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Saturday, June 29, 2013

Rethinking Researcher Education

Gertrude Elion won the Nobel Prize in Medicine and Physiology in 1988. After obtaining her Masters in Chemistry she worked as a secretary and a non-paid substitute teacher. Eventually she landed a research position fully putting her education to use. The education however, was merely information used to aid Gertrude on her journey to discovery. The education was a tool. Initially she was unable to pull that tool out of the toolbox to land a job. As a tool in landing a research position, it was like using a screwdriver to hammer in a nail. Those who evaluated Gertrudes ability and personality missed her Nobel Prize winning potential. Luckily for the human race, someone eventually recognized what Gertrude had and she was allowed to conduct research.

It is thus important for the researcher to find him or herself in that place of integrity, as Feymnan wished. It is not always easy. Gertrude grew up in an era where women were looked down upon in the work force, especially in the sciences. Women were secretaries and kindergarten teachers (not that there's anything wrong with those jobs). Gertrude undoubtably applied for many a position in research after obtaining her M.Sc. People in the position to hire her did not see her potential. I would suggest that even today, without the sexism, people in the biotech/pharma world have no way to spot that caliber of mind.

In todays world, Gertrude Elions Master degree would put her below the likes of Silvia Bulfone Paus, Phd. The two computer searchable terms, M.Sc. PhD., put Silvia Bulfone Paus ahead of Gertrude. Silvia however, is a known Cargo Cult Scientist, a non-searchable quality. Gertude had a non-searchable quality. All the HR gals and their computer programs in the world could not run a search discover a Gertrude Elion. 

 Douglas Prasher is an example of an individual having a difficult career in spite of Nobel Prize worthy research. He found himself in more than a few "wrong places". He did the reverse of Gertrude and went from researcher to menial task employee, driving a courtesy van for a local car dealership. The low level government employees that Prasher worked for did not see in him what the two individuals who won the Nobel Prize (based on Prashers cloned protein) had seen. Prasher was capable of research but was in the wrong place. His work spawned a multi-million dollar patent, hundreds of jobs, a powerful research tool and two Nobel Prize winners. He drove a courtesy van while all this was taking place.

Research cannot be measured hourly. The value of a person with a M.Sc. who runs the HPLC QC team at Trustus Rx. can be measured by the hour. Each hour of their work life that ticks away is just another stack of paperwork that is required by the FDA. Someone has to do it. The researcher is different. They might be working on the foundation of a skyscraper of an idea. Not everyone can see that foundation. They are the kind who look up to see the finished product. They do not know what holds tall buildings up. 

The latest suggestions for improving innovation and creativity from industry leaders:

... how best to innovate, and how to do it more often and efficiently, is top of mind for executives at many large corporations.
Constructing Innovation Supply Chains for the Pharmaceutical Industry - Noubar B. Afeyan, Venture Capitalist at Flagship Ventures
The innovators should be working closely with the acquirers from the early days, getting regular feedback. The pharma company can provide what Afeyan calls "Darwinian pressure" to force the startup to run the key experiments needed to prove the value of their idea, rather than simply guessing what the pharma companies want to see.
A Biotech Innovation Supply Chain: Reality or Fantasy? - Luke Timmerman, Bio/pharma Cheerleader, Xconomy 
Drug companies often lament that the firms from which they are sourcing innovations do not perform clinical trials to their specifications, forcing them to repeat the work. Nevertheless, they are reticent about providing such specifications in advance – even when innovators request them – perhaps to protect their market position or internal efforts. Moreover, the same companies compete directly in the supply of innovative technologies. The result is a broken supply chain. 
Fixing the Innovation Supply Chain - David Berry, partner at Flagship Ventures

While each thought-leader has ideas for fixing this broken system, they have each left out the notion that they themselves are in the position of their predecessors who had the option of hiring Elion or Prasher. Rather they focus on the innovations, they successes that come from people they have yet to find. If the innovators they speak of continue to fit in the usual mold, PhD, Ivy League school... you fail to acknowledge the biases that get in the way. Gertrude was a woman. Prasher went off to work for fools. How can the leadership wade into a pool of unconventional candidates and find the people who are creative?

Formal public education began in the early 1800s to create workers for the industrial age. Currently, our education system continues to churn out potential workers, innovators, and the geniuses who put it all together. We now have a good assessment of how the system is working. Each company is a mirror of the education system. Often PhDs will serve as the "dissertation committee" that judges the work of the B.Sc. lab staff, just as they were judged as grad students. They all thrive for a consensual approval. Yet the consensual approval, that leads to publications in grad school, needs to be put to the test of developing technology. In other words, innovation is suppose to be the end product, not a published paper that no one will read. It is thus the education process that tends to teach that the end product is a piece of paper, be it a diploma or a published paper. Innovation is different.  The education is a tool for the individual to use to apply to research. Innovation requires a highly engaged workforce, free to be creative, constantly learning new techniques and skills. Research is different than those who work on a conveyor belt, churning out a product they hope will be accepted by executives and venture capitalists.

They say in computer science, a degree above a bachelors is not important. The education for the work and the innovation comes on the job. Education only provides you with the tools to get started. It's up to the individual to know how to use those tools. That is currently not the case in biotech/pharma. The leaders are not using any scientific tools to spot the talent. In the case of Gertrude Elion, that gap in science employment, post graduation, would have kept her from obtaining a job in 2013 just as surely as being a female kept her from a job in 1940. We have many rules and ideas in selecting who gets to shine and who gets to drive courtesy vans. We have HR gals scanning resumes with software tools. They aren't working. It's time we study what has worked and see if we can find a new way of learning how to innovate. In time the innovators will teach the VCs and executives how to spot talent. 

Monday, June 24, 2013

Breast Cancer Profiteer

I want to revisit the roots of this blog. What made me go crazy and start this thing? I make the claim that my biotech career resembled a Cargo Cult. We only pretended to do scientific research. Our hands were tied by the narratives of our leaders. Here is a specific example of a leader who defines Cargo Cult leadership.

Back in 2007 a little Cargo Cult company called Nastech was almost single handedly dismantled by the leadership of a megalomaniac CEO. Steven Quay can be heard here.

Nastech went on to tank, giving rise to MDRNA then Marina which is now a penny stock with one employee. Dr. Quay disappeared but came back with a new company Atossa. The company consists of a  breast cancer screening device that sucks fluid out of the breast through the nipple. The fluid is then sent off to test for breast cancer bio-markers. The FDA has a few things to say about the progress of the new company.

The warning letter from the FDA highlighted a few issues that resemble some of the observations I have made regarding Cargo Cult leaders. Take the first issue:

1.      Failure to establish and maintain procedures to control the design of the device in order to ensure that specified design requirements are met, as required by 21 CFR 820.30(a). For example, (b)(4), your firm’s Regulatory Consultant, indicated that you have not established design control procedures for the MASCT System.
We reviewed your firm’s response and conclude that it is not adequate.  While a procedure titled SOP-007, Design Control for the MASCT System was submitted in the response, no evidence of implementation or training on this procedure was provided. In addition, you did not provide evidence that you retrospectively reviewed all devices to ensure they had design control procedures in place as required for all devices.

When working for Dr. Quay it was clear that he had little interest in these kinds of details. He was a big picture kind of guy. Yet, as you can see, the very product that is intended to be sold seems to be an afterthought. Start company, get rich, design product as you go along. Maybe someday it will work as advertised. Which takes us to another claim from the warning letter:

Our inspection, and subsequent review of your websites and determined that your devices are misbranded under Section 502(a) of the Act [21 U.S.C. 352(a)] and within the meaning of 21 CFR 807.97, in that your websites contain statements that create an impression of official approval of a device due to clearance of a premarket notification submission. 

Imagine trying to follow the "bend over backwards" kind of honesty depicted by Feynman while working for this individual. 

One humorous side story related to the FDA warning letter: Dr. Quay was once a heavy set man. He embarked on a weight loss plan that involved the use of Equal in his coffee. He was the only person to use the Equal because people were afraid of him and they didn't want to get caught using up all of the Equal. Dr. Quay used the opportunity to spread fear among his subordinates. He let the Equal run out. He immediately notified several C level executives and their direct reports. Meetings were held and plans were put in place and an SOP was written to ensure that Nastech never ran out of Equal again.

Which brings us back to what a Cargo Cult is. If the issue is about a product that is of value to the leader, that issue will be dealt with in great detail. Much ado will be made. But if the product is the cargo promised by the Cargo Cult, not much happens. The leaders don't need the product as much as they need the narrative. In this case, Atossa has what the FDA considers to be a fairly flawed breast cancer testing device. The understanding of what goes into such a company, (engineering and FDA regulation issues...) is about as complete as the understanding the Cargo Cults have regarding airports. 

We jokingly referred to the Equal incident as Equalgate. It became an example of the emphasis placed on silly things, while research projects received little attention. It is not surprising then for me to read the FDA warning letter and see that some things never change. Dr. Quay started a new company with a new narrative. The FDA pulled the curtain back on the Great Wizard of Atossa. Behind that curtain was a man who knew very little about his breast cancer product, but at one point in his career had an SOP written, distributed among the highest ranking members of his staff, and followed to the letter, so that he would not run out of Equal. It's not clear what motivates such a man but his tactics are predictable. There is little pride in the quality of the product but great pride in the power of running your own cult. 

Wednesday, June 19, 2013

AstraZenecas Next Four Years

AstraZenecas new management team has made their decision on where to work to turn things around. They've even come up with a few specific ideas on what the work will involve. The new R&D and corporate HQ will be relocated to an 11-acre spread at the Cambridge BioMedical Campus. That's the where. How much? $500 million. How long? They plan to have the place done by 2016. The big question is how they intend to turn their ship around and build a brighter future. 

The first thing that will happen will be the elimination of another 700 jobs. In the recent past they have shed a lot of unnecessary workers. 1200 jobs were lost in Wilmington DE back in March. A few days after this announcement the total amount of jobs to be eliminated by 2016 was reported to be 5,050. One has to wonder what so many people were doing that no longer needs to be done. Those who survived the cuts will be moved around like chess pieces. From Fiercetech:

Soriot is moving R&D workers from the company's big facility in Alderley Park to Cambridge so they can get closer to the cutting-edge scientific work being done in the hub. And Soriot has been moving other pieces on the global R&D chess board as well, concentrating efforts at Medimmune in Maryland and in Sweden as well.

No matter where you go, there you are. What has really changed? The proximity to "cutting edge scientific work" has always seemed unnecessary. If an HPLC can quantitate the amount of a protein in a cell supernatant in the U.S., it can do the same thing in China. What matters most is the technology transfer skills of the workers, not their location. With computer technologies in fact, methods can be e-mailed, loaded into the HPLC and ran immediately. The only issue is the physical transportation of the material to be tested.

But that is only a small example. Perhaps the cutting edge technology they speak still requires leading researchers to be in close proximity of one another. I'm having a hard time remembering who set the precedence for this but perhaps this will work. We can however take a look at another aspect of the AZ plan that may not pan out, based on the news of this past week. Part of the new plan will involve acquisitions such as the purchase of Pearl Therapeutics ($1.5 billion) for their COPD pipeline and Omthera's omega-3 cardio program for $443 million. Acquisitions are a gamble. Acquiring rights to other peoples candidates in not far from giving the green light to your own ideas. Most often they all come from basic research that someone else started. Fostomatinib, a tyrosine kinase inhibitor, recently failed in clinical trials to help RA patients. Today AZ announced the end of the line for their type II diabetes candidate Onglyza. 

Part of the reinvention of AZ is to focus acquisitions on certain areas, cardiovascular and metabolic medicine, oncology, and respiratory and inflammatory drugs. Already we see this plan failing. Perhaps the people working on the project were located in the wrong part of the world.

"We will have people based here (Cambridge) potentially at the end of the year and we will start benefiting from the location," Soriot said.
Damn it Cargo Cult Scientist! There's that snark again. You have to give them a chance. 
"You've got to look at this over a horizon of three to four years, it is not a six-month horizon," Soriot said in a telephone interview from Cambridge. "And it is not going to be a smooth journey. We will have ups and downs."

Not five years? Three to four years specifically? Which drugs will get approved during this time? If it takes up to ten years or more to get a drug approved one would have to assume that the drugs that will turn AZ around in the next three to four years began their lives in a different location. Along with the people starting to benefit from the fresh Cambridge air, they had better get these drug projects moved? 

It's Cargo Cult business as usual. Layoff a whole lot of people. Close down sites, restructure the hierarchy, focus on the usual high profit disease areas, and promise to get things turned around in a few years. "We will have our ups and downs." Lest you thought it was all downhill from here. Of course we think of it as a large Cargo Cult Airport. Rearranging the people, the location, the projects are old ideas offered up by the same guys. The new AZ CEO, Soriot, came from Roche. But he is new to AZ. The R&D and corporate HQ are new. The old pieces have been rearranged to appear new. What has really been done scientifically to bring about change? The cults have been looking to the skies for cargo since the Allied forces packed up and went home. Something is still missing.

Tuesday, June 18, 2013

Allopathic Medicine

Allopathic medicine is an expression commonly used by homeopaths and proponents of other forms of alternative medicine to refer to mainstream medical use of pharmacologically active agents or physical interventions to treat or suppress symptoms orpathophysiologic processes of diseases or conditions.

The ability to conduct blinded clinical trials comparing a diet and exercise interventions to pharmacological interventions is not possible. The paradigm of allopathic single cause disease research culminates in clinical trials that compare the effects of real or fake pharmaceutical products. The diet and exercise method of treating illness does not fit this model. Nonetheless, we have several extraordinary claims of diet and exercise being used to cure disease. What prevents us from scientifically designing experiments to compare behavioral changes in diet and exercise to pharmaceutical interventions?

Of course, the first thing to note is that there is no money in getting people to become and remain healthy. It would be like asking the oil industry to try and get us all to drive electric cars. That doesn't mean that there is no money in health. We know there is profit in sickness. That is where going down the wrong path, single cause witch hunts, can be best for sickness profiteers. There is a bias not only exhibited by pharmaceutical executives but among scientists as well. If you are going to have a career in biochemistry or medicine, wouldn't it be easier to spend it looking for single causes? Gene hunters and medicinal chemists alike need to live in a world where their efforts will one day be packaged into a pill and sold to the sick. What kind of a scientist then would want to learn more about health and how we can eat, drink and exercise our way in and out of it? 

The study of health, what constitutes a healthy person, has led us to set standards for blood pressure, cholesterol levels, blood cell counts, and so on.  Doctors from the dawn of time have claimed to have a superior knowledge on how to quantitate an individuals health. They put their patients through a battery of tests based on their complaints. The degree of their disease state is summed up which leads to the treatment plan. Currently that most often means pills will be prescribed. Using the scientific wisdom of the pharmaceutical industry, the doctors prescribe the dosage. If the patient gets sicker the dosage is changed. If they get better they stay the course. If they die they must have come too late. 

If doctors can make these kinds of assumptions, why can they not assess the efficacy of a change in ones diet and exercise? 

It comes back to the Drunk Under the Streetlight effect. Doctors and medical science have found the easiest place to look for answers. The complexity of the body and what happens when we eat fruits and vegetables versus Twinkies is too hard to follow. Instead we offer monoclonal antibodies and follow a small set of biomarkers. Much easier. Unfortunately, the answers they are coming up with are not making the population any healthier. Conversely, the fast food and lazy lifestyles are definitely having an adverse effect. Since food and drink is put into the body, just as pills are, why can we not quantitate their effects like we do drugs that have only a miniscule effect at best?

I once worked for a company that claimed their pill reduced tumor size by 57%. That is pretty specific. Why have we never seen a pill get rejected but the methods of evaluation get moved up the ladder? When this particular drug product, an antibody against denatured collagen IV, crashed and burned, so did the methodology of evaluating tumor reduction. It was as if they had created a special tool that only works on their widget. Yet cancer is not the property of any biotech/pharma company. Why so many different protocols? We somehow have come to the conclusion that the drug industry, in conjunction with the FDA, employs a scientific method. A method, by the way, that cannot evaluate diet and exercise change.

The people who advocate diet and exercise as medicine do not get the same respect because they are somehow different. They don't have a single cause/cure disease narrative. They simply claim that a disease state is most often entered into by poor behavioral choices and exited by making better choices. 
Much like a religion, the pharmaceutical industry and the FDA have decided on an easy to follow narratives when designing answers. Feynman on religion:

"God was invented to explain mystery. God is always invented to explain those things that you do not understand. Now, when you finally discover how something works, you get some laws which you're taking away from God; you don't need him anymore. But you need him for the other mysteries. So therefore you leave him to create the universe because we haven't figured that out yet; you need him for understanding those things which you don't believe the laws will explain, such as consciousness, or why you only live to a certain length of time -- life and death -- stuff like that. God is always associated with those things that you do not understand. Therefore I don't think that the laws can be considered to be like God because they have been figured out. "

We haven't figured out the complexities of the human body and how diet, exercise and pills truly alter the path of our health. So we have the pharmaceutical industry that is based on taking the hard sciences of math, physics and chemistry into the soft scientific world of medicine. The foundation of the entire industry, one disease, one molecule, one metabolic pathway and one API, active pharmaceutical ingredient, is the doorway into which we enter the Cargo Cult Airport.

Monday, June 17, 2013

How To Succeed in Research

Watch this TED talk on memorization:

We can memorize faces, words, numbers... The important thing to note is that we aren't learning about faces, words or numbers. We are learning about memorizing.

What happens at an R&D group in biotech/pharma? People are hired to do research. They do research on IL-15, TNF alpha, HIV... How much time is spent learning about IL-15, TNF alpha, or HIV and how much time is spent learning about research?

Can we teach research like we can teach memorization? Has anyone in modern times written a manual on how to conduct research? Feynman himself admitted that we don't actually teach people how to conduct research.

But there is one
feature I notice that is generally missing in cargo cult science.
That is the idea that we all hope you have learned in studying
science in school--we never explicitly say what this is, but just
hope that you catch on by all the examples of scientific
investigation. It is interesting, therefore, to bring it out now
and speak of it explicitly. It's a kind of scientific integrity,
a principle of scientific thought that corresponds to a kind of
utter honesty--a kind of leaning over backwards. 

This TED talk on memorization demonstrates that average people can become better equipped at utilizing their minds. Drug developers, in my opinion, are average people. They tend to look at their education and experience as the thing that makes them superior at conducting research. Yet who among them could give a TED talk on the process of conducting drug research? Are we, as researchers, as smart as we think we are? Can we learn to be smarter? Why are we so often thrown out like a baby with the bath water? A daily perusing of the website Biospace will give you an example of what I'm talking about. 

Merck & Co., the second largest U.S. drugmaker, plans to cut jobs at it's research laboratories. 

No value? Not worth saving? Why do so many research teams suffer this ending? Is it just inevitable?
Gather all of the unemployed, turn the hierarchy upside down and make this group of people write a manual on how they conducted research. Not on what they learned, but how they learned.

Saturday, June 08, 2013

Avandia and the RECORD Trial Saga

Behind every great fortune lies a great crime. - Honore de Balzac

We are coming up on the one year anniversary of GlaxoSmithKline agreeing to pay a $3,000,000,000 fine for promoting its best-selling antidepressants for unapproved uses and failing to report safety data about a top selling diabetes drug. One of the antidepressants, Paxil, was the subject of Alison Bass's "Side Effect", A Prosecutor, A Whistleblower, and A Best Selling Antidepressant on Trial. Avandia, once the best selling oral diabetes drug in the world, was another piece of the GSK crime that built a great fortune. GSK hid safety data that pointed out serious cardiovascular risks. Nearly one year after GSK confessed their sins and agreed to pay the U.S. $3,000,000,000, an FDA advisory board has convened to reconsider their 2010 conclusions on Avandia.

Why? Steven Nissen has some interesting thoughts on the subject. 

In 2005 and 2006, GSK secretly conducted an analysis of the cardiovascular safety of Avandia and concluded that the drug increased the risk of heart attacks and related events by about 30%. This observation had grave implications: two thirds of diabetics, the intended recipients of the drug, eventually die of cardiovascular complications.
Cardiovascular side effects for pills given to a patient population where two thirds die of cardiovascular complications? Hiding something like this is one hell of a crime. It is ironic then that Paxil and Avandia made up only one third of the $3,000,000,000 fine. $2,000,000,000 in fines stemmed from a civil settlement over the sales and marketing practices from the asthma drug Advair and other drugs. What kind of an evil organization are we dealing with here?

The FDA and the CDER were created to deal with such problematic organizations and the harm they will inflict on us if we don't regulate. Unfortunately, in this case, it appears as though they decided to think of their own careers first. As Dr. Nissen points out:

In the middle of the sequester, CDER is willing to spend a large sum of taxpayer dollars to conduct a 2-day advisory meeting on a drug nobody uses, for the sole purpose of absolving its own bureaucracy of responsibility for a terrible drug safety tragedy. 

We have anti-depressant pills that come with a side effect of increased risk of suicide. We have diabetes drugs that put an already susceptible population at greater risk for having a heart attack. These are products from people who are suppose to be helping us. They have to gain approval through the agency that we put in place to prevent them from harming us. How does any of this happen?

In their response to the article written by Dr. Nissen, the FDA only explained why they did not invite him to speak. They failed to address the hard questions stating only:

FDA staff reviewed Dr. Nissen’s proposed topics and concluded they did not warrant a slot as an FDA guest speaker. The content of his proposed topics is expected to be covered by other speakers as agency staff plan to summarize the available data on the cardiovascular safety of rosiglitazone at the committee meeting, and multiple FDA speakers will address their review of the readjudication of RECORD trial based on the study reports submitted to the Agency.

But why are you revisiting the RECORD trial? As usual, the people with the power determine what subjects will be discussed. They determined that the RECORD trial needed another review without explaining what was wrong with the first one. It reminds one of the Baltimore Case. Keep holding government hearing with expert witnesses until you get the results you desire. Janet Woodcock explains here that:

Given the public interest in Avandia, the extensive history of the product, and the continued uncertainty of the risk surrounding this drug, FDA is holding this meeting to have a transparent, public discussion with experts across multiple scientific disciplines on the results of the readjudication of the study.

How much interest does the public have in a drug that no one uses? When did the risk uncertainty "continue" at the FDA? In 2010 the risk was certain. That is why the drug was pulled from the market. When did it fire back up?

To the lowly Cargo Cult Scientist, me, the RECORD trial saga demonstrates the anti-scientific method of drug approval and the role power plays in the approval process. Was there extraordinary bias in the conduct of the trial? Did GSK really change or delete data on unfavorable clinical events, sometimes months after they should have been reported? Will the FDA ever have to answer for the way in which they handled this trial in light of so many serious questions? It was a trial that exposed, more the most other trials, how flawed the system is and how far the FDA will go to absolve themselves of their mistakes. Just as Avandia poses a health threat to diabetes patients, the FDA poses a health threat to the general public.

We eagerly await the new and improved conclusions from the readjudication of the RECORD trial.

Wednesday, June 05, 2013

New Thoughts On Lack of Cargo

It is always a welcome read when a VC chimes in on what ails the Cargo Cults. What do the businessmen think causes the lack of Cargo? We here at the CCS have been trying to make the point since 2006 that cargo cult science is the problem. Feynman said it best:

Now it behooves me, of course, to tell you what they're missing. But it would be just about as difficult to explain to the South Seas Islanders how they have to arrange things so that they get some wealth in their system.
Wealth in their system. Literally, this is what a VC wants to figure out. How can they earn more money investing in people who seem to abandon their science degrees to pursue office jobs for which they are not prepared? Most often, no wealth is put back into a formerly wealthy VC fund. Most life science VC funds have given up since I began back in 2006. After billions and billions of dollars have been spent, they still don't understood why they failed, just as the Cargo Cults still do not know what they are doing wrong.

In this Xconomy article we get more insight as to what one VC thinks is missing. The author, Standish Fleming, starts out by admitting that things haven't been going well lately. "Today neither biotech nor pharma are producing a sufficient supply of new products. If we can't figure out a way to profitably finance early development, this industry will implode." It is interesting to see how the industry leaders are starting to break things down. Early development will ruin the industry. That is like saying that designing cars that don't run will destroy the automobile industry. Seems obvious. Early development is the foundation of this industry. It is the hardest part. Without it you don't have a product, just a pill filled with sand.

The article goes on to place the blame directly on the relationship between big pharma and biotech.

The problem lies in the market-driven relationship between biotech and pharma. The best way to explore outside the established frontier of knowledge is to run many small experiments, rather than pharma’s traditional approach of a few gold-plated studies designed not to end someone’s career.

We, of course, disagree. There is no difference between big pharma and biotech when it comes to science. Many small experiments are done at both big pharma and biotech. Studies are always designed not to end someone's career. The view from down here (the laboratory) where early development takes place is the same in big pharma and biotech. People fear for the careers. The studies that present a thumbs up or down for an entire project are studies you do not want to be around. Heads you win, tails you lose. How about we design the experiment more akin to the roll of the dice to increase our odds of maintaining our jobs after the outcome? What if we give that pair of dice to a young person and have them go into the laboratory to roll? Report back to us if you get a 7 or 11. We'll prepare a scientific explanation of how you got the desired numbers. If you fail, that is your failure. We are over here, doing business related things. Big Pharma or little biotech, the degrees of separation from science to business are all the same.

Let's look at a case of fraud first. Silvia Bulfone-Paus ran a laboratory rife with scientific misconduct. Silvia had the power. She was either the senior or corresponding author of six papers that contained image manipulations stemming from her lab. Who's fault was this? Silvia would like us to believe that it was two post-doctoral students in the lab, Elena Bulanova and Vadim Budagian. Silvia Bulfone-Paus stacked the odds in her favor by  sending post docs in to do her dirty work. She didn't have to run the risk because her people would not only do the work, they were there to take the blame. In the end however, science was not done. Without science, you do not have an early development project worth pursuing. 

Back to our VC theories. You can branch off from Silvias work on either a big or small study. Either way you are going to fail eventually. 

Now let's take the case of Dolly the Sheep. Here we have a non-fraudulent body of work that involved a small study. At least it appears small on the surface. One animal. Scientifically however, this was a huge step. A living being developed from a cell that came out of a laboratory. The bigger company came along and bought up the rights to advance the work. The scientists who cloned the sheep moved on. Geron, the big company could not develop the techniques of cloning however. The science needed more work at a level only dictated by science. Businessmen cannot create business models to make science projects succeed. Timelines put into Gant charts by MBAs or undereducated/over-employed PhDs miss that thing where wealth is put into the system. 

Back to our VC theories. You can branch off from Gerons inept business approach to science, big or small, and you will fail. 

What is the solution then? I too would like to mitigate risk. The fear of losing ones job because the results you get in the laboratory must not become a speed bump in reporting the truth. The most effective business model for scientific innovation is one where the truth is the boss. That cell culture where RNAi is suppose to prevent some protein  from being expressed is the boss. If it says the protein was expressed at the same level, RNAi or not, you must obey. That means a far greater understanding of what takes place in the laboratory is needed in big pharma and small biotechnology. If it is so easy to blame a technician for not seeing what you want to see, the methods your technicians are employing need work. Not to get the results you want but to believe what you are hearing. 

What Standish Fleming has completely sidestepped in his analysis is that of an under-trained workforce in early development. The culture has long been that of the Silvia Bulfone-Paus laboratory. A new paradigm must be set up. The laboratory must be feared. The lab must not have it's people ridiculed and forced to defend on any other principle than those laid out by the techniques they are applying. Often times the science and technology behind such techniques is far more sophisticated than any VC claptrap on how to make money from money. If the technician feels the need to photoshop in an extra band on the western blot, s/he has been subjected to a leadership problem.

To put this in VC terms, Bernie Madhoff gave his investors what they wanted. In order to do so however he had to run a Ponzi scheme until the day they locked him up. In the long run, it doesn't pay to keep running a system without the proper wealth building arrangement. The problem is happening in the power structure between science and businessmen. The power is in the hands of the latter, because they underestimate the power of science. It's not working out. 

Monday, June 03, 2013

Avastin Reducing Risk of "Disease Worsening"

Headline from Biospace:  Genentech (RHHBY)'s Avastin Fails Studies in New Brain Tumor Patients

That is discouraging but not surprising. Avastin is an anti-VEGF antibody. The blood-brain barrier is a mystery that has yet to be solved. What role does blood play in the brain? What about tumors in the brain? What happened to Avastin PKDM-wise? Did it go near the brain and the tumors? Did it enter the dying bodies and cause anything, good or bad, to happen?

You won't hear anything of value from the bullshitters of Genentech.

"We continue to be encouraged that people with newly diagnosed glioblastoma who received Avastin plus radiotherapy and temozolomide chemotherapy in the study experienced a significantly longer period of time without their cancer worsening," said Hal Barron M.D., chief medical officer and head of Global Product Development. "While the study did not show a significant increase in overall survival, delaying disease progression is considered to be an important goal for people with this aggressive brain cancer who have very limited treatment options."

Having known a few people with relatives and friends who have died from this disease, I know that it is a one way ticket out of this world. I have to think about that statement, "delaying disease progression is considered to be an important goal for people...". People with this cancer die and there is nothing we have yet to do about that fact. We don't understand cancer so we throw the kitchen sink at these poor souls. Drug approval means a whole lot to Dr. Hal Barron and his employers but little to the people with brain cancer. In the future we will have plenty of new patients, but no benefit from Avastin. Why then is Dr. Hal Barron encouraged?

If it's true that a person will feel better longer then die quicker, I think that is a good drug. The question is how Avastin allegedly brought that to be. How do we know?  Take two patients with brain cancer. One begins his decline at month 6 and dies at day 365. The other begins his decline at month 11 and dies at day 365, you have got a good pill. But we don't really know that happened in this case. A previous trial led the drug company to release the statement that Avastin plus radiotherapy and tmozolomid chmotherapy significantly reduced the risk of glioblastoma worsening or death by 36 percent compared to radiotherapy, temozolomide and a placebo. How do we compare the conclusions of the two trials? No survival benefits versus previously announced 36% reduced risk of disease worsening. The real scientific question here is to get Genetech to explain what they mean by "disease worsening".

What is the science of measuring "Disease Worsening"? Is there an organization or group of scientists who measure these measurements?