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Friday, November 04, 2016

All Trials TEDTalk

Wednesday, September 21, 2016

Sereptas Cargo Plane Has Landed

“there were serious methodological concerns identified by FDA,” according to the documents.

To measure the drug’s effect on muscle function, the company performed a six-minute walk test on the trial’s participants. The FDA reports there was “no nominally significant difference” between patients taking either the higher dose of eteplirsen, the lower dose or the placebo. The agency also griped about the fact that the company chose to compare the performance of the patients on the six-minute walk test against “historical controls,” or DMD patients who were in different trials in the past. - Forbes

You can read all about the "serious methodological concerns" here.

The simple description of Sereptas plan to demonstrate the efficacy of their product:

1) expression of an altered messenger RNA in muscle (pharmacodynamic)
2) production of dystrophin protein in muscle (pharmacodynamic)
3) improvement or preservation of muscle function (clinical).

Throughout the approval process, critics have expressed concerns with the small population — 12 patients — involved in clinical trials for the rare disease, along with flaws in how the clinical study was designed. These factors make “judgment on science difficult,” Califf (the FDA commissioner) said.

No it doesn't. More data points lead to better understanding of the accuracy of what is being measured. It is simple precision and accuracy. You may leave college with a poor grasp of the math behind statistics but you get the concept. The more data points the clearer the picture gets. Poor precision leads to greater doubts about accuracy. You aren't making a "judgment on science" that is "difficult". You are doing math.

Here is an example of data on the production of dystrophin protein in muscle.

Western blots and immunofluorescence were used to quantitate dystrophin.

Table 2: Applicant’s Quantification of Dystrophin by Western Blot and Immunofluorescence Analyses

Patient Western Blot % of normal Immunofluorescence % positive fibers
A 2.05 18.5
B 1.15 19.1
C 0.38 33.5
D 1.62 24.0
E 0.52 21.5
F 0.98 12.8
G 0 7.1
H 2.47 20.7
I 0.96 28.2
J 0 1.4
L 0.14 4.5

A quick glance at Figure 1: Correlation between Two Methods Used to Quantify Dystrophin in Skeletal Muscle: Patients from Study 201/202 tells you all you need to know. As the FDA put it, "Of note, the correlation between the two independent methods used to quantify dystrophin in muscle samples was weak." They also stated, "As discussed above, we believe that immunofluorescence analysis (percent positive fibers) is not a reliable method to quantify dystrophin content." What other criticisms of Sereptas methodology did the FDA panel mention?

Regarding the first pharmacodynamic goal, to demonstrate expression of an altered mRNA in muscle the FDA states;
Because even a minimal PCR signal is interpreted as “positive,” this biomarker provides little support of efficacy for eteplirsen; it does provide evidence that eteplirsen causes at least some degree of exon 51 skipping, as intended.

Regarding the second pharmacodynamic goal, the demonstrate production of dystrophin protein in muscle the FDA states;
FDA conducted an inspection of the facility where the data reported in the publication were generated. Significant methodological concerns were identified, which cast serious doubt on the reliability of assessments from the first three biopsies.
Thus, the review team does not consider “percent dystrophin‐positive fibers” to be a meaningful way to estimate dystrophin content, and we believe the results reported by the applicant on this measure do not establish that a significant increase in dystrophin occurred in response to eteplirsen treatment
In any case, the level of dystrophin was 0.9% of normal after 3.5 years, such that, in absolute terms, the increase from baseline would be, at most, 0.9%, assuming a “worst case” for untreated patients, i.e., zero dystrophin.

Regarding the clinical goal, improvement or preservation of muscle function, the FDA stated;
Two patients in the 30 mg/kg group became unable to ambulate soon after the study start. The applicant then pooled the six remaining eteplirsen patients and compared them to the four placebo patients, an unplanned post hoc analysis. No nominally significant difference between eteplirsen and placebo was identified in that post hoc analysis.
The applicant conducted a number of additional post hoc analyses, comparing the 6 patients who received eteplirsen in the 24‐week double‐blind phase of Study 201 and could still ambulate at the end of Study 201 (and continued on open‐label eteplirsen in Study 202) to those originally treated with placebo in the double‐blind phase of Study 201, and later switched to open‐label eteplirsen.
The applicant conducted a post hoc comparison of the patients in Study 201/202 to data from the “Italian DMD Registry” and the “Leuven Neuromuscular Reference Center” registry.
The problems of externally‐controlled studies are well recognized.

Dr. Ronald Farkas, who led the FDAs clinical team in the neurology products division, suddenly departed the agency just before the approval of Exondys 51. The arguments for the governments approval of Exondys 51 not come in a highly detailed document such as the one Dr. Farkas and his team presented.
Both FDA camps had “exercised reasonable scientific judgment,” Califf found, adding that it’s “exceedingly rare” to overrule a decision by the director of the Center for Drug Evaluation and Research. Without any additional technical expertise of his own, Califf said, he deferred to CDER Director Dr. Janet Woodcock.
An appeal to the authority of someone elses knowledge!

The jury is still out. Serepta still has to put up or shut up. The FDA has just bought them some time and money. How much money? $300,000 per year. Good grief. With BS artists like these, who needs scientists anymore?

Sunday, September 11, 2016

Risk of Cheating Barometer

Cheating in all areas of life is something that will always exist. We frown upon cheating. We throw people in jail if they cheat others out of their hard earned money. It is in general a bad thing for someone to get something through trickery or fraud. The problem is that we all cheat to some degree. We try to pay as little taxes as possible. We beef up our resumes. We tell little white lies when the need arises. That is why we have skepticism. We need a homeland-security-esque risk of cheating threat level system.

If Hillary Clinton debates Donald Trump, the threat level for cheating should be high for both candidates. They will cheat by exaggerating their accomplishments and lying about their failures. If you like Hillary you might think that Trump is the only one cheating up there on the stage, and vice versa. If you are a fact checker for the debate you operate under a different belief. Your job is to check what they say and compare that to the facts. That is the most honest person in the mix.

If you are a scientist and your job is to create new drugs, you are operating at a high level risk of cheating. The FDA will serve as the fact checker. Your boss is a different story. Your boss is also under a high level risk of cheating. He or she may have a lot of pressure to get the latest antibody drug to show the kind of data the CEO can show the board at the next meeting. Does this mean you are going to cheat? No. But you might end up on a path that will lead to the termination of your project/job. What does an honest person do under these circumstances?

The last post I put on the blog was about race. Black vs white in America is a high risk of cheating topic. "Hands up don't shoot" was the mantra after the Mike Brown incident in Ferguson MO. It is highly probable that that was an inaccurate description of what took place. Facts not supporting the narrative include a discharged weapon prior to the final lethal shots and the strong armed robbery committed by Brown prior to the incident. At his funeral a friend stated the Mr. Brown was out spreading the word of God prior to his death. That narrative would indeed make everyone skeptical about the police departments conclusion that the officer who shot Mike Brown, Darren Wilson, was defending his life. Who needs to shoot and kill a person out spreading the word of God? The problem is that the facts of the gunshot and robbery have been verified. The preaching has not.

Race is a topic where our Risk of Cheating threat level will be high. Was Mike Brown feeling invincible the day he died or was he out saving souls? That information is not proof positive of anything. It is information that only supports a narrative.

Back to BS - biotech science.

Our narrative is simple. We apply basic research as avenues to treating and/or curing disease. Science is the most honest and pure way of thinking. We set aside our biases and stick only to the facts. Narratives involving our motivations (money, fame, altruism...) are not factors in our scientific method. Those who have chosen to question underlying threats to our honesty are not understanding how science works. That is the big picture narrative behind the benevolence of BS - biotech science. We make drugs to help people because we have dedicated our lives to serve our fellow humans. Just don't bring up the history of that narrative.

Quick example: My favorite cargo cult of Seattle WA, Juno. August 31, 2016: Juno CEO Hans Bishop nets $1.28M from 42,673 shares of his stock. Sept. 8, 2016: Juno stock surges on positive clinical trial data.

The stock dives after four deaths in a trial of 129 patients are reported. It goes from $40-something per share to $20-something. The stock creeps back up to around $30 per share. The CEO socks away a cool million in spite of the narrative pointing to a bright future. Threat level HIGH!

Beware investors! Bullshit level high. Store your capital far from the shores of biotech.

Saturday, September 03, 2016

Inside Baseball and why judges should take it easy on black people

This has nothing to do with biotechnology cargo cults. This is about the cargo cult of race relations in the U.S.

Colin Kaepernick has done us a huge favor. He opened the door to let in the non-cargo cult thinkers. For every protest there is a counter protest. We fight to the death to defend even those whose speech offends us. Now they must be willing to hear the other side. Colin Flaherty is the other side of BLM and Colin Kaepernick.

Sunday, May 22, 2016

Should Science Be More Boring?

Price is what you pay. Value is what you get. -Warren Buffet

Try not to become a man of success, but rather try to become a man of value. -Albert Einstein

One of my favorite watchdogs of science is Retraction Watch. They have taken a far better path than I to point out the fly in the ointment of scientific research. In our common way of thinking, scientists are the most honest people in the world. Their discoveries have led to all of our modern comforts, including life saving medicines. As a result the general public has come to think of scientists much the same as they used to think of religious figures. If a scientist publishes a paper on his/her work in a scientific journal it must be Gods honest truth. How else could the scientist have gone through such rigorous judgements to get their work accepted? Retraction Watch is not saying how or why. They simply shine a light on the things that scientists and publishers got wrong. And that is a good thing!

Many people choose to criticize the whole concept of pointing out negatives in a positive world such as scientific work. For example, in the recent Tweet "Science Should Be More Boring" the following responses were posted:

True but in today's marketplace it is not very practical. -Elizabeth Leary

Who's gonna pay the bills with boring articles? -Sheila Shakoor

Agree but that will mean fewer science stories. Unsurprising research is less newsworthy. -Simon McGrath

As much as I agree with publishing negative results, the marketing here stinks. Will Dichtel

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 Sea Islanders how they have to arrange things so that they get some wealth in their system.

Aerodynamics, to most people, would be considered boring. The thing is, it is pretty damned important in the wealth of our system versus the wealth of the cargo cult system. The fact that civilized societies have useful things like airplanes is due to boring science. It is not boring however to the people who tend to obsess over understanding how things fly. The real question that follows from the above four comments is what is boring and what kind of non-reproducible science is preferable?

If you send an underling into the laboratory to conduct an experiment on the basic science on the Zeka virus, do you allow for that person to bring you results that they feel will best suit their career ambitions? Or do you expect them to present to you a completely transparent and clearly articulated accounting of what took place in the lab? At what point do we allow the above ideas (on practicality, bill paying, newsworthiness and the marketing of science) take precedence?

To link this concept to a real life biotech situation I must bring up the price of Seattle biotech investment and the value that has been returned. It was the marketing that raised the money to pay the price of funding the companies. It was the value created that led to the vast graveyard of failed companies.

If Sheila Shakoor came to me with an idea for a biotech start-up I would have to wonder, does she have good science as a foundation for her new company or has she been focused on paying the bills? If Simon McGrath has 300 publications on his resume should I be concerned about his focus on newsworthy research? As for Elizabeth and Will, I would ask them to stay in their side of the office and leave the science of the company up to the scientists.

The best comment from this tween was from Stephano Tonzani, "My prof of math methods for physicist once said "for researchers, science is boring 364 days of the year."

I do not find any of this boring. What makes science... science? Reproducibility is one way of truly assessing the value of published work. This idea is also one that meets great resistance among career minded scientists. But if you scroll through the latest postings from Retraction Watch you will find this article from Andrew Gelman.
Whatever the vast majority of retractions are, they’re a tiny fraction of the number of papers that are just wrong — by which I mean they present no good empirical evidence for their claims.
As someone who had to use these papers on a daily basis to conduct "newsworthy" research in the field of biopharma, I am far from bored when I read these words. For thirteen years I struggled with non-reproducible research and an inflexible chain of command that insisted the outcomes be true. In order to put wealth into our system we must change the attitude that subjective valuations on boring versus practical is what matters. Boring science can also be non-reproducible useless information. What matters is not the success of getting published. What matters is the value of the published paper.

Sunday, April 10, 2016

Born Sick, Commanded to Be Well

A cargo cult is an example of how any religion gets started. People see the complexity of the world and they can't accept not knowing how it works. They need answers. Faced with their ignorance they quickly seek anything that they can understand. Gods have always fit the bill. They created the world in which we live. Don't ask any more questions, just worship.

The actual cargo cults want to believe that someday they will have big metal birds delivering their food and medicine. Rather than focus on obtaining these things via the scientific method they take an easier route. To rectify the situation would be simple, at least in the beginning. Talk to the westerners and ask them how they built the airports. Learn that building your own airport is possible, but it is going to take hard work. They have to move from the simple belief system of religion to the complicated understandings of science and technology and progress at understanding the complexity of life on earth.

This clip of Bill Burr letting go of religion demonstrates a couple elements of the biotech cargo cult science. We often hear from the leaders that they cannot find the right people. The people they have to choose from are the ones the industry has educated and trained. They created us and now they want us to have a different skill set! Once again let me pick on Juno Therapeutics.

Hans Bishop, chief executive officer of Juno, said the state (Washington) needs to provide incentives to biotech companies in order to spur growth from existing companies and to attract small and mid-sized biotech companies to the region. Bishop said the state’s talent pool needs to be built up, which will happen through fostering innovation. He said Juno has had to attract more than half of its 300 employees from out of state.

Juno Therapeutics began when Lawrence Corey met David Fallace on a flight from Boston to Seattle. Fallace was in charge of special opportunities for the Alaska Permanent Fund. Ironic that a fund that wishes to be permanent would invest in biotech start-ups. Larry Corey was running the Fred Hutchinson Cancer Research Center. The two formed a partnership that got Juno off the ground.

Larry Corey. He once worked with Gertrude Elion, whom we at the CCS love and admire. At a presentation I attended in Colorado she ended with a slide that had a picture of the path she took in research. It went from chemistry to microbiology to biochemistry to medicine and so on. She was asked by a biochem professor how that path would have been altered if she had had the new technologies that we currently have. She said that it would not have mattered. The real work was done by thinking of the scientific problems and not the human constructs of technology. I'm paraphrasing but I believe her point was that research is a journey that takes you places. If you begin with technology and force it to take you to the land of milk and honey you will never get there. Larry Corey, on the other hand, took what Gertrude Elion had begun and headed off to the cargo cults. His career is in leadership, power, and money. In 1987 Corey directed the AIDS Clinical Trials Group, or ACTG, which conducted pivotal clinical trials confirming the use of the antiretroviral drug AZT to reduce maternal-fetal transmission of HIV and the usefulness of highly active antiretroviral therapy (HAART). Horrible research done without a heart and soul. He has authored 12 books and more than 690 scientific publications. Quantity over quality is a cargo cult career skill. Larry Corey has had one hell of a successful career in the cargo cults.

The "permanent fund" that invested in Juno no longer has Fallace and Corey to develop their idea. They have both moved on to other things. One has to wonder why anyone would leave such a promising narrative? Leadership in the cargo cults however requires one to keep moving. You don't want to be around when the followers look up to the skies to see once again that the planes will not be coming. The new leaders of Juno have already laid the foundation for failure. The state of Washington is somehow obstructing their ability to attract the right talent. "Washington state's talent pool needs to be built up, which will happen through fostering innovation." Has Corey innovated? The problems he set out to solve are now being left to people who must emerge from a talent pool that has not yet been built by our leaders. They need government money first!

The talent pool that currently exists in Seattle consists of ex-employees of the cargo cult companies that have come and gone. Resumes of people in Seattle life sciences include the companies that leave many an investor with a bad taste. Bad science is not sustainable nor is a talent pool that comes from such companies. The people naturally change their ideas on how to maintain employment. Like Lawrence Corey, they seek to distance themselves from the situation that makes science fun. That moment you go into the lab in the morning to see how your experiment turned out. The anticipation that your work is leading to bigger and better things. The confidence of mastering skills that once took so much of your time. The talent pool that innovates does not exist in Seattle. But unlike Bill Burr letting his religion go, it is the cargo cults that let their people go. The narrative lives on even though there is no talent to validate.

The problems facing life in the life sciences is daunting. Those who wish to have a career discovering new biotechnologies and helping mankind will soon run up against the need for survival. The likes of Lawrence Corey will be your competition. He, along with the other leaders of Seattle life sciences, have created a talent pool that is not good enough for their latest narratives. My advice to the young scientists is to stay away from biopharma, medical science and the gurus who start companies who seek massive profit. Develop technology, not drugs. Let go of the religion of western medicine. Biotechnology does not have to be synonymous with pharmaceuticals.

Sunday, March 27, 2016

The Money - Shkreli to Juno

Forbes had an article in their February issue called "Solving Pharma's Shkreli Problem". The subtitle, "The most hated entrepreneur in America did a public service in some ways: he revealed a fundamentally flawed system that threatens an entire industry".

My investors expect me to maximize profits. Not to minimize them or go half or 70% but to go 100% of the profit curve. -Martin Shkreli

This is a logical statement for any C level executive in Biopharma. They are not put in place to make wise scientific decisions. That is the task of lower ranking members of a biopharma company. C level execs are put in place to turn a profit for the investors. On one hand this works. Without profit or the promise or illusion of profit, no one has a job. Gone are the days where we had people like George W. Merck.

We try never to forget that medicine is for the people. It is not for the profits. The profits follow, and if we have remembered that, they have never failed to appear. The better we have remembered it, the larger they have been.
— George W(ilhelm) Merck

How prevalent are the Shkreli types in biopharma? We know that he did not operate in a vacuum. He had a board of directors. He had investors communicating with him daily. He also had counterparts at Valeant. As the Forbes article points out;

Shkreli had learned about price hikes by watching his elders. In 2007 a mechanical engineer and former defense chief executive named Don Baily took over Questor Pharmaceuticals and raised the price of a drug used to treat seizures in infants, Acthar Gel, from $50 to $28,000 a vial, and then marked it for diseases like multiple sclerosis where there was limited evidence it worked. Quester was sold to Dublin-based Mallinchrodt for $5.6 billion in 2014.

So we really ought to look into theories that don't work, and science that isn't science... Who told Forbes that Acthar Gel had limited evidence that it worked in treating multiple sclerosis? Where is the scientific publication that takes on the scientific claims both positive and negative against a drugs efficacy? It doesn't specifically exist. We have science journals. We have people who work as scientists and communicate much better than the average person. But they do not outrank the likes of Shkreli and Baily. They live perilous lives searching for a livelihood within organizations like Valiant and Mallinchrodt. They cannot rock the boat. Medicine is for the profits.

From Forbes:

In 2005 a banker named Steven Harr pointed out that the only barriers to sky-high prices for cancer drugs were pharma "companies" goodwill and tolerance for adverse publicity" but warned his clients that they risked subjecting the industry to increased regulation and quite possibly price controls. (Harr is now the chief financial officer of Seattle biotech Juno Therapeutics.)

Steven Harrs career is typical of biopharma executives. He was educated in science but quickly turned towards the money. His bio on the Juno website states that he joined Juno in April 2014. Previously he was Managing Director and Head of Biotechnology Investment Banking at Morgan Stanley from May 2010 until he joined Juno. Prior to his investment banking role at Morgan Stanley, Dr. Harr was Morgan Stanley’s lead biotech research analyst and Co-Head of Global Healthcare Research. Dr. Harr received a B.A. in Economics from College of the Holy Cross and an M.D. from The Johns Hopkins University School of Medicine. Dr. Harr was a resident in internal medicine at the University of California, San Francisco.

Johns Hopkins! UCSF!!! Banker?

The likes of Steven Harr could have been a force for good. He could have been one of those looking after our interests in medicine. Instead he is now a top level executive at the Dendreon spinoff Juno. Not as their CSO or CMO but their CFO! Ironically the mistakes of Dendron have proven that Steven Harr was wrong about drug pricing. Dendreon priced their dubiously efficacious product/service way too high and they ended up filing for bankruptcy. While Dendreon lacked the public arrogance of Martin Shkreli, they share his philosophy on drug pricing. They know that the investors want them to go after 100% of the potential profits. Having stumbled badly with Dendreon and the high price of Provenge, they are now ready to take another shot at making money off of their biotechnology.