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More From the Fourth

This, at least, I have observed in forty-five years: that there are men who search for it truth, whatever it is, wherever it may lie, patiently, honestly, with due humility, and that there are other men who battle endlessly to put it down, even though they don’t know what it is. To the first class belong the scientists, the experimenters, the men of curiosity. To the second belong politicians, bishops, professors, mullahs, tin pot messiahs, frauds and exploiters of all sorts – in brief, the men of authority. . .All I find there is a vast enmity to the free functioning of the spirit of man. There may be, for all I know, some truth there, but it is truth made into whips, rolled into bitter pills. . .

- H. L. Mencken, “Off the Grand Banks”, 1925

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Holiday

My impression over the years is that deals of this size are contemplated quite often, but that most of them never go through. The numbers don’t pan out, the other party gets cold feet, unrelated other developments throw things off. . .there are a lot of things that can go wrong with a potential deal. But talking after-the-fact with some people who’ve been in a position to see such things, I’ve been struck by how many feelers are put out, all the time.

So this seems rather unprofessional of someone up there at Sanofi-Aventis. All this sort of leak can do is crank up the speculation about who the targets might be, and raise their stock prices just when you’re working on a financial package. Smooth.

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Sanofi-Aventis Acquires. . .Somebody?

"We are excited by the opportunity to leverage our clinical, regulatory and commercial capabilities to provide metastatic breast cancer patients with an innovative treatment in Abraxane,” says Hugin. “We are also excited by the potential of ABRAXANE to treat additional solid tumor malignancies such as non-small cell lung and pancreatic cancer.”

Complete Story »

Glaxo’s experiment is a response to one of the industry’s most pressing problems: the failure of gigantic research staffs, formed through a series of mega mergers, to discover new drugs. The mergers helped companies amass potent sales-and-marketing arms, but saddled their R&D with innovation-stifling bureaucracy. . .

The company’s current strategy is to break things down into even smaller teams (often with their own names and logos) and to try to apply small-company incentives to them. That goes for both the positive and negative incentives:

The scientists in Glaxo’s new biotech-esque groups know the clock is ticking. Called discovery performance units, or DPUs, the groups are about halfway through the three-year budgets they were given in 2008. Glaxo has made it clear that if the team members don’t produce, they could get laid off. . .(the company also) says it’s trying to get closer to the financial rewards of biotech. In some cases, it is setting aside “a pool of money” for scientists involved in a certain project. . .each time their experimental drug clears a certain hurdle, they get part of the money. . .

Of course, as the article also makes clear, the company has been through supposed newer-and-better re-orgs before. And that included schemes to break the company’s research into more independent units. Those “Centers of Excellence in Drug Discovery” were supposed to be the last word eight or ten years ago, but apparently that didn’t quite work out. The current philosophy seems to be that the idea didn’t go far enough.

True or not? History doesn’t give a person much reason for optimism when a large company says that it’s going to get more nimble and less bureaucratic. You can make a very good living printing up the posters and running the training seminars about that stuff, but actually getting it to work has been. . .well, has anyone gotten it to work? Andrew Witty, the company’s CEO says in the article that he doesn’t see any contradiction in having “hugely successful entrepreneurial innovation” inside a big company, but real examples of that are thin on the ground – especially compared to the number of examples of such innovation being fought to the ground when it attempts to spring up.

That’s not to say that this approach can’t improve things at GSK. I think it’s bound to be a good thing to turn people loose to make more of their own decisions, without feeling as if there’s someone hovering over their shoulder all the time. But I don’t know if it’s going to be the revolution that they’re hoping for (or the one that they might need).

Read more from the original source
GSK’s Biotechy World

Overall, the agency would have $3.8 billion for oversight – roughly $214 million above last year’s bill – when including $1.2 billion in user fees, notes Rosa DeLauro, the Connecticut Democrat who chairs the subcommittee, who has been harping on drug safety lately. EDITORS’ NOTE: Yes, there was a math problem earlier and we have clarified the numbers. So the proposal includes an extra $65 million for reviewing generic drug applications, direct-to-consumer ads and ads that specifically target doctors. More funds would also be used for safety reviews of drugs already available, inspections of foreign plants and safeguarding clinical trials. There is also a directive that the FDA report on developing standards for a “track and trace system” that would document all parties involved in the supply chain in an effort to thwart counterfeiting.

Specifically, there would be a$15 million increase over the agency’s request for the office of generic drugs; a $3 million increase for the review of DTC ads; $2 million for reviewing industry communications to doctors and a $7 million increase over the request for the Center for Devices and Radiological Health. There is also language that “outlines the need to create an independent office on post-market drug evaluation,” De Lauro says in a statement. “As we learned from the hearing the subcommittee held about the Avandia case, there may be an inherent bias when those that approve drugs continue to play a role in determining their safety in a post-market environment.”

These people perform urine tests for toxic metals, and seem to cater to all sorts of alternative practitioners, many of whom I’d regard as misled at best and fraudulent at worst (see the list of medical board actions and lawsuits near the end of that link). The biggest issue seems to be that the test is administered under “provoked” conditions (after infusing some sort of chelating agent), but the reference values are for normal conditions. People are then told that they have high levels of toxic metals, need lots of therapy, and so on. . .

It looks to me like Quackwatch’s Stephen Barrett has performed a real service by detailing this problem and bringing together a lot of widely scattered information about it. But Doctor’s Data is suing him for defamation and seeking to have him remove all such material from his site (and not to post any such anywhere else in the future). I’ve donated to his legal defense fund and would ask that others consider doing the same.

Read more here
"Doctor’s Data": Telling the Truth and Getting Sued For It

The most recent candidate is been a series of gold-catalyzed reactions. Gold complexes have been quite fashionable in recent years, after a long period where they were considered next to useless. But perhaps things have gone a bit too far. A new paper in Organic Letters examines some gold-catalyzed couplings and finds, well. . .

Experimental reports claim that Au(I) is selective and very active, for instance, toward cross coupling of aryl halides with acetylenes (“Pd-free Sonogashira” for example), in the presence of mild bases. Surprisingly, this intriguing process has not been investigated mechanistically. We decided to set out experiments that would explain mechanistically the Pd-free cross-coupling catalysis with gold, but in fact what we are reporting is our failure to find a plausible mechanism. Furthermore, our experiments suggest that the presence of adventitious Pd might explain the positive “Pd-free Sonogashira” catalysis reported. . .

It’s the oxidative addition step (the first one in the cycle) that makes things go off the rails. Gold complexes (at least the ones reported) just don’t seem to be able to do it. On the other hand, as the authors mention, even high-quality gold often has a bit of palladium in it, and that bit is all it takes.

Read more here
Another Zero-Palladium Delusion?

There have been numerous claims that a medication caused a suicide, but few lead to sweeping changes. In Canada, however, the suicide of 18-year-old Sarah Carlin, who had taken the Paxil antidepressant, is a clear exception. Following a coroner’s inquest, Canada’s provincial and federal governments were told to ensure patients are better informed about drug risks, tighten regulations on drugmakers and establish an independent agency to regulate medications.

“If these things had been in place at the time Sara was prescribed Paxil, she would be alive today,” her father, Neil Carlin, said outside court. “We consider this a great victory…We are truly confident that if these are acted upon there will be young lives saved down the road.”

For more than a year before her death, Sara had been taking Paxil, an anti-depressant, which Health Canada warns can increase the risk of suicidal events in children and adolescents under 18. The teenager hanged herself in her parents’ basement in May 2007. The inquest made numerous recommendations, which you can see if you keep reading…

Of the various recommendations, the one that is garnering the most discussion appears to be the creation of a Drug Safety Board to investigate the side effects and issue warnings to the public, doctors and hospitals. The inquest specifically recommended the new board not receive any funding from drugmakers. Drugmakers must also report all adverse events to Health Canada within 30 days.

A Glaxo spokeswoman writes to says the drugmaker “is supportive of appropriate recommendations designed to prevent similar tragedies from occurring in the future, and will give the recommendations addressed to the broader pharmaceutical industry our full attention and consideration. Sara Carlin’s death was a tragedy and we continue to express our deepest sympathies to her family.”

1. The Ministry of Health and Long-Term Care (MOHLTC) should develop a Drug Information System. This system would promote:
• Patient safety in the prescribing and dispensing of drugs.
• Collection and compilation of data in a single repository for all drugs dispensed for all Ontarians.
• Research into drug and patient safety.

2. The Drug Information System should track and monitor all drugs dispensed in Ontario regardless of who is paying for the prescription.

3. The Drug Information System should collect, compile and release data upon request to scientists such as those studying population-based health outcomes at the Institute for Clinical Evaluative Sciences.

4. The Ministry of Health and Long-Term Care should commit to developing a province-wide suicide prevention strategy as has occurred in other provinces such as Alberta.

5. The objectives of the province-wide suicide prevention strategy should include:
• Enhanced mental health and well being for Ontarians.
• The education of the public to de-stigmatize mental health disorders, including depression and substance abuse disorders.
• Improving intervention and support for Ontarians affected by depression and substance abuse.
• Improving intervention and treatment for those at risk of suicide.
• Increased efforts to reduce access to lethal means of suicide.
• Increased research activities in Ontario on suicide, suicidal behaviour and suicide prevention.
• Improved suicide and suicidal behaviour-related surveillance systems.
• Inform and educate the media into strategies when reporting deaths due to suicide to prevent ‘copy cat’ suicides from occurring.

6. Strategies in the province-wide suicide prevention strategy should be humane, effective and evidence based, respectful of community and culture-based knowledge, inclusive of research, surveillance, evaluation and reporting and reflective of evolving knowledge and practices.

7. The ministry of Health and Long-Term Care of Ontario and Government of Ontario should commit to supporting the development of a national suicide prevention strategy for all Canadians.

RECOMMENDATIONS FOR THE ONTARIO COLLEGE OF PHYSICIANS AND SURGEONS AND THE ONTARIO COLLEGE OF FAMILY PHYSICIANS

8. The Ontario College of Physicians and Surgeons and the Ontario College of Family Physicians should develop practice guidelines and training to family physicians on administering and monitoring the use of selected serotonin reuptake inhibitors (SSRIs). Those guidelines should include, but not be limited to the following:

Prior to prescribing SSRIs the physician should:
• Give the patient a physical examination.
• Request laboratory investigations, including drug screen where appropriate.
• Inform the patient of the benefits and risks, inclusive of rare and serious side effects of SSRIs.
• Inform the patient of all reasonable alternative treatments.
• Inform the patient of the treatment plan should SSRIs be prescribed.
• Discuss with the patient alcohol and substance abuse as confounders in the illness.

B: Emphasize to physicians that best practice monitoring patients for drug-related adverse events arising from the introduction of SSRIs includes a regime in which the physician should monitor the patient with weekly visits for the first month, biweekly visits for the second month, and with a following visit in the third month. This effectively would monitor the period of time with the greatest risk for the development of serious drug-related adverse events.

C: Encourage physicians to utilize tools created to monitor both disease symptoms and adverse events of patients undergoing treatment with SSRIs. An example of such a tool is the SSRI Monitoring Form for Children and Adolescents developed in June of 2009 by the British Columbia Children’s Hospital in Vancouver, British Columbia.

D: Emphasize to physicians that while having due regard for the relevant health privacy legislation in the jurisdiction of the medical practitioner relevant to capacity and consent; patients undergoing treatment should be encouraged, repeatedly if necessary, to allow communication and engagement of family members, guardians and/or trusted friends by their treating physicians to ensure that the patient and their supports are aware of the nature of their disorder and the potential side effects of prescribed medications and can assist in the monitoring for adverse drug-related events.

RECOMMENDATIONS TO THE ONTARIO HOSPITAL ASSOCIATION

9. The Ontario Hospital Association should inform its hospital members that patients suffering with mental health disorders including depression, anxiety and substance abuse and attempted suicide may present for treatment to their hospitals and emergency department. While respecting the Personal Health Information Protection Act, 2004 every effort should be made to obtain consent from the patient to allow the release of the medical records compiled to the patient’s treating family physician.

RECOMMENDATIONS TO HEALTH CANADA

10. In order to maximize the effect of Health Canada Advisories detailed drug-related adverse events, Health Canada should consider that the Health Advisories:
• Be succinct.
• Clearly set out the warning.
• Should clearly set out the body of evidence giving rise to the warning.
• Should be specific.
• Should be profiled in a way to attract the physician’s attention.

11. Health Canada, as a regulator of companies seeking drug approval, should make their approval contingent on receiving results of all clinical trials from the drug manufacturers.

RECOMMENDATIONS TO REGULATED HEALTH PROFESSIONALS

12. All colleges legislated under the Regulated Health Professions Act, 1991 should require mandatory reporting to Health Canada by its members of serious drug-related adverse events as defined by Health Canada.

RECOMMENDATIONS TO THE PUBLIC HEALTH BRANCH OF THE MINISTRY OF HEALTH AND LONG-TERM CARE AND THE MINISTRY OF EDUCATION

13. These two ministries should develop an educational program regarding mental health and substance abuse for the adolescents and youth of Ontario’s school system. The circumstances of the death of Sara Carlin as presented at the inquest may be of assistance in the development of this program. The program should seek to inform the adolescents and youth in its schools that suffering with mental health disorders including depression and anxiety is common at their age. In addition the program should:
- Seek to de-stigmatize these illnesses.
• Provide information that these conditions are treatable.
• Emphasize the importance of abstinence from alcohol and other substances as utilizing these may contribute to mental health disorders and precipitate suicidal ideation and suicide.

RECOMMENDATIONS TO THE ONTARIO COLLEGE OF PHARMACISTS AND THE ONTARIO PHARMACISTS’ ASSOCIATION

14. When a prescription is filled the patient should receive a standardized and plain language information leaflet based on the product monograph. The information provided to the patient should include:
• What the medication is for.
• What the risks of taking the medication are.
• Under what conditions the medication should not be taken.
• Interactions with the medication.
• The proper use of the medication.
• Side effects and what to do about them.

RECOMMENDATIONS TO THE CANADIAN DRUG MANUFACTURERS’ ASSOCIATION

15. Drug companies should be required to report to Health Canada all serious adverse events associated with their drugs from all foreign jurisdictions within 30 days of the adverse event.

RECOMMENDATIONS TO THE CANADIAN FEDERAL GOVERNMENT

16. There should be an arms length body independent from Health Canada called the Drug Safety Board, which is solely dedicated to drug safety, which reports to Parliament, which is funded by the Federal Government and which receives no money from drug companies. Amongst its mandated responsibilities should be drug safety research, investigating adverse reactions and issuing warnings to the public and health care professionals and hospitals.

Hat tip to Bob Fiddaman
Read more in Inside Halton and The Toronto Globe & Mail

Well, regular readers will be expecting this to be a story of someone who did not remember to Treat Compressed Gases With Respect, but that’s not the case. No, this is what happens when you don’t Treat Hydrogen With Respect – and everyone in the audience who’s had a hydrogenation reaction get frisky on them will be nodding their head in agreement at that thought. Somehow, enough hydrogen and enough oxygen got together in an anaerobic culture hood, and the mixture found an ignition source, and well. . .

Problem is, just about any hydrogen/air mixture will do. Anything from about 4% hydrogen in air to about 75% will ignite, and everything except the two ends of that range will go ahead and explode if given the chance. (Only acetylene is worse in that regard). And it doesn’t take much to set it off, either, which is the other nasty thing about working with hydrogen. A static-electricity spark is plenty, as are the sparks generated by electrical switch contacts and the like.

As you can see, the lab was not improved by the resulting explosion. The latest report I have is that four people were injured, one seriously enough to still be in the hospital, although their condition has been upgraded to “good”.

Initial reports were that this was due to human error, although everyone seems to be backing off that judgment until an official investigation is finished. At any rate, the local fire department stated Monday night that the problem was one or more people in the lab “not being familiar with the warning systems designed to alert them when the hydrogen level was approaching explosive limits (and) the gas was left on”. If that was the case, then. . .you ignore a hydrogen level alarm at your peril. And here are seventeen blown-out windows, four people who are lucky not to have been killed, and one demolished lab as evidence.

(Photos are courtesy of the Missourian and the Columbia Fire Department).

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How Not To Do It: Hydrogen Gas Mixtures

The building block for all this is the smallest helical peptide yet reported, a cyclic pentapeptide (KAAAD) curled as as a lactam between residues 1 and 5. Joining two or more of these up give you more turns, and replacing the alanines gives you plenty of possible mimics of endogenous proteins. An analog of nociceptin turned out to be the most potent agonist at ORL-1 ever described (40 picomolar), and an analog of RSV fusion protein is, in its turn, the most potent inhibitor of that viral fusion process ever found as well.

Meanwhile, the paper states that these constrained peptides were stable in human serum for over 24 hours, as very much opposed to their uncyclized counterparts, which are degraded rapidly. (Exocyclic amino acids, when present, do get degraded off in a time span of hours, though).

I’m quite amazed by all this, and I’m still processing it myself. I’ll let the authors have the last word for now:

“This work is a blueprint for design and utility of constrained α-helices that can substitute for α-helical protein sequences as short as five amino acids. . .The promising conformational and chemical stability suggests many diverse applications in biology as molecular probes, drugs, diagnostics, and possibly even vaccines. The constrained peptides herein offer similar binding affinity and/or function as the proteins from which they were derived, with the same amino acid sequences that confer specificity, while retaining stability and solubility akin to small molecule therapeutics. . .”

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Stable Helical Peptides Can Do It All?

That’s a tough standard, but many biosynthetic routes reach 100% against it. I think that the highest figure from one of the Baran group’s own syntheses is 84%, but he emphasizes that comparing these figures across the synthesis of different molecules isn’t too meaningful, since they each carry their own issues. Comparing different routes to the same molecule is what he has in mind; it’s a pity that no one else is ever going to make maitotoxin.

He also emphasizes that “ideality” isn’t the only consideration in a synthesis. It gets at some key issues, but others (availability of reagents, ease of experimental procedures or purifications) can trump ideality out in the real world. You certainly see that in process chemistry in the drug industry. A reliable procedure that always gives the same (but lower) purity will win out over a temperamental one that sometimes gives wonderful material but sometimes craps out. And an elegant-looking route that gives a small amount of an intractable impurity isn’t so elegant, compared to a slightly longer one that delivers material that’s easily cleaned up.

The same goes for reagents. Ideally, you’d want to be able to buy all of them, and cheaply, too. But that’s where the comparison with those 100% ideal biosynthetic routes breaks down. The enzymes that accomplish them are nothing if not bespoke reagents, doing one thing only but nearly perfectly. And there’s that matter of a billion years of evolutionary overhead to factor in to the development costs. Of course, the other great thing about enzymes is that they’re catalytic, and can just keep turning over reactions constantly. If they were one-time-use, like many of our reagents from the catalogs, it wouldn’t matter how incredibly high-yielding and specific they were; the horrendous waste of time and material required to produce them for just one transformation would rule them out. Average those expenses out over the turnover numbers of a typical enzyme, though, and things look very good indeed.

I think that Baran’s criteria are well worth keeping in mind, although I also think that most synthetic chemists already think this way, to one degree or another. I always gritted my teeth when I put on a protecting group during my total synthesis days, because I knew that I was adding another step (and more potential trouble) down the line when it had to come off again. Mind you, I was putting the thing on to avoid what I saw as even more immediate trouble, but I guess that’s one of the things that Baran is saying, that it’s time to try to stop making such deals if we can.

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The Ideal Synthesis

Vos patients sur metformine seule n’arrivent plus à contrôler leur glycémie ?
Offrez rapidement un traitement efficace et simple

Brand name: Onglyza
Generic name/category: Saxagliptin
Company: AstraZeneca and Bristol-Myers Squibb (BMS)
Country/Market: Belgium, Europe
Indication(s)/use: Glycemic control in adults with type 2 diabetes
Target: Healthcare Professionals (HCP)
Medium: print ad
Size/duration: double-page spread
Publication/Aired: June 25, 2010

To see more of this brand’s ads, click here

To see a larger version of this ad and its details, click on its thumbnail.

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Maitotoxin: It’s On, All Right

The study, which evaluated data from 227,571 Medicare patients between 2006 and 2009 with an average of 74.4 years, found there 1,746 heart attacks, of which 21.7 percent fatal; 1,052 strokes and 7.3 percent fatal; 3,307 hospitalizations for heart failure, including 2.6 percent that were fatal; and 2,562 deaths for all causes. Although the analysis showed no differences in the risk for heart attack between the two drugs, the authors write that Avandia was associated with a 1.25 greater in risk of heart failure; a 1.27 greater risk of stroke and a 1.14 greater risk of death compared with Actos.

The official release of the data is certain to complicate life for GlaxoSmithKline, which has been arguing that Avandia is safe and effective. The drugmaker is also in the midst of conducting another long-term study, although is having difficulty enrolling a sufficient number of patients and the FDA is grappling with criticism that the effort is unethical (see here and here).

The July 13 meeting, in fact, is being considered something of a test for FDA commish Margaret Hamburg, especially after a Senate Finance Committee report released earlier this year revealed bickering inside the FDA over what to do about Avandia (go here to find the report). The meeting and its outcome will provide Hamburg and FDA deputy commish Josh Sharfstein an opportunity to promote the FDA as a public health agency while rectifying internal agency debates over safety issues and industry influence.

Among those speaking will be FDA medical reviewer David Graham, who co-authored the JAMA study along with others from the FDA and Centers for Medicare & Medicaid Servcies, and Steve Nissen, who updated an earlier meta-analysis also published today. . Graham, you may recall, arrived on the national radar screen five years ago when he testified before Congress that the FDA failed to protect public health by not forcing Merck’s to withdraw its Vioxx painkiller, which studies linked to increased risk of heart attacks. Late last month, Graham had complained to Hamburg and Sharfstein in an email that his effort to submit the paper for publication was being blocked by some FDA officials. The agency denied any attempt to suppress publication

The other study, which is published in the Archives of Internal Medicine and essentially updates a controversial meta-analysis from 2007 by Cleveland Clinic’s Nissen, looked at 56 clinical studies, including a Glaxo study known as Record, and shows an increased heart attack risk of 28 percent. The earlier analysis examined 42 studies involving Avandia and showed a 43 percent increase in the risk of a heart attack. Remove the Glaxo study and the risk of heart attacks rises to 39 percent.

“The public health implications of these results are considerable. There are more than 23 million persons with diabetes in the United States alone and nearly 300 million worldwide. Cardiovascular disease is the leading cause of death in patients with type 2 diabetes, representing approximately 68 percent of all causes of mortality,” writes Nissen, who has engaged in a nasty back-and-forth squabble with Glaxo over its handling of its Avandia data and the merits of his meta-analysis. “Although hyperglycemia has been associated with an increased risk of microvascular adverse events, there are now 12 classes of drugs that are approved to lower blood glucose levels, including insulin. Because no unique benefits of Avandia use have been identified, administration of this agent solely to lower blood glucose levels is difficult to justify.” (here is the complete study).

In a separate editorial in JAMA, David Juurlink of the Sunnybrook Research Institute and the Departments of Medicine, Pediatrics and Health Policy, Management, and Evaluation at the University of Toronto writes ““The epilogue of the rosiglitazone story has yet to be written, but a few observations can now be made with confidence. First, there is no direct evidence that rosiglitazone prevents vascular events in patients with diabetes. Second, converging lines of evidence suggest that rosiglitazone is less safe than pioglitazone, whereas no data suggest that the converse might be true. Third, because the evidence to date is not conclusive, differing views have emerged on how to proceed in the face of uncertainty.

“…Whether rosiglitazone and pioglitazone really do have different cardiovascular safety profiles is an intriguing question but one with a misplaced focus. Accumulating concerns about rosiglitazone make it difficult to advance a cogent argument why, exactly, a patient might want to receive the drug or why a physician would choose to prescribe it when there is an available and quite possibly safer alternative.”

UPDATE: A Glaxo spokeswoman sends us this statement: “We are aware of several new publications, including an updated meta-analysis and a new observational study, regarding (Avandia). There are strengths and limitations of each type of analysis that must be factored into their evaluation.

Randomized clinical trials remain the gold standard for evaluating scientific and medical questions. Results from six controlled clinical trials (RECORD, APPROACH, VICTORY, VADT, ACCORD and BARI-2D) have been reported since the Joint Advisory Committees reviewed questions about the cardiovascular safety of Avandia in 2007. Taken together, these trials show that Avandia does not increase the overall risk of heart attack, stroke or death.

In RECORD, a cardiovascular outcomes trial designed in conjunction with European regulators, there was no increase seen in the combined endpoint that includes death, myocardial infarction and stroke. HR=0.93, 0.74-1.15, p=0.5. Glaxo also has updated its prior meta-analysis to include data from 52 clinical trials and it does not show an increase in myocardial ischemia. HR=1.1, 0.89-1.35, p=0.38. There also have been several new observational studies published since 2007. Review of these studies with tighter confidence intervals have risk ratios that are very close to one, indicating no difference in the risk of myocardial infarction between” Avandia and Actos.

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Maitoxin: It’s On, All Right

Now, as Jim Edwards points out, this case has not gone away. In fact, the most recent attempt to get it thrown out has failed, and former CEO Fred Hassan faces a possible deposition on the matter. This will be quite interesting to watch, since Merck is on the hook for any judgments that might result. Stay tuned. . .

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That Schering-Plough Lawsuit Isn’t Going Away

Recent accomplishments for Avanir (AVNR) marked the most exciting quarter in the history of the company, and it is highly likely that big news is on the near-term horizon. Avanir’s share price closed at $2.67, a gross undervaluation, in Friday’s trading session. I expect Avanir’s share price to easily double prior to October when the FDA is expected to approve its key drug, Zenvia. And the stock price should easily reach $10 per share by early 2011, the expected launch time of Zenvia. The details of my analysis will be presented later in this article, but first, I will address the key drivers that make Avanir a compelling “buy and buy more” proposition:

1. Patent protection – The Company received long-term (15 year) patent protection on Zenvia, securing its monopoly on Zenvia for years to come.
2. Extremely Positive Data – Avanir provided extremely positive safety and efficacy data at the American Academy of Neurology meeting and American Psychiatric Association meeting. They also showed tolerability with common drugs Paroxetine (a common antidepressant) and Memantine, a drug Merz +Co and Forest Labs (FRX) market for ALS patients. Commenting on the AAN meeting, Keith Katkin, CEO of Avanir, states "…the physician interest level in PBA is significant and reinforces our belief there is a large unmet medical need". As a Merriman Analyst commented, "Avanir Pharmaceuticals is advancing its lead product, Zenvia, for the unique indication of pseudobulbar affect, a hitherto little-known neurological condition that may affect millions of individuals…In our view, the Phase III STAR trial data are compelling…” Evidence of the excitement about Zenvia is apparent when looking at the stock price action after the Jeffries & Company (JEF) Health Sciences presentation by Avanir on June 8. The stock price had greater than a 25% upward move in a matter of a few days. Also notable is the trading volume in the $5.00 December calls. And furthermore, Avanir boasts institutional holders such as Blackrock, which is one of the most respected hedge funds on the street.
3. Early start on marketing/awareness efforts- Awareness of PBA is growing and the management team is diligently preparing for commercial launch. Top talent Michael McFadden was hired. Mr. McFadden previously managed markets at Amylin Pharmaceuticals (AMLN). When asked by an analyst of upcoming events prior to approval, Keith Katkin responded, "…you’ll see PBA awareness advertorials within all of the medical journals. You’ll also see them in the patient-focused journals…"Also, Avanir will attend "a dozen" different neurology and psychiatry meetings. Also, quite noteworthy is that AVNR partnered with ITV and PBS and will be airing a series on PBS stations (estimated late-June to early July) about the impact of PBA on patients’ lives. Cannacord Adams analyst comments “AAN doctor opinion on Zenvia has been positive; we think that Zenvia will see good patient and doctor acceptance…”
4. Raised Capital – Debt-freeAvanir raised over $26 million through a recent stock offering such that Christine Ocampo, CFO of Avanir, stated "we expect our current cash on hand will be adequate to fund continuing operations and the clinical development of Zenvia through the anticipated FDA approval decision date…"
5. FDA Submission – The Company provided the FDA with all data needed to assess Zenvia in PBA. Approval is extremely likely as Zeniva’s two major components are not new molecular entities and the response letter submitted was solid. After reviewing the submission, Cannacord analyst commented “…any delay would be minor and not reflect negatively on Zenvia’s approvability or sales potential.” Investors will remember Dendreon’s (DNDN) situation after receiving an approvable letter from the FDA, its engagement in subsequent studies, and ultimately approval which turned a $4 stock into one that now trades above $37.

Let’s examine a price/sales multiple. Cantor Fitzgerald estimates $675 million in peak sales for Zenvia, ramping up and seeing those peak sales in 2015. Personally, I think the estimate is a bit conservative when one factors the indefinite prescribed period and the other applications of Zenvia that should be approved following the PBA approval. But, let’s go with Cantor’s sales estimate. Although there is wide variation in price/sales ratios, the average biotech trades at 3 times peak sales. Since Avanir has rights to the drug longer than most drug companies (15 years), it could reach much higher multiples. But, even using a more conservative estimate of half that figure (1.5 times price/sales), the market cap of Avanir should be over $1 billion. That’s approximately $10 per share, indeed compelling with a potential upside of over 400%! And for more short-minded investors, there are two near-term catalysts:

1. A Barron’s article this weekend mentions that 9 pharma companies (Pfizer: PFE, Merck: MRK, Eli Lilly: LLY, Bristol Myers: BMY, Novartis: NVS, Roche: RHHBY.PK, AstraZeneca: AZN, Sanofi-Aventis: SNY, and Glaxo Smith Kline: GSK) are undervalued and could rally 30%, and
2. There should be a nice run prior to FDA acceptance, easily pushing the stock to $6. I’ve taken a sizable position and am quite ready to enjoy the ride!

Disclosure: Long AVNR, DNDN, PFE

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The insurer studied 26,000 members on osteo meds, comparing Boniva, which is marketed by Roche and GlaxoSmithKline with Actonel, which is sold by Sanofi-Aventis and Warner Chilcott, and Merck’s Fosamax. Although randomized clinical trials suggest the drugs should be equivalent, WellPoint data found differences. Now, WellPoint other drugs must be tried before Boniva is approved.

The drug remains where on Tier 3, or non-preferred level, on the formulary. WellPoint actually made the change last year, Dow Jones writes, although last month, WellPoint announced it had developed standardized comparative effectiveness guidelines to evaluate a drug’s ability to improve outcomes. Another approach is taken by RegenceRx, the not-for-profit arm of the Regence Group that includes several BlueCrossBlueShield insurers, by analyzing the quality of clinical trials promulated by pharma (see this).

Three months ago, by the way, the FDA determined there is no link between these drugs and thigh-bone fractures, even though a warning had been issued two years ago (background here). Nonetheless, the agency is continuing to work with outside experts to analyze more info.

Biotechnology has helped improve the lives of many people. Naturally, many biotech stocks boom or bust based on the success of products in their pipeline. But if you’re looking for a more diversified and steady approach to biotech investing, look no further than ETFs.

Matthew D. McCall of Index Universe is bullish on biotech stocks because he believes they have a good shot at treating and curing cancer. But because it is hard to predict who will come out with the next blockbuster treatment, he recommends using ETFs to ride the upside. He goes on to describe five biotech ETFs.

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For organic chemistry, those are occupied by papers that report new compounds of little interest to anyone. But you never know – they might be worth someone else’s time eventually. It’s unlikely that any of these things will be the hinge on which a mighty question turns, but knowing that they’ve been made (and how), and knowing what their spectra and properties are could save someone time down the line when they’re doing something more useful. These are real bricks in the huge construction of scientific knowledge, and while they’re not worth much, it’s more than zero. That’s the value I assign to the hunks of mud that some people offer instead, or the things that look like real bricks but turn out to be made out of brick, yes, but about one millimeter thick and completely hollow.

So what to do with work that’s mostly reference data for the future? It shouldn’t have to appear in physical print, you’d think. How about the peer-reviewed journal part? Well, peer review is not magic. As it stands, that sort of information is the least-reviewed part of most papers. If someone tells you that they’ve made Compound X and Compound Y, and the synthesis isn’t obviously crazy, you tend to take their word for it. It’s a rare reviewer that gets all the way down to the NMR spectra in the supplementary material, that’s for sure. And if one does, and the NMR spectra look reasonably believable, well, what else can you do? Even so, every working chemist has dealt with literature whose procedures Just Don’t Work, and all those papers passed some sort of editorial review process at some point.

No, peer review is not going to do much to improve the quality of archival data. If someone really wants to fill up the low-level bins with junk, there’s not much stopping them. You could sit down and draw out a bunch of stuff no one’s ever made before, come up with plausible paper syntheses of all of it, use software to predict reasonable NMR spectra (which you might want to jitter around a bit to cover your tracks), and just flat-out fake the mass spec and elemental analyses. Presto, another paper that no one will ever read, until eventually someone has a reason to make similar compounds and curses your name in the distant future. The problem is, such papers will do you no real good, since they’ll appear in the crappiest journals and pick up no citations from anyone.

Perhaps there should be a way to dump chemical data directly into some archives, the way X-ray data goes into the Protein Data Bank. That wouldn’t count for much, but it would capture things for future use. Having it not count much would decrease the incentive for anyone to fill it full of fakery, too, since there would be even less point than usual. And before anyone objects to having a big pile of non-peer-reviewed chemical data like this, keep in mind that we already have one: it’s called the patent literature, and it can be quite worthwhile. Although not always.

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What To Do With The Not-Quite-Worthless

If fingolimod makes it, it’ll also be the first drug I’m aware of that has a flippin’ n-octyl chain hanging off it – a flagrant violation of everything that a medicinal chemist learns in their first month on the job. Hydrophobic bulk, metabolism bait, entropic penalty – well, there it is. I’m not suggesting that we all go out and slap pennzoilane and crico-cene side chains on our lead drug candidates, but it’s worth remembering that the race is not always to the swift, nor the battle to the strong.

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Fungal Structures to the Rescue

This is only the latest in a string of big setbacks for the big drugmaker, starting with torcetrapib, a cholesterol pill that Pfizer hoped would not only revolutionize treatment, but its financial statement. Earlier this year, an experimental Alzheimer’s drug that Pfizer had licensed failed two-late stage clinical trials; known as dimebon, Wall Street quickly called it dimebomb. And two phase III studies of its Sutent breast cancer drug failed to meet their principal goals. Feel free to write in with others. Of course, with fewer drugs, Pfizer has fewer concerns about properly reporting adverse events (see this).

Wall Street is, predictably, scornful of Pfizer’s R&D track record. Here is a sampling of analyst remarks this morning: “Pfizer has probably lost its advantage in lead time over the competition, and at worst, tanezumab is a clunker and another major phase III failure to add to a lengthy, expensive list,” write Deutsche Bank analyst Barbara Ryan, in an investor note.

In his own note, Jon LeCroy of Hapoalim Securites, opines: “We view a clinical hold as a major negative and are removing tanezumab from our Pfizer model. We also view this as a major blow against Pfizer, as we considered tanezumab to be Pfizer’s most promising pipeline drug.” He concludes by noting that Pfizer has the “worst pipeline” among big drugmakers.

Leerink Swann analyst Seamus Fernandez offers an equally dismal outlook: “This represents yet another phase III pipeline failure removing another upside opportunity from Pfizer’s late-stage pipeline. Despite the fact that this failure has only a small impact on our P&L forecasts, it is further evidence of Pfizer’s R&D productivity challenges.”

Finally, consider what Sanford Bernstein analyst Tim Anderson had to say: “The commercial case for tanezumab in osteroarthritis pain has long baffled us….

“…Tanezumab would have to be given as an injection, and would compete in a category (pain) filled with many existing medicines the vast majority of which are given orally. Naturally, the product seemed destined to be a last-line therapy for OA pain. What this does is cast a pall over Pfizer’s broader R&D abilities as the company has been highlighting tanezumab as one of its promising late-stage products worthy of phase III development.”

While brilliant and progressive research continues apace here and there, the amount of redundant, inconsequential, and outright poor research has swelled in recent decades, filling countless pages in journals and monographs. Consider this tally from Science two decades ago: Only 45 percent of the articles published in the 4,500 top scientific journals were cited within the first five years after publication. In recent years, the figure seems to have dropped further. In a 2009 article in Online Information Review, Péter Jacsó found that 40.6 percent of the articles published in the top science and social-science journals (the figures do not include the humanities) were cited in the period 2002 to 2006.

As a result, instead of contributing to knowledge in various disciplines, the increasing number of low-cited publications only adds to the bulk of words and numbers to be reviewed. Even if read, many articles that are not cited by anyone would seem to contain little useful information. . .

If anything, this underestimates things. Right next to the never-cited papers are the grievously undercited ones, most of whose referrals come courtesy of later papers published by the same damn lab. One rung further out of the pit are a few mutual admiration societies, where a few people cite each other, but no one else cares very much. And then, finally, you reach a level that has some apparent scientific oxygen in it.

The authors of this article are mostly concerned about the effect this has on academia, since all these papers have to be reviewed by somebody. Meanwhile, libraries find themselves straining to subscribe to all the journals, and working scientists find the literature harder and harder to effectively cover. So why do all these papers get written? One hardly has to ask:

The surest guarantee of integrity, peer review, falls under a debilitating crush of findings, for peer review can handle only so much material without breaking down. More isn’t better. At some point, quality gives way to quantity.

Academic publication has passed that point in most, if not all, disciplines—in some fields by a long shot. For example, Physica A publishes some 3,000 pages each year. Why? Senior physics professors have well-financed labs with five to 10 Ph.D.-student researchers. Since the latter increasingly need more publications to compete for academic jobs, the number of published pages keeps climbing. . .

We can also lay off some blame onto the scientific publishers, who have responded to market conditions by starting new journals as quickly as they can manage to launch them. And while there have been good quality journals launched in the past few years, there have been a bunch of losers, too – and never forget, the advent of a good journal will soak up more of the worthwhile papers, lifting up the ever-expanding pool of mediocre stuff (and worse) by capillary action. You have to fill those pages somehow!

If this problem is driven largely by academia, that’s where the solution will have to come from, too. The authors suggest several fixes: (1) limit job applications and tenure reviews to the top five or six papers that a person has to offer. (2) Prorate publication records by the quality of the journals that the papers appeared in. (3) Adopt length restrictions in printed journals, with the rest of the information to be had digitally.

I don’t think that those are bad ideas at all – but the problem is, they’re already more or less in effect. People should already know which journals are the better ones, and look askance at a publication record full of barking, arf-ing papers from the dog pound. Already, the best papers on a person’s list count the most. And as for the size of printed journals, well. . .there are some journals that I read all the time whose printed versions I haven’t seen in years.

No, these ideas are worthy, but they don’t get to the real problem. It’s not like all the crappy papers are coming from younger faculty who are bucking for tenure, you know. Plenty more are emitted by well-entrenched groups who just generate things that no one ever really wants to read. I think we’ve made it too possible for people to have whole scientific careers of complete mediocrity. I mean, what do you do, as a chemist, when you see another paper where someone found a reagent to dehydrate a primary amide to a nitrile? Did you read it? Of course not. Will you ever come back to it and use it? Not too likely, considering that there are eight hundred and sixty reagents that will already do that for you. We get complaints all the time about me-too drugs, but the me-too reaction problem is a real beast.

Now, I realize that by using the word “mediocrity” I’m in danger of confusing the issue. The abilities of scientists are distributed across a wide range – I doubt if it’s a true normal distribution, but there are certainly people who are better and worse at this job. But I’m complaining on the absolute scale, rather than the relative scale. I know that there’s always going to be a middle mass of scientific papers, from a middle mass of scientists: I just wish that the whole literature was of higher quality overall. A chunk of what now goes into the mid-tier journals should really be filling up the bottom-tier ones, and most of the stuff that goes into those shouldn’t be getting done in the first place.

I suppose what bothers me is the number of people who aren’t working up to their potential (although I don’t always have the best position to argue that from myself!) Too many academic groups seem to me to work on problems that are beneath them. I know that limits in money and facilities keep some people from working on interesting things, but that’s rare, compared to the number who’d just plain rather do something more predictable. And write predictable papers about it. Which no one reads.

Read more here
All Those Worthless Papers

ROCHE HOLDING and AMYLIN PHARMACEUTICALS (AMLN)

A diabetes drug produced by Roche has experienced a setback after the firm said adverse reactions to the drug – Taspoglutide – have forced the company to make changes to ongoing clinical trials, creating concern over both the drug’s timeline to approval and its ability to compete successfully with other similar therapies.

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So Eli Lilly is, yes, bringing a statin of their own to market. Livalo (pitavastastin) will try to make headway based on a slightly lower price than Crestor (the big dog, after next year, among the patent-protected statins) and a different metabolic profile that might decrease drug-drug interactions.

Lilly brought this one in from Kowa of Japan, and it’s hard to see how they’ll get too many people excited about it. And while I certainly understand to need to make some money, one way or another, making it this way doesn’t add mmuch to the case for Big Pharma innovation, does it? Maybe there are enough people out there who will benefit from another alternative – but no one can say that the world was waiting for another statin, that’s for sure.

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Lilly’s Statin – Yes, It Is 2010

The study found that only 2 percent of men aged 40 to 80 suffer from the condition, which is also called male menopause, andropause or late-onset hypogonadism. The researchers measured testosterone levels in 3,369 men between those ages and then correlated their levels with different symptoms. Of 32 possible symptoms, only nine were linked with decreased testosterone. Three were physical – unable to engage in strenuous activity, walk about a mile or to bend over or kneel – and three were psychological — low energy, sadness and fatigue. However, these six symptoms were only mildly linked to the problem, while three sexual symptoms – less frequent morning erections, low sex drive and erectile dysfunction – were closely related to low testosterone.

“Our results also highlight the substantial overlap between late-onset hypogonadism and non-specific symptoms of aging. The application of these new criteria can guard against the excessive diagnosis of hypogonadism and curb the injudicious use of testosterone therapy in older men,” conclude the researchers, who noted the condition is usually associated with advancing age, yet there is little evidence about the “exact criteria for identifying testosterone deficiency in older men.”

Meanwhile, Abbott’s Solvay Pharmaceuticals unit actively promotes on its site that low testosterone affects more than 13 million men in the US over the age of 45. An Abbott spokesman points to a pair of studies used to bolster the notion that low testosterone will increase substantially with age, including in men well past 65 years old, although these were published in 2004 and 2007 (look here and here). Yet the AndroGel prescribing info acknowledges there haven’t been enough men 65 and older who have participated in clinical trials to know whether the treatment is safe or effective. And it is now 2010. Of course, now that the NEJM study dismisses the notion that older men are more likely to develop the problem, Solvay may not have to conduct a study.

The Low T site also states that the risk of developing low testosterone is 2.4 times greater if one is obese; 2.1 times greater if is one has diabetes; 1.8 greater with high blood pressure and a 1.5 higher risk if one also has high cholesterol. The evidence for this claim comes from this 2006 study. These may be accurate, although for the record, all five authors had ties to Solvay (click on authors and disclosures in the link to the study). Similarly, six of the seven authors of the Endocrine Society Clinical Guidelines for treating low testosterone have ties to Abbott (see page 31). This may confuse some people, since the ‘Low T’ site is identified as a Solvay site. However, a summary of the older version of the guidelines lists financial ties to Solvay (see this).

Also interesting is the pop quiz….

To gauge its usefulness, we deliberately answered ‘no’ to each of the 10 questions, which asked about whether we had lost our libido, energy, strength, height, enjoyment of life, and a few other choice topics. In other words, we deliberately avoided offering any indication that a problem may exist. Just the same, we received this reply: “Your answers show that you have a lower risk for low testosterone (Low T). But it’s still important to talk with your doctor about your symptoms. They may be caused by treatable condition.” What symptoms? Hard to say. Unless one is being pushed to ask a doctor for something.

In response to questions, the spokesman tells us that the site is “designed to simply raise awareness about the condition so that men who believe they’re suffering from the problem can have a conversation with their doctor about it…The quiz is not a diagnostic tool, but is a trigger to have that dialogue with the physician. Someone who takes the quiz may be feeling something isn’t right, so this says that perhaps they should still explore that. But it’s not intended to be diagnostic.”

And what about the site? Will Solvay modify it to reflect the findings from the NEJM study? “We believe there’s plenty of data that would suggest there’s a constellation of symptoms that may be associated with Low T,” he says. “We certainly always encourage continued scientific discovery and continue to look at this, but we still feel sufficient data out there that suggests this whole array of symptoms maybe associated with Low T.”

At issue, is whether Schering-Plough and Merck (which were partners) handled the release of the trial data properly, given a two-year delay, a brief change in the primary endpoint without consulting the lead investigator and huge stock sales by some Schering-Plough execs. The trial, by the way, found Vytorin wasn’t any better at reducing arterial plaque in the carotid artery compared with Zocor, and even found a statistically insignificant buildup. Former Schering-Plough execs have repeatedly argued they knew nothing of the results until after the behind-the-scenes controversy was disclosed (see here).

In his opinion, US District Court Judge Dennis Cavanaugh took the lawyers for the former execs and board members to task for their latest attempt to have the case dismissed, calling it a ‘classic attempt at a second bite at the apple,’ and simply a vehicle to “rehash arguments which have already been briefed by (the defendants) and considered and decided by the court.” This is very much a procedural step, but an important one. The upshot is that Hassan and friends will likely soon find themselves being deposed about those controversial events, which were widely followed as a lesson in how executives must manage the release of important clinical trials, among other things.

Hat tip to Shearlings Got Plowed

And figuring out what the structures of these things were wasn’t so easy, either. I once had the unenviable assignment of trying to break down a stack of their patent applications to see if I could find the lead structure for one of their compounds, and after a week or so I had to concede. None of my usual tricks worked – untangling and charting out the synthetic pathways from the experimental section to see the common threads, looking for sudden upticks in the amounts of intermediates or final compounds being prepared, looking to see if some compounds had been more completely characterized than others, and so on. No, these folks had done a fine job of sweeping up after themselves, and over the years I’ve run into other people who came to the same conclusion.

The company has had a long relationship with Bristol-Myers Squibb. There have been many twists and turns, but in 2008 the companies agreed to develop a compound called XL-139. (You won’t quite be able to figure it out from that Exelixis page, but that announcement also marked the end of one of the broader agreements that the two companies had signed). Later that year came an announcement (also on that link above) about two more kinase inhibitors, XL-184 and XL-281, whose status hadn’t been resolved earlier.

Now comes word that XL-184 has been returned to Exelixis. The press release, as press releases will, makes it seem as if the problem was that the compound was just too darn good:

“Given the recent progress of BMS’ wholly-owned oncology pipeline and positive data generated by XL184, Exelixis and BMS were not able to align on the scope, breadth and pace of the ongoing clinical development of XL184.”

They say that they’re pleased to have the chance to develop the compound outside the meddling influence of BMS (well, not quite in those words naturally). But I’ll bet they’re not pleased to have to do it without BMS cash. Having the drug sent back makes you think that the larger company put it in the category of “Nothing we can’t live without”, although it’s true that XL-184 is surely worth more to Exelixis. (Development of the other compound, XL-281, is apparently continuing).

My guess is that kinase inhibitors of this sort just look a lot less attractive than they did a few years ago. Several of them have made it to market, and while they can be profitable, the field is getting crowded. Mind you, they’re all different from each other, but sorting out what works in the clinic is a long process. None of them seem (so far) to do anything dramatic against the most common tumor types. (Here’s a recent article on just that problem). What Exelixis will make of XL-184 remains a mystery, probably to them just as much as to anyone else.

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Exelixis Gets a Compound Back

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Andrew Witty’s Advice

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Free Software

Now, though, a new report quantifies the extent to which drugmakers are researching their meds in other countries and the results suggest the concerns will not go away – 80 percent of drugs approved in 2008 had trials in foreign countries, and 78 percent of all patients were enrolled at foreign sites, according to the US Human & Health Service Inspector General. And 10 drugs approved in 2008 were tested entirely abroad with no patients in the US. Meanwhile, the FDA inspected 1.9 percent of domestic clinical trial sites and just 0.7 percent of foreign sites. And while Western Europe accounted for most foreign trial subjects and sites, Central and South America had the highest average number of subjects per site.

The issue and ensuing worries are not new, of course. An HHS OIG report in September 2001 found that “sponsors have expanded research sites into many countries that appear to have limited experience in clinical trials” and the “FDA cannot assure the same level of human subject protections in foreign trials as domestic ones.” In its latest report, the HHS suggests the FDA should require standardized electronic clinical trial data, create an internal database, inspect trials in more countries and monitor trends in foreign clinical trials not conducted under Investigational New Drug applications. But critics say the findings illustrate the ongoing problems plaguing the FDA.

The report “highlights a very frightening and appalling situation,” Congresswoman Rosa DeLauro, a Connecticut Democrat, tells The New York Times. “By pursuing clinical trials in foreign countries with lower standards and where FDA lacks oversight, the industry is seeking the path of least resistance toward lower costs and higher profits to the detriment of public health.” Adil Shamoo, editor of Accountability in Research, adds that “I think this report just confirms the potential problems with foreign trials. There is less liability, patient recruitment is far easier, the concept of informed consent is not well established, and it’s cheaper.”

Drugmakers and clinical research operators, however, argue that rising costs are a legitimate concern and, moreover, clinical investigators in the US appear less interested in participating in studies. As if the HHS study was anticipated, in fact, a recent survey by the Association of Clinical Research Organizations found that between 2004 and 2007, the number of clinical trial investigators who are regulated by the FDA fell 5.2 percent in the US and 6.1 percent in Western Europe, while increasing 16 percent in Eastern Europe, 12 percent in Asia and 10 percent in Latin America.

The reasons cited by US investigators: regulations make trials difficult to manage, medical liability, and conflict of interest mandates that docs disclose financial relationships with pharma. In fact, 24 percent of US investigators are less likely to participate in trials if they are required to disclose income. And US investigators are more concerned with making money – 68 percent say this is a “very important” factor in their participation (read more here).

UPDATE: At about 4:30 pm EST, the PhRMA trade group writes us to say that the same regulatory standards apply to foreign trials as those conducted in the US. “Is it ethical to conduct such studies outside of the US? In a word: Yes. Whether the clinical research occurs in the US or outside its borders, our member companies must adhere to Good Clinical Practice guidelines.

“In fact, PhRMA has conducted educational seminars and symposiums – at times, in conjunction with the FDA – in other countries to educate potential clinical trial principal investigators about Good Clinical Practices, ethics oversight by outside review boards, and the need to maintain the highest standards for data quality.

“Regardless of the location, however, companies seeking US approval must maintain the FDA’s high standards for conducting the trial. For instance, any related trials conducted outside the U.S. must comply with FDA requirements covering Good Clinical Practices, in addition to meeting the requirements mandated in these important emerging markets.” Here is the complete PhRMA statement.

The great syndication site Alltop is listing many of the best sites gathering infographic examples. This is great because in pharmaceutical communications, we often find ourselves having to design some pretty complex charts and graphs. And lets face it, most of the time they are not very interesting to look at. Of course infographics are not exactly the same as drug comparison charts but they may inspire designers in making those charts and graphs more compelling.

See the Alltop infographics listing here: http://infographics.alltop.com/

Or course you can also have a look at our “charts in ads” section in the AdPharm gallery. There you can find pharmaceutical advertisements showing charts, graphs or infographics in context.

Infographics in header from junkcharts

That’s the sort of thing. If you want a good example of this, take a look at Myotarg. Wyeth developed this oncology agent years ago for some forms of leukemia. It’s a monoclonal antibody to CD33 (a cell-surface receptor found on leukocytes), conjugated to ozogamicin, a fairly aggressive chemotherapy agent. It was approved back in 2000 under “accelerated approval” rules, which are supposed to bring drugs for life-threatening conditions to market more quickly. The requirement is that companies continue to study such drugs after they’re marketed, though.

Well, the studies have been completed on Myotarg. It’s not a very widely used drug, since it’s only indicated for people 60 and older with particular forms of leukemia who aren’t candidates for the more common therapies. But the numbers are in. . .and it turns out that while taking it than while taking the standard of care. Oh, dear. The drug has now been pulled from the market.

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Myotarg and the FDA

That’s the sort of thing. If you want a good example of this, take a look at Mylotarg. Wyeth developed this oncology agent years ago for some forms of leukemia. It’s a monoclonal antibody to CD33 (a cell-surface receptor found on leukocytes), conjugated to ozogamicin, a fairly aggressive chemotherapy agent. It was approved back in 2000 under “accelerated approval” rules, which are supposed to bring drugs for life-threatening conditions to market more quickly. The requirement is that companies continue to study such drugs after they’re marketed, though.

Well, the studies have been completed on Mylotarg. It’s not a very widely used drug, since it’s only indicated for people 60 and older with particular forms of leukemia who aren’t candidates for the more common therapies. But the numbers are in. . .and it turns out that people die more quickly while taking it than while taking the standard of care. Oh, dear. The drug has now been pulled from the market.

And there you have the FDA’s dilemma: if they had sat on Mylotarg longer and required more studies, this probably wouldn’t have happened. On the other hand, Wyeth might have decided to abandon it at that point – and not everything that gets accelerated approval is a Mylotarg. Some compounds that could actually help people could get lost that way. It’s a real tightrope, and the rope is set up completely differently for every new drug. There’s no way to get all these decisions right, but for life-threatening diseases, letting through more iffy compounds is still probably the right way to do it, I think.

Update: fixed all sorts of formatting and spelling issues, after taking a break from my real job to have a look (!)

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Mylotarg and the FDA

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Cease and Desist

Today, I want to share a personal experience.  Last week my team led an advertising shoot for a prescription product’s new multi-channel campaign we are intimately involved with.  There was much to feel good about – the creative idea tested very well and is strong. We also had a terrific creative and production team, a wonderful photographer who we’ve all worked with before, and we were shooting in a venue that turned out to be magical…not to mention the beautiful picture- perfect, dry sunny days … [How can you  complain about spending two days on an unspoiled 200 acre ranch in northern California?]

But as I flew home from the shoot, reflecting upon the previous few days, I kept feeling there was something even more special … something that I rarely feel after shoots … and then I realized …

Our work included real patients and in some cases their families as well.   We shot three different print executions using three different patients.  In one case, the mom brought her daughter who was not only proud of her Mom, but also proud to be photographed.

You might ask, what’s the big deal? As everyone knows, so often in branded consumer and healthcare advertising — TV, print, web etc., ads are created using models or professional talent.  Certainly, using real patients or ‘real people’ adds a great deal  of complexity and tension, as these shoots require much prep and planning, and have a sizeable cost … Using real patients means you’re never quite sure until ‘it’s a wrap’ — that you have captured the idea you are trying to communicate … It also takes more time and requires special artists and production types to work with real patients…

We decided to use real patients because the idea behind our ‘first person’ campaign  ‘demanded’ authenticity. Lest you dismiss this as just a current buzzword, keep listening. These are real patients who are living their lives to the fullest extent they can, and genuinely grateful for their prescription product’s ‘contribution’ to their improved health and QOL. Additionally, these patients were willing to step up and be photographed about a medical condition that is embarrassing to most and difficult to manage.  These patients weren’t participating in these ads because they were going to get rich (hardly), they were participating in my client’s campaign because they are thrilled to be living their lives in a fuller way -they had reached a milestone so to speak, and wanted to give back. They each stepped up in the hopes of leading others like themselves to try to get the right help for themselves (It may be this prescription product, or it may be another)… to help spread the word, and bring hope and attention to a medical condition that gets little attention otherwise…

Each patient joined in the production process…they were not just models that showed up for their ‘job’; they were on mission, … tasked to rise to the challenge of being center stage and photographed…something that none of them had ever done in their lives…and in itself a huge personal risk.  There were times that you could feel the wheels in their heads spinning, “this sounded like a good idea when I was in the comfort and safety of my home, but now that I’m here, this is more than a little overwhelming and scary …”

As a result, everyone on site joined in to support these patients to be able to do their personal best … It was also a continual reminder to each of us why we were at the shoot … certainly to capture DTC advertising and patient communications for our client, but it was more than that … we were there to shoot a new campaign that would  help the many patients with this condition that are still not feeling their best … to help spur and initiate awareness, education and dialogue so that these patients can participate in their own health decisions and have more enlightened discussions with their doctors … The vulnerability was gripping.  I’m confident that we at the shoot will not be the only ones to respond.

It leaves me wondering what the increasing use of using real patients will mean for “direct to consumer/patient” advertising and relationship marketing in the future?  Are we witnessing the birth of a new standard that will demand real patients who are advocates for themselves and others? … Who make a difference each day by being true participants in their health? Will consumers be touched by their ‘less than perfect’ delivery as actors and models?

I suspect this trend is here to stay. The pressure is on to “come clean” when the ad suggests that it’s a real patient and it isn’t (See the Abilify example).  There’s no faking ‘real patients’ who are actively participating in their health; time will tell what impact they will have on our industry going forward–and how they potentially transcend  advertising and marketing…

My heartfelt thanks to the three patients who made a choice to join us this past week.  I learned with each conversation, and I hope they learned a little too. I also made three new friends
See other examples of current DTC Print Ads Using Real Patients, click on image below

The press coverage of this compound has not been good. Far too many headlines have called it “Female Viagra”, which is ridiculously off-base. Viagra, for its part, does absolutely nothing for the libido; it’s plumbing, a pure cardiovascular effect. The assumption (a reasonable one, for many men) is that the desire is already there. Meanwhile, flibanserin is a central nervous system agent, affecting the mental state of sexual satisfaction, not any cardiovascular sequelae. The drugs are completely different.

And the FDA panel’s problem (one of their problems) with the drug was that it doesn’t seem to do much for desire, either. We can argue all day about whether low desire is a disease or not, but even if someone does want to do something about it, flibanserin doesn’t seem to be the answer.

Boehringer is taking a lot of criticism for bringing the drug this far, actually. It was originally developed as an antidepressant, but during the trials reports came in of the sexual effects in female patients, so they repurposed it – taking the drug out of a crowded field and into completely new territory. You can admire that as showing flexibility, or you can worry that the company found a possible drug and then went shopping for a disease, with a willingness to invent one if it didn’t quite exist.

I don’t know where I stand on that latter point; I’ve no idea what the statistics are on low sexual desire as a problem (and I’m willing to bet that what numbers might exist have whopping error bars on them). But I think that we’re not going to be revisiting this topic any time soon. The FDA panel officially encouraged Boehringer to continue research, but the vote tallies are not the sort of thing that would encourage anyone.

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Flibanserin: Not a "Female Viagra" At All

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The outcome is hardly surprising, given concerns outlined by FDA reviewers in briefing documents that were released prior to the meeting. The pill did show a statistically difference in generating sexually satisfying experiences compared with a placebo (read the report) – women reported an average of 4.5 per month compared with 2.8 before taking the pill, while the rate jumped to 3.7 for those on placebo.

But there was no statistically significant improvement on the co-primary endpoint of sexual desire as measured by diary entries. And there had been some to-ing and fro-ing over the diaries – the FDA required daily entries by women in the studies, but Boehringer provided monthly reports.

Meanwhile, the drug was only moderately tolerable, with nearly 15 percent stopped taking the pill due to possible side effects. The FDA reviewers also noted many medicines and medical conditions were excluded from the trial, suggesing it was not clear whether the safety and efficiacy data from the clinical trials could be extrapolated to the general population (read more). Hardly a selling point.

The run up to the meeting was characterized by a full-scale promotional push and heated debate over the validity of using medication to treat HSDD, which some refer to as Female Sexual Dysfunction. Some critics even question the extent to which HSDD has been legitimatized in the Diagnostic and Statistical Manual of Mental Disorders (more here). In any event, the FDA panel vote leaves US women without what some like to call a female equivalent to Viagra, at least for now.

She’d be interested in hearing from recent grads who have managed to find positions, those who are currently looking, as well as those who are technically working but underemployed. Her e-mail (de-spamified) is l-underscore-wang-at-acs-dot-org, or you can call her at 202-872-4579.

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Chemistry Employment in New England?

I have to say, I hadn’t thought of it in those terms. My first thought is that this is a negative event, something that didn’t happen, so it’s pointless to speculate about what might have been. But the author, Mike Mandel, is also talking about the opportunity cost of all the genomics frenzy, which is a real consideration. That time and money could have been spent somewhere else, doing something more useful. Where would we be then?

I’ve wondered about that myself, having seen first-hand what happened. Many companies really did cut a deep notch in their development pipelines during that era, abandoning (to one degree or another) their traditional approaches while piling resources into the genomics gold rush. (The current economic environment is cutting a similar gouge into the list of start-up companies – many of the ones that “normally” should have formed during the last couple of years just haven’t happened).

Mandel’s larger point, though, is something I’m not so sure about. He’s talking about all the manufacturing jobs that haven’t been created by the basic research, holding that these are the ones with real economic effect. But even if the genomics era had been wildly successful, we wouldn’t have seen manufacturing jobs picking up from it for some years – 2008, maybe? His charts, which tend to cover from the early 1990s to date, are reflecting other issues entirely.

Then the talk turns to balance of trade:

Now let’s turn to trade. China, India, and the rest of the developing countries sell the U.S. an increasingly diverse array of goods and services. What does the U.S. provide in return? There’s the usual list of suspects, such as commercial aircraft (which is increasingly drawing on parts made outside of the country). But they are not enough to avoid a huge trade deficit, even now.

The logical candidate for the next wave of U.S. exports should have been biotech products and knowledge. The U.S. is the acknowledged world leader; the research is expensive and lengthy; the production processes are complicated, delicate, require skilled technicians, and cannot be easily offshored. And the category–treatments to deal with major medical problems–is something that everyone wants.

But what happened? Without compelling new biotech products, the big pharma companies were “me-tooed” to death. In fact, pharma trade went from roughly balanced to a big deficit.

That’s illustrated by another chart from 1994 on. But what it’s showing isn’t what he thinks it’s showing. It illustrates the move to less costly manufacturing sites, which would have taken place whether genomics would have delivered or not. The only mitigating factor is that any big protein-based biologics would have had a better chance of being produced domestically, but production of all the small-molecule drugs that might have come out of the genomics frenzy would have migrated offshore just like everything else.

And what if the genomics revolution had delivered? We’d have a lot more drugs on the market, none of which would be selling cheaply, you can be sure – and there would be even more anxiety over the amount of our GDP going to health care. (Never mind that some of these drugs would, one hopes, be keeping people from going into even more expensive therapies later – people don’t seem to pay attention to that, either). So overall, I take the point about opportunity cost. But his broader economic implications, as least as regards the US economy alone, don’t seem to me to hold up.

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The Economic Impact of the Genomic Revolution’s Failure

So if you have some suggestions, hop over there and add them to the fray, or vote for the ones that you like so far. I’m racking my brain a bit myself.

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What Has Bioinformatics Ever Done For Us?

It’s interesting to compare that ratio to those found at other companies and in other industries. The rule of thumb is that a dollar of SG&A is worth three in revenue. The big drug companies look to have ratios of about 3.2 to 3.5 or so. For apples versus oranges comparisons, Pier 1 is at 3, Best Buy is at 4.2, and Dollar General is at 4.4. Tiffany is 2.4, and CVS is an impressive 7.1.

Another thing to check is the trend over a longer time period. This Nature Reviews article suggests (in its table 1) that the overall ratio for all publicly traded drug companies has been deteriorating slowly since 1975, going from above 3 down to 2.6 or 2.7. (And there are indeed some companies who bring down the average – Genzyme, for example, is at 1.9, partly because of its recent troubles, and Shire is around 2 as well).

Another interesting thing is how Amgen is included on the graph. Perhaps it’s an artifact, but what it looks like is that the company starts out like a high flier, and gradually sinks into the same mire as the rest of the big pharma companies. Parallels between that and Amgen’s real situation are, I hope, coincidental.

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Checking the Business Ratios

Amgen Inc. (AMGN), a biotechnology medicines company, discovers, develops, manufactures, and delivers human therapeutics based on advances in cellular and molecular biology primarily in the United States, Europe, and Canada. The company markets primarily recombinant protein therapeutics in supportive cancer care, nephrology, and inflammation. Its principal products include Aranesp and EPOGEN erythropoietic-stimulating agents that stimulate the production of red blood cells.

How valuable is the stock?

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Merck Layoffs – Underway?

The situation is different than for an industrial chemical shortage, like the acetonitrile crunch that we went through a while back (and which has long since eased up). It’s quite unusual for a bulk chemical like that to go down; several factors hit all at once in that case, and it affected an awful lot of people who needed the solvent. But fine chemicals are much weirder. When you trace some of them back to their real sources, you sometimes find that there are really only a couple of people in the world at any given time making some of these things. Or, in many cases, you find that there’s no one making it at all – someone made a bunch a few years ago for some reason, sold the excess to a supplier, and everyone else has been buying it from that same bottle ever since.

So when one of these small-scale itemsevaporates, the reason can be supply: no one makes it any more. Or it can be demand-driven: a single drug company’s scale-up group can deplete the world’s commercial supply of some strange little molecule when they suddenly switch to a 500-gram run. Everyone working in such a group knows to call all the suppliers when they have a prep calling for some weirdo starting material, and they’ll often take the precaution of ordering whatever’s out there to be had. (That serves as a cushion while they contract someone else to crank out a batch or figure out how to make it themselves). Naturally, you’d rather have your drug candidates depend only on things that can be ordered in tank car lots, but that’s just not always possible.

So it could be that someone needed a lot of (-) sparteine for an asymmetric synthesis recently, and bought up the existing world stocks. But this one sounds like more of a supply problem. There would appear to be customers out there, who have been draining the existing stocks, but no one’s been able to replenish them. TCI apparently stated that it’s the starting material for (-) sparteine that has become unavailable, but that sounds a bit funny, since it would surprise me if the material on the market is synthetic. Sparteine is a naturally occurring alkaloid, found in several species of plant, and it’s very hard to compete with isolation of the natural product in those cases.

Perhaps TCI means that the usual plant source is unavailable – that’s happened before, too. A spike in Tamiflu demand a few years ago suddenly sent the price of star anise up to record levels, since the chiral starting material (shikimic acid) in the usual synthesis was most conveniently isolated from that source. But for sparteine, it looks as if the isolation comes from plants in the broom family, which are not exactly rare shrubs, so I’m not sure what’s going on. Any ideas?

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Sparteine and Other Fine Chemical Shortages

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It was not too long ago that leading biotechnology companies fetched premium multiples to their large-cap pharmaceutical competitors. As the large, well-known pharma companies face many patent expirations in coming years, smaller and more growth-oriented biotech firms commanded both higher valuations and more favorable outlooks among investors. However, for some reason in recent months we have seen biotech stocks give up much of that premium. For the first time I can recall, many biotechs trade for below-market prices, in-line with slower growth pharmaceutical counterparts.

Here is a summary of some leading large cap stocks in both the biotechnology and pharmaceutical areas. You can see that the P/E ratios are very similar but the projected growth rates are meaningfully higher for the biotech sector, by a factor of nearly 5x. The only conclusion I can draw from this is that biotech stocks continue to deserve higher relative valuations, but for some reason Wall Street has lost sight of this recently. (Click to enlarge)

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But in general, lack of compliance in taking prescribed drugs is a pretty big problem. And fixing it takes more than exhortations or appeals to one’s better nature:

“We’ve made our best efforts to say, ‘If you didn’t take your beta blocker or asthma medicine, you have a greater chance of ending up with a heart attack or dead or hospitalized,’ ” said Dr. Lonny Reisman, Aetna’s chief medical officer. “It’s going to take more. It’s going to take incentives.”

I’m just glad that the insurance companies are taking the lead on this one. I can imagine the press a drug company would get for suggesting it.

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Paying People to Take Their Medications

On Tuesday, a letter went out to all of the university’s faculty members from the California Digital Library, which negotiates the system’s deals with publishers, and the University Committee on Library and Scholarly Communication. The letter said that Nature proposed to raise the cost of California’s license for its journals by 400 percent next year. If the publisher won’t negotiate, the letter said, the system may have to take “more drastic actions” with the help of the faculty. Those actions could include suspending subscriptions to all of the Nature Group journals the California system buys access to—67 in all, including Nature.

The pressure does not stop there. The letter said that faculty would also organize “a systemwide boycott” of Nature’s journals if the publisher does not relent. The voluntary boycott would “strongly encourage” researchers not to contribute papers to those journals or review manuscripts for them. It would urge them to resign from Nature’s editorial boards and to encourage similar “sympathy actions” among colleagues outside the University of California system.

NPG’s testy response is here, and this is the reply from California. The current points of dispute are how much the publishers are actually raising the prices (site license fees versus the base rate) and how much of a discount the UC system is getting already.

Could there really be a UC boycott? They’re large enough (and productive enough) to make that a reasonably credible threat. The Nature journals will certainly survive without submissions from the UC system, although over the last six years they’ve contributed over five thousand papers to them. But the real danger, I think, is the damage that this could do to Nature‘s position, and to the whole idea of the high-prestige journals. The scientific publishing world has been feeling the earthquake tremors for some time now. The traditional model (1. Start an academic journal. 2. Charge whopping subscription fees. 3. Profit) seems to be breaking down, in the same way that many other traditional content-distribution pricing models have been.

Nature and its related journals, along with the other top-tier publications, have managed to stay on top (and to charge accordingly). But journal prestige is an artificial construct, a fiction by common consent. A journal has a good reputation because it’s hard to publish in and can afford to reject all but the most high-impact papers that it’s offered. If people stop offering such papers to it, its prestige will decline. The big-splash papers will go somewhere else, and will perhaps manage to signal their importance in some other way than by the name of the journal they appear in.

This dispute will be worth watching closely. Which side will give in? Will a UC boycott be effective, and could it spread? Remember, from one perspective, other journals have an interest in seeing this happen, since they’ll now see the papers that NPG won’t. But they might also fear the same thing happening to them if this succeeds. . .

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California vs. Nature

The authors wisely refuse to take the data any further, and call for more investigation, which certainly seems warranted. The whole renin-angiotensin system is certainly involved in angiogenesis, and thus could very plausibly have effects in oncology. But the surprising thing is that there’s evidence that blockade of the receptors could actually cut down on tumor formation, too. If you’d taken a survey last week, you’d probably have gotten a lot of people to bet that these drugs would actually have a protective effect.

So what’s going on? It’s going to be quite a while before we find out. But an awful lot of people take these drugs, and now they’re all wondering what to do. . .

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Angiotensin Receptor Blockers and Cancer: For Real?

The recent market volatility has really beaten down some biotech stocks. With the S&P, Dow, NASDAQ, and Russell 2000 down close to 5%, with some wild swings, the selling had been vicious. It seems that biotech stocks have taken a disproportional beating over this same period, shedding their aggressive gains seen in the first few months of this year in a very short time. This global can be represented by the losses in more popular biotech ETFs over the same time frame: IShares NASDAQ Biotechnology (IBB) is down 11%, First Trust AMEX Biotechnology (FBT) is down 13% , and finally the Biotech HOLDRs (BBH) is down 15%. Apart from individual factors for each company, the market’s woes are what probably caused an unprecedented ASCO sell-off this year, with the most popular ASCO stocks shedding 20% or more within a few days.

What does this all mean? In a broad sense, nothing. Stocks go up and down for a variety of reasons, and what we have witnessed recently seems to be a culmination of overbought technicals, market conditions, cyclical patterns, ASCO, and the general summer doldrums. “Sell in May and go away”, they say. Although apparently exacerbated by the market’s troubles, this selloff should not have been a huge surprise: Many biotech stocks rise in anticipation of some key clinical data presented at ASCO, and tend to fade away when investors lose their enthusiasm. In fact, overall biotech stocks tend to have a cyclical pattern, where there is thought to be an established cycle to biotech where biotech stocks tend to rally in the last 3 months of the year (ending January/Feburary of the following year) and sell of slowly after that. An interesting analysis of this cycle is described here.

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It does make a person cringe to go back and read the press releases and speeches that were made back when the genome was first announced. How about Bill Clinton’s statement that the genome sequence would “revolutionize the diagnosis, prevention and treatment of most, if not all, human diseases”? Or Francis Collins, predicting “a complete transformation in therapeutic medicine”? He’s got about five more years on that one, but I’m not holding my breath.

As I’ve written here before, though, there was already a deep sense of nervousness among the people searching the sequences for disease clues – not to mention the nervousness among the people who had given them huge piles of money to do so. When the total estimated number of genes came out far lower than most people expected, there was a collective “Hmmm. . .” across the field. That number meant that the simpler possibilities for gene sequence-protein-disease linkage could already be ruled out – complicated things were clearly going on in transcription, translation, and further downstream.

That certainly doesn’t mean that genomic sequencing has been a waste of time. It’s been a tremendous boon, actually, because this complexity was out there waiting to be uncovered and understood. It’s no one’s fault that it hasn’t led to speedy drug discovery; biology isn’t set up for our convenience. And the further improvements that we’ve seen in sequencing speed and accuracy are going to be crucial if we’re to have any chance of figuring out what’s going on.

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Looking Back at the Genome

Comes now a highly placed pharma executive warning about America’s competitive edge in the life sciences:

The American pharmaceutical and life sciences industry is in danger of losing its edge in innovation, said John Lechleiter, chairman and CEO of Eli Lilly & Co. today at the Detroit Economic Club.

Lechleiter blamed the loss on tax and immigration policies over the last 10 years that have reduced research and investment funding and driven away foreign-born, U.S.-trained scientists.

Now, as regular readers know, I’m not an opponent of outsourcing. But you can’t have it both ways, sending as much research and development as you can to India, China, and what have you, and then complaining about the US losing its R&D position. Can you?

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Eli Lilly, Meet Eli Lilly. Topic: Outsourcing!

Now the Coalition Against Major Diseases has announced an open-access database of clinical trial results from failed drug candidates in the area. J&J, GlaxoSmithKline, Abbott, SanofiAventis, and AstraZeneca have contributed data from 11 failed drug candidates, and more look to be on the way from other companies. I hope that Eli Lilly, Merck (their own compounds and those from Schering-Plough), and Pfizer all join in on this – right off the top of my head, I can think of failed drugs from all of them, and I know that there are plenty more out there. (Pfizer seems to have dodged a question about whether or not they’re participating, to judge from that Wall Street Journal article linked to above).

It’ll be difficult to comb through all this to extract something useful, of course. But without sharing the data on these compounds, it would be utterly impossible for anything to come out of their failures. I think this is an excellent idea, and well worth extended to other therapeutic areas.

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Alzheimer’s: Extracting Data From Failed Trials