Dong-A wants you to stay up,

if you know what I mean. But, I have to give them a heartfelt congratulations on their “positive results” for their new “long-acting” drug. I’m glad they met all their “endpoints.”

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Silver-tongued execs or gullible shareholders?

Somehow this just strikes a sour chord with me. I mean, any clinical trial in the development of a drug is a gamble. The odds are worse than high-stakes poker.

The kicker: Nuvelo expects further similar suits. I smell a rat.

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After that, you will die of a heart attack

I have no idea what this is all about. With 4 grams of transfat per doughnut, I think I’ll be gagging over the toilet rather than, well, just click the link.

h/t apostropher, who else?

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While I lay here sick, I speculate on the future of my industry

Of course we are all a bit concerned about job security. So it’s been with a bit of interest that I’ve been keeping an eye on Eye on FDA and other pharma blogs to catch up on the latest of drug development legislation, industry pipelines, and anything else that might affect the industry. Granted, I’m not as jumpy as drug/biotech investors, because I’ve seen enough about how risky trials are and know exactly how little I know about investing, and considering the minefield of insider trading, I keep out of drug/biotech stocks entirely.

The thing is, translating changes in the pharma industry to changes in the CRO industry (where I work) is not straightforward. Granted, CROs depend largely on pharma companies for revenue (and on government contracts for most of the rest), so the two are related, but few news analysts ever discuss how CROs are going to react to news about pharma. Needless to say, I’ve been a little nervous about R&D budgets. However, Steve Nissen Thomson Centerwatch seems to think that R&D job cuts in pharma are going to lead to more business for the larger CROs. That sounds nice on the surface, but I keep wondering what this will mean for the smaller CROs.

In the near future, I’ll probably continue with the light posting schedule. It’s probably time for a new installment of my review of Neil Miller’s book about vaccines.

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We have a new party in charge of the houses, and many have anticipated that this would bring changes in the way we develop and market drugs. And the potential is there. Eye on FDA summarizes new legislation.

Quick thoughts:

  • Kennedy-Enzi – yes, the FDA needs greater authority for post-marketing enforcement, and I’m glad to see it on the table. The “other things” might be worrisome, given this is a Kennedy bill.
  • Fair Prescription Drug Competition Act – not sure what impact this is going to have, except having a company have the 180 day exclusivity for a generic of its own branded product. That could be a big deal, keeping an effective 6 month patent extension. Other competing bills may make this one obsolete.
  • Stem Cell Research – I’m glad this one is passing.
  • Drug Expiration Date Study – I’m glad this one is passing. I don’t like the way we calculate shelf life right now. It’s what I call “voodoo statistics.”
  • Pharmaceutical Market Access and Drug Safety Act – drug reimportation. I think this one will make people feel good if it passes, but in the long run I’m not sure how much of an impact this one is going to make.
  • Medicare Prescription Drug Price Negotiation Act – probably a good thing for seniors. What remains to be seen is whether this is going to squeeze drug R&D. Looks like superfluous drug rep positions are going to be cut first, so maybe not.
  • RU-486 Suspension and Review Act – RU kidding me? A bunch of politics taking precedence over science and ethics is par for the course for this administration. I doubt it’s going to pass, either.
  • Counterfeit Drug Prevention Act – counterfeiting is getting to be a problem. Dirty labs, herbal medicines cut with non-quality-assured drugs, and similar issues are getting worse. Hopefully this will help some.
  • Preserving Medicare for All – gotta read this one first before commenting.
  • Generics First Act – you mean this is not already the case?
  • Cloned Food Labeling Act – Probably not a bad idea.

Please ILLUMINATE me on these questions

So, now that Pfizer has discontinued development of its star candidate, I have a couple of questions about this trial, mostly concerning the size of the trial.

Why 7500 patients per arm?

For example, this trial is sufficient to detect, with 95% confidence, an adverse event that has an occurrence rate of 1 in 2500 = 0.0004. Regulators want to see at least 1 in 500 from the whole development program for new families of drugs. Conservatism is fine and good, though this kind of data has been collected through post-marketing adverse event reporting and can be used, if needed, to discontinue marketing of a drug (e.g. Baycol).

On efficacy: this is sufficient to detect an effect size of 0.046 standard units with 90% power (the high end used in clinical trials). The standard deviation seems to be around 13 for males and 15 for females. So they’ve powered a trial to detect a difference of around 0.046*14*sqrt(2) = 0.7 g/dL of HDL cholesterol. Why do they need to detect a difference this small? Even without the mortality and cardiovascular adverse drug reactions, does the cost of taking this drug once a day merit a 0.7 g/dL increase in HDL cholesterol?

Now, Pfizer being the pharma giant that it is, I imagine it takes advantage of every discussion possible with the FDA to design its trials, and certainly the FDA had seen the design of this trial before it was executed. I’m very curious as to what was discussed when it came to sample size for this trial.

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Pfizer drops the bomb on investors

A mere 3 days after painting a rosy outlook for investors and talking about its “robust drug pipeline,” Pfizer killed development for its star candidate due to an unexpected number of deaths and “cardiovascular events” (usually heart attacks or other serious heart damage). This is the drug for which Pfizer released information about elevated blood pressure just a few months ago, and while analysts considered those dark clouds on the horizon, no one anticipated the clouds to grow to such monstrous proportions so quickly.

And, while I know no one likes to talk about the potential for hugely bad news such as this for their products under development, this news does seem a bit sudden.

Pfizer closed at 27.86 on Friday. Let’s see how low they go on Monday.

Update: Dr. Peter Rost comments, and doesn’t mince words.

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Other trends that affect clinical research

Lilly is “outsourcing”: jobs to India. This is nothing new; pharma companies often outsource their clinical trial operations and analysis, but what is interesting about this move (besides the fact it comes on the heels of a similar announcement by Novartis) is one of the reasons given:

bq. “The goal of our relationship with TCS has several dimensions beyond reducing cost and risk, including gaining access to a global talent pool, increasing flexibility and scalability of our resources, and maintaining a global workflow that is operational 24 hours a day,” said Dr. Steve Ruberg, Group Director for Global Medical Information Sciences at Eli Lilly, in a statement.

Not sure what Ruberg means by global workflow. It’s not like you can ask for a statistical analysis, have it performed overnight (like the analysis of X-rays like some Indian companies are doing), and have it sitting in your INBOX when you arrive in the morning. At least, not if you want some degree of confidence that your data is correct and your analysis doesn’t have any bugs.

However, access to global markets is a powerful motivator. Going with an Indian CRO gives Lilly immediate regulatory expertise in the region. Look for India and China to be hotspots for clinical research and development in the coming years.

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Tea leaf reading for clinical research

Now that the Democrats have taken over Congress, a lot of analysts (professional, amateur, and armchair) have tried to noodle out what this means for Big Pharma. And, of course, whatever happens to Big Pharma is going to impact what’s going to happen in clinical research.

“Forbes”: has examined “six pieces of legislation”: that Democrats are likely to push through. Some of these will involve sweeping changes, some may not be so serious. I’m going to take a stab at analyzing what these are going to mean to me as a biostatistician in clinical research, who sometimes does work for big pharma but usually for little biotech/pharma. In addition, there were additional bits throughout the article that deserve comment.

|*Legislation*|*Projected impact on big pharmaAccording to the Forbes article*|*Projected impact on clinical research*|
|Medicare reform|Could allow government to force lower drug prices|Shrinking budgets for Big Pharma will probably mean shrinking R&D budgets for large CRO(clinical research organization)s. This is less likely to directly impact smaller CROs, but the indirect impact will be felt. Given that Big Pharma is facing shrinking pipelines, they are looking to buy compounds or whole companies from little pharma. The smaller R&D budgets will mean that Big Pharma is more risk averse, and will probably want to buy compounds during Phase III trials rather than Phase II or Phase I. Small and agile CROs will be able to adapt to this environment rather quickly. The larger ones such as Quintiles or Kendle will have to adapt as well, and may find themselves in an uncomfortable position at times. However, it will merely be uncomfortable.|
|Drug importation|Probably minimal, but the industry would lose face|I see little impact|
|PDUFA reauthorization|A delay could slow the FDA; drug safety laws could be attached to it|Drug safety is a hard problem, and our ways of describing it are rather old. Legislation could either motivate biostatisticians to innovation for drug safety analysis, or simply require the establishment of more safety databases. It really depends on whether the emphasis of drug safety is placed solely on post-marketing, or on pre-marketing as well.

PDUFA will almost certainly be reauthorized in time, because the Democrats don’t want to be seen as being ineffectual as well, but if it’s not, it could put the squeeze on pharma and clinical research for an uncomfortable year.|
|Patent reform|Limits on whether big pharmaceutical firms can make deals with generic drug makers are possible.|This won’t have an impact on clinical research except through R&D budgets.|
|Medicaid reform|Many prescription drugs, like those for schizophrenia, actually have much of their market share here.|Again, this won’t have an impact on clinical research except through R&D budgets.|
|Enzi-Kennedy bill and competitors|May be attached to PDUFA IV, or stand on its own, or some combination of the two.|Several provisions stand out as impacting clinical research. Perhaps the most major is the possibility for a five-year post-marketing re-evaluation for all drugs. This may drive innovation in data mining of adverse events, or it simply may mean setup and maintenance of more post-marketing safety databases with some additions to a report each year. It will, however, burden the FDA with more reviews, and will definitely drive up costs. At any rate, CROs could either benefit if they position themselves correctly, or they will lose out because pharma companies would insource post-marketing safety and put a further crimp on R&D budgets.|

At any rate, shrinking R&D budgets are the major concern from my standpoint, because that’s what pays for my services. The trick is going to be embracing and adapting to the new drug development environment by using such initiatives as the Critical Path, adaptive designs, and the emerging pharmacogenomics efforts as well as designing new ways of describing and assessing drug safety.

One thing’s for sure. Drug development will be changing. The question is: will it be a source of adventure or fear?

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More autism news

Recently J&J’s Risperdal, a drug formerly approved to treat schizophrenia, was approved to treat irritability symptoms stemming from autism. A group has taken issue with the ruling, claiming that the risks (including the risk of tardive dyskinesia) outweigh the benefits.