AllTrials vs PhRMA

The AllTrials campaign asks for all trials to be registered and their results published. Ben Goldacre says we need the evidence to make informed decisions about medicines. John Castellani says mandatory disclosure could affect patient privacy, stifle discovery, and allow competitors or unscrupulous actors to use the information.

There is a very interesting battle taking place between AllTrials and  PhRMA.

PhRMA Mission Statement:

PhRMA's mission is to conduct effective advocacy for public policies that encourage discovery of important new medicines for patients by pharmaceutical and biotechnology research companies. To accomplish this mission, PhRMA is dedicated to achieving these goals in Washington, the states and the world:

• Broad patient access to safe and effective medicines through a free market, without price controls;
• Strong intellectual property incentives;
• And transparent, effective regulation and a free flow of information to patients.

AllTrials:

It's time all clinical trial results are reported.

Patients, researchers, pharmacists, doctors and regulators everywhere will benefit from publication of clinical trial results. Wherever you are in the world please sign the petition:

Thousands of clinical trials have not reported their results; some have not even been registered.

Information on what was done and what was found in these trials could be lost forever to doctors and researchers, leading to bad treatment decisions, missed opportunities for good medicine, and trials being repeated.

All trials past and present should be registered, and the full methods and the results reported.

We call on governments, regulators and research bodies to implement measures to achieve this.


 
The Cargo Cult Scientist is pretty transparent with opinions on the honesty of the pharmaceutical industry. I think we need help being honest. It's not that we're bad people, just that we are in bad situations. Specific outcomes make or break our careers. We have an incentive to highlight the good and hide the bad. In science however, we have to leave our hopes and dreams at the door. What we perceive as good and bad should not effect our judgement. The problem is that we are all human beings. The solution is transparency. 

If you've made up your mind to test a theory, or you want to explain some idea, you should always decide to publish it whichever way it comes out. If we only publish results of a certain kind, we can make the argument look good. We must publish both kinds of results. - R. Feynman 

There's No Business Like Science Business

It didn't work. I only got four hits in a day. Perhaps the words Trayvon Martin and George Zimmerman are saturated on the internet. It was just a test.

I mentioned The Bonfire of the Vanities. A real life tragic human situation became became useful to powerful people. The whole story becomes a screenplay to the powerful people. They, like Hollywood producers and directors, began to rewrite and tweak the script to fit their careers. Al Sharpton, for example, turned the Trayvon Martin Story into yet another case that requires one of his world famous protest marches. Lesser players, wanting to brand themselves as the next Al Sharpton, took the script and wrote themselves in as the civil rights leader in the scenes following the verdict.

The case is not unlike the world of science. Leaders often go astray for years but find new hope in a new screenplay. How many old scientists became RNAi experts? A producer or director in Hollywood becomes successful by making movies that make money. It's "Show Business". The same goes for science. It's "Science Business". The RNAi story, real or not, was a script that anyone could sell.

When selecting a screenplay to produce and direct, a scientist must look at the ones that will get published by the best journals. Here is what the journal Science has to say about what they will publish:

Science's Mission: Science seeks to publish those papers that are most influential in their fields or across fields and that will significantly advance scientific understanding. Selected papers should present novel and broadly important data, syntheses, or concepts. They should merit the recognition by the scientific community and general public provided by publication in Science, beyond that provided by specialty journals.

Ones adherence to the truth, and the ability for others to reproduce your work, is not mentioned in Science's Mission. Your screenplay need only influence, be novel, seem important and merit recognition. The skill of the new scientist is to select the topic of their career. In most cases however, the scientist does not get to select his/her topic. It is given to them by the person with the money. That person has already selected the topic/screenplay. The new PhD is then brought in as an expert witness. What happens next is very creative. The simple FACS data, western blots and ELISAs come to life and tell the story. 

Great science and art begins where our hopes and dreams leave off. The hopes and dreams of the journal Science is that all of their articles are influential, novel and will advance scientific understanding. It is thus, up to the current editors to select that caliber of screenplay. It is a scary job to tackle. Lets see what can go wrong.

Vitaly Komar and Alexander Melamid were two artists who took a scientific approach to creating the best painting ever. They began with an extensive poll of peoples art preferences. Subjects were asked if they preferred interior or landscape scenes, what kind of animals they liked, favorite colors, what kinds of people and so forth. Taking the aggregate results, the artists produced this painting.

Hilarious. The painting is called America's Most Wanted. This is what the people wanted, according to the survey.

What the journal "Science" (and the others) want, is like this. The journal tells you in advance what they expect. You take their expectations and write your story. You pitch the story, first, in your own mind. What kind of experiments and results do they want from me? How about some Resverotrol making old mice appear more youthful! Maybe RNAi knocking out TNF alpha! You design experiments to provide results like the elements in this painting. George Washington, pretty kids, deer, a nice lake, some mountains... You put them all together and you have provided the customer with what they asked for. You have written the screenplay that people want. It is Science Business 101.

What people outside of science do not know is that most of what gets published is to science what America's Most Wanted is to art. But science is abstract. It is complicated and complex. It is not easy to separate the good from the bad, especially when you are dealing with an accomplished writer. They know what the "best story" is, and exactly where to place it on their canvas.

In the end, our leaders do not have much of an impact on the real world. Al Sharpton will not change racial attitudes. David Sinclair will not make Resveratrol into the fountain of youth in a pill. They will however, remain at the top of their game until a better story comes along.

George Zimmerman and Trayvon Martin

It is clear that certain topics elicit a massive amount of reads and comments. The Huffington Post kept the George Zimmerman / Trayvon Martin verdict as their headliner for over 12 hours. I may be wrong but I think they set a record for the most comments from this story. There were close to 100,000 comments last time I checked. Everyone has something to say about George Zimmerman and Trayvon Martin.

My only goal for this post is to see how many people click on my blog. I will add this link to homicides in Los Angeles, Jan 1, 2007 to July 10, 2013. It is disturbing.

What we are witnessing is a story that was told in The Bonfire of the Vanities.

Scientific Myth

But it's not clear that a direct effort to "build community" will work in the absence of common ideals or values for which individuals are willing to sacrifice. Athenian citizens, for example, had to swear an oath to uphold "the ideals and sacred things of the city." The most common use of the word "sacred" in our public life is in relation to "cow." For the most part, we treat each other not as citizens but as consumers. 

John Stuart Mill said something about happiness that applies to this notion of building community. He said that happiness is the test of all rules of conduct and the end of life; but he also said that this end--happiness--is only attained by not making it the direct end. The same can be said of community. Community is not a direct end, but arises as a kind of by-product when people are working for common ideals that are larger than themselves--such as "the ideals and sacred things of the city. 

- Betty Sue Flowers - The American Dream and the Economic Myth

The same can be said of the scientific community. A cure or a new paradigm for improving health is not a direct end but arises as a by-product when scientists pursue the truth. I want to highlight a few concepts from this essay, as they pertain to Cargo Cult Science.

Direct End Research - Quest For The Cargo

Here is an example of the problems one encounters when seeking a "direct end".  "The Death of a Drug Class Shows Difficulty of Using Gene Data to Design Drugs"The "direct end" is diabetes. Scientists found a correlation between mutations on the PPAR gamma gene and an increased risk for diabetes. An intervention on PPAR activity was designed with the hopes and dreams of altering the "direct end". They took a shot and exacerbated the direct end!

Why call it quits? Is there nothing to be learned from all of this "science"? Wouldn't it be interesting to be put on a project to explain how this drug target brought about an opposite direct end? The current view is that there is no money in explaining what happened. Yet a by-product of this project could be a greater understanding of cardiovascular health. It could lead to a greater understanding of gene "mutations" and their consequences.

How Tall Is Your Building?

The mythologist Joseph Campbell used to say that you could always tell what the dominant myth of a culture was by looking at its tallest buildings. In medieval times, the tallest buildings in any city were the cathedrals; later, princely palaces and government buildings dominated the landscape; now the tallest buildings are commercial, reflecting the economic myth within which we now live.

I once went in for a job interview at the now defunct Targeted Genetics, a gene therapy company. 1100 Olive Way, Suite 100 downtown Seattle. I got to the building and looked up at the towering structure surrounded in glass. The men entering the building were dressed in suits and ties, the women in dresses looking fine. "Finally," I thought, "a work space worthy of a scientist." I went inside, "Targeted Genetics 17th floor. "Wait a minute, suite 100? This can't be." I went back outside. There to the west was an old one story building with the number 1100 above the door. People dressed in jeans and t-shirts were coming and going. Alas, the laboratories were here. The people on the 17th story of 1110 (not 1100) Olive Way had a different function. They handled the money, the narrative, the legal issues and investor relations.

The Economic Myth / Good Science = Good Money

American culture knows the price of everything and the value of nothing.
The economic myth honors quantity over quality.

If you were a Martian who speaks English and you came to this planet to study our understanding of the life forms that exist on planet earth, you may wonder why earthlings have placed a financial value on science. Publicly traded companies see their stock price going up and down based upon stories. Sometimes a patient will die during a clinical trial. Sometimes the CEO will be sent to jail for insider trading. The real value of a science based company, to a Martian, may be in their grasp of what is true and what is false. Each company boasts of their techology. Alnylam, for example, "is focused on developing a new class of innovative medicines with the potential to revolutionize the treatment of human disease by harnessing a powerful and natural biological mechanism known as RNA interference." Yet laying off the scientific staff boosts the stock price. Leaving only a product, and not an ongoing harnessing of RNAi potential increases the company value. 

The real value of a biotech/pharma company is in the lead product/s and the ability of key players to get approval, make sales, and not get caught cheating. The quality of the science and technology (the community of scientists and their rules of conduct) that produced the product takes a back seat the the potential quantity of money involved in future sales.  

The Loss of Self Worth to Scientists

In addition to a loss of the values embodied in our earlier myths, there is a danger for the society dominated by the economic myth that its citizens can lose their sense of a larger significance--or even of significance on an individual level. 

The thousands and thousands of highly educated people have gone through the system of scientific employment at biotech/pharma companies. When people lose their jobs we all think, in the back of our minds, that we/they were not good enough. We were hired to fill up the pipelines, yet they are drying up. The direct end, the reason we were hired, is often not accomplished. We are hired to fill up the journals with new exciting avenues for ourselves and others to pursue. Yet we are a community that lives in fear of job loss. We live in fear that the results from our experiments will not match up to the hoped for direct end. Our self worth is tied to understanding the things in nature that make others wealthy.

Our community is deteriorating. Those Athenian citizens, who swore an oath to uphold "the ideals and sacred things of the city" were different than us. We don't slow it down and talk much about our ideals and sacred things. We have deadlines and money to make. So much that much of what passes for science is purely mythological story telling. How do we tell science from Cargo Cult Science in this age of increasing deception? Start a conversation. Here is a good one. 

Our journals offer up depictions of scientific work. But do they speak for the entire community of scientists? Do they protect the truth in nature as "our ideals and sacred things"?

Reproducible

The number one argument in favor of working towards reproducible science is the "The Drunk Under the Streetlamp". "The Drunk Under the Streetlamp"looks for his keys where the lighting is good. His friends threw his keys in the ditch far from the light so he wouldn't find them and drive home drunk. His mind is not clear so instead of hailing a cab he looks for the keys under a streetlamp. Non-reproducible narratives work in this manner. Non-reproducible narratives will never get the job done. Why do we allow them to predominate the journals? Because they are easier to work with, just as it is easier to see under a streetlamp. Just ask Diederik Stapel! But they are not science. Science works. Science is powerful. When you work on non-reproducible narratives, "the best story", you are not conducting science. We know the current system of publication does not involve the scientific method. The scientific method is too hard. It would be too expensive to bring about reproducible work. Lets take a look a few arguments in favor of the current system.

The first set of arguments comes from yesterdays Retraction Watch comment section. The article was about creating a reproducibility index (RI).

Rather than rate journals on how often their articles are cited by other researchers, let’s grade them on how well those papers stand the most important test of science: namely, does the work stand up to scrutiny?

Seems reasonable. Hold the journals feet to the fire and let them know that we are going to test the research on which they are putting their stamp of approval.  They judge the scientists without using the scientific method. Why not judge them? Not for spite but as a professional courtesy to other researchers trying to use their journal to do work. The first argument against RI:

Reproducibility would take years to achieve, depending on the discipline. It could be one measure to enforce quality control, but it wouldn’t work accross the board. For example, it would be rare to find any group who would be willing to repeat 3-5 season/year agronomic experiments. - Jaime A. Teixeira da Silva

It would take too long. True, those who are the fastest get the rewards. But how is that working out for us? The drunk under the streetlamp, looking for his keys that he knows he lost in the darkened ditch, because the lighting is better, also feels he has a limited amount of time.

Discounting the huge resources necessary to establish a ranking system for which bits of data matter, and which conclusions do not, the whole issue of reproducibility is a hot potato that no publisher’s legal division will want to touch. I foresee litigation in which an author sues a journal for defamation because they down-ranked a paper based on inability to reproduce, when actually the experiment was perfectly sound and the “reproducers” were just not paying attention to experimental details. - Paul Brookes

I will first discount the "huge resources" because we already spend huge resources conducting mostly non-reproducible science. The solution to legal issues is a simple waiver. You waive the right to sue based on the (RI) which is not dictated over by the journal. It is an index that rates reproducibility. If you are trying to publish bad science, you should expect a low rating. If you think the (RI) will hurt your career, be very careful in what you put out into the world. People are watching. You can't just sue a journal because no one else can reproduce your work. But let the lawyers work out those details on protecting journals.

...the idea that journals will somehow willingly accept manuscripts that conflict with established results or confirm what is already known is laughable. 

That is the current situation that people are trying to change. Conflicting with "established results" is what sets science apart from other human endeavors. That is how we "self correct". And yes, even scientists have to fight against "established results" that are not true. In time, the truth will prevail. Think of the (RI) as an index that will make the journals less resistant towards challenging things we know, that aren't so.

Of course the biggest road block here is curating such an index because it’d probably require a lot of reading (or a genius to write an accurate text reading algorithm…key word being accurate).

Again, it's too hard. Too hard because it would require a lot of reading? Why not read a lot? Why not work towards a world where "a lot of reading" is done and reproducibility of what is read is part of what scientists do? It would actually create more work for scientists. Perhaps reproducibility studies could one day employ the minds that would otherwise go to waste looking for jobs at Pfizer running the HPLC department.

In our current system we have plenty of proverbial drunks looking for their keys under a streetlamp. You can spend all night looking. You can put on your glasses and break out a metal detector, but you are not going to find the keys. They are in the ditch where the lighting is not so good. The amount of people defending this foolish system, this system of taking the easy route, maintaining the status quo, works against future generations of scientists. But in 100 years there will be a different system. The truth has a way of making itself known whenever real science is lurking. I can see it now. Real science is making people think about the problems with reproducibility in the year 2013. The current leadership doesn't want a change but real science is lurking. A change is coming, like it or not. You may laugh at those who are fighting for the change but put yourself in historical context. Change does not come easily. If you think reproducibility is not worth fighting for, you are standing in the way. You are now the Nattering Nabob of Negativity. Get out of the way and let this experiment begin.

Stewart Lyman made his arguments against The Reproducibility Initiative back in 2012. Why won't it work? Money, Ego, Time and Science. His argument on Science begins:

Some types of data are easy to replicate, whereas others are much more difficult to reproduce. Cutting-edge experiments may be harder to replicate than “average” data, because, as one of my profs used to tell me “if it was easy, someone else would have already done it”. If you’ve worked in a lab for any length of time, you know that when trying to reproduce someone else’s results, the devil is in the details. 

Science can be hard. The devil is in the details. That is why the Reproducibility Initiative and Index, PloS ONE, and all of the other efforts to clean up this mess, should be considered scientific pursuits. If it was easy, someone else would have already done it. The lack of money and time are the weapons of egotistical scientists who always seem to have more money. They always seem to get results faster than others. They are winning but real science is lurking in the background. Real science is hard. It takes time and plenty of money. But it's worth it. Bad science is not worth fighting for.

Diederik Stapel Lessons in Honesty

Stapel did not deny that his deceit was driven by ambition. But it was more complicated than that, he told me. He insisted that he loved social psychology but had been frustrated by the messiness of experimental data, which rarely led to clear conclusions. His lifelong obsession with elegance and order, he said, led him to concoct sexy results that journals found attractive. “It was a quest for aesthetics, for beauty — instead of the truth,” he said. 

If you agree with Diederik Stapel that you will someday have to make the choice between beauty or the truth, you may be a Cargo Cult Scientist. Diederik, the former Tilburg University psychology professor is also a former PhD. He voluntarily gave up the PhD. He also retracted 53 papers because he fabricated the data. He'll do some community service and give up some government support as punishment. He's also lost his career. We don't feel bad about that. We like his counter-human; R. Feynman.

In physics the truth is rarely perfectly clear, and that is certainly universally the case in human affairs. Hence, what is not surrounded by uncertainty cannot be the truth.

The truth is beautiful. Take this question. Sally gets a degree in "Female Studies" from Oberlin U. She marries her girlfriend and sets out to start her professional life. What is more likely? A) She becomes a banker. B) She becomes a banker and an advocate for gay marriage? The answer is A because B is A with an additional condition. Sally becoming an advocate for gay marriage is more likely than her becoming a banker, but that is not the question. The truth is beautiful here. Once you hear the logic you start to think. It doesn't matter who Sally is or what she does for a living. She could have been a Young Republican who became a advocate for gay marriage and then a banker. You can change the words but you can't change the logic. That is what draws some people to science.

I have asked this question to friends and family. Not all agree with the answer. The arguments against B being the answer, are not beautiful. The individuals who make the arguments often times get tripped up in faulty logic. They use more words than those used to describe the simple truth. It gets ugly.

Once again let's revisit the Amgen study:

Part way through his project to reproduce promising studies, Begley met for breakfast at a cancer conference with the lead scientist of one of the problematic studies. 

"We went through the paper line by line, figure by figure," said Begley. "I explained that we re-did their experiment 50 times and never got their result. He said they'd done it six times and got this result once, but put it in the paper because it made the best story. It's very disillusioning."

See any similarities between Diederik Stapel and the scientist who got away with his crime of telling "the best story"? A true scientists keeps looking for the truth and the beauty. Diederik and the lead scientist from The Amgen Story decided on what they consider to be more beautiful. Notice how few benefit from their dishonesty. Notice that those who do benefit always benefit from the status quo and beautiful stories. Those with the power over publication, be it in an oncology journal or a social psychology journal, prefer pretty stories. They do not see beauty and the truth co-existing.

Imagine stripping away the words to the point where you are just looking at the logic. There is the beauty. A is more likely than A plus B. Boil down your biases and see the truth as beauty.

GSKs Honesty Tour Rolls Into China

I mentioned here that GSK has a history of dishonesty. They obscured safety data on Avandia that put their patients at risk. They produce an antidepressant that spawns a book called "Side Effect", A Prosecutor, A Whistleblower, and A Best Selling Antidepressant on Trial. They pay three billion dollar fines from sales and marketing practices from the asthma drug Advair and other drugs. In this post I asked the question, "What kind of an evil organization are we dealing with here?"

China Probes Staff of GlaxoSmithKline After Corruption Claims Aired 

Corruption is rampant in China’s health system, according to industry insiders. Public hospital budgets depend on commissions from the sale of medicines and doctors’ low salaries are supplemented by payments from patients and kickbacks from equipment and drug suppliers.  

Corruption is rampant in GSKs sales and marketing department. We've established that fact with the $3 billion fine. Some things never change.

The whistleblower’s allegations, according to The Wall Street Journal, which broke the story, included claims about fees paid to doctors, both in kind and cash, and all-expense trips. The quid pro quo was prescription of Glaxo-supplied drugs. 

Who are the men and women behind the curtains that make The Great Wizard of GSK such a dishonest entity? While I think it would be a good idea to put them in jail and air their names so the consumers know who the bad guys are, I fear that the rest of the industry giants will end up standing at the prison gates when these guys get out of jail. They'll shuffle them off in limousines to corner offices in tall buildings throughout the world to seek new grifts.

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. 

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.

http://video.cnbc.com/gallery/?video=591437325

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 www.atossagenetics.com and www.nrlbh.com 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. 

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.

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.

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.

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.

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.