I agree with just about everything you said in the last post. As for abandoning areas I’m not sure it’s totally due to M&S projections. I think at some companies some is due to look at how much we’ve put in over the past X years and do we see anything possible on the horizon. If not let’s focus elsewhere.

I agree with what you say in the last post about Sen Grassley’s aid. As I recall the news articles at the time said they had no known motivation. Personally when I’ve been out shopping and told clerks where I worked I literally became afraid because they took a header on the company’s stock when a drug didn’t pan out.

On the other hand nothing should be considered off the table especially when it’s clear that certain activities have foreseen consequences.

Violence like this is typically not done by companies. Why should they they have very effective tried and true ways of dealing with troublemakers. Why according to Peter Rost 10% of whistleblowers commit suicide. So it shouldn’t come as a surprise to top psychiatrists that if they are personally involved in activities to cause severe psychological stress to someone that they know has the propensity for mental illness that suicide has a much, MUCH higher probability. Plus we know that violence is really rare even in such situations, and when violence does occur it is typically turned inwards to self (suicide) or results in secondary violence to the person’s family. It rarely results in ‘going postal’ against the employer or coworkers. It fact it’s so rare that it typically makes the national and international news. Yet we simply don’t even hear about all the cases of suicide, and when we do we typically hear things in the press about, well he was under investigation… or that he was having problems (which might have been intentionally induces) but all of which implies that where there’s smoke there’s fire.

And you’re right - THAT is a development problem, not a discovery problem. However, though I have no hard evidence to back up this statement, I believe that most companies use the same kind of thought process demonstrated above in determining which discovery programs are “worthy” of funding. Marketing and finance have convinced many decision makers that they, using monte carlo simulations, have Delphic abilities and can predict future sales more than 10 years out. When Pfizer sent out its press release regarding DISCOVERY areas it’s abandoning, I couldn’t come up with any other explanation.

Re: Pharma and extreme measures - I didn’t know that the attack on Grassley’s aid was ever linked to any work activities. I don’t doubt that some rogues are capable of such things, but I couldn’t believe that the attack was in any way officially sanctioned (or even discussed). I’m pretty sure that these kinds of tactics are used by corporations overseas (in countries with lax criminal enforcement), but if anyone ever linked the two here, any corporate entity would surely go under and the people in charge would be spending substantial time in jail. Executives are often passionate about their jobs . . . but not that passionate.

You raise several points. As for being in high demand that’s not what I’ve found. You’re only in high demand if you toe the party line. If you speak truth to power, that power will try to utterly and completely destroy you. Look what happened to Senator Grassley’s aid during Vioxx someone stepped out the bushes when she got home beat her up with a baseball bat and put her in the ICU. If someone will do that to someone who’s so high profile and has connections then what about the rest of us.

As for bad management decisions, yes I agree there are many bad management decisions such as preemption, trying to completely take over the FDA, attacking anyone who tries to raise a safety issue, paying off KOL’s, etc.. However this does not get around the underlying problem and that is that the rate of growth people wanted was simply unsustainable (PERIOD). I think that perhaps an agreement of some sort to maintain exclusivity with negotiations for lower prices and with a slower decrease in price over time to maintain current levels of income without a patent cliff and then adding new drugs for the growth would have been a better strategy. However these problems go back to the 1960’s and even Senator Keafauer back then said that companies were gouging due to their exclusivity and this resulted in the move to generics by the late 1970’s.

As for other bad management decisions. I’m not sure you really get what the problems are in coming up with new drugs. (You talk about discovery but you include what I would consider development). The sr execs (even the business people) they see the problems from a range of different drugs and the same problems occur over and over again and so it becomes readily apparent that this is a much more basic issue of fundamental biology. So you can either deal with it honestly and either kill drugs and/or let people know so they can decide for themselves is it worth the risk or you can cover them up and kill people to maintain profits. But if you do the latter you won’t be able to maintain the ROI.

As for Vioxx I understand that these are extrapolations, but these are the numbers for deaths. As to MI’s and other serious cardiovascular events the numbers as I recall are in the 150,000 - 200,000 range. As for how many fewer people bled out, Merck did those studies using endoscopy. In fact that’s why they weren’t first to market, and you know what, they couldn’t find any decrease in bleeding out.

All this talk about risk aversion etc. I don’t buy it. FDA has been saying our job is to promote the public health by making drugs available. Who pushed that line? That doesn’t sound like risk aversion to me. Pharma says kill early or don’t kill at all. But what’s kill early and based on what? Instead it’s been let’s pull phase IV into the regulatory process. That’s simply another way of saying if we suspect a problem and then we see it in people well if we see some efficacy we’ve already put in too much money with so many drugs that don’t show efficacy so let’s get it onto the market anyway and we’ll worry about covering up later. Another way of saying this is that kill early might imply to some people that it’s let’s not kill things in phase III, but in my experience it’s gotten so that really nasty things are showing up early in Phase I and companies are simply going ahead anyway no matter what.

Just look at the FDA Amendments Act of 2007 it mandates looking at class effects and keeping a drug on the market because someone may benefit. In the past we’ve seen what Pharma does delay, delay, delay. At the same time Pharma has been pushing preemption.

Let Pharma put all the cards on the table as to the real risks (i.e. actually give the information to FDA like they’re supposed to, have real public hearings, allow publcation of the FDA submitted data along with honest analyses by both Pharma and the FDA) and then let the public (patients and unbought physicians and academicians) weigh in and decide for themselves. Finally let the courts decide if Pharma was really forthcoming with the risks or not. I’ve said it before I don’t want to kill Pharma, but we’ve got to have some measure of honesty with people.

This is a highly regulated industry for a reason. Instead Pharma has acted to completely takeover the FDA and remove all regulation except what they believe they want to live with and will help them competitively.

Lastly we need to put people in jail. In particular those in the FDA who have violated the law. Because if we don’t have some level of confidence in the FDA which Pharma has currently nearly completely taken over then no one is going to or should trust anything Pharma says.

And are you sure that Graham was talking about deaths caused by Vioxx, or was he talking about MIs? In the studies, there was an increase in MI risk, but a less substantial increase in risk of death due to MI.

Though the GAO numbers (and at this point, I’m not sure how they included/excluded raw data in their analysis) are different from the FDAs numbers (raw, I believe), the current status of the pipeline of almost every major drug company demonstrates, at least in part, the inefficiency built into the system. I personally believe that the inefficiency results in LARGE part from the one factor mentioned in the GAO report that wasn’t discussed in great detail — bad management decisions. This factor is influenced by the other factors mentioned, but it is the most proximal cause of the problems we currently see.

So it is discovery — but it’s not the people in discovery who fail to accomplish the goals of discovery. It’s the people who direct discovery. Direction has been so limited due to financial constraints that the kind of innovation seen in decades past hasn’t been seen recently. For example, it was reported here that Pfizer, one of the biggest players in the cardiovascular market, is GETTING OUT of the cardiovascular market. Have we solved heart disease . . . or is it just no longer a low hanging fruit (from a financial perspective). I think Pedro Cuatrecasas is absolutely right. Risk aversion WITHIN Pharma is inhibiting those trying to engage in drug discovery–to the detriment of the entire industry.

I found the GAO report and yes I’ve read it before. The figures are somewhat misleading and don’t even match FDA’s own numbers on their web site.

http://www.gao.gov/new.items/d0749.pdf
http://www.fda.gov/cder/rdmt/cyactind.htm

For example commercial INDs have were flat from 1993 to 2000 then have risen by 68% from 2000 2006, and there is a lag from the time you put money into discovery until an IND is filed. However according to the GAO report the increase is 38% in INDs from 1993 to 2000 and R&D spending is a 147% increase. So there is a disconnect but not as quite as bad as the GAO report makes out.

Also if you actually go and plot the numbers from FDA from much farther back it’s really a linear increase overall since the 1960’s. By choosing to start at 1993 you actually are seeing the effect of the increased rapidity of approvals and the hurry up and submit a lot of stuff right away because of PDUFA that occurred in 94 an 95 and that resulted in a whole bunch of drugs being withdrawn from ‘95 to ‘97.

It also talks about Pharma tackling more complex diseases where the cost of development is higher (Cancer they mention and Psych which I mention) both of which are where we see the greatest numbers of INDs and NMEs.

Regulatory uncertainty, well part of this is we’re trying to hide something and we’re not sure if we’ll get caught or not which will make us go back and do more work.

Business decisions they mention but don’t really explain.

My favorite about not knowing how to develop drugs is:

“the inability of drug sponsors to effectively utilize new technologies and a shortage of highly trained researchers who possess the ability to effectively translate basic discoveries into new drugs, were seen as factors that further contribute to the increased clinical failures and costs.”

“translational researchers—who possess both medical and research degrees and thus the expertise needed to translate discovery-stage research into safe and effective drugs—was seen by panelists and other experts as a fundamental barrier to increasing the productivity of drug development.”

I agree wholeheartedly with this but then that’s what I do and people refuse to listen to me on the drugs I work on. Maybe if they did they might get more drugs approved, because I usually turn out to be right about what’s going to kill the drug and I often have ways around it. The problem is that my suggestions might limit sales and some people can’t live with that.

I say it’s better to have 50% of something than 100% of nothing.

55,000 was an earlier number that was reported in an article on CNNMoney.com on Feb 9, 2006.

I have heard/read some of those articles but haven’t looked in a long time. Plus it’s not my area of expertise. I had thought that ref 1 had been severely criticized.

I’m not in drug discovery but I sure wouldn’t want to be. It’s got to be the toughest area of all.

It’s easy for business people, even scientists farther down the line, and even patients who complain about me toos to complain about discovery. If discovery doesn’t listen to people further along I would assign blame to discovery but most of the people who complain that companies aren’t coming up with new drugs simply don’t know what’s the real basis for the difficulties in doing so are.

Everybody likes to blame someone and it’s easy to blame someone who can’t come up with something new because the biology, chemistry, or physics simply prevents it or they like to blame the person who points out real safety issues.

It’s a tough business and sometimes it’s just not possible to get something to work no matter how much money you throw at it.

I and many others hope that we will see a turnaround in discovery when there are lots more targets to go after due to better understanding of genetics and post gene modifications.

Pharma says that will happen in the next 4 years. Maybe but from publications I would think it’s going to be more like 10 years.