Monday, September 01, 2014

Cancer Drugs Fund receives boost but will no longer fund “overpriced” drugs = BMJ

Cancer Drugs Fund receives boost but will no longer fund “overpriced” drugs
BMJ 2014; 349 doi: (Published 01 September 2014)
Cite this as: BMJ 2014;349:g5382

Nigel Hawkes

The Cancer Drugs Fund has been given a 40% increase in funding and has agreed to remove from its list any drugs that are overpriced or produce little clinical benefit. The fund’s chairman also promised to try to align the fund’s assessments more closely with those of the National Institute for Health and Care Excellence (NICE).

NHS England, which is responsible for the drugs fund, has agreed to increase the amount the fund receives for the next two years from £200m (€252m; $332m) to £280m a year. The fund has treated 55 000 people since it began, using drugs that NICE did not recommend as cost effective because, in most cases, they offered patients only a few more months of life.

Originally launched by Andrew Lansley, the former health secretary, as a way to satisfy political pressures,1 the fund has succeeded in that objective but has always been regarded by NICE and its supporters as something of a fudge: it covers only cancer, not other end of life conditions.

The major beneficiary of the fund (apart from the patients treated) has been the leading manufacturer of cancer drugs, Roche. The fund was originally meant to act as a bridge between the NICE dominated era—with its hard luck stories of patients denied drugs that were available in other countries—and a new era of value based pricing, where every new drug would carry a price tag that reflected its value. But that never happened, and instead the Pharmaceutical Price Regulation Scheme was renegotiated to set a global ceiling on drug spending. Every costly new drug sold to the NHS now means less money for other medicines.

This has driven a wedge between Roche—which was suspended from the Association of the British Pharmaceutical Industry (ABPI) in 2008 for breaching the rules and has never rejoined—and the rest of the industry. In the ABPI’s view the fund is no longer a cost-free offering. Its chief executive, Stephen Whitehead, welcomed the cash injection but warned, “However, it is only a short term solution and ultimately the NICE value assessment process needs to be reformed urgently, so that more innovative cancer medicines can be made available to NHS patients.”

The fund’s existence has eased the downward pressure on cancer drug prices, which NICE believes are too high. Roche’s latest breast cancer drug—Kadcyla, for advanced breast cancer—costs £90 000 for a course of treatment with outcomes that, under NICE rules, would make it worth £10 000 to £25 000. NICE rejected the drug on cost effectiveness grounds, but it is available through the Cancer Drugs Fund.

In a letter to NHS England the fund’s chairman, Peter Clark of the Clatterbridge Cancer Centre in Merseyside, said that the fund paid for drugs that showed good benefit but also for “minority drugs of much less clinical value.” He added that the fund had offered an alternative funding source “on price terms which in some cases have represented poor value.” He also undertook to review drugs and withdraw reimbursement for any found to be ineffective or too expensive. But this would not affect patients already taking those drugs or others that were the only confirmed treatment, he wrote. “The result will be to ensure patients continue to access worthwhile cancer medicines whilst also creating financial headroom for new medicines within the significantly expanded funding allocation,” he added.

The fund’s assessments will still diverge widely from those of NICE, despite Clark’s promise to try to ensure “greater alignment” between the two bodies. He also promised a new “evaluation through commissioning” option that would reimburse new drugs in clinical practice but would also review outcomes to assess value for money.

While the fund has made many drugs available to patients who would not otherwise have got them, its overall effect is less clear-cut. A study published in the British Journal of Cancer earlier this year2 found that English patients were as much as seven times more likely to be prescribed drugs rejected by NICE than patients in Wales, which is not covered by the fund. But three new drugs that NICE approved (pazopanib, bendamustine, and abiraterone) were adopted more slowly in England than in Wales. The existence of the fund, the authors concluded, did not speed up access to cost effective drugs.

Cite this as: BMJ 2014;349:g5382

↵Wise J. Charities welcome £50m interim cancer drugs fund. BMJ2010;341:c5464.FREE Full Text
↵Chamberlain C, Collin SM, Stephens P, Donovan J, Bahl A, Hollingworth W, Does the cancer drugs fund lead to faster uptake of cost effective drugs? A time trend analysis comparing England and Wales. Brit J Cancer2014; published online 25 Feb. doi:10.1038/bjc.2014.86.

A "must read" - Cargo Cult Science by Richard Feynman

From a Caltech commencement address given in 1974 
Also in Surely You're Joking, Mr. Feynman!

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.

But even today I meet lots of people who sooner or later get me into a conversation about UFO's, or astrology, or some form of mysticism, expanded consciousness, new types of awareness, ESP, and so forth. And I've concluded that it's not a scientific world.

Most people believe so many wonderful things that I decided to investigate why they did. And what has been referred to as my curiosity for investigation has landed me in a difficulty where I found so much junk that I'm overwhelmed. First I started out by investigating various ideas of mysticism and mystic experiences. I went into isolation tanks and got many hours of hallucinations, so I know something about that. Then I went to Esalen, which is a hotbed of this kind of thought (it's a wonderful place; you should go visit there). Then I became overwhelmed. I didn't realize how MUCH there was.

At Esalen there are some large baths fed by hot springs situated on a ledge about thirty feet above the ocean. One of my most pleasurable experiences has been to sit in one of those baths and watch the waves crashing onto the rocky slope below, to gaze into the clear blue sky above, and to study a beautiful nude as she quietly appears and settles into the bath with me.

One time I sat down in a bath where there was a beautiful girl sitting with a guy who didn't seem to know her. Right away I began thinking, "Gee! How am I gonna get started talking to this beautiful nude woman?"

I'm trying to figure out what to say, when the guy says to her, "I'm, uh, studying massage. Could I practice on you?" "Sure," she says. They get out of the bath and she lies down on a massage table nearby. I think to myself, "What a nifty line! I can never think of anything like that!" He starts to rub her big toe. "I think I feel it," he says. "I feel a kind of dent--is that the pituitary?" I blurt out, "You're a helluva long way from the pituitary, man!" They looked at me, horrified--I had blown my cover--and said, "It's reflexology!" I quickly closed my eyes and appeared to be meditating.

That's just an example of the kind of things that overwhelm me. I also looked into extrasensory perception, and PSI phenomena, and the latest craze there was Uri Geller, a man who is supposed to be able to bend keys by rubbing them with his finger. So I went to his hotel room, on his invitation, to see a demonstration of both mindreading and bending keys. He didn't do any mindreading that succeeded; nobody can read my mind, I guess. And my boy held a key and Geller rubbed it, and nothing happened. Then he told us it works better under water, and so you can picture all of us standing in the bathroom with the water turned on and the key under it, and him rubbing the key with his finger. Nothing happened. So I was unable to investigate that phenomenon.

But then I began to think, what else is there that we believe? (And I thought then about the witch doctors, and how easy it would have been to check on them by noticing that nothing really worked.) So I found things that even more people believe, such as that we have some knowledge of how to educate. There are big schools of reading methods and mathematics methods, and so forth, but if you notice, you'll see the reading scores keep going down--or hardly going up--in spite of the fact that we continually use these same people to improve the methods. There's a witch doctor remedy that doesn't work. It ought to be looked into; how do they know that their method should work? Another example is how to treat criminals. We obviously have made no progress--lots of theory, but no progress--in decreasing the amount of crime by the method that we use to handle criminals.

Yet these things are said to be scientific. We study them. And I think ordinary people with commonsense ideas are intimidated by this pseudoscience. A teacher who has some good idea of how to teach her children to read is forced by the school system to do it some other way--or is even fooled by the school system into thinking that her method is not necessarily a good one. Or a parent of bad boys, after disciplining them in one way or another, feels guilty for the rest of her life because she didn't do "the right thing," according to the experts.

So we really ought to look into theories that don't work, and science that isn't science.

I think the educational and psychological studies I mentioned are examples of what I would like to call cargo cult science. In the South Seas there is a cargo cult of people. During the war they saw airplanes with lots of good materials, and they want the same thing to happen now. So they've arranged to make things like runways, to put fires along the sides of the runways, to make a wooden hut for a man to sit in, with two wooden pieces on his head to headphones and bars of bamboo sticking out like antennas--he's the controller--and they wait for the airplanes to land. They're doing everything right. The form is perfect. It looks exactly the way it looked before. But it doesn't work. No airplanes land. So I call these things cargo cult science, because they follow all the apparent precepts and forms of scientific investigation, but they're missing something essential, because the planes don't land.

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. It is not something simple like telling them how to improve the shapes of the earphones. 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 say explicitly 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. For example, if you're doing an experiment, you should report everything that you think might make it invalid--not only what you think is right about it: other causes that could possibly explain your results; and things you thought of that you've eliminated by some other experiment, and how they worked--to make sure the other fellow can tell they have been eliminated.

Details that could throw doubt on your interpretation must be given, if you know them. You must do the best you can--if you know anything at all wrong, or possibly wrong--to explain it. If you make a theory, for example, and advertise it, or put it out, then you must also put down all the facts that disagree with it, as well as those that agree with it. There is also a more subtle problem. When you have put a lot of ideas together to make an elaborate theory, you want to make sure, when explaining what it fits, that those things it fits are not just the things that gave you the idea for the theory; but that the finished theory makes something else come out right, in addition.

In summary, the idea is to give all of the information to help others to judge the value of your contribution; not just the information that leads to judgement in one particular direction or another.

The easiest way to explain this idea is to contrast it, for example, with advertising. Last night I heard that Wesson oil doesn't soak through food. Well, that's true. It's not dishonest; but the thing I'm talking about is not just a matter of not being dishonest; it's a matter of scientific integrity, which is another level. The fact that should be added to that advertising statement is that no oils soak through food, if operated at a certain temperature. If operated at another temperature, they all will--including Wesson oil. So it's the implication which has been conveyed, not the fact, which is true, and the difference is what we have to deal with.

We've learned from experience that the truth will come out. Other experimenters will repeat your experiment and find out whether you were wrong or right. Nature's phenomena will agree or they'll disagree with your theory. And, although you may gain some temporary fame and excitement, you will not gain a good reputation as a scientist if you haven't tried to be very careful in this kind of work. And it's this type of integrity, this kind of care not to fool yourself, that is missing to a large extent in much of the research in cargo cult science.

A great deal of their difficulty is, of course, the difficulty of the subject and the inapplicability of the scientific method to the subject. Nevertheless, it should be remarked that this is not the only difficulty. That's why the planes don't land--but they don't land.

We have learned a lot from experience about how to handle some of the ways we fool ourselves. One example: Millikan measured the charge on an electron by an experiment with falling oil drops, and got an answer which we now know not to be quite right. It's a little bit off because he had the incorrect value for the viscosity of air. It's interesting to look at the history of measurements of the charge of an electron, after Millikan. If you plot them as a function of time, you find that one is a little bit bigger than Millikan's, and the next one's a little bit bigger than that, and the next one's a little bit bigger than that, until finally they settle down to a number which is higher.

Why didn't they discover the new number was higher right away? It's a thing that scientists are ashamed of--this history--because it's apparent that people did things like this: When they got a number that was too high above Millikan's, they thought something must be wrong--and they would look for and find a reason why something might be wrong. When they got a number close to Millikan's value they didn't look so hard. And so they eliminated the numbers that were too far off, and did other things like that. We've learned those tricks nowadays, and now we don't have that kind of a disease.

But this long history of learning how to not fool ourselves--of having utter scientific integrity--is, I'm sorry to say, something that we haven't specifically included in any particular course that I know of. We just hope you've caught on by osmosis

The first principle is that you must not fool yourself--and you are the easiest person to fool. So you have to be very careful about that. After you've not fooled yourself, it's easy not to fool other scientists. You just have to be honest in a conventional way after that.

I would like to add something that's not essential to the science, but something I kind of believe, which is that you should not fool the layman when you're talking as a scientist. I am not trying to tell you what to do about cheating on your wife, or fooling your girlfriend, or something like that, when you're not trying to be a scientist, but just trying to be an ordinary human being. We'll leave those problems up to you and your rabbi. I'm talking about a specific, extra type of integrity that is not lying, but bending over backwards to show how you're maybe wrong, that you ought to have when acting as a scientist. And this is our responsibility as scientists, certainly to other scientists, and I think to laymen.

For example, I was a little surprised when I was talking to a friend who was going to go on the radio. He does work on cosmology and astronomy, and he wondered how he would explain what the applications of his work were. "Well," I said, "there aren't any." He said, "Yes, but then we won't get support for more research of this kind." I think that's kind of dishonest. If you're representing yourself as a scientist, then you should explain to the layman what you're doing-- and if they don't support you under those circumstances, then that's their decision.

One example of the principle is this: 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.

I say that's also important in giving certain types of government advice. Supposing a senator asked you for advice about whether drilling a hole should be done in his state; and you decide it would be better in some other state. If you don't publish such a result, it seems to me you're not giving scientific advice. You're being used. If your answer happens to come out in the direction the government or the politicians like, they can use it as an argument in their favor; if it comes out the other way, they don't publish at all. That's not giving scientific advice.

Other kinds of errors are more characteristic of poor science. When I was at Cornell, I often talked to the people in the psychology department. One of the students told me she wanted to do an experiment that went something like this--it had been found by others that under certain circumstances, X, rats did something, A. She was curious as to whether, if she changed the circumstances to Y, they would still do A. So her proposal was to do the experiment under circumstances Y and see if they still did A.

I explained to her that it was necessary first to repeat in her laboratory the experiment of the other person--to do it under condition X to see if she could also get result A, and then change to Y and see if A changed. Then she would know the the real difference was the thing she thought she had under control.

She was very delighted with this new idea, and went to her professor. And his reply was, no, you cannot do that, because the experiment has already been done and you would be wasting time. This was in about 1947 or so, and it seems to have been the general policy then to not try to repeat psychological experiments, but only to change the conditions and see what happened.

Nowadays, there's a certain danger of the same thing happening, even in the famous field of physics. I was shocked to hear of an experiment being done at the big accelerator at the National Accelerator Laboratory, where a person used deuterium. In order to compare his heavy hydrogen results to what might happen with light hydrogen, he had to use data from someone else's experiment on light hydrogen, which was done on different apparatus. When asked why, he said it was because he couldn't get time on the program (because there's so little time and it's such expensive apparatus) to do the experiment with light hydrogen on this apparatus because there wouldn't be any new result. And so the men in charge of programs at NAL are so anxious for new results, in order to get more money to keep the thing going for public relations purposes, they are destroying--possibly--the value of the experiments themselves, which is the whole purpose of the thing. It is often hard for the experimenters there to complete their work as their scientific integrity demands.

All experiments in psychology are not of this type, however. For example, there have been many experiments running rats through all kinds of mazes, and so on--with little clear result. But in 1937 a man named Young did a very interesting one. He had a long corridor with doors all along one side where the rats came in, and doors along the other side where the food was. He wanted to see if he could train the rats to go in at the third door down from wherever he started them off. No. The rats went immediately to the door where the food had been the time before.

The question was, how did the rats know, because the corridor was so beautifully built and so uniform, that this was the same door as before? Obviously there was something about the door that was different from the other doors. So he painted the doors very carefully, arranging the textures on the faces of the doors exactly the same. Still the rats could tell. Then he thought maybe the rats were smelling the food, so he used chemicals to change the smell after each run. Still the rats could tell. Then he realized the rats might be able to tell by seeing the lights and the arrangement in the laboratory like any commonsense person. So he covered the corridor, and still the rats could tell.

He finally found that they could tell by the way the floor sounded when they ran over it. And he could only fix that by putting his corridor in sand. So he covered one after another of all possible clues and finally was able to fool the rats so that they had to learn to go in the third door. If he relaxed any of his conditions, the rats could tell.

Now, from a scientific standpoint, that is an A-number-one experiment. That is the experiment that makes rat-running experiments sensible, because it uncovers that clues that the rat is really using-- not what you think it's using. And that is the experiment that tells exactly what conditions you have to use in order to be careful and control everything in an experiment with rat-running.

I looked up the subsequent history of this research. The next experiment, and the one after that, never referred to Mr. Young. They never used any of his criteria of putting the corridor on sand, or being very careful. They just went right on running the rats in the same old way, and paid no attention to the great discoveries of Mr. Young, and his papers are not referred to, because he didn't discover anything about the rats. In fact, he discovered all the things you have to do to discover something about rats. But not paying attention to experiments like that is a characteristic example of cargo cult science.

Another example is the ESP experiments of Mr. Rhine, and other people. As various people have made criticisms--and they themselves have made criticisms of their own experiements--they improve the techniques so that the effects are smaller, and smaller, and smaller until they gradually disappear. All the para-psychologists are looking for some experiment that can be repeated--that you can do again and get the same effect--statistically, even. They run a million rats--no, it's people this time--they do a lot of things are get a certain statistical effect. Next time they try it they don't get it any more. And now you find a man saying that is is an irrelevant demand to expect a repeatable experiment. This is science?

This man also speaks about a new institution, in a talk in which he was resigning as Director of the Institute of Parapsychology. And, in telling people what to do next, he says that one of things they have to do is be sure the only train students who have shown their ability to get PSI results to an acceptable extent--not to waste their time on those ambitious and interested students who get only chance results. It is very dangerous to have such a policy in teaching--to teach students only how to get certain results, rather than how to do an experiment with scientific integrity.

So I have just one wish for you--the good luck to be somewhere where you are free to maintain the kind of integrity I have described, and where you do not feel forced by a need to maintain your position in the organization, or financial support, or so on, to lose your integrity. May you have that freedom.

Saturday, August 30, 2014

Novartis fails to report side effects, fatality

Jiji PressNovartis Pharma K.K. said it has failed to report to the health ministry at least 2,579 cases of serious side effects, including a fatality, from its drugs for leukemia and other diseases even though its employees were aware of the problems.

Of the total, 1,313 cases were related to Glivec and 514 cases to Tasigna, both drugs for leukemia treatment, and 261 cases involved cancer drug Afinitor, said the Japanese unit of Swiss drug giant Novartis AG on Friday.

The findings were reported to the Health, Labor and Welfare Ministry the same day.

Marketing employees at the firm had recognized the side effects, but failed to report them to its division in charge in violation of its internal rules, Novartis Pharma said. They were not fully aware of the seriousness of the problem, while higher-ranking officials failed to supervise them properly, it said


Saturday cartoons

Saturday, August 16, 2014

Pharmalot is THE BEST

Illinois Suspends Michael Reinstein's Medical License

Michael Reinstein (Gerald Rich/ProPublica)

Illinois medical regulators have indefinitely suspended the medical license of psychiatrist Michael Reinstein, who prescribed more of the most powerful and riskiest antipsychotic drug clozapine than any other doctor in the country.

The decision by Illinois' Department of Financial and Professional Regulation, signed Friday, suspends Reinstein's license for a minimum of three years, at which time he can apply to have it reinstated.

The state's medical disciplinary board recommended the sanction in May after determining that Reinstein, 71, received "illegal direct and indirect remuneration" from the maker of generic clozapine; did not consider alternative treatments for his patients; and disregarded patients' well-being because of potentially life-threatening side effects of the drug. Reinstein's motion for a rehearing was denied Friday, making the matter public.

Clozapine is approved to treat patients who don't respond to other medications. But it can have dangerous side effects, including seizures, inflammation of the heart muscle, and a drop in white blood cells. The drug is considered particularly dangerous for elderly patients.

Reinstein's prescribing patterns have been explored in two ProPublica reports.

In 2009, ProPublica and the Chicago Tribune detailed how he had prescribed more of the antipsychotic clozapine to patients in Medicaid's Illinois program in 2007 than all doctors in the Medicaid programs of Texas, Florida and North Carolina combined. Autopsy and court records showed that, by 2009, at least three patients under Reinstein's care had died of clozapine intoxication. At that time, Reinstein defended his prescription record, arguing that clozapine is effective and underprescribed.

Last year, as part of an investigation into Medicare's failure to monitor problem prescribers, ProPublica reported that Reinstein prescribed even more clozapine in Medicare's prescription drug program for seniors and the disabled. We found that the program continued to let him prescribe even after the U.S. Department of Justice accused him of fraud and Illinois' Medicaid program suspended payments to him.

Reinstein's attorney did not return a phone call or email seeking comment. An outgoing message on Reinstein's cell phone said, "Due to a personal emergency I will not be working as of today. I will return to work as quickly as I can."

In their response to the medical board's accusations, Reinstein's lawyers invoked his right against self-incrimination.

The state of Illinois has the authority to permanently revoke a doctor's license, but typically only does so for sex crimes or assaults on patients, a spokeswoman said by email. When a doctor's license is indefinitely suspended, as is the case with Reinstein, the doctor must apply after a set time to return to practice; the state's approval is not automatic.

The federal fraud lawsuit against Reinstein is pending in U.S. District Court in Chicago. In a November 2012 news release announcing the case, the government said that Reinstein "received illegal kickbacks from pharmaceutical companies and submitted at least 140,000 false claims to Medicare and Medicaid for antipsychotic medications he prescribed for thousands of mentally ill patients in area nursing homes."

Prosecutors allege that Reinstein's prescribing decisions were motivated by money and perks from pharmaceutical companies. He allegedly switched patients from one brand of clozapine to another based on money and other enticements he received from a drugmaker.

In March, Teva Pharmaceutical Industries Ltd., the maker of generic clozapine,agreed to pay more than $27.6 million to settle state and federal allegationsthat it induced Reinstein to prescribe the drug.

Reinstein's prescribing of clozapine appears to have declined after the 2009 articles about him. From 2007 to 2009, he wrote an average of 20,000 Medicare prescriptions annually for clozapine and a brand-name version, FazaClo. That figure dropped to about 8,000 in 2012, according to data obtained by ProPublica.

Check out how your doctor's prescribing within Medicare compares to others in his or her specialty in your state. Visit ourPrescriber Checkup tool.

Sunday, August 10, 2014

Friday, July 25, 2014

Dr. Frances Oldham Kelsey is 100

Happy 100th birthday to Dr. Frances Oldham Kelsey, the pharmacologist whose bold stance against inadequate drug testing saved countless newborns from the perils of thalidomide, a drug which caused severe birth defects in over 10,000 infants. On her first month on the job at the U.S. Food and Drug Administration in 1960, the Canadian-born scientist resisted pressure from thalidomide's manufacturer to quickly approve the drug, which was already being widely prescribed in Europe as a painkiller for pregnant women. As a result of Dr. Kelsey's insistence on further safety testing, the drug was never approved in the US, saving an untold number of children from its devastating effects.
When Dr. Kelsey started working at the FDA, she was part of a new generation of scientists who wanted to ensure that drugs were proven safe and effective before being marketed to the public. At the time, the FDA did not have the authority to enforce these requirements and pharmaceutical companies often engaged in minimal safety testing. It was even a common practice for companies to send new or experimental drugs to doctors for them to try out on their patients.
When Dr. Kelsey received the application from the Richardson-Merrell Company for approval of thalidomide, the company expected a fast approval since the drug was already in use in numerous countries including Germany, the UK, and Australia. Distrustful of the information provided by the company and, as she later explained, feeling that its representatives were "at no time being wholly frank with me" about the drug's safety, Dr. Kelsey told the company further tests were needed. Over several months, the company continued to submit their application and Dr. Kelsey continued to reject it citing the need for additional tests.
Throughout this period, the company complained to her supervisors, contacted her repeatedly, and, as written in a 1962 Washington Post story, she "[lived] the while with insinuations that she was a bureaucratic nitpicker, unreasonable – even, she said, stupid." Dr. Kelsey's determined stance was vindicated eight months after the company's initial filing when evidence from Europe showed that thalidomide was the cause of severe birth defects. In Germany alone, between 5,000 and 7,000 children were born without limbs or with flipper-like limbs, of which only 40% survived, and numerous cases emerged in other countries.
After news of the thalidomide disaster broke, there was huge public outcry for better drug testing and the U.S. Congress unanimously passed the Kefauver Harris Amendment in 1962 to strengthen drug regulations and gave the FDA enforcement authority. Dr. Kelsey was selected to help write the rules governing clinical trials -- rules that have since been adopted throughout the industrialized world -- and then oversee their enforcement as the chief of the Division of New Drugs.
On August 7, 1962, Dr. Kelsey became the second woman ever to receive the country's highest civilian honor when President John F. Kennedy awarded her the President's Award for Distinguished Federal Civilian Service. Dr. Kelsey's far-reaching impact on science and drug testing was described by Harvard historian Daniel Carpenter as follows: "She had a huge effect on the science that we all take for granted today... She and the F.D.A. had a huge role in determining the terms and sequence of what is now modern clinical science."
Dr. Kelsey retired from the FDA in 2005, after 45 years of service, at the age of 90. The FDA has established the Dr. Frances O. Kelsey Award to "celebrate courage and scientific decision-making."
To read more about Dr. Kelsey, the NY Times wrote an excellent tribute for her 96th birthday at

Sunday, July 20, 2014

Poetry Corner - Cancer's a funny thing

J.B.S. Haldane retained his wit even while undergoing cancer treatments — he wrote this poem in a hospital in 1964:

I wish I had the voice of Homer
To sing of rectal carcinoma,
Which kills a lot more chaps, in fact,
Than were bumped off when Troy was sacked.

Yet, thanks to modern surgeon’s skills,
It can be killed before it kills
Upon a scientific basis
In nineteen out of twenty cases.

I noticed I was passing blood
(Only a few drops, not a flood).
So pausing on my homeward way
From Tallahassee to Bombay
I asked a doctor, now my friend,
To peer into my hinder end,
To prove or to disprove the rumour
That I had a malignant tumour.
They pumped in BaS04
Till I could really stand no more,
And, when sufficient had been pressed in,
They photographed my large intestine.
In order to decide the issue
They next scraped out some bits of tissue.
(Before they did so, some good pal
Had knocked me out with pentothal,
Whose action is extremely quick,
And does not leave me feeling sick.)
The microscope returned the answer
That I had certainly got cancer,
So I was wheeled into the theatre
Where holes were made to make me better.
One set is in my perineum
Where I can feel, but can’t yet see ‘em.
Another made me like a kipper
Or female prey of Jack the Ripper,
Through this incision, I don’t doubt,
The neoplasm was taken out,
Along with colon, and lymph nodes
Where cancer cells might find abodes.
A third much smaller hole is meant
To function as a ventral vent:
So now I am like two-faced Janus
The only* god who sees his anus.

*In India there are several more
With extra faces, up to four,
But both in Brahma and in Shiva
I own myself an unbeliever.

I’ll swear, without the risk of perjury,
It was a snappy bit of surgery.
My rectum is a serious loss to me,
But I’ve a very neat colostomy,
And hope, as soon as I am able,
To make it keep a fixed time-table.
So do not wait for aches and pains
To have a surgeon mend your drains;
If he says “cancer” you’re a dunce
Unless you have it out at once,
For if you wait it’s sure to swell,
And may have progeny as well.
My final word, before I’m done,
Is “Cancer can be rather fun.”
Thanks to the nurses and Nye Bevan
The NHS is quite like heaven
Provided one confronts the tumour
With a sufficient sense of humour.
I know that cancer often kills,
But so do cars and sleeping pills;
And it can hurt one till one sweats,
So can bad teeth and unpaid debts.
A spot of laughter, I am sure,
Often accelerates one’s cure;
So let us patients do our bit
To help the surgeons make us fit.


Haldane succumbed to his cancer in December 1964.

Hat tip:

Thursday, July 17, 2014

GlaxoChinaGate contd. - now GSK admit they had previous form

GlaxoSmithKline China: Company admits to bribery scandal in 2001

GlaxoSmithKline (GSK) has admitted that members of its staff were caught bribing Chinese officials back in 2001, according to the Financial Times.

The new information has emerged as the pharmaceutical giant faces intense scrutiny from authorities in the UK and US regarding the alleged bribing of doctors and officials to boost drug sales to China. Police in the country have accused GSK of "ordering" the bribes.

The FT report suggests that GSK was forced to fire 30 employees back in 2001 after it found staff were taking kickbacks and bribing Chinese officials.

The older allegations are relevant to the new case because if it were to emerge that there was a pattern of such behaviour from GSK, the US department of Justice (DoJ) would be likely to treat the current allegations more seriously and impose tougher sanctions. 

The current GSK chief executive, Sir Andrew Witty, was in charge of the company's operations in Asia Pacific in 2001, but China was not within his purview. GSK has said that Witty was neither involved in, nor aware of, the case. 

Chris Baron was head of the vaccination program in China at the time. Mr. Baron indicated that he was cleared of wrongdoing, but that it was suggested he should have exercised greater diligence.

Wednesday, July 16, 2014

AllTrials News - Out of 400 trials on, 30% haven’t reported results

A new study found that 118 of 400 clinical trials had not reported results four years later in either a journal or on The researchers randomly selected trials that were registered on and listed as completed in 2008. They found that trials were equally likely to report results regardless of whether or not they were funded by industry.

This is yet one more study to look at the reporting of clinical trial results. The best available evidence is still that around half of all clinical trials have never been published or reported their results.

Dr Christopher Gill, the study’s lead author and director of Boston University School of Public Health’s Pharmaceuticals Program:

Promoting transparency in clinical trials is an intrinsic public health good.

Individuals who volunteer for clinical trials often do so out of a sense of altruism. I can imagine that many would be dismayed to learn that the results of a study that they participated in, that they took physical risks for, might never generate results known beyond the company that sponsored the trial.

Science learns from mistakes, as well as successes. If we only learn about the scientific success stories, we are really only seeing part of the picture.

Dr Ben Goldacre, co-founder of the AllTrials campaign:

We should never lose sight of how frightening these results are. Many in industry and academia have tried to brush this problem under the carpet: AllTrials is the beginning of that being impossible. Now that the mainstream narrative has shifted, we need concerted, concrete action from patient groups, professional bodies, regulators, policy makers, health services, and individual companies. The entire medical community needs to work together to ensure that the full methods and results of all trials, on all uses, of all currently prescribed treatments are made fully available. Without that, doctors and patients cannot make informed decisions about which treatment is best.

Thursday, July 10, 2014

Big Pharma pushes the Snake Oil approach

FDA has free-speech, safety issues to weigh in review of ‘off-label’ drug marketing rules

Should a pharmaceutical sales rep be allowed to tell a doctor that Topamax, a drug approved to treat seizures and prevent migraine headaches, might also help combat alcohol dependence? Or suggest the epilepsy drug Neurontin could also help treat bipolar disorders or insomnia? Or offer data showing that any number of other drugs could have uses beyond those listed on their labels?

For decades, the answer overwhelmingly has been no. The Justice Department has aggressively pursued companies that run afoul of rules against such “off-label” marketing — racking up billions of dollars in settlements. And the Food and Drug Administration has held firm to the idea that sales pitches generally should not include information on uses not approved by the agency.

But in the long-running conflict between federal regulators and drugmakers over how companies promote their drugs for unapproved uses, the landscape could be shifting, if only in subtle ways, and the outcome could affect doctors and patients alike.

Prompted in part by recent federal court decisions, the FDA is reviewing its rules on what kind of data drug companies should be allowed to distribute to doctors regarding off-label uses, as well as how they should respond to unsolicited questions from physicians about those uses. Its goal is to issue new guidelines by the end of the year.

Critics of the current rules say allowing pharmaceutical companies, which know the most about their drugs, to share more information about off-label uses would lead to better-informed physicians and ultimately benefit patients. Others are skeptical, saying the industry could exploit even a minor loosening of the restrictions to hype drugs for unapproved uses, exposing patients to ineffective and potentially harmful treatments.

Tablets of varying doses of Johnson & Johnson's Topamax migraine medicine. (JB Reed/Bloomberg News)

Traditionally, the FDA has approved drugs for specific conditions, and only after rigorous clinical trials for safety and effectiveness. It bars companies from promoting their products for off-label uses, a practice known as “misbranding.” Doctors are free to prescribe drugs for unapproved uses, and many do. The government, through Medicare, recognizes some off-label uses and covers their prescription.

In recent years, pharmaceutical companies have petitioned the FDA for clearer guidance, arguing that the rules are confusing and overly restrictive, especially in an age of social media and widespread access to reams of data beyond what is on any drug label. In addition, high-profile court decisions have bolstered drugmakers’ argument that the off-label rules violate their free-speech rights under the First Amendment, as long as the information being provided to doctors is truthful and not misleading.

In 2011, the Supreme Court struck down a Vermont law banning drugmakers and data-mining companies from accessing records about the prescribing habits of doctors as part of their marketing strategies. In late 2012, a federal appeals court reversed the conviction of a New York pharmaceutical representative, Alfred Caronia, who had been charged with promoting a litany of off-label uses of the narcolepsy drug Xyrem. Caronia, whose conversations with doctors had been recorded, argued that the government had violated his free-speech rights because it had not shown that his sales pitches were false or misleading. By a 2-to-1 vote, the federal appeals court agreed. The government chose not to appeal the case.

Some industry officials say the FDA has been slow to adjust to the reality of those court rulings.

“They were in denial,” said John Kamp, executive director of the Coalition for Healthcare Communication, which represents drug marketing agencies and medical publishers. “If doctors can talk to each other and major researchers can talk about off-label uses, the drug’s manufacturer should be able to talk about those uses, too.. . . If something is true and can be said by one party, it can be said by all other parties.”

That interpretation worries some regulators and public health officials who say relaxing the rules could undermine the FDA’s traditional gatekeeper role.

If First Amendment legal challenges prove successful, they “would turn back FDA’s proactive role in American medicine and jeopardize the safety of patients, as well as the future of innovation and medical progress,” FDA Commissioner Margaret A. Hamburg said in a 2010 speech.

She pointed to legislation, passed by Congress a half-century earlier, requiring drug manufacturers to provide robust evidence of a drug’s effectiveness before it begins promoting it. That meant “the best drugs, rather than the most aggressively marketed drugs, could rise to the top,” she said, adding, “Removing these protections would ignore the lessons of history.”

There are practical problems, too, said Aaron Kesselheim, a Harvard Medical School professor who has studied off-label promotion. Who gets to decide what qualifies as “truthful” information when it comes to sharing data about unapproved drug uses?

“Is it what the company with a financial conflict of interest says it is?” he said. “Or is it what a scientist at the FDA says it is? That’s the central tension here.”

So why don’t drugmakers more routinely seek FDA approval for new uses for existing drugs?

“In the ideal world, clinical trials would be quick, easy to conduct and free. Unfortunately, none of those conditions are true,” said Jeff Francer, vice president and senior counsel at the Pharmaceutical Research and Manufacturers of America. “Depending on where a drug is in its life cycle, it may not make economic sense for a company to pay for years of clinical study when the medicine is going to lose its patent in a short amount of time.”

That does not mean pharmaceutical companies should be barred from giving doctors legitimate information that comes to light after a drug’s initial FDA approval, Francer said. “Right now, the FDA essentially prohibits the communication of large swaths of information that is truthful and not misleading,” he said. “That information can be extremely beneficial.”

But doctors in hectic, real-life settings often do not have the time to sort through the literature or decipher which data is solid and which is suspect, said Michael Wilkes, a medical professor at the University of California at Davis who has written about drug promotion. “It’s hard to know what’s legitimate and what’s not,” he said. “I’d like to see [the FDA] err on the side of overregulation and making companies prove that these drugs work” for off-label uses.

For their part, FDA officials say they are trying to find a reasonable balance. In a statement, the agency said that given “the emerging case law,” it is working to “harmonize the fundamental public health interests underlying FDA’s mission and statutory framework with the interests in the dissemination of truthful and non-misleading information.”

The agency permits companies to share certain off-label information with doctors, though with plenty of strings attached. For instance, the FDA has said manufacturers can distribute certain peer-reviewed medical-journal articles, but the articles should be unabridged and handed out separately from drug promotional materials. Also, the FDA says, companies should disclose any funding of the research behind such articles.

Thus far, the wrangling over the rules appears to have had little effect on the Justice Department’s determination to take on misbranding cases.

Last fall, Johnson & Johnson agreed to pay $2.2 billion to resolve civil and criminal allegations involving the marketing of off-label, unapproved uses for the antipsychotic drug Risperdal to the elderly, children and mentally disabled people, among other accusations. The previous summer, British manufacturerGlaxoSmithKline agreed to plead guilty to criminal offenses and to pay $3 billion to settle charges that included promoting its best-selling antidepressants for off-label uses.

Kamp, of the Coalition for Healthcare Communication, said the FDA has an opportunity this year to provide clarity on what has long remained a murky and contentious issue. 

“As this plays out and the rules get more clear and more consistent with the First Amendment, the doctors who prescribe drugs and the patients who take them are going to know more about the safety and efficacy of those drugs than they would without these changes in the rules,” Kamp said. “It’s going to be a step forward.”

Wilkes, the medical professor, disagrees. Without maintaining stringent rules and harsh penalties for violating them, he says, companies could too easily push drugs for uses without the solid evidence to support them.

He pointed to the case of Vioxx, a once-popular painkiller that Merck, its manufacturer, illegally promoted for rheumatoid arthritis before the drug was discovered to actually increase risks for heart attacks.

“Our fiduciary responsibility is to our patients. This isn’t about profits. It’s really about patient safety,” Wilkes said. “As a rule, we ought to be offering our patients treatments and cures and interventions that have been proven to work.”

Wednesday, July 09, 2014

Servier distort competition

BRUSSELS — The European Union's antitrust body is imposing a fine of 428 million euros ($580 million) on France's pharmaceutical company Servier and five producers of generic medicines for distorting competition.

The 28-nation bloc's executive Commission on Wednesday said Servier struck a series of deals with the producers of generic medicines to protect its bestselling blood pressure medicine, Perindopril, from price competition.

EU competition chief Joaquin Almunia says Servier's practices of "systematically buying out any competitive threats" to protect its market was "clearly anti-competitive and abusive."

The Commission says Servier must pay a fine of 331 million euros ($450 million). The remaining fine of about 100 million euros is split between the five producers of generic medicines according to the extent of their involvement. They are Niche/Unichem, Matrix, Teva, Krka and Lupin.

Tuesday, July 08, 2014

Advocate Groups Reach Out to President's Science Advisors Ahead of Antibiotics Meeting | Food Safety News

The President’s Council of Advisors on Science and Technology (PCAST) will meet Friday to discuss its work on antibiotic resistance and nanotechnology and to hear from speakers about oceans policy.

A group of public health, consumer, and environmental protection organizations have sent a letter to PCAST expressing concern that the U.S. Food and Drug Administration’s Guidance for Industry #213 and a proposed Veterinary Feed Directive (VFD) rule do not go far enough in addressing antibiotic overuse on farms.

By March, FDA had heard from 25 of the 26 drug manufacturers affected by Guidance #213 that they would comply. In a six-month progress report issued last week, the agency announced that the final sponsor has also confirmed its engagement.

The letter to PCAST reiterates the criticism that the focus on removing growth promotion from labels will still allow for overuse under the guise of “disease prevention.”

And a recent letter to FDA from Keep Antibiotics Working noted that companies might still continue extra-label marketing for growth promotion and other benefits.

“Another key policy flaw is the proposed removal from the existing VFD regulations of a federal valid veterinary-client-patient relationship (VCPR) standard,” reads the PCAST letter. “FDA has stated that one of the goals of the revision is to end over-the-counter use in feed, but there is no clear substitute in federal or state law that ensures on-farm veterinary engagement regarding antibiotic use in animal feed.”

The list of more than 20 signatories includes the American Academy of Pediatrics, the Center for Foodborne Illness Research and Prevention, the Center for Science in the Public Interest, the Consumers Union, the Environmental Working Group, Food and Water Watch, the Johns Hopkins Center for a Livable Future, Keep Antibiotics Working, the Natural Resources Defense Council and the Pew Charitable Trusts.

The groups are calling for PCAST to recommend restoring the CVPR standard and “additional policy measures that would rein in all indiscriminate, untargeted, and unnecessary antibiotic use in meat and poultry production.”

Laura Rogers, director of Pew’s campaign on human health and industrial farming, told Food Safety News that the groups were worried that PCAST seemed uncertain as to how to proceed after its initial meeting regarding antibiotics in April.

The committee was trying to ascertain just how much agriculture usage contributes to the antibiotic resistance problem in humans, but this is a very difficult question to answer because of lack of pertinent data.

Pew and many others await PCAST’s report on antimicrobial resistance. It won’t be issued before Friday, but it could come soon after.

“Our worry is that because it’s the animal side and they were asking questions like, ‘What’s the biggest contributor?,’ that they’re going to cordon off this issue and set it aside and just focus on human medicine and the need for spurring innovation of new drugs,” Rogers said.

She added that Salmonella antibiotic resistance data released by the National Antimicrobial Resistance Monitoring System (NARMS) last week illustrates the need for more granular-level data to figure out how to stop creating superbugs.

In early May, the World Health Organization (WHO) released a global report finding that surveillance of antibiotic resistance is generally “neither coordinated nor harmonized, compromising the ability to assess and monitor the situation.”

“I can’t imagine a [PCAST] report that would come out that wouldn’t address the need for better surveillance both in human medicine — how we’re using them and why — and on the animal side,” Rogers said. “We have enough data to act, but we need more information to know the strategic ways we can go in and cut out broad overuses of the drugs.”

The U.S. is “woefully behind much of the rest of the world,” especially Europe, in terms of confronting antibiotics overuse, Rogers added.

France recently published an assessment of the risks of emerging antimicrobial resistance related to patterns of antibiotic use in animal health, following the government’s decision to reduce the use of antibiotics in veterinary medicine over the 2012-2017 period (the Ecoantibio 2017 plan).

Sweden has challenged the European Union to match its own livestock welfare standards, which include medicating animals only when they are ill.

On June 25, the Netherlands hosted an international conference on antibiotic resistance as a follow-up to the WHO report. During her address, the Dutch Minister of Health, Welfare and Sport, Edith Schippers, said that, “When it comes to agriculture — it is my firm belief that we should ban the use of our last-resort antibiotics in animal husbandry all together.”

And, on July 1, U.K. Prime Minister David Cameron announced the creation of a new review panel that will investigate antibiotic overuse generally and why new drugs are not being developed.

“To my knowledge, no one with an equivalent position in the US government has ever spoken so directly or substantially about antibiotic resistance — and particularly not about the politically contentious (though scientifically settled) problem of drug use in agriculture,” wrote Maryn McKenna in her Wired blog post about Schippers and Cameron. “Imagine Obama speaking out about antibiotic resistance. What a powerful statement of priorities that would be.”

Although the PCAST report on its own will not be able to compel FDA action, Rogers said she hopes it will prompt the Obama administration to follow with an action plan on how to address the issue.

“FDA has taken this step [with Guidance #213], but the agency is just moving at a pace that is not equal to the public health crisis that we’re facing when it comes to antibiotic resistance,” she said. “Hopefully, the report will add some fire to getting the agency to move more quickly.”

What is called "guolaosi" in Chinese and "karoshi" in Japanese?