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Monday, July 31, 2006

FDA Hard At Work

"During the Middle Ages there were all kinds of crazy ideas, such as that a piece of of rhinoceros horn would increase potency. Then a method was discovered for separating the ideas--which was to try one to see if it worked, and if it didn't work, to eliminate it. This method became organized, of course, into science. And it developed very well, so that we are now in the scientific age. It is such a scientific age, in fact, that we have difficulty in understanding how witch doctors could ever have existed, when nothing that they proposed ever really worked--or very little of it did. "

That's the first paragraph in Richard Feynmans Cargo Cult Science. He started off real simple. Some things don't work. Why did people think they did? That's a good question. Science is simple if you look at it that way. Yet not everyone looks at science that way. Let's see how the FDA regards this new thing called science.

Pseudoephedrine, the active ingredient in Sudafed, is also the main ingredient in methampetamine. It's a big problem. New regulations will be pulling the drug off the shelves soon. To combat a loss in revenue the scientists at Pfizer developed Sudafed PE. The active ingredient is phenylephrine.


In a peer-reviewed letter released this week to the editor of the Journal of Allergy and Clinical Immunology, University of Florida researchers argued that there's little evidence to suggest that the active ingredient in the new Sudafed PE or similar medications will do anything to relieve a stuffy nose.

In their letter, Hendeles and colleague Dr. Randy Hatton contended that when the U.S. Food and Drug Administration approved the use of phenylephrine in 1976, the agency was only able to find four studies that suggested it worked at a dose of 10 milligrams, the size of Sudafed PE pills. Two of those studies were sponsored by drug companies, and all were unpublished and not reviewed by peers, Hendeles said.
Seven other studies, according to the authors, found that phenylephrine didn't work better than a placebo.
"It does nothing," Hendeles said. "Clearly the 10 milligram (dose) does not work."

So what is happening here? We're not living in the middle ages. We're not being sold snake oil from a stage coach. It's 2006. The FDA has examined the evidence on our behalf and approved a drug that does not work. Four studies suggested that it worked, 2 of which were funded by the industry. Seven others said that it did nothing. The FDA however has accepted only the positive results. They had the same opportunity as the scientists at the University of Florida but they came up with a different conclusion.

The science that has escaped the cargo culture has lifted us up as though the entire society were enlightened invidivuals. My question is how far from the truth that is. How many are enlightened and how many would burn a witch if they were presented with "the proper evidence"? How many in the latter group work at the FDA?

Thursday, July 27, 2006


Imagine a real scientist living before there were computers. These days, long difficult calculations can be done in nanoseconds with a computer. When the groundwork was being laid for our modern conveniences everything came the hard way. Yet to those engaging in the work, it was done for pleasure. Archimedes was one who engaged in finding things out for the fun of it.

The following was taken from an article by J J O'Connor and E F Robertson:

"Archimedes possessed so high a spirit, so profound a soul, and such treasures of scientific knowledge, that though these inventions had now obtained him the renown of more than human sagacity, he yet would not deign to leave behind him any commentary or writing on such subjects; but, repudiating as sordid and ignoble the whole trade of engineering, and every sort of art that lends itself to mere use and profit, he placed his whole affection and ambition in those purer speculations where there can be no reference to the vulgar needs of life; studies, the superiority of which to all others is unquestioned, and in which the only doubt can be whether the beauty and grandeur of the subjects examined, of the precision and cogency of the methods and means of proof, most deserve our admiration. "

One of the things Archimedes deemed worthy of writing about was his method of discovery. In 'The Method' he writes, "... certain things first became clear to me by a mechanical method, although they had to be proved by geometry afterwards because their investigation by the said method did not furnish an actual proof. But it is of course easier, when we have previously acquired, by the method, some knowledge of the questions, to supply the proof than it is to find it without any previous knowledge. "

This is a very complex statement. The modern day scientist has so much information and so many tools at his/her disposal that it's hard to keep track of everything involved in an experiment. Are we certain that we have the proper knowledge of the questions we are asking? Are we Martians who've come to earth to discover that diet coke makes people fat?

Plutarch, an ancient historian, describes Archimedes genius; "It is not possible to find in all geometry more difficult and intricate questions, or more simple and lucid explanations. Some ascribe this to his natural genius; while others think that incredible effort and toil produced these, to all appearances, easy and unlaboured results. No amount of investigation of yours would succeed in attaining the proof, and yet, once seen, you immediately believe you would have discovered it; by so smooth and so rapid a path he leads you to the conclusion required."

I can recall a professor in college describing the PCR method discovered by Kary Mullis. He said it was so simple that everyone who first read about it immediately slapped their forehead and cursed themselves for not thinking of it. It was as if the professor was saying it was too simple for his big brain. Yet he didn't think of it and he never would have. He was never put in the position to ask the question of how to make more DNA. Everyone had accepted the laborious methods being used prior to PCR. Kary Mullis was bored with what his superiors wanted him to do. He thought up a better way to amplify DNA. When you saw what he did you were impressed. Heath, a mathematical historian, described Archimedes work in a more eloquent way:

"The treatises are, without exception, monuments of mathematical exposition; the gradual revelation of the plan of attack, the masterly ordering of the propositions, the stern elimination of everything not immediately relevant to the purpose, the finish of the whole, are so impressive in their perfection as to create a feeling akin to awe in the mind of the reader."

Tuesday, July 25, 2006

Curing Cancer

A common form of biotech R&D is finding something that binds to a drug target and seeing what affect that has on the disease. Antibodies are very popular because they bind to proteins. They were designed to do so by God (insert your god here). The immune system makes antibodies against foreign proteins, they bind to the foreign protein and the rest of the immune system removes the antibody and what it is binding to.

One approach to curing cancer was to make an antibody against denatured collagen. The concept was that it will bind to areas who tissue is breaking down. If a cancer is invading a tissue the antibody will go to that area. Good idea so far. The leap of faith in this research was that denatured collagen held a criptic binding site for angiogenisis factors. There is no evidence of this. The way around it was to simply inject the antibody into a mouse with a tumor and see if it prevented the tumor from growing. A tumor needs blood vessels to provide oxygen and carry away its waste. If you inhibit angiogenisis then the tumor will shrivel up.

Another protein target to prevent tumor grown was VEGF (vascular endothelial growth factor). The antibody against this target binds to the target and it prevents tumors from growing in mice. This I have witnessed first hand. As a control for the anti-angiogenisis antibodies we had, we used the anti-VEGF antibody. In this group of mice the most you could see was a red swelling where the tumor cells had been injected. In all other groups tumors had formed, of all different shapes and sizes. Our antibody didn't come close to the results of the anti-VEGF antibody.

The concept has been proven, in mice at least. An antibody can be developed and used as a drug. Rituxan, (anti-VEGF) does not work as well in humans but it is for sale for cancer treatment. The anti-collagen antibody is in preclinical development, just where it was when I left the project over four years ago. Each year a presentation is given at a biotech seminar on how well it reduces tumors. 57% in nude mice, 67% in female Balbc mice. The truth is, it doesn't work at all. It didn't work in laboratory assays such as adhesion and cell migration assays. It didn't work in mice. A graduate student showed us how to measure the tumors to get "better data". After measuring and getting the numbers she wanted she made the mistake to ask if I had any questions. I handed her one of the mice she had already measured. She was immediately embarrassed. "Which one is this?" she asked. "If I told you it would take away from the experiment of testing the reproducibility of what you just demonstrated," I answered. She took a shot. She was off by 30%. Imagine how the measurements of entire groups of mice are treated. Then think about the presentation to the big time scientists at the biotech conferences. Any questions?

By the time it's all said and done, we still do not have a good anti-cancer drug. We have a ton of molecules that bind to something that may be involved in cancer. How do we know when our drugs reach their targets? How much is needed and where? Biotech is swinging for homeruns by finding targets and finding something that binds to them. Peptides, antibodies, enzymes, phage, viruses, small molecules and other sythetic compounds. One thing can be said about an antibody however. It binds to a protein but it also is part of a system that protects us from harm. It does not work alone. Binding alone is not enough.

The CEO of a Few Cargo Cult Airports

He was a smart young man. After receiving his PhD and MD from the University of Michigan he began teaching at Stanford. Not satisfied with the slow pace of life in academia he went into business. In 1984 he convinced a few venture capital groups to back him. He was now the founder of a biotech company. As the clinical-trial process ate up early funding, he returned for two more rounds of funding causing his hown financial interest in the company to dwindle. This loss of control grated on him. His backers, seeking more seasoned management, brought in a new CEO, who began spending heavily on a large building and dozens of new employees. By the time they were ready to go to market with their first drug, the company needed more money--and its backers were looking for a way out. The founder reluctantly agreed to sell the company. He left bitter, a year later, convinced that more patient investors could have reaped far higher returns in a year. But he also pocketed $7.5 million.

Cargo Cult Scientist note: No drug was brought to the market. The airplanes did not land. A company was sold, not a drug.

In 1991 he founded his next biotech company. The product was almost identical to the previous companies product. They spent years developing the company. During that time the drug was under development as well but it wasn't all that impressive. In spite of the products weak performance they filed an IND (Investigational New Drug application) with the FDA. In 1998 the FDA issued a warning letter to the CEO. The FDA found that the company was promoting their product as safe and effective for numerous applications. None is this had been approved by the FDA. The CEO and his company had 14 days to comply with the FDAs demand to cease promoting the drug. All managers within the company were to receive a copy of the warning letter.

Disappointed with the progress of work and the arrogance of the CEO, the board voted to replace him in 1999. In 2000 the company withdrew its NDA (New Drug Application) and ceased development.

The airplanes, once again, did not land.

In 2000 he began his latest adventure. This time the product was different. They would focus on generic products delivered nasally with a new technology that employed biological materials instead of the standard nasal formulations. However, there has been no INDs filed that employ the highly touted delivery technology. A major deal with a Merck was shut down to to lack of efficacy. Nonetheless they continue to pump money into the project. The decision was labeled as one of the top five stupidest things on Wallstreet that week. One investor on a blog commented, "I was never a big fan of (the Company) because I remember (the CEO) from a company he ran called (previous company). In my opinion he wasn't always truthful."

The latest disappointment was a letter by the FDA stating that the most advanced drug in their pipeline was not approvable. The good news for investors was that this drug did not employ the delivery system so highly touted. The rest of the pipeline, which may or may not use the delivery technology, was safe.

The highly touted biological drug delivery system simply does not exist. It was an idea or a hypothesis but it was not what they claimed it to be. Once again, investors have been duped. Only white lab coat wearing individuals know of the trouble. Every week they have to report on the progress of the "technology". But a hypothesis is not technology. Only a cargo cult would believe it is. The cargo cults beliefs are what prevent them from making progress in the field of aviation. The same goes for biotechnology.

The CEO of this story is another hypothesis. He is said to posess great skills in running a business. I suppose he is no different than many of the leaders running biotech companies. He's got the PhD and the MD as well. He's ran other companies. He has assembled a team and they run the daily operation. In the end, nothing happens. People lose their jobs. Investors lose their money. Is there another way? Is there another hypothesis that we could apply to making money and drugs at the same time? I can only think of one. Develop a highly effective drug and bend over backwards to prove that it doesn't work. If you fail, you win.

Give up the pedigreed CEOs. Search out useful drugs and everyones work will be easier.

Monday, July 24, 2006

The FDA Can't Do It's Job

The FDA is trying to decide if they should ban scientists with financial interests in certain drugs from serving as advisors to the agency. There are review panels set up by the FDA to assess the value of a drug. The FDA argues that banning certain scientists would deny the FDA access to advisers with the expertise and experience it seeks.

"We probably couldn't recruit department chairmen. It would hinder us from recruiting all but junior faculty members" said Dr. Scott Gottlieb, the FDA;s deputy commisioner for Medical and Scientific Affairs.

Congress argues that scientists with a financial interest in a drug, serving as advisors for the scientific assessment of the drug have a conflict of interest. The FDA does not deny this fact. They just don't want to admint that the conflict of interest manifests itself as decisions based on financial gain. They believe that what they do is pure science and thus they need scientific advisors.

The question is however, why can't the FDA do their job without having to hire consultants? They hire people to explain things they should really have a firm grasp on themselves. The budget for approving, labeling, and monitoring drugs is roughly $290 million per year.. Still they cannot make decisions without consulting with the experts who have a conflict of interest?

Congress is simply trying to get the FDA to make better decisions. The conflicts of interests cause the FDA to make bad decisions. The reason the FDA was set up was to protect the American people from potencially harmful food and drugs. We needed a government agency who had only the interest of the people to protect. We needed people who could protect us from harmful products sold by people whose main interests were in making money. Now our FDA is telling us they can't make good decisions without hiring people who cause them to make bad decisions.

"It just doesn't make any sense to me. When you have this problem-conflicts of interest on critical panels-the solution is eliminate the conflict. It's simple and easy to do," said Rep. Maurice Hinchey D-NY.

1937 — Over 100 people died after consuming a raspberry-flavored sulfa elixir which had been rushed to market by the S.E. Massengill Company without any testing. About 70 percent of the elixir was diethylene glycol, which is now known to be poisonous (related to antifreeze). However, the FDA was able to remove the sulfa elixir from the market because elixirs at the time were to contain alcohol as a solvent (not diethylene glycol).

1938 — The resulting sulfa elixir scandal and public outcry led to the passage of the Federal Food, Drug, and Cosmetic Act of 1938, which gave the FDA the power to preapprove all new drugs introduced into interstate commerce.

It is important to point out that the scientist who developed the rasberry-flavored sulfa elixir was so devestated by what happened that he committed suicide. Most of the deaths he caused were young children. No one in their right mind would purposely kill young children by poisoning their medicine. This was a tragic mistake that was corrected by making the FDA our guardians. They are now telling us that they can't do their job.

Monday, July 17, 2006

A Place to Think

Is it true that our best thinkers wind up in board rooms, senate floors, or behind college classroom podiums? What about the farmer who sees his crops growing better after planting in a new formation? Who told him to change the formation? Did he take his own idea from start to finish resulting in the desired outcome? If that same farmer was placed in a different situation could that brain work to solve other kinds of problems?

I am certain that there are people who work in low level jobs who have the kind of mind that can solve complex problems that are not being solved by people who are currently in the highest levels. With the system that we have however, it is difficult for certain types of thinkers to be put in a place where they can do the most good.

Perhaps the current popularity of the blogs is that it's a place where people can rest their thoughts. There are tons of blogs with zero comments. No visitors yet the bloggers continue to post their thoughts. This is a place to think until you find a better place to send your ideas. Just start searching through the blogs. You'll find some good ideas just sitting there.

Wednesday, July 12, 2006

Time to Think

Whenever you write an angry letter it's best to leave it for awhile. Come back and read it see if it is as forceful as you thought or if it is just some angry guy blowing off steam. One of my first e-mails was to the editor of the college paper. I vented about everything I could think of. I felt pretty stupid as I read it published in the paper. I was out of control, not making any points, just bitching about things. Should have sat on it for awhile.

We need time to think. There is a scene in "Planes, Trains and Automobiles" where John Candy is driving down the wrong side of the interstate. He looks across the median that separates the two roads (going in opposite directions). The people in the car parallel him yell out, "you're going the wrong way"! He hears them, thinks about it, then says, "how do they know which way we're going"?

It makes you wonder what is going on when our leaders vote on tax reform legislation that is written up in 10 thousand page documents. It makes you wonder about the decisions made in board rooms in 1 hour meetings. Is the proper way of conducting business always done in meetings? Is there enough time to properly process the information that goes into making a decision?

In science we have come up with statistical analysis. The more data you have the better off you'll be at determining what it means. For instance, if you have 20 people in a clinical trial you may come to a different conclusion than if you have 2000. This is called the N value and as it increases the more accurate your data analysis will be. As you increase the N value you may just be increasing the time needed to gather the data. You need that time.

By slowing down we give ourselves a better chance. We can't always wait but when we can we should. The Cargo Cult Scientist often times does not have the time to wait for the best data. It could be that there is another lab working on the same problem. If they publish first the competitors might lose the race. One less publication. This is just one of the problems associated with the publishing of scientific papers. They don't allow enough time due to the competition. Believe it or not, competing scientists don't call each other up with congratulations for getting to the answer first. Even if it's validation of their own work, scientists must be first. Now one would think that it would be exciting to see someone else come up with the same conclusions you did. It is validation of you thoughts and experiments. Sadly, that is not how the real world works.

The cargo cult airport is forever looking to the skies to see the airplanes. They don't arrive but there is still a sense of urgency down below. Deadlines are set for the shape of the coconuts that go over the air traffic controllers ears. Management has to get things done! That's different than really getting things done. Just like when the senators sign tax bills, there is no chance that they information is fully understood and acted upon accordingly. Things needed to get done so they were.

Make time to think. If you want a better job, take the time to figure out what you really want to do and where you can do it. If you want to divorce your spouse, take time to think about what life will be like as a divorcee. When signing that mortage make them wait while you read the whole contract. Take time to think. Complicated issues need time.