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Is anyone really focused on fighting cancer in this country?

by Nick Jacobs

As a young, Baby Boomer, I remember President Nixon’s declaration of war on cancer.  Billions of dollars and thirty years later, I became part of the Medical Industrial Complex, and now marvel at the disconnect called cancer research that exists in this country.

In a recent New York Times op-ed by Shannon Brownlee, she posed the following question, “Has the profit motive gotten in the way of finding a cure for cancer or better treatment?”  She goes on to question, “Could it be that at least some of the $100 B we spend each year on detecting and treating this disease is . . . to prop up hospital finances?”

Obviously, with my hospital administrator hat on, that question felt very uncomfortable, but I’m carefully avoiding the obvious answer and will point you in the direction of our already seriously strained health care system, a system that is attempting to preserve the status quo in a time of significant demographic change that, in my opinion, is not sustainable.

It always reminds me of the chilling question posed by one of my professors in Graduate School, “If the town has three brain surgeons and it only needs two, which one doesn’t drive a Mercedes?”  The answer then was, “They all do.”

Concurrently, the issue of funding cancer research continues to raise it’s ugly head, and, reading the opinions of people like Dr. Susan Love, Nancy G. Brinker from the Komen Foundation and David Perlin, director of the Public Health Research Institute regarding this issue, it has become painfully clear to me that the research system in this country is broken as well.

The problem is that it is a system of small science, a system that currently dominates our NIH/NCI, academic medical center approach.  Organizations that have embraced the concept of sharing information, working collaboratively on all levels, and not rewarding individuals for keeping secret their theories and discoveries can easily become causalities in the fiscal environment that dominates our federal research funding mechanism.

We are spending 30% of our health care dollars on the last thirty days of life with little or no possibility that we will cure or improve the status of the dying individuals.  We are continuously, financially stroking those individual divas that discover their secret sauce and then have no incentive to share their findings because it may interfere with their personal grant streams.

We are rewarding unendingly the finances of our oncologists through profit sharing relationships with pharma, but do not see that as a conflict in any way.  We will radiate, administer chemo, and treat unnecessarily or unproductively until death actually arrives.  All of these decisions represent huge health care expenditures.  The majority of our medical schools have still not embraced hospice and palliative care, and the result is also a financial train wreck.

The United States has no science policy and no health care policy except to feed the current system.  If you doubt that, visit the $1B hospital constructed on the campus of NIH that has an average daily census of well under 100 patients as just one example of a broken system.

Someone has to stand up and be counted or this system will crash and burn with no significant steps taken to fight the war or find the cure.

Interview with Mike Totterman, iCardiac’s Chairman and CEO (transcript)

by David Williams

Here’s the transcript of my recent podcast interview with iCardiac’s Chairman and CEO, Mike Totterman.

David Williams: This is David Williams–co-founder of MedPharma Partners and author of the Health Business blog.

Drug safety is a big issue these days. The FDA has been criticized for allowing drugs with safety problems to reach the market. Merck’s embroiled in thousands of lawsuits over heart problems allegedly caused by Vioxx, and not a month goes by without the cardiac safety profile of a marketed drug being questioned.

I recently joined the board of iCardiac Technologies, a start-up company that’s developing new tests using ECGs to find cardiac safety problems with drugs early in their development. iCardiac has already signed a research alliance with Pfizer and attracted investment from venture capitalists. I visited the company today in Rochester, New York and spoke with its chairman and CEO, Mike Totterman. Mike thanks for joining me today.

Mike Totterman: Thanks. Pleasure to be here.

David: Mike, tell me a little bit about iCardiac Technologies.

Mike: iCardiac is a leading developer of advanced ECG-based cardiac safety biomarkers. What we do is address what has become possibly the single largest bottleneck in pharmaceutical development today.

It’s estimated that roughly 80% of all delays and drug withdrawals currently are related to cardiac safety issues. What we do is we provide the next generation of cardiac safety biomarkers. And what this allows the pharmaceutical companies to do much earlier in the development phase is to determine the true cardiac safety profile of their in-development drugs.

Obviously this is significantly beneficial from an economic perspective; really allowing the companies to safely and confidently either move forward with development or identify very early on potential cardiac risks, and then move on to the next molecule to develop.

David: Now you use the term biomarker, can you explain what a biomarker is?

Mike: Sure. Biomarkers are essentially quantitative signals. In this case we derive them from the ECG signals. Today the commonly accepted marker for cardiac safety is QT prolongation. It is well known, and the FDA has also commented on this, that there’s a significant opportunity to improve upon the efficacy of QT prolongation.

This is really where iCardiac comes in. We provide markers that are more sensitive and more specific than the current QT prolongation methodology.

David: How long has the company been around?

Mike: In terms of the company, it is based on research that was conducted at the Heart Research Follow-up Program over a period of almost 30 years. The focus of the research was on something called the congenital long QT syndrome, which is very analogous to what is the acquired form of QT prolongation. This technology that was developed by the Heart Research Follow-up Program was then spun into iCardiac, and the company was founded in the early part of 2006, and we received our financing at the end of 2006.

David: I noticed that with the name iCardiac it sounds like something that I might plug in to my MP3 player or something. Was that just a coincidence that you called it iCardiac or is there some connection?

Mike: Some time was actually spent on thinking about the appropriate name, and there were a couple of different thoughts that we had in terms of what we wanted the name to communicate. Obviously we wanted to make sure that people understand that we’re in the cardiac space and really relate it to cardiac technologies. One of the many names that we played with was Intelligent Cardiac Technologies, and then ended up shortening that into iCardiac Technologies. We’ve been very happy with the choice, it’s an easy to remember name.

David: I saw on your website that you have announced a strategic alliance with Pfizer. Is Pfizer your only customer or is that the only company that you would work with?

Mike: We’re very excited about the Pfizer alliance. Let me say a few words about that. Pfizer is providing an equity investment as well as research and development funding, and has licensed certain of their internal cardiac safety technologies to us. Pfizer is quite visionary in terms of what their objectives are and they are very much in line with what we’re looking to do; and they recognize that this is really a problem that impacts the entire industry.

As a result, the decision was made collectively to ensure that this alliance is non-exclusive and there are no specific technologies that would be excluded from anybody else who would be looking to work with iCardiac Technologies.

In addition to that, Pfizer has been very encouraging of us working together in order to recruit other pharmaceutical companies into what we believe is a very pivotal effort for the industry.

David: Mike, when there is an actual clinical trial underway how are your tools actually used? What’s involved and what’s different compared to a trial that iCardiac is not involved with?

Mike: What’s very exciting about the tools and services that we offer is they plug very nicely into the standard clinical trials process. Frequently, early on in the development, electrocardiograms, or ECGs, are collected. Currently those ECGs are measured for the QT prolongation, which as I mentioned earlier, has a number of limitations. We can take essentially those same electrocardiograms and perform our advanced analytics on them and then report those results back to the pharmaceutical companies for decision-making.

David: What sort of results would the pharmaceutical company receive? Is it just a matter of “Yeah this looks safe; this doesn’t look safe”? How would the output actually be represented to them?

Mike: There are two sets of activities that we’re currently undertaking. As I mentioned earlier, that Pfizer alliance is focused heavily on the validation of the markers. So currently we’re engaging with a number of other pharmaceutical companies to look at retrospective data and analysis that they’ve done and collected as ECGs.

So the first step that generally we do with a pharmaceutical company is to demonstrate the effectiveness of the markers on historical data that has been collected. Then after that the pharmaceutical companies can start using the markers, initially for internal decision making on a go/no-go decision making process in terms of moving forward with the drugs.

The objective of the Pfizer alliance as well as a number of our efforts within the industry is really to influence the guidance and to be able to drive towards a set of markers that are industry accepted for decision-making in this area.

David: So, obviously cardiac safety has been in the news enough that the general reader would know about it. I’m wondering, if you think about a drug like Vioxx, which was on the market for a long period of time and then these heart problems were discovered; how would the Vioxx development and launch have been different if you’d been involved? If iCardiac had been involved would Vioxx have been kept off the market in the first place?

Mike: Excellent question. Just to clarify, there are a few different classes of cardiac problems that end up occurring with drugs. One of the big ones, which we address, is essentially electrical disturbances that occur with the drug.

There were also other issues that were very problematic with Vioxx, and that’s what ended up getting it pulled from the market. Subsequently there have been publications that in meta-analysis of the subjects who had taken Vioxx, that there may have also been some abnormalities in terms of the electrical properties of the heart. So while it’s hard to, with specificity, to say if we would have been able to prevent the Vioxx issues, there is some indication that we would have been able to lend some useful data to do some early decision-making regarding the product.

David: Now all the headlines that you read are about drugs that have made it to the market, and then a cardiac safety problem is discovered and the drug is pulled from the market, and sometimes there is some legal action. Are there also examples of drugs that maybe are killed in the product development stage that in fact weren’t particularly harmful and maybe should have been allowed on the market? Would you be able to detect those drugs and perhaps save them?

Mike: A very good question. That is one of the big challenges currently with cardiac safety testing–kind of the combination of both the false positives and the false negatives. Really there, with QT prolongation it is a well-known fact that by looking at QT prolongation alone you may be very well screening out drugs that actually do not end up causing torsade or any cardiac events. So our hope is obviously to be able to also address those issues.

This is definitely the case with a variety of different drugs. One of them in particular is used as the positive control in cardiac safety studies, which is moxifloxacin. That is a drug that’s well known to increase QT prolongation; it is actually used as the benchmark to determine if an analytical tool can detect the prolongation of QT. And it’s also a drug that is known to be safe. As a result of that it can be used as a positive control in these studies. So clearly we believe that we can use our tools to identify drugs that would have otherwise been unnecessarily killed in the development process.

David: So the FDA has obviously been under a lot of pressure in the post-Vioxx era to be more careful about approval. And then we saw yesterday the Senate passing legislation for more surveillance post-launch. What does the FDA think about what you’re doing? Do they know about it? What are its plans and its reactions?

Mike: It’s actually very exciting what’s happening with the agency, especially in this area. I think for a number of different reasons they highlighted cardiac safety relatively early on as an important area for development of new tools and better tools. In their critical path initiative, cardiac safety is prominently discussed. And I believe the quote goes something along the lines of that there’s an urgent need for better tools to identify some of the residual risk that current QT prolongation tools leaves in the development process.

In addition to that, there is a cardiac safety consortium that has been formed which has a number of participants from the industry, academia, and the agency. And we’re very much looking forward to participating in that set of activities.

David: You mentioned early on about the Heart Research Follow-up Program at the University of Rochester. What’s the connection between the company and the University of Rochester?

Mike: As I mentioned earlier on, the Heart Research Follow-up Program has been working in this area for a very long period of time, and started doing software tools for ECG analysis almost a decade ago. So the relationship really there is that the technology that was developed at the Heart Research Follow-up Program has been licensed over to iCaridiac Technologies for commercialization.

David: What kind of companies would you compete with? I know a lot about companies like eResearch Technology that have made a big business out of these thorough QT studies that need to be done as part of drug development over the past few years. Do you compete with them? Do you complement them? What other companies are out there that you think about as being in your space?

Mike: I think we’re very complementary to the current set of clinical research organizations that exist out there. Obviously QT prolongation will stay as a metric for some time to come. And where we are positioning ourselves is really the ability to deliver incremental information above and beyond the simple measurement of QT prolongation.

The other thing which is very exciting, and we feel quite proud of is, there are not too many commercial entities, whether it’s equipment manufacturers or small start-ups, that are working on specifically this problem and who have as much data that they have collected to validate their tools or as much technology or funding to drive this process forward. So we feel very fortunate to have the kinds of partnerships, for example, that we have with Pfizer.

David: You mentioned Pfizer as an investor. Are there other investors, and who are they and why did they think to invest in iCardiac?

Mike: Sure. We’re venture-backed, have several venture capital firms who have backed us–Advantage Capital as well as Stonehenge Capital and Trillium. These are actually individuals that to some degree parts of the management team had worked with before, so very good working relationships. In addition to that, clearly the investors recognize the significant market opportunity in terms of being able to provide these types of tools to the pharmaceutical industry. So we’re all quite excited about being able to provide these commercially to the marketplace.

David: Now what would you list as some of your key challenges? It sounds like there’s a lot that’s been validated, you’ve got Pfizer on board, you’ve got investors, it’s a clearly recognized problem, but what are some of the challenges that you face as a start-up company?

Mike: I think what is always the case, especially with the pharmaceutical industry, you want to make sure that you’ve been able to demonstrate your tools on as many different drugs and as many different situations as possible. So we’re actively working throughout the industry to identify–and we have done so already a number of critical data sets–that we can continue to move forward with the validation process. And it is quite exciting that the FDA recognizes that this is an important issue and has created a forum specifically for helping drive and move forward new guidance in this area.

David: Mike thanks very much for speaking with me today. I’ve been speaking with Mike Totterman, chairman and CEO of iCardiac Technologies, a cardiac bio-marker company located in Rochester, New York. Mike, thanks again.

Mike: Thanks a lot as well.

Podcast interview with Mike Totterman, Chairman and CEO of iCardiac Technologies

by David Williams

Drug safety is a major issue these days. FDA has been criticized for allowing drugs with safety problems to reach the market, Merck is embroiled in thousands of lawsuits over heart problems allegedly caused by Vioxx, and not a month goes by without the cardiac safety profile of a marketed drug being questioned. Recently, the Senate passed a bill granting the FDA greater authority to restrict the use of drugs when safety problems are discovered after launch.I recently joined the board of iCardiac Technologies, a start-up company that is developing new tests that use ECGs to find cardiac safety problem with drugs early in development. iCardiac has already signed a research alliance with Pfizer and attracted investment from venture capitalists.

I visited the company recently and spoke with its Chairman and CEO, Mike Totterman. Listen in and hear what he has to say.

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Innovation through collaboration and confrontation

by David Williams

I commented earlier on how innovative models of collaboration among researchers are showing promise in accelerating drug discovery. The Myelin Repair Foundation’s Accelerated Research Model is a leading example of how challenging existing paradigms can yield impressive results.

If anything, the problems in drug development are worse. The FDA sometimes seems to speak out of both sides of its mouth, with high-level officials promulgating “podium policies” that encourage innovation, while mid-level reviewers want to see the same old thing. That’s why you still see widespread use of old endpoints with little clinical value, like the Hamilton Anxiety Scale.

HIV/AIDS is a good place to look for innovations that can be copied more widely. Early on, AIDS groups like ACT UP (”united in anger and committed to direct action“) undertook fairly extreme measures to pressure pharmaceutical companies, researchers, governments and clinicians into dropping business as usual practices and finding ways to move faster and more dramatically. As is often the case when there are extreme groups like ACT UP, it increased the willingness of the establishment to take more moderate groups seriously.

I’m struck by the success of HIV/AIDS activists in spurring research funding and changing how  bureaucracies work considering the stigma attached to homosexuality and intravenous drug use.

One of the more interesting organizations to arise from this activism is the Forum for Collaborative HIV Research, a group which I’ve consulted to for the past few years. The Forum brings together a diverse set of constituents that don’t normally collaborate: pharmaceutical companies, various branches of the federal government including FDA, CDC and NIH, academic researchers, health care providers and patient advocates. By bringing these groups together in a neutral forum–including competing pharmaceutical companies and their regulators– the Forum has been able to grapple with important issues that otherwise would be left unresolved.

For example, back in 1999 the Forum convened a meeting to review the scientific and logistical issues in the design and implementation of salvage therapy regimes in heavily pre-treated patients in whom anti-viral therapies were no longer working. Such patients were generally excluded from trials in favor of so-called treatment-naive patients in whom it’s easier to demonstrate whether a new drug is working. Of course the salvage patients are the ones who really need the new drugs, since they are out of options. The Forum’s activities led to the FDA issuing guidance on the inclusion of salvage patients in trials, and this guidance has been used in the development of new drugs. A related problem is that patients who’ve developed resistance to their therapies are also likely to quickly develop resistance to a new drug if they just receive one new drug at a time. The Forum helped devise protocol designs to allow clinical trial subjects to receive two new drugs while still preserving the ability to measure efficacy.

These issues could not have been addressed without a collaborative effort. Normally when a pharmaceutical company and FDA interact it’s in the context of a specific submission. Neither party can step outside of the narrow bounds of that regulatory review, even if the issue at hand may be related to an entire class of drugs or the interaction among multiple drugs. More recently, the Forum has been active in addressing the safety and other issues involved in the development of CCR5 antagonists. The Forum brought together all the companies developing these drugs with US and European regulators, the companies making the diagnostic tests that are used with the drugs, clinical trial cohorts, advocates and academics. The results of this effort may be apparent shortly when an FDA panel meets on Tuesday to discuss Pfizer’s CCR5 drug, maraviroc. Just this morning, FDA reviewers announced their initial, generally positive findings.

Meanwhile, more than 10 years after the Forum’s founding we’re yet to see counterparts emerge in other areas that could benefit from similar approaches, such as oncology. Innovation tends to occur when cross-disciplinary groups come together. In general individuals and organizations find it more comfortable and convenient to work in their own areas. Anti-trust, regulations,  competitive rivalries and inertia stand in the way of fuller, sustained collaboration.

We may need some more ACT UP types to confront us and shake us out of our complacency.

Dirty Little Secret

by Nick Jacobs

After working in a research institute for the past several years, traveling to numerous continents and meeting with Nobel Prize winners and scientists from all around the world, I’ve decided to dedicate this blog to The Secret.

Day after day, the same words have been whispered to me by those scientists who appear to be in the know. What is it? The dirty little secret seems to be that the academic research model, lovingly referred to as little science, is being acknowledged to have done more to hurt the progress of medical research than almost anything else imaginable.

According to the hundreds of scientists with whom I have spoken, the problems revolve around this little science concept and a very close knit club of friends who appear to guarantee the continuation of each other’s programs.

Although this depiction would definitely come under the heading of scathing indictment, you must realize that I’m just the writer, not a scientist and not a doctor. (I don’t even play one on TV.) I’m only repeating the recurring theme that has been communicated to me month after month, week after week, day after day for the past seven years.

From the NCI website:

Richard Nixon declared war on cancer when the American people made clear their desire for a cure for the second-leading cause of death in the United States. President Nixon responded during his January 1971 State of the Union address: “I will also ask for an appropriation of an extra $100 million to launch an intensive campaign to find a cure for cancer, and I will ask later for whatever additional funds can effectively be used. The time has come in America when the same kind of concentrated effort that split the atom and took man to the moon should be turned toward conquering this dread disease. Let us make a total national commitment to achieve this goal.”

Although this author was still a very young man in 1971, and Watergate had not become a national incident yet; we all hoped that Nixon would lead our country to the cure. Interestingly, since 1997 alone, approximately $45,000,000,000 has been budgeted for the NCI, the entire budget for the country of Greece, and no one believes we are close to the cure.

How can we have invested that much money in the past ten years alone and still be so far from conquering this iniquitous malady? Maybe that question is naive. The pundits blame it on the broken system, the making of individual grants to individual scientists to enable them to buy their equipment and hire their lab techs and keep their data on their personal computers equals small science.

If each scientist is rewarded for trying to find his or her secret sauce and discouraged from sharing that discovery by rewarding that secrecy over and over again, our efforts to find the elusive cure will continue to be stifled.

So, for all of you who do not believe that this is the way things are in science in these United States, please comment below . . . because I’m really very curious about this topic

Generic Biologics?

by Derek Lowe

David and Matt have mentioned the possibility of price controls on patent-expired biologics. But that brings up a big issue which is being hashed out right now: what a generic biologic would look like, and how it can be approved.

As a small-molecule guy myself, I find the industrial production of large proteins rather intimidating. Quality control, which can be a backwater in some companies, is a cutting-edge challenge in this area. Just making sure that the same substance is being produced every time is enough to keep a lot of people busy. And that’s the issue when these things go off patent: how do you show equivalence for the generic form?

For traditional small molecule drugs, the question is fairly straightforward. There are plenty of well-established methods (NMR, liquid chromatography/mass spectrometry) to assess the identity and purity of such compounds, and similar techniques to make sure that the formulation is identical. I’ve spent all my career working at large research-driven drug companies, but I have no doubts about generic equivalence for our drugs once their patents have expired. The generic folks can copy us just fine.

Proteins, though, are another question entirely. NMR is quite a difficult technique for these things, and requires a lot of computational horsepower to interpret. LC/MS-based technologies are getting better and better, and are a key way to establish purity. But there are still important things that could be missed, and the only way to really be sure that two protein drugs are equivalent is in human trials.

That’s going to be a much higher entry barrier than the standard ANDA process for small-molecule generics, which isn’t going to help bring down costs. There are a number of tricky regulatory issues as well, and in the end we’re probably going to have to settle for “biosimilar” instead of “bioequivalent”. For more details, I can recommend this recent post at PatentBaristas.