Personalized Medicine vs. Comparative Effectiveness Mailbag

Better late than never. Readers of IN VIVO Blog responded to a previous post on whether proponents of personalized medicine can also be supporters of comparative effectiveness research. We asked readers to weigh in on that question. Their emails initiated a lively discussion on the future of healthcare so we’ve picked excerpts from the most noteworthy responses to share. Here they are:

“Here’s an example to answer your query: Drug A is generic, Drug B is not. Compare their effectiveness and B works “better” so we all pay more for the newer drug. However, Biomarker Q indicates that some people do not respond to A at all. Remove those people from the analysis and now A&B work the same except for in the people with Biomarker Q, who have to get Drug B, although most would benefit from the less expensive drug A.” -Amy Miller, PhD, public policy director, Personalized Medicine Coalition

“Sure they go together. Right now, we characterize the groups in whom we compare therapies for ‘effectiveness’ based on their clinical diagnosis. For example, in cancer research we might compare a new treatment with an older one in ‘breast cancer’ as diagnosed by a pathologist reading a biopsy slide of a breast mass.

In the future, the ‘groups’ will be characterized not by their tumor biopsy’s look under a microscope, but by the unique genes expressed by the tumor. It’s the grouping parameters that will change and that’s how personalized (or genomic) medicine assists comparative effectiveness research. Personalized medicine just means we have better tools.” -Leonard Zwelling, MD, University of Texas M. D. Anderson Cancer Center

“The end-goal of personalized medicine and pharmacogenomics (the right drug in the right dose for the right person at the right time – comprising multiple, different ‘right’ answers) is very, very different from so-called ‘evidence-based medicine’ or comparative effectiveness, which looks to find a single best answer across an entire population. And it’s surprising how often people mix up the concepts—after all, each is an approach to improving medical care, but the underlying unit of analysis (individual versus population) is completely different.” -Bryan Walser, CEO Perlegen Sciences Inc.

“I hardly see the two options as diametrically opposed. The key concern for any legislator is getting the most value for every healthcare dollar spent. Comparative effectiveness attempts to divine the best option among multiple treatment options. Personalized medicine does the same thing, albeit for a narrower subset of patients. If one concedes that personalized medicine will always focus on smaller and smaller subsets of patients, it is not hard to imagine that comparative effectiveness will always be one subset above.” -Howard Hechler, director of business development, XL TechGroup

“Consider that personalized medicine can never be unique for each individual patient. Rather, it will be various medicines aimed at specific subsets within a disease state. For instance, multiple genetic defects can be responsible for inhibiting the production of a specific vital protein. One drug can treat one specific defect, while another drug could be used when the defect is at another location within the same gene. We could end up with dozens of drugs to treat the same disease, yet each treats very different specific defects.” -Steve Evans

“Think of personalized medicine as The Promised Land. Even its biggest boosters concede that it’s some way out on the horizon. There’s still a lot of progress to be made on the biomedical, informatics, education and training, and economic fronts. So, while we’re still wandering around in the wilderness treating patients with one-size-fits-all drugs, comparative effectiveness trials seem like a good idea.” -Michael Goodman, VP research products, AVOS Life Sciences LLP

“Personalized medicine and comparative effectiveness may indeed be strange bedfellows as you say in your post. In some ways, though, I think they both represent the triumph of science over marketing, and that appeals to a certain segment of the health policy community. With both of those principles fully in place, drug firms couldn’t use promotional muscle to get scripts written; they’d have to use data. And while it’s true the generalizations of comparative effectiveness are the opposite of the specifics of personalized medicine, I don’t think CE advocates would really object to a step therapy formulary that would eventually bring patients to the treatment that’s best for them personally.” -Anonymous

“My understanding is that the concepts are consistent because both personalized medicine and comparative effectiveness are based on making the best use of available information. In some cases we have enough information to craft therapies to particular patient situations (e.g. we might know that someone with a certain gene will respond in a certain way). Whereas comparative effectiveness deals with those cases where we simply do not have enough specific information but we do have statistical averages suggesting what the best practice would be given no other information about the specific case. Sometimes that’s all the information we have.” -Jason Bradfield

“Perhaps the similarity is that both personalized medicine and comparative effectiveness medicine use comparative measures. The difference is that one is in an individual population, while one is in a “smeared” population. The lowest standard for the measure of the safety and effectiveness of personalized medicine is on a comparative scale to other therapies used within the broader population. A higher, and probably unachievable standard, is for personalized therapy to be measured on an absolute scale for safety and effectiveness within a single person. Because this former standard is the more achievable standard, the two proponents can align, at least for now.” -Anonymous

The Other FDA Drug Chief

The drug industry is breathing a sigh of relief now that Janet Woodcock has permanently assumed the role as head of FDA's drug center.

But let's say Woodcock had turned down returning to oversee the Center for Drug Evaluation and Research, who would have been Commissioner Andrew von Eschenbach's next choice? Well, you can take a look at my incredibly accurate odds-making piece I wrote a few months ago. There were a number of internal candidates who may have been the choice. To read it, click here.

However, if von Eschenbach had decided to look outside, there were a number of names being thrown around as candidates. Two that I've mentioned before are Cornell pharmacologist Marcus Reidenberg and former University of Utah cardiologist Jeffrey Anderson. You can read a little more about them in The RPM Report by clicking here (registration required for non-subscribers).

Recently, I learned that another outside candidate was being pushed heavily by former FDA officials: Indiana University pharmacologist David Flockhart.

Flockhart appears to be exactly the type of candidate the agency would have been looking for in an external contender. Flockhart, chief of the division of clinical pharmacology at Indiana, is a believer in the personalized medicine revolution and the basic tenets behind FDA's Critical Path Initiative. To read more about his points of view on medicine, science, genetic testing and drug safety, click here.

A former Georgetown University researcher, Flockhart is credited with establishing Indiana as a site for NIH/National Institute of General Medical Sciences’ Pharmacogenetics Research Network. He received his MD from the University of Miami School of Medicine and PhD from the Welsh National School of Medicine in Cardiff.

So why does this matter? Well, it's interesting, isn't it? But more importantly, these are the types of thought leaders to keep on your radar for later down the road in different administrations or as possible liaisons between FDA and the academic world for key FDA/NIH/CMS initiatives. That's why they matter.

I'll keep my ear to the ground for other candidates that were interviewed or championed for the CDER director position so we can start a whole web series on "People Who Weren't Named CDER Director."

Finally, tune in next week for my Personalized Medicine Mailbag blog post. I wanted to thank everyone for the overwhelming response to my personalized medicine post. Apparently, people care about this issue. It's not too late to email me with your take on the personalized medicine vs. cost effectiveness debate.

While You Were Finally Watching Some Football

Autumn's here, and the NFL is back. IN VIVO Blog's contingent of Philadelphia Eagles fans is predictably feeling a little uneasy about the season ahead. Meanwhile, here are a few odds and ends from the weekend.

• More GSK hand-wringing in the UK papers, this time it's the Financial Times. (Hat Tip: Pharmagossip.)
  
• Hey look, free access to medical journals. (via the NYT)
• The SF Chronicle looks at personalized medicine, and how the FDA is encouraging drug developers to find genetic patterns in responses to treatment.

(Photo by Jonathan Daniel/Getty Images)

Science Matters: A small personalized medicine bailout for Cox-2s?

There was little attention paid to last week's paper suggesting that PPAR delta agonists might be used to prevent the cardiovascular side effects of Cox-2 inhibitors (coxibs) such as Vioxx and Celebrex.

The study in the Journal of Experimental Medicine (JEM) showed that Cox-2 suppresses the expression of tissue factor (TF) -- the primary activator of blood clotting and a proximal cause of coxibs' CV problems -- via the activation of PPAR delta.

Of course, there are no approved PPAR delta drugs, although pharmas including GSK have tried developing them to treat cardiovascular disease. (One news outlet suggested GSK's drug could be an "unlikely savior" for Vioxx, but that's a far stretch.) And no one would think to couple a PPAR delta with a coxib for use as a combination analgesic--the risk/benefit ratio of that presumably is way off.

But there's another, intriguing aspect to this research result.

The problem with Vioxx is that it is associated with cardiovascular complications in a small number of patients. "We should look at these patients in terms of their TF levels and other clotting parameters," suggests Timothy Hla of the University of Connecticut Health Center and a principal author of the JEM paper. "Is the TF gene in these people somehow different? Is it regulated differently? Are they more sensitive or more resistant to the effects of the PPAR delta they produce? Instead of looking at the selectivity of Cox-2, let's look at patients' sensitivity."

Hla has a longstanding interest in Cox-2's role in normal blood vessel physiology and angiogenesis: he cloned the gene from human vascular cells in and named it Cox-2 in 1992, while at the American Red Cross Research Institute.

A first step would be to measure TF levels, which can be easily collected from plasma, in patients taking Celebrex and correlate them with treatment results. It's all well and good to talk about testing PPAR delta agonists for their therapeutic effects regulating the TF gene. (The most advanced may be GSK's GW 501516, which the Hla group used in its experiments. GSK in-licensed the compound from Ligand Pharmaceuticals, but its development has lagged at Phase II. Ligand's most recent 1o-K says the drug's development is 'on hold' pending the review of preclinical studies, and there is no mention of it on GSK's own clinical trials web site or in any recent publicity [clintrials.gov lists a 'completed' Phase II study], so for all we know it has been terminated.)

So that's a long way off. Most of the focus on the mechanism of Cox-2 has centered on its effect on platelets. A simple blood test might go a long way towards refining that effort.