How to move forward - published results don't replicate

Powering better drug discovery research(ers):

Most people working in and around the pharmaceutical industry agree that it must become more efficient, more effective, and less costly.  How to do this is still being debated. One prominent view is to reduce internal research within larger companies, relying on academia and start-up companies to provide grist for the development mill.  Another view is that stand-alone pharmaceutical companies must retain strong internal research groups (see John LaMattina).  Both sides agree that a primary goal is to lower the cost of products going to the market.
There is little doubt that novel drug discovery must be grounded in unfettered academic-type research.  The question is how best to apply those findings to drug discovery.  I’ve written previously that a primary hurdle lies in the evaluation of which early stage findings to follow up on.  Academic research has no incentive to provide replication of findings or presumes that other researchers will provide for replication.  Those of us in pharmaceutical research know that replication of published biological results is not common.  This leads pharmaceutical researchers to using gut instincts, read subjective preferences, to decide which new ideas to follow up.  It also leads to hard feelings among academics about pharmaceutical companies. This real concern has recently been given quantitation (James Choi, The .Plan: A Quasi-Blog)); fully 2/3 of published findings could not be replicated! 
The situation makes it impossible for pharmaceutical companies to efficiently, cost-effectively, start drug discovery programs.  With the goal of containing the final cost of new drugs, dependent on the amount of money the company selling the product spent to develop it, pharmaceutical development companies simply cannot follow up on one-shot publication discoveries.  The hurdle posed by the irreproducibility of findings is compounded by the fact that non-replications, i.e. negative results, are extremely difficult to publish.  Information that a result cannot be replicated is primarily carried word-of-mouth and is not directly verifiable.  The presumption by academics that replication will occur elsewhere is, in reality, nowhere.
This reality means that the view that pharmaceutical companies should cut internal research and rely on discoveries from academia and start-ups can only come from people who have never attempted to discover a novel drug.  It is a dead-end approach.  It is true that development and sales companies cannot afford to add to the consumer price of drugs by footing large, permanent research groups.  However, they must have experienced pharmaceutical scientist-consultants who can, in their own labs or by contract, efficiently validate (replicate and more) novel ideas and findings.  However, even these groups will be overloaded by the number of novel ideas that ought to be evaluated.
Still, the bigger issue is how to breech the grand canyon between novel ideas and exploratory drug discovery projects.  One way novel ideas progress to a stage that they can be assessed by companies is for an individual scientist to start a company to gather more information about their idea.  Much money and other resources have been made available to facilitate this path.  There are at least two gigantic faults with this approach.  One, many excellent scientists simply have no interest in taking this route, preferring to continue basic research, teaching, etc.  Their ideas may simply be lost.  The other fault is that the academic scientists who do form a start-up must now convert themselves into pharmaceutical scientists, without training.  Notwithstanding that these scientists are all the smartest people in the room, the conversion to pharmaceutical researcher has as much to do with weltanschauung and experience as intelligence.  I conclude, simplistically, but truthfully, that this is primary a waste of time and money.  The graveyard of genomics start-ups is a testament to this opinion.  It is only the fact that these costs are not directly factored into the overall price of a drug that makes this a viable path.
Moreover, this approach distracts academics from their role of digging up new ideas.  And, the breech between academic ideas and pharmaceutical exploratory programs is, very often, a matter of whether to believe results are reproducible and generalizable.  Replication of results needs to become a standard expectation from academic laboratories.  Results should, first of all, be repeated by the original investigator/postdoc, but in a blinded fashion.  The dividends this will pay in the education of new investigators are enormous, if initially painful.  Secondly, someone else in the same lab (graduate student, junior postdoc) should repeat the findings, in a blinded fashion.  Again, this provides specific training to these less experienced researchers, as well as experience with equipment and procedures used in the lab.  If these two levels of replication cannot be met, the results should not be published. This scenario obviously leads to young investigators staying longer in their training lab, but the benefits that can occur – more time to learn how to write successful grant applications, taking on the role of lab manager and learning how to manage a lab, etc. – will pay off greatly in terms of new faculty better able to adjust to having their own position, their own lab, etc.
The gap between one-publication new ideas and exploratory drug projects must be bridged!  Pharmaceutical companies and/or NIH could form institutes whose goal is to replicate published results.  However, the multitude of new publications every day would quickly overwhelm such efforts.  Much better that young investigators and their lab chiefs, universities and journals, take on the responsibility of replicating their own results.  Huge benefits would accrue to the development of new drugs, and in increased trust and communication between companies and academic investigators.  In addition, I strongly believe that the lessons learned, and new wisdom developed, from the experience of non-replication will lead to tremendous progress in all of biological research.

Accuracy in advertising

Accuracy in advertising

Truth in advertising is an important requirement to help protect citizens from overzealous claims and characterizations of
products.  Potential customers must be allowed to judge their purchases against some objective standards presented in
a standard format designed to facilitate comparison.  Still, truth does not need to involve stunningly detailed accuracy in cases where the consumer is not the person who chooses which products to try and not try. I’m addressing television and radio ads for prescription medicines, ads that must provide a listing of most of the reported mild side-effects and
serious, adverse effects that have been observed in clinical trials and post-approval use.  The verbalized lists,
or even written ones presented over a few second period, are simply too long for a consumer to recall.  About seven
numbers is what most people can recall and that’s when they are attending.  After hearing more than a couple ads for
medicines, I’m very sure that the consumer is not specifically attending to the laundry list of side- and adverse effects, unless perhaps there is one they have had trouble with.  And what would consumers do with the list even if they could remember them?  Almost all chemical compounds can produce life-threatening reactions, allergic reactions if nothing else. Will a consumer not mention a new, to them, drug because the list contained life-threatening?  And, if they
don’t recall exactly what the conditions leading to life-threatening are, they are probably more likely to confuse rather than inform their physician.  In addition, I feel it is doubtful they would compare the list between possible medicines for their ailments, and such comparisons would be incorrect anyway because they weren’t (in most cases)
directly compared between products in a statistically relevant manner. 

In this case, truth is overwhelmed by detailed accuracy, in a manner largely useless to the consumer. It is useful to present approved medicines so that people can ask their physicians’ about whether ailments they have (seem to have) might be reduced pharmacologically and/or whether a new medicine might be more effective than ones they have been using.  But, the consumer does not, cannot, choose the medicinal product.  Only certified physicians can do that!  The physician must be allowed the data by which to make their own judgments about the usefulness of medicines for their patients, and which medicines are likely to be best tolerated by their patients’ with specific histories of diseases and concomitant medicine use. 

The FDA has, as always, erred on the side of safety.  However, advertisements for medicines aimed at general, non-prescribing, audiences are not made safer by listing all/most/many of the side-effects and adverse effects reported.  I fully believe that these listings are simply tuned out, and even if attended to, would be of little value to the potential consumer – the consumer is not the person who will, must, evaluate the product and make the choice to use it. 

Truth would be well served by carefully stating the use which the FDA approved, and not overstepping that boundary, coupled with a statement that one’s physician will judge the product against the side- and adverse-effects that have been observed in people and their relevance to a particular patient.  Advertising to the general public in no way reduces physicians’ obligations to make these choices.  They must consult with the patient to ensure they have considered the patient fully, but the patient does not have any right to self-prescribe prescription medicine.

I would prefer to watch the Super Bowl, for example, without hearing about nausea and drowsiness and whatever else has been reported.

 I am not the first to voice this opinion, and am not likely to be the last… still, accuracy can overwhelm truth in advertising, and in so doing, reduce the critical value of the truth.  And that's an important truth to tell.

National Center for Advancing Translational Sciences

National Center for Advancing Translational Sciences

Finally the wraps are off and we can assess how the Federal government intends to address the apparent – real – decline in the number of new medicines.  As presently configured, the pharmaceutical industry cannot support the cost and time required for new drug discovery.  Drug developers and manufacturers need an ally who can evaluate novel potential drug targets and provide enough information for pharmaceutical companies to invest in drug development.  This new Center sounds exactly like the right kind of approach.

In order for National Center the Advancing Translational Sciences (CATS?) to be successful, it must be able to take naked discoveries from academic investigators and fill out their resume enough that pharmaceutical companies can evaluate their feasibility as products.  This should mean taking scientists and managers, and leaders, who are already experienced in this art and putting them into this less financially volatile (hopefully) institute.  Who carries out this role now?   Who has experience?  Well, mainly a large number of un/underemployed pharmaceutical industry scientists and managers.

Will this new Center bring in these experienced professionals?  While this should be a no-brainer, I expect this new and critical part of drug discovery will be staffed by academic-type investigators. The only justification for this that I can imagine would be that the present process of drug discovery and development is wrong, broken.  I don’t believe this!  It is costly, time-consuming, and has a fairly low success rate, but much of that is because the end-products are ethical pharmaceuticals.  These require enormous attention to detail and to safety. As I’ve mentioned earlier, this is not, and I believe should not, be the main charge of academic research. Academic research can be non-generalizable (read, not reproducible) because its function is to stimulate further research, not make a product.  Furthermore, I believe that there are a large number of novel ideas, novel targets that could be worked on.  The bottleneck is providing tools (compounds)
and information (reproducibility, efficacy, safety, among others) in order for drug discovery and development to be objectively triggered.  I don’t believe it is reasonable to ask academic or internal NIH scientists to learn to become pharmaceutical scientists overnight, or even over a 5-10 year period.  Who will teach them?  Are they expected, allowed, to learn from personal experience?! Staffing this new Center with academic investigators and managers will also set the stage for a politically charged battle between this Center, claiming that it has great things for pharma to invest in, and the
industry saying that it doesn’t have the information it needs to start programs.  What will be next, a National Center for the Development, Manufacture, and Sales of Medicines?  Far-fetched?  I sure hope so.

One of the best things about staffing this Translational Sciences Center with a goodly percentage of pharmaceutical research professionals is that so many are currently very available…  They can probably be snatched up for 70-80c on the dollar…   On the other side, Federal stimulus funds have allowed many universities to hire more assistant professors and postdocs so that the academic community doesn’t have as strong a need for new positions.

I call for more pharmaceutical professionals for this important Center for another reason, success. The NIH Genome project was touted to provide a plethora of new medicines.  With the huge, possibly unnecessary, outlay of Federal funds, the medicines are yet to come.  Even at the time of the Genome project it was clear that determination of physiological function would be necessary in order to prioritize gene products as potential drug targets.  This type of effort was going on, slowly, in some academic labs, and, in a much higher throughput manner in some companies.  Belatedly, NIH started
programs like KOMP, the knock-out mouse project.  But, again, the reality is that huge sums of money were spent for KO mice that in many cases already existed, delaying any chances for success stories for years. Sure, there are lots of reasons for why NIH had to reinvent the wheel, but I maintain that those reasons were/are mainly hypothetical as no one –
almost no one – has worked with enough KO mice to understand the real hurdles.  If NIH, and friends, have to reinvent translational sciences, it is likely that a large amount of money will be needlessly spent, and the delay to real successes will be long. [As an aside, KO mice, mice in general could provide a very nice, and presumably less costly, vehicle for most pharmaceutical testing.  However, the industry is built on years of experience with rats.  Let NIH, and industry, work to either solidify KO rats as a general tool, or build up a large amount of disease model and toxicology data on mice!]

I fully believe in and support the need for a Center for Advancing Translational Sciences.  I only hope that it will provide answers and not just a call for a National Center for Developing, Manufacturing, and Selling Medicines in a couple of years.

Women's tears

Women’s tears

“I heard the news today, oh boy…”   We’ve all been affected by women’s tears.  I have to specify women because the recent study published in Science Express only involved tears from women.  The TV news reporter said that these tears
were a turnoff to men.  Turnoff?  Yep, make men less interested.  That didn’t resonate with me, so I looked at a few     write-ups about this study.  There the headline was that “Women’s tears lowers testosterone in men”.  That alters things a lot.  Still, a quote from one of the authors was that tears “was one way of saying ‘no, I am not interested.’”  Really?! If you, you man-thing, speak to a woman in a bar and she starts crying, you’ve probably got a lot more to worry about than her not being interested…  Or, in fact, that might be a good sign to crank up your protective, white knight skills – presuming that you aren’t the reason she’s crying.

My immediate thought is that this effect is more related to aggression, that tears may soften a man, reduce his aggressive behavior and thoughts, by reducing testosterone.  Testosterone is strongly associated with aggressive behavior and thoughts and so it makes sense to try to lower it for self-protection.  And, maybe turn aggression towards something
that is hurting the person crying.

So, these results are pretty exciting!  The results suggest that tears contain a chemical that can reduce testosterone levels, and possibly reduce or redirect aggression.  The authors’ mention using this chemical to reduce testosterone levels in conditions such as prostate cancer.  A worthy goal, but appears to overlook the direct effect noted in the study – reduction of sexual, aggressive arousal.  I hope that the industry will rapidly look to identify this chemical and evaluate whether it can be a lead to a new anti-aggression therapy.

As for the sound bites of TV news...  you get what you pay for.