On Deciding . . . Better 3.0

Not Practicing

It looks like I’m not alone in Maryland as a non-practicing physician:

State lacks practicing physicians — baltimoresun.com: “While the state has about 25,000 licensed physicians, the second-highest rate per capita of any state, nearly 40 percent are engaged in teaching, research and administrative duties, according to the study, and some of the rest spend part of their time in such nonclinical work.”

One the insights that I had many years ago was that in practice, one had no way to leverage one’s activities. Economically a physician is valued for their direct time in providing care. And procedural activity, like surgery or angioplasty, is valued per unit time way above examining and diagnosing. In research and business, there are value multipliers as others participate in the enterprise. The return on time is potentially much higher for a phyisician outside of practice.

Low FDA Approval Rates

The rate of new drug approvals for the pharmaceutical industry is dropping. One reason may be FDA delay:

Eye on FDA: Impact of Approvable Letters 2007 - Part 1: “However, it is important to think about the implications of so many approvable letters.  They represent more than an inconvenience to companies and to patients who are awaiting therapies with serious implications for both, as well as for investors in companies, particularly smaller companies that do not yet have a product on the market.  ”

The drug is safe and effective, but is not yet allowed to market. This in between status for a drug can drag on for years, destroying companies.

Worth the Subscription

I subscribe to the online edition of The Lancet Neurology. The 2007 Round-Up was worth the subscription price itself. I need to keep up very broadly and these are the kind of overviews that help me the most.

Also in The Lancet Neurology:

The Lancet Neurology: “We used a unique response-conditional crossover design to provide rescue treatment if needed, and patients who showed an improvement in inflammatory neuropathy cause and treatment (INCAT) disability score during treatment were re-randomised into a 24-week extension phase.

I’m reading this both to gain some insight into immunologic treatment successes, but I’m trying to figure out how useful the trial’s design might be. I’ve been skeptical of enrichment designs in the past, but this may be a more clinically relevant way to study the reality of clinical responses.

Memories

I did my MD, PhD training as well as my medical internship at Emory School of Medicine in Atlanta. I’m sorry, but not surprised that it may close.

A Safety-Net Hospital Falls Into Financial Crisis - New York Times: “Once admired for its skill in treating a population afflicted by both social and physical ills, Grady, a teaching hospital, now faces the prospect of losing its accreditation. Only short-term financial transfusions have kept it from closing its doors.”

When I trained, Grady was a resident’s hospital. Care was provided by residents under the direction of Chief Residents who had completed training and were often specialty fellows continuing training and a group of incredibly knowledgeable teachers who ran the services and provided checks on care through morning rounds. There were teaching attending physicians, but their function was to teach and supervise, not provide care.

After I left, medical reimbursement rules changed so that the attendings had to provide care and sign off everything if the school was going to be able to bill at all. Having to switch from resident care to medical faculty care kicked a big prop out from under academic medicine and was one of the forces that eventually led me to my career in industry.

Video: Trepanation

Retrospectacle: A Neuroscience Blog: “Trepanation is a procedure where a hole is drilled into the skull, exposing the dura mater and brain for either medical (releif of pressure) or mystical (supposed heightened consciousness)purposes. ”

Pharma Marketing

For reasons I don’t really understand, this report is getting lots of attention in the media and pharma-related weblogs. These are large businesses with shareholders expecting return on investment. They market where they believe the return will be found. The same is true of R&D and the relative rate of spend between the two.

Big Pharma Spends More On Advertising Than Research And Development, Study Finds: “A new study by two York University researchers estimates the U.S. pharmaceutical industry spends almost twice as much on promotion as it does on research and development, contrary to the industry’s claim.”

Up and Coming: Metabotropic Glutamate Receptor Modulation

It seems that since the September announcement by Lilly showing efficacy of a metabotropic glutamate receptor agonist in Schizophrenia, there’s more activity in the area than I’ve ever seen before:

Pfizer’s in:

Pfizer Inc. and Taisho Pharmaceutical Finalize Deal on Schizophrenia Drug; to Pay Initial $22M - News, Search Jobs, Events: “TS-032 is a novel mGluR (metabotropic glutamate receptor) agonist that may offer a new treatment option for central nervous system disorders. Although the characteristics of mGluR are still only partly understood, mGluR is believed to play a role in the transmission of glutamate and other substances in the brain. Abnormalities in the neurotransmission through mGluR may be one cause for symptoms related to schizophrenia as well as other CNS disorders. Data show that mGluR agonists, such as TS-032, offer potential as new treatments for schizophrenia.”

As is Merck:

Addex Pharmaceuticals : 3 January 2008 ADX63365: “Allosteric modulation company Addex Pharmaceuticals (SWX:ADXN) announced today that it has entered an exclusive worldwide license agreement with Merck & Co., Inc. (”Merck”) to develop ADX63365, an orally available drug candidate for the potential treatment of schizophrenia and other undisclosed indications. Allosteric modulators are an emerging new class of therapeutic agents. ADX63365, currently in preclinical development, is a positive allosteric modulator (PAM) that targets the metabotropic glutamate receptor 5 (mGluR5), which is believed to be important as a target for the treatment of schizophrenia and other conditions. The deal also includes mGluR5 PAM backup compounds discovered by Addex.”

It seems to be Guilford Pharmaceuticals day here. Sol Snyder, scientific founder of Guilford has this wonderful piece in the New England Journal:

NEJM — Seeking God in the Brain — Efforts to Localize Higher Brain Functions: “In seeking a general relationship between religious states, poetry, and music, Trimble ascribes all three to the right, nondominant side of the brain. He assumes that integration of the activity of the right-sided emotional brain with that of the left-sided analytic brain gives rise to the greatest intellectual achievements in the arts. I suspect that major advances in science, too, are the product of more than pure reason — in the finest scientists I have encountered, I have always detected a notable creative, artistic flair. ”

Can we be better scientists by practicing art? The specificity principle of general adaptation would suggest that scientists would be best practicing science like art.

On the subject of Guilford Pharmaceutical drugs that I’ve worked on, the second NIND NET-PD trial has been published, a futility design that included GPI-1485.

A randomized clinical trial of coenzyme Q10 and GPI-1485 in early Parkinson disease — The NINDS NET-PD Investigators 68 (1): 20 — Neurology: “Coenzyme Q10 and GPI-1485 may warrant further study in Parkinson disease, although the data are inconsistent. ”

This trial was independently conducted by NINDS. We supplied the drug. Their results in untreated patients were consistent with our own 2 year long study of patients who were already on dopamine agonist monotherapy. There are important lessons to be learned from these studies about the challenges of designing studies to test disease modifying drugs in Parkinson’s Disease and other neurodegenerative diseases.

Of interest:

Aetna to End Payment for a Drug in Colonoscopies - New York Times: “Aetna, one of the nation’s largest private health plan managers, is the latest insurer to clamp down on the use of a powerful anesthetic during an increasingly common form of colon cancer screening.”

This insurer’s reaction to the use of anesthesiologists to administer propofol for colonoscopy is of interest to me because of my work with AQUAVAN over the years. At Guilford Pharmaceuticals (and then MGI Pharma after their acquisiton of Guilford) I directed the first in man study of AQUAVAN and worked on trials on and off through the recent NDA filing. AQUAVAN, as a prodrug of propofol, is not expected to require the same FDA mandate for administration by an anesthesiolgist that propofol does.

AQUAVAN is a prodrug of propofol, extending its action enough to make it a better sedative and a less powerful anesthetic. It’s an interesting, perhaps unique example of how making a drug worse for one use makes it more suitable for another.

This Times article doesn’t mention the alternatives like AQUAVAN or midazolam, but with pressures like this on physicians from insurers and pressures from patients for comfort during procedures, I expect that AQUAVAN will find its niche as a sedative for procedures. Eisai is now in the process of acquiring MGI, so AQUAVAN’s future now rests with them.

Investor’s Business Daily: Upturn In Biotech Spending Drives Covance’s Growth: “Growth in the CRO sector is driven by biopharmaceutical research, development spending and a robust biotech funding environment, which hit $20.1 billion last year.”

As large pharmaceutical companies struggle with their cost structures they turn increasingly to outsourcing. Development stage biotechs often choose not to build their own infrastructure from the start to avoid the fixed costs. It’s driving CRO growth, where I currently work.

Mind Hacks: Personalised drugs:

The idea of genetically testing people for drug suitability is causing them [Drug Companies] a bit of a headache at the moment, as they’re desperately trying to think of ways to make money out of it.

Pharmacogenomics has to be one of the most misunderstood areas of drug development today. We’re used to the idea by now that our genes do not determine who we are. Genetic inheritance puts us at risk for some diseases more than others, makes us more or less likely to excel at certain mental or physical tasks, influences our adult height or weight. But strong effects of single genes are rare. Instead there’s a complex interacting system of multiple genes and environmental effects that, based on what we now know about complex systems, will not act deterministically, but rather affect the probability of future events.

It seems clear that, unless there is a strong single gene effect on something like proteins involved in drug metabolism and clearance, genes will have an uncertain influence on response to drug.

In the end, knowing some one’s genetic background, like knowing their particular symptom complex, will inform the physician about where to start therapy and the chances of success. But there will never be a way of “knowing” if that means a high degree of confidence in knowing the outcome of therapy.