The already long and expensive process of bringing a drug from discovery to market is further challenged by the entrance of personalized medicine products, which don't neatly fit into industry's existing business models or the US Food and Drug Administration's regulatory pathways.
Genomically guided personalized medicine products have so far emerged most readily in oncology. But even drug and diagnostics companies developing genomic medicines in the cancer space have experienced setbacks due to regulatory and market challenges.
Jay Tenenbaum, CEO of the software company CollabRx and founder of the non-profit Cancer Commons, believes that the emerging personalized oncology industry can address these challenges by approaching the discovery-to-market process from a completely new perspective: the patient's.
A cancer survivor, Tenenbaum launched Cancer Commons last year with a vision to change the way oncology drugs are developed, reduce the number of late-stage drug failures, and improve patient care. Cancer Commons is an online community that aims to link doctors, patients, industry, researchers, and insurers around the common goal of giving the right drug to the right patient. Seed funding for Cancer Commons was provided by the non-profit CommerceNet and by CollabRx, which is operating with a collaborative grant from the Melanoma Research Alliance.
In Tenenbaum's view, the current clinical trial paradigm centered on the randomized-controlled trial may be a gold standard for diseases that aren't as molecularly heterogeneous as cancer, but it doesn't work when it comes to efficacious personalized cancer drugs.
By building an open and collaborative online community of stakeholders from all parts of the healthcare enterprise, Cancer Commons hopes to facilitate smaller, proof-of-concept trials that enable patients to get the drugs that work for them and allow drug companies to identify new molecularly targeted indications for their candidates. To this end, Cancer Commons has established an editorial board that develops treatment recommendations tailored to the molecular subtype of a patient's cancer.
The expert panel has so far developed a Targeted Therapy Finder for melanoma. In the coming months, Cancer Commons hopes to build similar applications for other types of cancers, enable patients and doctors to report outcomes back to the initiative, and also get industry and insurers to join the partnership.
However, changing the drug-development paradigm is an uphill battle that requires dealing with healthcare players who are invested in keeping things just as they are. In a recent interview with PGx Reporter, Tenenbaum discussed Cancer Common's vision for improving care for cancer patients, and the difficult road ahead in trying to achieving it.
Below is an edited transcript of the interview.
Why was Cancer Commons formed? And how does it hope to advance genomic medicine?
Cancer Commons was formed out of my personal necessity. I had a lot of difficulty when I was first diagnosed [with melanoma] trying to determine which treatments were for me. I would talk to different doctors, different specialists, and they would have different recommendations. It was clear that there needed to be a more objective way for patients to be able to select treatments.
When I was first diagnosed, I went to a half dozen different doctors and got a half dozen recommendations for what I should do … Each doctor saw the answer in what they did, whether it was surgical oncology, or radiation oncology, or immunotherapy, or what have you. I was frustrated that there wasn't a rational basis for selecting among these things. In the end, I wound up making a gut call, picking a therapy that felt right to me.
I made a good choice. I'm still alive. But, ironically, the clinical trial I enrolled in failed. That [melanoma] drug, [called Canvaxin] was being developed by CancerVax. But it did apparently help some of us. It's hard to know if that is what is responsible for me being alive. The thing that I took away from that was some of the issues with clinical trials as they relate to oncology.
Many of these trials fail. It's very frustrating. Particularly in melanoma, there were 70 successive trials that had failed before a successful Phase III trial with ipilimumab [Bristol-Myers Squibb's Yervoy] was reported at the American Society of Clinical Oncology's annual meeting [Editor's note: The US Food and Drug Administration approved ipilimumab for melanoma last week]… Every one of these trials, while failing, helped some patients. So the question is, 'What disease do these people have, that we have a successful drug for, that we used to call melanoma?'
These trials all basically had two randomized arms, each of which were very heterogeneous, had [patients with] lots of different subdiseases. So, evaluating drugs in that fashion may be a gold standard in diseases [that] have homogenous populations, but in cancer they aren't a good predictor for what drugs will work well for an individual.
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That was one of the starting points. Clinical trials are very valuable for predicting which drugs work best, but the fact that one drug worked on 50 percent of the people who tried it and another drug worked on 20 percent, doesn't necessarily mean that the first drug is a better drug for me. We need to capture a lot more information on patients enrolled in trials than we are typically in order to determine with a finer granularity how to match patients to drugs. So, I looked for inspiration in what was going on in the oncology world.
Only a small percentage of patients go into clinical trials anyway. The vast majority of patients get treated in medical centers or in community oncology settings. Every day thousands of patients get treated with off-label drugs and cocktails, based largely on the personal experience and professional judgment of their doctor. These are unobserved and uncontrolled experiments that we capture very little of the learning from.
In some sense, it's a real tragedy. It's as if the nation's 30,000 oncologists are conducting hundreds of thousands of these N-of-1 experiments and we're not learning very much from them. So, I asked: 'What if we could figure out how to coordinate these N-of-1 experiments and capture the learnings from them?' This wouldn't be an alternative to [traditional] clinical trials but it would be a way to supplement the information from those trials. That's what gave birth to Cancer Commons.
How do you hope to join researchers, patients, and drug companies to do these N-of-1 trials?
We're just at the very beginning of the journey. Cancer Commons is a very large vision. Right now, what we have is a Targeted Therapy Finder [online application] for melanoma. The major accomplishment so far has been to get a group of experts, who are really the top people in the field, to get together and agree what the major melanoma subtypes are that are actionable, and recommend treatments and tests that can be used to treat those subtypes.
So, all the melanoma subtypes included in the Targeted Therapy Finder are actionable. There is a test to determine whether a patient is in or out of that subtype and there's at least one rational treatment or trial that the patient might be able to consider … And this is really for advanced cancer patients who have failed the standard of care.
This is set up as a way to pose hypotheses, and get them rapidly tested in a very ethical way, by giving patients who are beyond the standard of care — who would be otherwise treated by the professional judgment of an individual … or by medical guesswork — a chance to participate in an experiment that has a reasonable chance of helping them and capturing results.
We are not yet at the stage where we're capturing the results. Where we are is at the stage of providing information as to the things they should try. A future release of the melanoma application, hopefully before summer, will allow patients to take the advice given but also report what treatment they chose and what the outcome was.
Will this be information that only the doctor can report, or can the patient also report their experience?
We're going to pursue both channels. It's clear you can get more clear information from the doctor, but patients have a lot more urgency to participate in these kinds of things, so we're certainly going to encourage patients to report their clinical data.
We're also going to try, with the patients' help, to get the physicians involved as well. One of the things we're going to want is the genomic information from the tests that were given. The patient is not likely to know this information directly.
How long did it take you to pick the tests and drugs for each melanoma subtype included, and how do you plan to scale this process through your advisory panel for other cancer types?
It took about six to nine months for melanoma. It took a long time. One of the things we learned is that of the 10 or so subtypes for melanoma, only four or five are really actionable today with drugs that are available today. Based on that, we've developed a streamlined process for developing models for additional cancers that really focus on the subtypes that are plausibly actionable. That means there are validated targets with available diagnostics to be able to determine that available investigational or approved drugs are applicable in a given patient. Given that streamlined process, we currently have a half dozen models under development, with plans to launch them by the end of the year. By next year we hope to have models covering all of cancer.
In your advisory board you have very knowledgeable people, but there are also professional guidelines for each type of cancer. What happens when your expert panel's recommendations conflict with those issued by other professional societies or patient groups?
That's not a problem we faced in melanoma because there are no good guidelines. It's basically interferon, and there is a lot of debate about whether it does any good. If patients have metastatic disease, they go beyond standard of care very quickly. For other cancers we're looking at — breast, colon, lung, and so forth — there is a very elaborate set of standard-of-care guidelines that we have to incorporate. We will be incorporating those guidelines, but … the things we're trying to do are going to be a substantial advance beyond traditional guidelines. We clearly will use traditional guidelines where they're effective and for those who haven't exhausted their options, but we're really focusing on those who are beyond standard of care.
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It's not like there is one set of guidelines. Guidelines from ASCO and the National Comprehensive Cancer Network, for example, can be very different because they have different processes for developing them. Beyond that, there are many variations on those guidelines developed by major cancer centers … No one even knows if anyone follows these guidelines, less whether they work or not, and they only get updated periodically.
Cancer Commons will offer a way to test the guidelines in the same way that we're testing options for patients who are beyond the standard of care. The existing guidelines become a hypothesis for us to test. Furthermore, these guidelines aren't available to people in a convenient way, so building them into the kinds of apps we're developing will make it much easier for a doctor or a patient with a few clicks to figure out where they fit within the guidelines and what choices are available to them.
Off-label use of drugs is common in cancer. Can you describe how a doctor makes the decision to put a patient on an off-label drug?
It's different depending on whether it's an FDA-approved drug or an investigational drug … When a patient gets beyond the standard of care, has a particular molecular lesion, and there is an approved drug that appears to be able to block that, and there's a rational reason to try it, then … one can start a small Phase I/II trial to see if the drug has activity in this disease. Or without any FDA paperwork a doctor can on his own prescribe the drug and see if it works.
In the latter case, the insurance company wouldn't pay for that.
That's, of course, the issue. In Cancer Commons we're not recklessly trying to recommend drugs. There has to be a strong rationale based on research literature … that justifies that there is a good chance this drug is going to work. We will make all that information available to physicians and patients in the form of a package that can be taken to the insurer and try to make a case for coverage.
Beyond that, it's my hope that we can convince payors and pharmaceutical companies, doctors and patients, that there is a way to align everyone's interests.
This can done by creating a process whereby a doctor suggests, [for] a drug that is indicated by information through Cancer Commons or the app, … that the drug company agrees to make it available for compassionate use at no cost for a period of time, during which we can look at objective measures, activity on a PET scan, or biomarkers, to determine the effect of the drug. If it does appear to be working, then the insurance company agrees to pay in a kind of pay-for-performance kind of deal. If the drug doesn't work, then it doesn't cost the drug company very much … and the insurance company gets data to build a case that this drug is not effective in this population.
But, if it does work, then the drug company does get reimbursed and they get a free and early look at another possible indication for their treatment. It's at that point that Cancer Commons makes it very easy for a drug firm to file for a very small study with the FDA and with institutional review board approval, and look at a half-dozen more patients with the same molecular characteristics of the tumor and attempt to replicate the findings.
You can think of Cancer Commons as a quick and inexpensive hypothesis generator. Because of the way the community is formed, the patients have indicated their molecular subtypes and their willingness to participate in trials, so companies could recruit patients quickly for a small study. These are activist patients. If results are replicated in smaller studies, then the company can move on to bigger trials, and eventually go to the FDA and try to get approval for the drug … It would be very surprising to see a trial formulated on the basis of these preliminary studies fail efficacy in a larger study. I'm not against trials. I'm just against trials that fail.
Most of what I've talked about can be done for investigational drugs as well, but it requires the cooperation of the drug companies to make the drug available. Pharmaceutical companies in the past have been reluctant to make available a drug that's already going through the approval process and risk trying it on another indication. That's simply a perceived risk on their part, a fear of derailing an ongoing approval process with something that's discovered in an unknown disease.
The FDA has shown amazing foresight in being able to very rapidly approve compassionate use trials when there are a small number of patients. The FDA doesn't appear to be part of the problem.
Have you at this point solidified the cooperation from drug companies for any of the programs underway or for the melanoma effort?
We have not yet done that and that's been a disappointment. There have been a number of melanoma drugs that are very close to being approved, such as Yervoy, and Plexxikon's PLX4032. We saw Cancer Commons as a natural channel to build awareness for these drugs pre-approval, in a way that we thought would be acceptable to the FDA, because drug companies would not be able to influence putting their drugs on Cancer Commons' list of treatments that would be helpful in these subtypes of melanoma. A complete arms-length, independent panel would decide that. So we thought drug companies who did have drugs on the list would be willing to put up sponsorship money to promote awareness of the drug.
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But basically, in all cases, the companies have been very skittish in getting involved in something like Cancer Commons. This may be because they've been slapped so hard for doing anything that might smell or hint of promoting off-label use of a pre-marketed drug. I had not really been aware of how sensitive these companies were to the fines that have been levied recently. So I think we're going to have to wait until the drugs are actually approved and then we'll find the companies with the new melanoma drugs are much more receptive.
Have you reached out to the FDA to see if there are partnership opportunities in the same way they've linked up with some industry players, research groups, or even the Critical Path Institute?
I've had informal conversations, for example with [FDA Commissioner] Margaret Hamburg. We were thinking of talking to the Critical Path people. They are a good example of someone we can partner with since they already have relationships with most of the pharmaceutical firms. It's an excellent idea, but not one we've pursued yet, because at the moment we're really focusing on patients. It's the patients who have the urgency and their hair on fire. When you're dealing with big, international companies, it just takes a very long time to get anything done, and we just don't have that time right now.
You said that these are activist patients. Do you find that a lot of patients that turn to Cancer Commons have knowledge of the genes that are implicated in their cancers, or have gotten tested through direct-to-consumer genomics firms?
Most patients don't know the genotype of their tumor. The most important service that we can render is just getting the patient tested. It's amazing how long it can take a simple idea like that to disseminate through the medical system.
Are you working with other diagnostic companies to get the word out about their tests?
We're trying through Cancer Commons to connect physicians, scientists, and patients with all the other players, mainly labs, molecular diagnostics companies, insurance companies, pharmaceutical companies, and biotechs, in order to ensure that the information we're providing can be acted on.
It's one thing to tell someone that they should be tested for BRAF mutations. It's another thing if you're a community doctor to figure out how to get your patient tested for BRAF. It's not obvious how to do that. We're really focusing on removing barriers to act on this knowledge and help someone figure out how to order a test, how to enroll in a trial, how to get a drug for compassionate use, how to get a referral to a medical center or doctor with experience in doing the kinds of things we're talking about.
These are relatively simple things, but over time, it leads to building an ecosystem for this nascent personalized oncology industry. At the moment, there are just lots of companies and lots of organizations focused on personalized medicine, but nothing connects them in a system.