patented, but the cost is now about \$12,000 per year. With brand-name protection, companies can be assured of profit while the Chinese can be assured of treatment access.

Whatever the outcome, Gleevec, which proved the principle of targeting cancer at its root cause, continues to be a canary in the pharmaceutical industry’s coal mine.

Category: drug patents | | 3 Comments

## Indian Court Rules in Favor of Generic Gleevec

Yesterday, the Indian Supreme Court ruled against Novartis’s claims of patent protection for Gleevec, which would have prevented generic drug makers in India from producing and selling the drug, which is used in the treatment of the otherwise fatal blood cancer chronic myeloid leukemia and other types of cancer.

There are many issues to delve into with this decision. For the moment, in honor of this landmark decision, here is a reposting of my write-up on the case, originally posted here last September, which offers some background on the case.

* * *

The Battle Over Generic Drugs in India (and Elsewhere)

A few days ago, in a courtroom in India, a landmark ruling was made that could impact future legal battles over the sale of generic versions of expensive medications in India. When the Delhi High Court rules that Cipla, the country’s largest drug maker, could sell its own version of the lung cancer drug, Tarceva (erlotinib), made by Roche. The generic version will reportedly cost about a third of the proprietary version.

The lawsuit had been brought by Roche against Cipla. Roche accused Cipla of patent infringement, but the judge, Justice Manmohan Singh, sided with Cipla, agreeing that the generic version has a different molecular structure from Roche’s original. The ruling upholds Roche’s patent on its molecular structure, but allows Cipla to produce its own version, which (presumably) has the same mechanism of action and yields the same outcomes as the Tarceva molecule. The case had been ongoing for four years and the ruling is considered to be a landmark judgment, though Roche could very well appeal.

The timings are interesting, as they seem to set the stage for the reopening of another years-long drama involving yet another cancer drug. The Switzerland-based pharmaceutical company Novartis sued the Indian government years ago over its decision to allow generic versions of the drug to be sold there. First filed six years ago, the case was reopened just yesterday. At the same time, Pharmalot reports that the Indian court has just told Novartis to lower the price at which Gleevec (Glivec outside of the U.S.) is sold in India.

The patent battle over Gleevec is, needless to say, bitter and complicated. Gleevec is a tyrosine kinase inhibitor that treats chronic myelogenous leukemia (CML), a rare cancer that is slow-growing but fatal. Gleevec targets a malfunctioning enzyme that is the product of a genetic abnormality present in more than 95% of patients with CML. For almost all patients with CML, Gleevec or its second- or third-generation counterparts enable people with CML to live a normal, healthy life (and lifespan) with minimal, if any, side effects. (Forgive this brief commercial interruption, but my forthcoming book, The Philadelphia Chromosome, tells the incredible story behind the creation of this groundbreaking drug. More on that another time!)

Gleevec is expensive, but somewhere in the neighborhood of 90% of CML patients in India get the drug for free. So either the company is still making a bunch of money from the remaining 10% of paying patients (some of whom receive a deep discount) or Novartis is fighting the ruling as a way to establish clear guidelines for future branded drugs that may be sold in India.

Although the drama between Novartis and the Indian government is a fascinating case study in its own right, the fight also raises larger questions about drug patents abroad. Cipla was established in the 1930s by Khwaja Abdul Hamied, a nationalist and follower of Mahatma Gandhi. The company became famous in 2001 when it decided to sell a triple-combination antiretroviral therapy for HIV/AIDS for a price that came to less than a dollar per day, a shock in light of the \$10,000-per-year cost of antiretroviral therapy produced by other pharmaceutical companies.

Patents on pharmaceuticals are a contentious issue for many countries around the world, for the obvious reason that the average person in most countries can’t afford to pay for brand-name drugs. The high price of many patented drugs goes against the belief held by many governments that citizens should be guaranteed the best possible delivery of healthcare. In 1994, the World Trade Organization administered The Agreement on Trade Related Aspects of Intellectual Property, known more commonly as TRIPS. The agreement increased the scope of protection for intellectual property that has had the possibly unforeseen consequence of restricting access to medications among impoverished people.

Interestingly, when the discussions that eventually led to TRIPS first began in 1986, fifty countries did not provide patents for pharmaceutical products. Stretching back even further, India had implemented a policy in 1970 that permitted “reverse engineering,” a process used to create generic versions of medications in developing countries — essentially, the Indian government was disallowing patented drugs.

Currently, all WTO Members except for those categorized as “least developed countries” are required to issue 20 years of patent protection in all fields. The purpose was to spur innovation (isn’t that always the stated purpose behind patent regulations?) but the outcome has been restricted access because many people in WTO countries cannot afford to pay for the drug, and no one is allowed to sell a generic version.

Subsequent amendments have attempted to solve the problems resulting from TRIPS. There’s TRIPS flexibilities, the Doha Declaration of 2001, and measures taken by individual governments (for example, rulings in Brazil, Venezuela, and South Africa that ensured access to antiretroviral therapy).

Reverse engineering, the process that allowed Cipla to become one of the world’s most prominent generic drugmakers, has been ruled unlawful by India’s Patents Act, passed in 2005, and will no longer be permitted as of 2015. When that Act comes into play, it could mean the end of an era for generic drugs in India.

In the meantime, the patent battle over Gleevec in India continues, as do concerns about ever-diminishing access to medications worldwide. Once again, it’s the tussle between the fact that drug making is a for-profit business and the wish for unrestricted access to beneficial medications for people with serious illnesses everywhere. At the very least, people with lung cancer in India can look forward to generic Tarceva.

## The Problem of Sticking With It – HIV Prevention Failure and Beyond

According to the World Health Organization, 60% of people living with HIV in sub-Saharan Africa are women. Worldwide, the latest estimate is that women account for 50% of all people living with HIV. Clearly, finding ways to prevent sexual transmission of this potentially fatal virus is vital.

Beginning in 2009, Jeanne Marrazzo, an infectious disease specialist at the University of Washington, tried to do just that. Marrazzo and colleagues launched a study that enrolled 5,029 women from South Africa, Uganda and Zimbabwe. The women were assigned to one of three different HIV prevention strategies using so-called pre-exposure prophylaxis, or PrEP. In one study arm, women took the oral anti-HIV drugs tenofovir and emtricitabine. In another arm, it was tenofovir alone. In a third arm, women were given a tenofovir-containing vaginal gel. Some participants received a placebo in the form of a drugless gel or drugless pills.

The study (called VOICE, for Vaginal and Oral Interventions to Control the Epidemic) didn’t work. A total of 312 women became infected with HIV during the trial, and there was no statistically significant difference between women on any of the prophylaxis arms versus the placebo group.

How could that be? PrEP measures prevent transmission of the virus, so how could a fake gel or fake pills be just as effective? The answer, Marrazzo reported recently at the 20th Conference on Retroviruses and Opportunistic Infections, was that the enrollees did not adhere to the prevention measures.

Although the women in the study reported using their assigned PrEP 90% of the time, blood tests revealed that only 30% or fewer of the participants had anti-HIV drug in their bodies at any one time.

The abstract of the paper presented at the conference concluded:

In this population of predominately young unmarried women with high HIV incidence, adherence to study drugs was low, and no study drug significantly reduced risk of HIV acquisition. The VOICE results … suggest that products that are long acting and require minimal daily adherence may be more suitable for this population. Understanding of HIV risk perception and biomedical, social and cultural determinants of adherence in this high-risk population is urgently needed.

The headline to the ScienceNOW report on this study read, “Human Nature Sinks HIV Prevention Trial.” And although the circumstances surrounding this particular trial raise questions about why, exactly, these women might have foregone HIV prevention medication, there is a long tradition of medical non-adherence into which this study falls.

The phenomenon of non-adherence (or the less popular term, noncompliance) seems so obvious at first glance that it must be a non-issue. Of course many people don’t take medicines as they are prescribed. We joke about not following the doctor’s order. That can mean something as common as not completing the entire course of antibiotics. But it also stretches to the more alarming scenario of not following the exact regimen for a take-at-home oral cancer drug. A world of entrepreneurs has galvanized around improving adherence, with such inventions as electronic pillboxes that remind us to take our medicines and bottles that are somehow alert our doctors when they are opened. (Here’s an article on this topic that I wrote for Slate a few years ago. My personal favorite was the drug-filled prosthetic tooth.)

So is it accurate to call it human nature? Maybe, considering that it seems to be a global phenomenon. A 2012 meta-analysis in the American Journal of Medicine looking at adherence to cardiovascular disease prevention measures found that, across all studies (encompassing 376,162 patients), people stuck with their assigned prevention strategy just 57% of the time after a median 24 months. According to that analysis, adherence was unrelated to age of the patient or whether he or she paid for the medication.

Studies examining adherence rates for chronic conditions all reveal the same issue. Secondary adherence (that is, prescription refill) for cardiovascular conditions ranges from about 57% to about 74%. For diabetes, study findings range from 40% to 81%. For respiratory conditions, one study reported secondary adherence to be 7.0% (Stempel et al, 2005, for adherence to the asthma-controlling medications fluticasone and montelukast.) Secondary adherence to drugs for ulcerative colitis appears to be below 40%, and hovering closer to 24%, according to a 2011 study by Kane et al.

The pharmaceutical industry is concerned because non-adherence costs money. A recent report by Capgemini found that worldwide, pharmaceutical companies lose \$564 billion annually as a result of us not taking medicines as prescribed. (The report is available online at the in-your-face named website Adherence564.com) In the U.S., that amount is \$188 billion. That’s a lot, right? The estimate might be a teensy bit high, considering that the last such calculation, from 2004, put losses at \$30 billion annually. The pharmaceutical industry is, in general, extremely profitable. But patients not filling prescriptions results in a loss of revenue for drug makers. Imagine what would happen if we all adhered better to our medication.

As for HIV prevention strategies, clearly any psychological, communication, and social barriers to making good use of these effective approaches need to be broached before headway can be made. Speaking at the Conference on Retroviruses and Opportunistic Infections and as reported by ScienceNOW, Marrazzo said of the study findings, “We think all the time about these grand interventions, and maybe people don’t want to use them from the get-go. We need to start listening to people, and if you’re not going to use this, we’re not going to test this.”

## Book Trailer for The Philadelphia Chromosome

Readers of this blog have been hearing about my first book, “The Philadelphia Chromosome,” out this May. Well, the book now has its very own trailer. If you’re curious to learn a little more about the story told in this book, then here is the video, for your viewing pleasure…

More typed words coming soon, but in the meantime, some spoken ones.

## “Borne Out of Necessity and Data”: Conquering Mutations in Leukemia

A couple of months ago, the FDA approved the latest drug to treat chronic myeloid leukemia (CML). Called ponatinib (brand name Iclusig, made by Ariad), the drug is a third-generation tyrosine kinase inhibitor, the latest in a class of agents founded in 2001 with the approval of imatinib (Gleevec, Novartis). Imatinib, followed by dasatinib and nilotinib, and now ponatinib, are tyrosine kinase inhibitors. These drugs block the activity of a mutant kinase that triggers the growth of white blood cells in an uncontrolled way. By plugging up the site at which the kinase binds with ATP (the energy storehouse of the cell, from which the kinase plucks a single phosphate and then transports that phosphate to the next protein in line on the pathway that leads to white blood cell production), these drugs essentially stop the process that defines CML.

Cheerleading new drugs isn’t always warranted. But there is something truly impressive going on with this particular line of medicines. They work well, often with few side effects, and are among the most successful cancer drugs ever made.

How did a rare disease like CML, which strikes about 5,400 people in the U.S. annually, come to have three generations of highly successful treatments? That is a story for another time. (Well, shameless plug, it’s the story told in my forthcoming book, The Philadelphia Chromosome, out this May.) However, the story of ponatinib stands on its own because it is yet another targeted drug that is offering a treatment to patients who would otherwise have died from their disease by now, having run through all other options.

Recently I spoke with Michael Mauro, of Oregon Health & Sciences University (OHSU), who was a lead investigator both on the early lab studies of ponatinib and on the clinical trials that led to its approval. Here’s what he had to say about this new drug and why it matters.

JW: What distinguishes ponatinib from other tyrosine kinase inhibitors for CML?

Michael Mauro: Probably the most significant finding before we gave the drug to patients was that in laboratory studies it was shown to prevent the growth of all mutated clones. So it really held the promise of a drug that could treat more broadly resistant CML, or maybe help stop resistance.

When it went into the clinic, ponatinib was given to patients with multi-drug resistant CML. Among these patients, who had taken on average three or more prior medications, the response rate was very good. The majority responded in a significant fashion. In particular, it could broadly treat chronic phase CML that was resistant to multiple medications.

JW: What are mutated clones?

MM: CML has a mutation in the Abl kinase. But there can be more than one mutation, and depending on what mutations are present, a drug may or may not work. For example, some people with CML have a mutation known as T315I. When that mutation is present, none of the kinase inhibitors available before ponatinib could bind. In the laboratory, ponatinib worked against CML cells with multiple mutations, and also stopped the occurrence of new mutations.

JW: Can you further explain how mutations confer drug resistance?

MM: The binding site on the kinase enzyme works like a lock and key. Mutations in the kinase change the shape of the lock. With each new mutation, the lock changes shape a little more. If the shape is changed in subtle ways, some inhibitors might still work. For others, the change is too severe. For example, the T315I mutation is a very dramatic alteration in the lock, so none of the keys worked for patients with this mutation. But ponatinib does work for these patients. T315I is one example, but the significance of this drug extends beyond that one mutation. In preclinical and clinical studies, there was not one mutation against which ponatinib did not work.

JW: Is there any reason why patients with the T315I mutation seemed to do particularly well on this drug in the clinical trial?

MM: It’s true that patients with this mutation had a dramatically better response rate compared to the overall population of the clinical trial, although the average response rate among the entire population was also very good. The reason for this increased rate of response may be because these patients had had fewer prior treatments, or because they were younger. The mutation was just one part of the story.

(The primary mechanism behind CML: the Philadelphia chromosome translocation and the mutant bcr/abl kinase encoded by that mutation)

Interjection:

Here are some of the results of the clinical trials of ponatinib:

Phase I:
• Among 43 patients with chronic CML (the earliest stage, with a life expectancy of 4-6 years in the absence of treatment), 98% (42) had a complete hematologic response; 72% (30) had a major cytogenetic response; and 44% (18) had a major molecular response [more about what these responses mean another time].
• Among 12 patients with the T315I mutation, 100% (12) had a complete hematologic response and 92% (11) had a major cytogenetic response
• The full report is published here.

Phase II:
The “pivotal” phase II trial was known as PACE, for Ponatinib Ph+ ALL and CML Evaluation (Ph+ refers to the Philadelphia chromosome, the spontaneous genetic mutation that triggers CML in the first place). This trial served as the basis for FDA approval.
• 49% (126 out of 258 evaluable patients) had a major cytogenetic response, 41% (105/258) had a complete cytogenetic response, and 26% (68/265) had a major molecular response.
Here is the full chart of response rates. You can see that among patients with the T315I mutation, the response rates were higher than for the overall population, but the population size isn’t large enough to be considered truly rigorous.

Back to the Q&A…

JW: What is it about the chemical structure of ponatinib that allows it to work so broadly?

MM: Imatinib (the first tyrosine kinase inhibitor for CML) binds to a certain receptor in a leukemia cell. It is active against the target, bcr/abl, when the target is in its normal configuration. It’s a very tight-fitting drug. The contact points have to be exactly right.

All of the other inhibitors of this kind are built on the backbone of imatinib. With the second-generation drugs, the chemical had fewer requirements – fewer contact points. The kinase flips back and forth between active and inactive states. For imatinib, the kinase needs to be in an active state, like a door opening that allows the drug to get in. For some of the second-generation drugs, that requirement is removed. The chemical structure retains some of imatinib, but it’s altered slightly. The same is true for ponatinib.
The structure of ponatinib enables the drug to work against other targets, not just the bcr/abl kinase that triggers CML.It also blocks VEGF (vascular endothelial growth factor) and FLT3. FLT3 is associated with acute myeloid leukemia, which is why the drug was also tested for that disease. VEGF is present in many cancers.

JW: What is the significance of a molecular remission?

MM: A molecular remission is often predictive of a survival benefit because it’s such a deep indicator of the disease disappearing. When blood counts normalize, as indicated by a hematologic response, that points to a disease remission. When you sample the bone marrow and see the Philadelphia chromosome disappearing, that’s an even greater depth of remission. When you sample the entire system to look for any cells with RNA made from DNA that has the Philadelphia chromosome – the molecular response – that is the deepest level of remission. A molecular response measures leukemia burden in thousands… is the leukemia burden a thousand times smaller in a treater versus untreated patient?

This level of response takes time to develop. In the trials of ponatinib, we saw these responses occur fairly rapidly, which may seem odd to hear. Why would the molecular remissions occur faster with one drug versus another? When the disease is resistant, the drugs either work or they don’t. In this case, the drug worked for almost all patients in the studies and the responses tended to be fairly rapid.

JW: What does the advent of ponatinib reveal about how to create effective targeted drugs? Are there any lessons learned here?

MM: Ponatinib is really building on history. It was borne out of necessity and data. Imatinib (Gleevec) was unprecedented. It was a small molecule that worked against a selected targeted. No one thought it would be a comprehensive treatment, but it was. Just as the drug was gaining traction, we saw that there are mutations that can arise that prevent the drug from binding. So you go back to the lab and ask: How can we overcome this mutation? You have to make the chemical as slick and as strongly binding as possible.

This drug, and other kinase inhibitors, are really an evolution, not an epiphany. It wasn’t, “Oh we didn’t get this right the first time, what should we have done?” It’s really, “What were the problems with the other drug and how can we fix that?”

Mutations in CML cells happen whether you give these drugs or not. They are fast-growing, unstable cells and these genetic errors happen. A study in our laboratory found that among patients with advanced forms of Philadelphia chromosome-positive leukemia who had never had other treatments, 30% had mutations that were resistant to imatinib or other drugs.

Some people think that if you give these medications, you kill off the grass and the weeds grow. That’s not how mutations occur. It’s more like popcorn popper. Mutations happen.

JW: For a newly diagnosed patient, does it make sense to start with Gleevec and then move to other inhibitors if this drug stops working? Or is the prevalent thinking to start with the latest drug?

MM: There is a healthy debate in the field. All of these drugs yield good results. The data on dasatinib and nilotinib showed that if these drugs put more patients into remission compared to imatinib, but they didn’t lead to a huge shift in practice. Some people continue to use imatinib first because its side-effect profile is so mild and it’s the one we know best, especially when more serious complications arise.

I think the benefits outweigh the risks of using a new drug. Over the years, we’ve learned that if a patient doesn’t have a good response to imatinib, we can improve on the outcome, but it might not be as good as if the patient had started on a more recent drug first.

We need to move forward cautiously. The current official recommendation is that all of these drugs are reasonable first-line choices. It’s an individual decision for each patient that needs to consider what side effect you might predict and what other medications the patient is taking that might interact with this one.

The biggest issue is getting patients into remission, and getting them there quickly. But we always need to exercise caution.

JW: Is it possible to profile patients for what mutations are present and make a decision based on what you see?

MM: No. For one thing, the mutations are not always there at the beginning. You’re looking for a needle in a haystack, and you need to clear away the haystack before you see them, and sometimes new needles appear as the haystack shrinks. A drug-resistant mutation may be present at the start, but you usually can’t see it. We are not very good at profiling patients at the start of their care. It’s one of our biggest challenges: we don’t have a tool that allows us to discern which drug would be best for which patient. All we can say is the odds of response.

JW: Any stories you can share from your experience treating patients with ponatinib?

MM: One of my patients is a middle-aged woman who I’d been treating for at least ten years. She’d been through five clinical studies at our center – she’d tried imatinib, interferon, arsenic trioxide, sunitinib, and nothing worked. She had nagging symptoms from CML, including being cold all the time due to anemia. She enrolled on the phase I trial at a starting dose of 4 mg (the approved dose is 45 mg, so she had just one tenth that amount). She started to respond even at very low doses. She worked up to 15 mg, then 30, and she went into a complete molecular remission. She’s had some side effects, but overall she is feeling so much more … normal. Her long battle was so worth it.

With another patient, the story was more internal. He was a younger man, didn’t know much about CML, and didn’t care very much, it was more of an irritation for him because it was still in the early stages and wasn’t causing many symptoms. He had all sorts of mutations, and had taken imatinib only. I treated him on the phase I trial, and it was like he was starting fresh with treatment again, after having no response to imatinib. He went into a very orderly remission. I wanted to say to him, “Do you realize how lucky you are? You dodged a bullet.” He had never had any problems from his disease, but they would have come if he didn’t respond to this drug. We were able to switch gears just in time to a highly experimental drug with unknown side effects. For him, as a recently diagnosed patient, he didn’t realize the significance.

Images:
The mechanism behind CML: The Philadelphia chromosome translocation and bcr/abl kinase by Piotr Zurek.

## Why Do People With Advanced Cancer Undergo Chemotherapy?

“Self-deception is a valuable personal coping tool. It allows us to aspire to significance, strive for new knowledge, and yearn to make a lasting contribution to the world despite the certainty of our inevitable end.”

Interesting words, and printed in an interesting place. No, they were not spoken by a post-election apolitical pundit. They are the opening lines to an editorial in the October 25 issue of the New England Journal of Medicine, entitled “Talking with Patients about Dying.” The editorial, by Thomas J. Smith, MD< and Dan L. Longo, MD, accompanies a newly published study, "Patients' Expectations about Effects of Chemotherapy for Advanced Cancer," revealing that a surprisingly high percentage of late-stage colon and lung cancer patients who think chemotherapy could be curative.

The study, by Jane Weeks, of the Dana-Farber Cancer Institute, and colleagues (the senior author is Deborah Schrag, also of DFCI), used data from the Cancer Care Outcomes Research and Surveillance (CanCORS) study. In the CanCORS study, about 10,000 cancer patients from five geographic regions diagnosed with lung or colorectal cancer were surveyed on various matters pertaining to their care in order to assess the quality of cancer care and health outcomes in the United States.

Weeks and colleagues honed in on 1,193 participants in the CanCORS study, all of whom had stage IV – metastatic; terminal – disease. All of these patients had chosen to receive chemotherapy treatment. Through a survey, the questions were asked about what they believed chemotherapy could accomplish. What was the likelihood that chemotherapy could cure their disease? What was the likelihood that chemotherapy could extend their lives? Alongside these questions, patients were asked whether they’d discussed the benefits of chemotherapy with their physicians.

In response to the question, “After talking with your doctor about chemotherapy, how likely did you think it was that chemotherapy would … help you live longer, cure your cancer, or help you with problems you were having because of your cancer?” Within the confines of the survey, patients could respond “very likely,” “somewhat likely,” “a little likely,” “not at all likely,” or “don’t know.”

Patients were asked to assess how carefully and how often their doctors explained their disease, the treatment options, the prognosis, and answered any questions patients had. The cohort was also asked to assess their role in choosing what treatment to pursue: how much was it their choice, and how much had their family members (or physician) weighed in?

And here is what the survey showed:

“Overall, 69% of patients with lung cancer and 81% of those with colorectal cancer gave answers that were not consistent with understanding that chemotherapy was very unlikely to cure their cancer,” the authors write.

More than 20 percent of patients with lung cancer (N=710) and more than 30 percent of patients with colorectal cancer (N=483) responded that they thought chemotherapy was “very likely” to cure their cancer. A nearly equal proportion responded “somewhat likely.” Plenty of patients did also respond that chemotherapy was “not at all likely” to cure their disease (more than 30 percent and more than 20 percent, respectively).

About 50 percent of lung cancer patients and nearly 70 percent of colorectal cancer patients said that chemotherapy was “very likely” to extend their lives. Fewer than 10 percent from each group responded that chemotherapy was “not at all likely” to offer life extension.

And, more than 30 percent and nearly 50 percent from each group, respectively, said that chemotherapy was “very likely” to relieve symptoms of advanced cancer.

The authors have a lot to say on the matter. Such as:

“Chemotherapy may offer palliation and some prolongation of life, so it represents a reasonable choice for some patients. However, an argument can be made that patients without a sustained understanding that chemotherapy cannot cure their cancer have not met the standard for true ongoing informed consent to their treatment.”

In other words, if a patient is under the impression that chemotherapy might cure advanced cancer, then is offering chemotherapy to that patient ethical, under the principles of informed consent? Such thinking reflects a lack of accurate information, so consenting to treatment could only be seen as uninformed.

Maybe. The survey also raises questions about how well physicians are doing at having the most difficult of conversations. As Smith and Longo write in their accompanying editorial:

“Truthful conversations that acknowledge death help patients understand their curability, are welcomed by patients, and do not squash hope or cause depression. We need help breaking bad news. This is not one hard conversations for which we can muster our courage but a series of conversations over time from the first existential threat to life.”

Interestingly, patients who were treated in integrative networks were a bit more likely to accurately understand what chemotherapy could offer compared to those treated outside of an integrative network, a result that, the authors suggest, might indicate that providers “may be able to improve patients’ understanding if they feel it is part of their professional role.”

Clearly patients themselves are also responsible for understanding the reality of the treatment they are seeking. The authors raise an intriguing point about “collusion” between patients and physicians, where the discussion moves too quickly from the facts of the prognosis to the potential treatment options, a phenomenon reported in this study from 12 years ago exploring the reasons behind false optimism about recovery among cancer patients.

The editorial also highlights the stubborn clinging to an inaccurate belief about chemotherapy. “When patients are given their actual prognosis, one third or more will not admit that treatment will not cure them,” Smith and Longo write, citing two studies on the matter (this one [on which Smith is first author] and this one).

As Weeks and colleagues note, the primary concern with inaccurate expectations about chemotherapy for late-stage cancer is that they can get in the way of dying well. End-of-life planning takes time and thorough, honest conversations. If someone is holding onto hope of a cure, such conversations are far more difficult if not impossible.

The editorial also mentions cost issues. About one quarter of all Medicare spending is done in the last year of life, a percentage that is the same as it was 20 years ago. “Costs reflect care for multiple severe illnesses typically present near death,” the authors of the Health Affairs report noting this percentage wrote. What’s more, say Smith and Longo, “Chemotherapy near the end of life is still common, [and] does not improve survival…” This isn’t to say that all of that last-year-of-life Medicare spending is on chemotherapy, but that cost is definitely a significant contributor.

Weeks et al note some weaknesses of their study. The survey was done several months after diagnosis, so patients who died shortly thereafter were not included. And, the survey was done on a single occasion, so any shifts in belief over time were not documented. Also, patients may have been biased toward optimism by the simple presence of an empathetic interviewer. Finally, the survey was not set up to probe into the underlying psychologies that may have impacted or guided patients’ beliefs about their treatment.

The authors make an interesting point at the end of the publication. “…we need to recognize that oncologists who communicate honestly with their patients, a marker of a high quality of care, may be at risk for lower patient ratings.”

## For a Song: Bartering Music for Healthcare

The O+ Festival is a gathering of artists, musicians, and healthcare providers in which art and medicine are bartered – mainly as a way for those on the art/music side to obtain medical care that they otherwise cannot afford, but also as a way for healthcare providers to gain exposure to visual art and music that might otherwise not come to their community.

The annual festival, which takes place in Kingston, a town of about 20,000 people in upstate New York, started three years ago, and runs this weekend from October 5 through October 7. All participants – performers and volunteers – are given free access to all of the services available at the clinic set up for the festival. Those services include a general physical; dental exams; blood pressure, vision and hearing tests; vouchers for eye exams; psychology screening; and numerous other types of health-related care provided by primary care physicians, nurses, dentists, psychologists, and other providers. About forty bands will perform over the three days, and work will be exhibited by dozens of artists.

I spoke with Joe Concra, 47, an artist from Kingston who helped start the festival and continues to be one of the core organizers, about the motives behind the festival and how it has grown over these past three years.

Jessica Wapner: How did the festival originate?

Joe Concra: It started with a dentist. He and I had been at the same festival, in a small town up in the Catskills, called Truck America. He saw me at a party and thought I was one of the organizers of that festival, and he started telling me all these things that he thought could be done differently. And I said, I was just there for the band, I had nothing to do with it.

He told me that there was a band he really liked, Monogold, and said, “I would clean their teeth and fill their cavities if they came and played.”

I went home and spoke to my wife and our friend, Alex. We called Dr. Art Chandler, he runs the emergency room at Columbia Memorial Hospital in Hudson, NY. I called him and said, “There’s this crazy dentist. What do you think of this? And he said yes, and that he keow some doctors who love music who he thought would be interested in the idea, too. And then we altogether said, this is crazy but maybe we can pull it off. The way we got it going was with a few phone calls to different musicians, different artists, and different doctors. We had a meeting, then another meeting, and four months later we had the first festival.

Monogold played at the first festival. He (the dentist) just wanted to bring music to the town he lived in. This will be our third year.

JW: So it wasn’t, at first, an idea sprouted by starving artists with no health insurance?

JC: [The dentist's] idea was sort of the spark. Then we sat around saying, “That’s amazing. I wonder if anyone else would do that.” Because none of us had any healthcare at all, we didn’t have any access.

Definitely the “we” is a big part of it. That initial idea formation took about 10 to 20 of us, to figure out: What is value? It’s culture that is valued, it’s our culture, our community that we value, as artists, musicians, and doctors. That’s where it sprung from. [The dentist’s] idea was the a-ha! moment. The structure was put together by people hammering out the details, figuring out how this could work. Will doctors respond to this idea that they are treating people for a weekend to give them access, but they get to see music in their town and art up on the wall? To everyone’s surprise, it worked out, to the point where it’s really growing.

JW: How has the healthcare aspect grown? How many providers will be there this year?

JC: This year we have four dentists and about 60 healthcare providers. Dental is such a sought after thing and nobody has dental insurance, so we count them differently. The healthcare providers are everything from infectious disease specialists to massage therapists.

This year we are going beyond access at the clinic. We have ongoing care this year so people can see doctors after the festival and pay on a sliding scale.

(Outside the clinic set up for the festival)

JW: Is Kingston an area where artists have gravitated for its affordability?

JC: Yes, artists and musicians have come to Kingston for all the usual reasons, and more so since the festival has started (though not because of the festival). People congregate in places for strange reasons. Artists live here for all the usual reasons that you hear for the Hudson Valley: because it’s affordable, close to New York, beautiful — and there are all these amazing doctors who live here.

JW: Has raising awareness about the inability of so many people to afford healthcare been part of the festival’s motives?

JC: I think that’s one of the by-products. We are this Western country and one of two Western civilizations that does not provide healthcare for the population. So there’s that side of it. That’s the cause of why we have to have this festival: because it’s not there. Our solution is gaining access to doctors and healthcare providers in the Hudson Valley that we wouldn’t normally have access to, breaking down this barrier. Healthcare isn’t this monumental, scary thing to deal with. You can meet doctors in your area who will treat you post-festival on a sliding scale.

We are trying to take care of each other in a very, very, very small way. To point out that your care is in your hands. We aren’t political. It’s such a political issue, no matter how we all feel about it. If you were to privately ask everyone, probably everyone involved with the festival would say we should have universal healthcare, but we don’t. But isntead of bemoaning it, this is our way of saying, well, let’s do somethign about it, that we can do because we can’t afford it.

So many artists and musicians quit being artists and musicians because healthcare is so expensive. At some point you have to make a decision. Everybody sacrifies all these things to make their music and art, and one of the things you sacrifice is buying healthcare coverage because it’s so expensive. If it’s running you \$1,000 per month, that’s \$12,000 per year, and that’s the difference between recording a record or staying in the street. O-Positive is not providing that coverage for anyone. We’re just providing them access on a weekend, they get to meet all these people, get treated, see a doctor for the first time in five or ten years, realize everything is okay, and then go on.

JW: Is the festival expanding to other areas of the country?

JC: We are talkign wiht people in other towns about O+ Nashville and O+ Minneapolis. We gave a talk at the Society for the Arts in Healthcare conference in Detroit back in the spring, and after our talk a bunch of people came up to us and said, I have this arts organization or I have this or that, and would love to bring it to your town. So now we’re sort of putting together this playbook.

JW: Has this become a bigger and bigger part of your life these past few years?

JC: I would love for it to grow and be everything that it needs to me, and I would lvoe to be able to get back to my regular life. It’s overwhelming, but I think anything you start, at this point is like this. Anyone who starts projects that are this big says the first five years are all –consuming. We are attracting really great professionals now to help us run it. For the first time this year, we have a fundraiser. She was able to get us sponsorship, which was fantastic, because barter can be rather expensive. We pay for some of the dental costs, the clinic. It take s money to run the festival itself.

We are now a nonprofit organization, we will have our status in January. We are laying the foundation underneath the festival. The festival is an amazing idea, and now for it to sustain itself we need the foundation underneath it. It will always be open to all comers and all ideas so it can go whatever way it wants to, to grow.

JW: How do the logistics work for the artists? Also, do audience members seek healthcare, or is that only for people with something to barter?

JC: The clinic is in the ballroom of an old hotel. For me, that’s where everything happens. We fill it with all the doctors, staff, nurses. That’s where all the musicians who’ve been accepted – they fill out a medical questionnaire online – and go to the ballroom to see the doctors.

Everybody sees a doctor. Then, if they have dental, we take them to their dental appointment. We have vouchers for optometry for artists so they can get their eyes checked. We have slips for blood work, for x-rays, colonoscopies. We have all these things to give to people so they can get care post-festival.

For the general public, they give a donation for a wristband that gets them into all the events. This is our most stunning year in terms of scheduling. Also this year we have a public health expo on Saturday from 9:00 AM to 2:00 PM, everuthing from blood donations to onsite HIV testing and counseling, Planned Parenthood—everythign you can think of comign to be there for a public health expo. So if you come to the festival and you have a wristband on, and you’re walkign through the farmer’s market, you can just walk into the expo and talk to people.

JW: It sounds like the people who come are genuinely getting help, that this isn’t just a demonstration of the need for healthcare coverage.

JC: Yes. It’s for real. That’s why we always say we don’t provide health insurance, we provide community reassurance.

Doctors, artists, and musicians get to co-mingle at appointments. They get to know each other during the day. This Friday, a bunch of musicians will meet a bunch of doctors, and then those musicians will be playing on Friday or Saturday and the doctors will be in the audience.

JW: As the festival has become more popular, are there sponsorship offers or other ideas that you need to say no to?

JC: We are nonpolitical. We put art on the sides of buildings, and it could offend somebody or someone could write a ticket, and that has happened. When a new mayor was elected, people said “you gotta go meet with him.” So I met with him and told him about the festival, and he asked what did we want from him, and I said “We want nothing, we just want you to know that we’re doign this in your town.” He asked if we wanted the old parking garage wall as a spot for a permanent mural. It was an amazing offer, but I was [concerned] because what if people don’t like it? What kind of push back will there be? But it looks incredible. The whole neighborhood loves it. It was a jail-like wall that now looks beautiful. So that was a lesson for me: Don’t be afraid of what people offer, just embrace it. As I’m talking to you, I’m looking down on a 250-foot mural that was finished last night.

That said, what do you do if the company that makes Viagra comes and says, we want to help you out. That’s an internal debate that we have. One of our big sponsors is HealthQuest, and my immediate question was, what do they want? How many banners and where do they go? We are a DIY festival. We make all these things ourselves. Let’s not go the traditional route of a big, vinyl banner behind the stage. We will give them credit, but make sure it’s credit because they are donating doctors services to us. It’s an interesting predicament.

JW: Yes. You have to be cautious about ulterior motives.

JC: Right. All we want is for people to have access to care. That’s what we want. We don’t provide health insurance. We provide community reassurance. We are reassuring you that your community is here for you.

JW: Do you have a vision that you’d love to see become a reality out from this festival?

JC: I would love it if we had a clinic or a database of health services available for artists and musicians, where we of someone wrote to us asking if there any dental trades available for March, I could say, “It just so happens that this dentist is giving one visit per month and no one has spoken up for March, so here you go.” That would be amazing. It’s not a solution to the healthcare problem, but it’s something.

JW: Any memorable moments you can recall?

JC: There was a musician who played the first year, Nina Violet. Her teeth were all cracked in the front when she got here. She got up for her performance, the room was packed. The first thing she said was, “I just want you all to see my new smile.” The dentist had capped all her teeth that morning.

The first person we saw, year one, was a volunteer (volunteers get access to care). The first person Art Chandler saw was a 71-year-old volunteer who had high blood pressure, who was basically about to have a heart attack. Art got her to a hospital and she lived. The first person we saw had to go to a hospital, and he wouldn’t have seen her if we hadn’t been doing the festival.

One of my favorite things the first year was that the bands Phosphorescent and Amazing Baby had a kind of bet about who would get more fillings. Phosphorescent won with, I think, thirteen fillings done among the members. The other band had nine, I think.

JW: Does the donated healthcare follow the usual HIPAA confidentiality rules?

Yes, we have layers of confidentiality.

JW: What do the participating doctors say about having this outlet for their practice?

JC: They love it. The doctors get so much out of it. We have people coming from all over the place to help, and everybody walks away feeling amazing. On Sunday night, when we shut it down, there are tears of joy. A lot of musicians I run into tell me that they now have these doctors as their regular doctors.

[When I saw my family physician, Jack Weeks, for a physical, he asked me what’s going on with my life, and I told him about the festival. He wanted to be involved but he was busy that weekend. So he offered that post-festival, he would see any artists or musicians from the festival for fifty dollars. So now we have this doctor who has opened up his office year-round for \$50 per appointment. That amount might still be a stretch but you can get there.

JW: Is supporting local businesses part of the festival’s motive?

JC: This neighborhood needs a kick in the pants. It needs people to rent storefronts. So from the beginning we talked about using existing venues, so for the weekend we can guarantee that those bars and restaurants will be full. That’s a big part of it, too, because it’s a neighborhood event. Everyone donates time and money to make it happen.

JW: Has media attention been growing?

Yes, a lot. But I think that the story is economics. We get plenty of music press, art press, local coverage. But the real gist of this is that it’s a community taking care of itself through bartering. You don’t know where that’s going to go. That’s what I like about it.

It’s exposure, too — exposure to a problem, and to a solution. It’s a Band-aid solution, but it’s a solution. And it’s growing.

_______________________________________________
All photos courtesy of the O+ Festival.
Musicians pictured in the two photos above are
Nicole Atkins (top) and Spirit Family Reunion
(bottom)

This interview was edited for clarity.

## Industry’s Influence

Do they or don’t they?

It’s the question that paper after paper after paper after paper has tried to address over the past decade: does industry sponsorship of clinical trials bias the outcomes of the study? Does such sponsorship influence how doctors interpret the research findings? Does it affect healthcare professionals’ willingness to believe the results and integrate an experimental treatment into their practice?

The latest attempt to navigate the thicket of pharma funding is in this week’s New England Journal of Medicine. In a paper titled, “A Randomized Study of How Physicians Interpret Research Funding Disclosures,” Aaron S. Kesselheim and co-authors report their results of a study designed to test how scientific rigor and funding disclosure influence the credibility of a clinical trial in the eyes of doctors.

(And let’s just get the obvious out of the way now: Kesselheim et al’s study was not funded by a pharmaceutical company. The disclosure forms are available online as a PDF.)

Survey says…

Here is how the authors set out to determine how funding disclosure affects what doctors make of a study’s findings. First, they made up studies for three new drugs for common disorders: hyperlipidemia, diabetes, and angina. And really, the invented drug names are spectacular: lampytinib, bondaglutaraz, and provasinab. Bondaglutaraz! Fantastic.

Then, after what must have been a very enjoyable name-creating session, the authors wrote fake abstracts describing fake trials. The abstracts varied according to their level of scientific rigor (high, middle, and low for each drug) and funding status (no funding source mentioned; funded by the NIH; or funded by a pharmaceutical company with a lead author that was financially involved with the sponsoring company). The companies fake-sponsoring the studies were selected at random from the 12 pharmaceutical companies on this list.

So – three drugs, three study designs, three funding types, for a total of 27 abstracts. Then it was time for the survey, which was mailed to 503 physicians randomly selected from a total 45,398 applicable physicians listed with the American Board of Internal Medicine. The physicians were offered \$50 for completing the survey in several notifications. Nonrespondents were even mailed a crisp five dollar bill, with promise of the remaining \$45 upon return of the completed survey.

The physicians weren’t asked to review all 27 abstracts. Rather, each participant was asked to review three abstracts, each for a different drug. The physicians knew that these were made-up drugs and they were told to assume that the drug had recently been approved by the FDA and was covered by insurance – in other words, satisfying all the criteria that would otherwise be needed for a doctor to consider a drug safe and practical to prescribe. The levels of rigor and funding were selected at random for each of the three studies provided to each physician.

The survey asked the respondents to score each abstract according to their likeliness to prescribe the drug.

What is a rigorous clinical trial?

It’s worth pausing here to talk about what makes a clinical trial rigorous. The question at the heart of this NEJM report is: If a trial is conducted in a highly rigorous manner, will industry funding still diminish its credibility? And the accompanying, more editorial question: Should industry funding diminish the credibility of a rigorous clinical trial?

Here is what makes a clinical trial rigorous (according to the NEJM paper authors, and just generally speaking):
• The study should randomized
• The study should be double-blind; that is, neither the investigators nor the participants know who’s receiving which treatment (the experimental or the control)
• The study should have an active comparator; that is, it should not be a single-arm study, but should be comparing two or more regimens
• The dropout rate (the number of enrolled patients who leave before the study is concluded) should be less than 9%
• For these hypothetical new drugs, the study was to have a sample size (ie, total study population) of 5,322
• The enrolled patient population should accurately represent patients with the disease/condition in question. In other words, if the average age of patients with the condition in question is, say, 65, then the average age of patients in the study should not be, say, 35.
• The drug should be documented as being safe
• For the hypothetical drugs, a rigorous study was one with a follow-up of 36 months; that is, patients had been treated for at least three years with the experimental drug

Okay, so. With the three abstracts in hand, the physicians were asked to say how likely they were to prescribe the new drug (1=very unlikely; 7=very likely), and to score the methodological rigor of the trial (1=not at all rigorous; 7=very rigorous), and to score their confidence in the conclusions reached by the investigators (you guessed it: 1=not confident; 7=very confident). And participants were also asked to respond to the juicy question:

“Do you think that pharmaceutical company funding is likely to influence the outcome of scientific studies about the efficacy and safety of pharmaceuticals in favor of the drug in question.”

(Survey respondents were also asked to disclose their own financial support received in the previous year.)

Dim the lights, it’s time for the results!

Well, despite the promise of fifty bucks, only about half of the solicited physicians responded to the survey (53.5% to be exact, for a total of 269 respondents). Interestingly, about 75% of the respondents reported receiving at least one type of industry support in the past year. And they generally agreed with that question about whether industry funding can influence trial outcomes.

Also – there was a high correlation between the rigor of the abstract and the perceived rigor. In other words, the respondents correctly discerned which abstracts were for the most rigorous studies and which for the least. The confidence in the study outcome matched the level of rigor; the least rigorous studies engendered the least confidence in the results.

More interesting, there was a definite, clear association between the funding disclosure and how physicians perceived the rigor and results of a trial. When industry funding was disclosed, the trial was perceived as less rigorous compared to abstracts where no funding was disclosed. And, regardless of the design, physicians had less confidence in the results of industry-sponsored trials, even when the trial was highly rigorous (I know, the word “rigor” is getting irritating right about now. Sorry for that. My inner thesaurus is on a coffee break right now). The respondents were also less willing to prescribe drugs tested in industry-funded trials compared to drugs tested in trials with no funding listed.

Also:
• Industry-funded trials were considered less important than NIH-funded trials
• Respondents were less interested in reading the entire report of an industry-funded study than they were in reading the entire report of an NIH-funded study
• The distaste for industry-funded research was evident at all levels of scientific rigor
• US-trained physicians were less likely to say they were willing to prescribe any of the pretend drugs than were physicians who’d trained outside the US.
• Older physicians were more likely to say they’d prescribe the new drugs than were younger physicians

As the authors write in their discussion:

“…respondents downgraded the credibility of industry-funded trials, as compared with the same trials randomly characterized as having NIH funding or having no source of support listed. The magnitude of this reduction in perceived methodologic rigor was about the same as that for low-rigor trials as compared with medium-rigor trials. Physicians’ skepticism of industry-funded research affected their responses to high-rigor and low-rigor trials similarly.”

The authors see the results of their survey as problematic. They point out that the pharmaceutical industry has funded the study of many major drugs that are now clinically important, and express their concern that excessive skepticism could hinder the translation of research findings into clinical practice. They call on the pharmaceutical industry to address this thinking so that the credibility of clinical trials will be more weighted in its rigor than in how its paid for. “The methodologic rigor of a trial, not its funding disclosure, should be a primary determinant of its credibility.”

The source of skepticism

The skepticism evident in the surveys has accrued over years. There was this lawsuit, in which GlaxoSmithKline was accused of concealing data. There’s the recent \$322 million fine of Merck over off-label promotion of Vioxx, just a year after the company paid a \$1 billion penalty for the way it promoted rofecoxib. Abbott recently paid \$1.6 billion for promotion of unapproved uses of Depakote. And then there are the many disparaging insights in The Truth About the Drug Companies.

Yet in an editorial accompanying the report of the survey results, Jeffrey Drazen, MD, points out how many investigators in NIH-sponsored studies have incentives such as academic promotion and recognition that could influence the outcomes of their trials. He writes:

“A trial’s validity should ride on the study design, the quality of data-accrual and analytic processes, and the fairness of results reporting. Ideally, these factors – not the funding source – should be the criteria for deciding the clinical utility. Patients who put themselves at risk to provide these data earn our respect for their participation; we owe them the courtesy of believing the data produced from their efforts and acting on the findings so as to benefit other patients.”

That last clause might be a bit of a stretch. Feeling beholden to the patients who enrolled in the trial as justification for believing the results of the study? I’m not sure that I’d want my doctor prescribing me a drug because he owed it to the patients who’d been part of its investigation. But the call for balance seems warranted. After all, unless some very vast change sweeps across the twisted world of medical care, industry funding of clinical trials is here to stay.

## The Battle Over Generic Drugs in India (and elsewhere)

A few days ago, in a courtroom in India, a landmark ruling was made that could impact future legal battles over the sale of generic versions of expensive medications in India. When the Delhi High Court rules that Cipla, the country’s largest drug maker, could sell its own version of the lung cancer drug, Tarceva (erlotinib), made by Roche. The generic version will reportedly cost about a third of the proprietary version.

The lawsuit had been brought by Roche against Cipla. Roche accused Cipla of patent infringement, but the judge, Justice Manmohan Singh, sided with Cipla, agreeing that the generic version has a different molecular structure from Roche’s original. The ruling upholds Roche’s patent on its molecular structure, but allows Cipla to produce its own version, which (presumably) has the same mechanism of action and yields the same outcomes as the Tarceva molecule. The case had been ongoing for four years and the ruling is considered to be a landmark judgment, though Roche could very well appeal.

The timings are interesting, as they seem to set the stage for the reopening of another years-long drama involving yet another cancer drug. The Switzerland-based pharmaceutical company Novartis sued the Indian government years ago over its decision to allow generic versions of the drug to be sold there. First filed six years ago, the case was reopened just yesterday. At the same time, Pharmalot reports that the Indian court has just told Novartis to lower the price at which Gleevec (Glivec outside of the U.S.) is sold in India.

The patent battle over Gleevec is, needless to say, bitter and complicated. Gleevec is a tyrosine kinase inhibitor that treats chronic myelogenous leukemia (CML), a rare cancer that is slow-growing but fatal. Gleevec targets a malfunctioning enzyme that is the product of a genetic abnormality present in more than 95% of patients with CML. For almost all patients with CML, Gleevec or its second- or third-generation counterparts enable people with CML to live a normal, healthy life (and lifespan) with minimal, if any, side effects. (Forgive this brief commercial interruption, but my forthcoming book, The Philadelphia Chromosome, tells the incredible story behind the creation of this groundbreaking drug. More on that another time!)

Gleevec is expensive, but somewhere in the neighborhood of 90% of CML patients in India get the drug for free. So either the company is still making a bunch of money from the remaining 10% of paying patients (some of whom receive a deep discount) or Novartis is fighting the ruling as a way to establish clear guidelines for future branded drugs that may be sold in India.

Although the drama between Novartis and the Indian government is a fascinating case study in its own right, the fight also raises larger questions about drug patents abroad. Cipla was established in the 1930s by Khwaja Abdul Hamied, a nationalist and follower of Mahatma Gandhi. The company became famous in 2001 when it decided to sell a triple-combination antiretroviral therapy for HIV/AIDS for a price that came to less than a dollar per day, a shock in light of the \$10,000-per-year cost of antiretroviral therapy produced by other pharmaceutical companies.

Patents on pharmaceuticals are a contentious issue for many countries around the world, for the obvious reason that the average person in most countries can’t afford to pay for brand-name drugs. The high price of many patented drugs goes against the belief held by many governments that citizens should be guaranteed the best possible delivery of healthcare. In 1994, the World Trade Organization administered The Agreement on Trade Related Aspects of Intellectual Property, known more commonly as TRIPS. The agreement increased the scope of protection for intellectual property that has had the possibly unforeseen consequence of restricting access to medications among impoverished people.

Interestingly, when the discussions that eventually led to TRIPS first began in 1986, fifty countries did not provide patents for pharmaceutical products. Stretching back even further, India had implemented a policy in 1970 that permitted “reverse engineering,” a process used to create generic versions of medications in developing countries — essentially, the Indian government was disallowing patented drugs.

Currently, all WTO Members except for those categorized as “least developed countries” are required to issue 20 years of patent protection in all fields. The purpose was to spur innovation (isn’t that always the stated purpose behind patent regulations?) but the outcome has been restricted access because many people in WTO countries cannot afford to pay for the drug, and no one is allowed to sell a generic version.

Subsequent amendments have attempted to solve the problems resulting from TRIPS. There’s TRIPS flexibilities, the Doha Declaration of 2001, and measures taken by individual governments (for example, rulings in Brazil, Venezuela, and South Africa that ensured access to antiretroviral therapy).

Reverse engineering, the process that allowed Cipla to become one of the world’s most prominent generic drugmakers, has been ruled unlawful by India’s Patents Act, passed in 2005, and will no longer be permitted as of 2015. When that Act comes into play, it could mean the end of an era for generic drugs in India.

In the meantime, the patent battle over Gleevec in India continues, as do concerns about ever-diminishing access to medications worldwide. Once again, it’s the tussle between the fact that drug making is a for-profit business and the wish for unrestricted access to beneficial medications for people with serious illnesses everywhere. At the very least, people with lung cancer in India can look forward to generic Tarceva.