Tuesday, May 21, 2013
Monday, May 20, 2013
This system, which has been in place for decades, at one time benefitted doctors by keeping them up to date on new medications, and always provided generous amounts of "free" samples to get patients started on the newest drugs, as well as other supplies and gifts.
But it's actually a powerful marketing process into which the pharmaceutical industry pours tens of billions of dollars a year, with more than 90,000 drug representatives providing gifts and advice. There is one drug representative for every eight doctors in the United States. This doesn't necessarily serve the best interests of the patient in terms of economy, efficacy, safety or accuracy of information, experts say.
In one of the first reports of its type – titled "Breaking Up is Hard to Do" - researchers from Oregon State University, Oregon Health & Science University and the University of Washington outlined the deliberate process that one central Oregon medical clinic went through to remove drug company representatives from their practice. It explored the obstacles they faced and the ultimate, successful result. The findings were just published in the Journal of the American Board of Family Medicine.
The study found that avoiding conflicts of interest and becoming "pharma-free" is possible, but not easy.
"This is a culture change, one that's already happening but still has a ways to go, especially in smaller private practices," said Dr. David Evans, now with the Department of Family Medicine at the University of Washington, and previously a physician at the Madras, Ore., clinic featured in the article.
"The relationship between physicians and drug company representatives goes back generations, and it took a methodical, deliberate campaign to change it," Evans said. "We ultimately decided something had to be done when our medical clinic was visited by drug reps 199 times in six months. That number was just staggering."
Part of what allows the change, the researchers said, is that information on new medications is now available in many other forums. These may have less bias and be more evidence-based than the material traditionally provided by the pharmaceutical industry, which wanted to sell the latest product. In the Madras clinic, the physicians replaced information previously supplied by drug reps with monthly meetings to stay current on new medications, based on peer-reviewed, rather than promotional literature.
"In the past 5-10 years there's been more of a move toward what we call 'academic detailing,' in which universities and other impartial sources of information can provide accurate information without bias," said Daniel Hartung, assistant professor in the OSU College of Pharmacy. "This is being supported by some states and the federal government, and it's a move in the right direction."
Moves to separate the drug industry from the practice of medicine have been more aggressive in large medical teaching hospitals, Hartung said, but much less so in smaller private practice. Of the 800,000 physicians in the U.S., only 22 percent practice in academic settings, the study noted, and 84 percent of primary care physicians still have close relationships with the pharmaceutical industry.
The stakes can be high, the researchers said. In the study example, the "sample cabinet" of medications at the Madras clinic, provided for free by the pharmaceutical representatives, had an average price of $90 for a month's supply of the medications. Less expensive, generic medications were identified for 38 of the 46 sample drugs, which would have cost $22 a month.
The new analysis explored the necessary steps that a private clinic can take to help address this concern, including quantifying the clinic-industry relationship, anticipating clinician and staff concerns, finding new ways to provide up-to-date information, and educating patients and the public.
By: Reuters With CNBC.com
Generic drugmaker Actavis, which has been the subject of intense takeover speculation, said on Monday that it had struck a deal to buy specialty pharmaceuticals company Warner Chilcott for $8.5 billion in stock.
The move comes as Actavis has spurned approaches from Canadian pharmaceutical company Valeant Pharmaceuticals International and Mylan. Analysts have said that if Actavis were to buy Warner Chilcott, it would kill the chances of its being taken over.
Ketamine Associated With Rapid Antidepressant Effect In Largest Clinical Trial To Date
|Patient / Public:|
Thalidomide, despite its sordid past is undergoing a sort of renaissance and is being manufactured and used worldwide for a variety of illnesses including leprosy
The Thalidomide story had a complex course, full of unintended discoveries, with unforeseen consequences including the elements of an adventure story; heroes and heroines, bad guys, villains, intrigue, deception, antagonists and protagonists, even Nazis.
It was December 25, 1956. In Stollberg, Germany. A young, nervous, to-be Dad was waiting for news from the delivery room. His wife was giving birth. He worked as a chemist for the German pharmacy company Grunenthal. Later, the doctor gave him disturbing news; his child had no arms, and only vestigial flipper-like hands, a condition known as phocomelia, Greek for seal arms.
No one could know that in reality the world had received its first Thalidomide baby. The chemist had been given some samples of his company’s new wonder drug for nausea, especially nausea of pregnancy. Later he would learn that only one such baby had been born in Germany with phocomelia within the last twenty years, and that it was thought to be rare birth defect that ran in families. This is where most narratives of Thalidomide usually start.
But the story began much sooner; in the 1930’s. Persistent investigations by independent investigators and representatives of the England-based Thalidomide Trust have uncovered a different beginning. And, slowly, more and more information is coming to light. And now it’s probably safe to assert there was a very different beginning to this story.
The scope of the Thalidomide disaster was worldwide. Over the course of four years, from 1957 to 1961, it was licensed for manufacture and sales in over 50 countries and was the cause of uncountable miscarriages and still births and over twelve thousand “flipper babies.”
As a result, requirements for new drug applications were changed and the drug companies themselves modernized using more science than anecdote before declaring new drugs safe and effective.
Even after all this time some questions remain: what was its origin and why are its effects so different in humans than in animals?
Drug #4589 will end up being Thalidomide in our story. But before we get there we need to tell the story of Sarin, the deadly nerve gas stockpiled by Germany during the Second World War, and also by the United States and Russia after the war.
In 1938, near the town of Wuppertal Germany, Gerhard Schrader, a chemist, was working for the drug company I. G. Farbin to develop insecticides. He had been interested in some 1932 experiments done by the German biochemist Willy Lange and his graduate student Gerde von Krueger. The role of a chemical called acetylcholine in the transmission of nerve impulses was well known, and the effects of the organophosphate class of drugs, by inhibiting the action of a component of that transmission, acetylcholine esterase, had been investigated in the 1932 experiments. Schrader was trying to use Lange’s work to help him develop insecticides.
The story developed quickly after a laboratory accident occurred. A vial of the experimental insecticide spilled onto a bench causing distressing symptoms in the unprotected scientists. They were salivating and tearing uncontrollably, had a tightness in their throats and dim vision. All survived. At this point, Schrader was required by German law to report his discovery to the German war ministry. Law required any discovery that might be of possible military use to be reported.
Shortly thereafter, in mid-1939, Schrader found himself in occupied France at the Rhone-Poulenc chemical plant helping to produce mass, war-grade, amounts of what was eventually named Sarin. It was one of several reported mass production plants.
The nerve gas Sarin was named after the names of its developers at the French chemical plant Rhone-Poulenc.
S for Gerhardt Schrader
A for Otto Ambrose
R for Rudiger
IN for Vanderlind
Hitler visited one of the plants and when he proposed using the gas he was told the Allies would be able to manufacture much more of it than Germany could. After this, the war ministry instructed the scientists to develop an antidote to Sarin. Documents discovered by the investigative journalist, Carlos De Napoli, clearly show that the job of developing an antidote was given to Otto Ambrose, an executive with the I.G. Farben plant in Germany.
Ambrose was joined by Schrader and together, at the Rhone-Poulenc lab and at other locations did experiments on humans and animals, gathering information on their antidote drug. During their testing of the compound as an antidote to nerve gas, the scientists noted that it was also a very effective sedative and tranquilizer, and that it was impossible to overdose on it.
For their human experimentations Ambrose and Schrader were convicted of war crimes. Ambrose was in prison for eight years and later worked for Grunenthal. Both men died in 1990, within weeks of each other.
And as far as being an antidote for Sarin, a memo dated November 13, 1944 from Fritz ter Meer, an I.G. Farben executive to Karl Brandt, an SS officer and Hitler’s personal physician, stated that a drug referred to as Drug #4589 had been tested and was ready for use. The lab at the Rhone-Poulenc plant where Ambrose had done his original work was in reality producing Thalidomide.
Soon after the war, Rhone-Poulenc and all its secrets were purchased by a German based chemical firm named Astra Laboratories after. The smoking gun in this investigation is a recently discovered 1946 memo from Astra to its subsidiary in Norway which says “We cannot use the name Contergan in your area as rights to the name and the right to distribute it was sold to Grunenthal in an agreement with Rhone-Poulenc shortly after the war.”
Grunenthal has always held that it was the sole inventor of Contergan and that three of its employees developed the drug without any knowledge of earlier work. One of those employees: Otto Ambrose, after he was released from being in prison for his war crime convictions. Grunenthal was founded in 1946 by Alfred and Herman Wirtz, members of the Nazi party who also happened to be twins. Otto Ambrose began working for Grunenthal in 1952 two years before the patent for Contergan was awarded to the drug giant.
The question is, why would a post-war drug concern in Germany want to develop an antidote to Sarin?
Answer: They didn’t. It was thought, because of the findings when the drug was tested during the war, that Contergan could be a powerful antihistamine, and possibly a sedative. During the Grunenthal testing, it was noted it wasn’t a good allergy medicine but it was a very effective sedative/hypnotic and anticonvulsant. And animal testing showed it had a peculiar characteristic of rarely being fatal despite massive overdose. And it was particularly effective for treatment of nausea, including nausea of pregnancy. A curious observation, seen as unimportant at the time, was that human subjects seemed to be well sedated with the drug, while the animals tested didn’t seem to be sedated at all.
It was during these two years that Grunenthal also claimed to have done multiple animal experiments showing absolutely no mutagenic effects, no birth abnormalities. None. Contergan would be marketed as a treatment for nausea of pregnancy. Interestingly, when Grunenthal documents regarding the history and development of Contergan were subpoenaed for the civil actions against the company, it was reported that, regrettably, virtually all had been lost. Every last shred. Not one memo or lab note.
And now we’re up to where the story of Thalidomide usually begins; Christmas day, 1956, and the first seal baby.
Grunenthal claims to have started testing and development of their new wonder drug, Contergan, in 1953 and, as noted above, they thought they would have a antihistamine, but testing showed Contergan was fantastic as a sedative, tranquilizer, even anticonvulsant.
Animal testing showed it was virtually impossible to overdose with it and it was safe in pregnancy—not a single instance of teratogenesis, or malformation, was noted in hundreds of animal subjects. They received a patent in 1954 and began sales October 1,1957. They also licensed other companies for overseas production and sales; a total of 149 countries. Two major players: Distillers Limited of England and Merrell Laboratories of Cincinnati, Ohio.
England received quick approval for sales, in part due to the glowing reports of effectiveness and safety supplied by Grunenthal. They called their new product Distaval and the first packets were sold in April 1958. Merrell’s approval was not so easy, and the drug giant was frustrated by the Federal Drug Administration (FDA). A single low level clerk thought the reports were just too glowing, and she denied repeated applications from Merrell. “The reports are just anecdotal,” she would later write, “Too good, not a single side effect.”
One of the first people to surmise that something was wrong with Thalidomide was a young German lawyer living in Hamburg named Karl Shulte-Hillen. Both his sister and his sister-in-law had recently given birth to babies with phocomelia. He wondered if there was something wrong in his hometown, some contaminant perhaps, that might have affected both mothers. In June of 1961 he called the local medical university, asked for help, and was put in touch with a genetics professor, Widukind Lenz.
Professor Widukind Lenz was the sone of the infamous Dr. Fritz Lenz who, as a member of the Nazi party, had done genetics experiments on prisoners-of-war during the second world war.
Karl Shulte-Hillen with his wife and daughter, Jan. Shulte-Hillen was the attorney who was suspicious of the cause of two phocomelia babies in his neighborhood. From January 1962 Life.
Dr. Lenz was reportedly dubious of the young lawyer’s conviction that something was wrong in Hamburg, but he agreed to research the matter. Looking through birth stastistics for the last 25 years before 1960 he discovered that there had been only one documented case of phocomelia in the entire country. Since 1960 there had been 50. He was no longer dubious. And now convinced, Dr. Lenz tracked down the affected families and carefully interviewed them for any common thread that may have caused the deformities.
At exactly the same time, June, 1961, an Australian obstetrician, William McBride, had become suspicious after he delivered his third baby with phocomelia. He also had asked about a common element in all the cases and quickly concluded Distaval, the English brand name, was the prime suspect.
McBride had access to an animal lab and began experiments to reproduce the deformities. He was unable to induce phocomelia in any of the animal subjects. Nonetheless he went to the Australian manufacturer, DCBAL, and pleaded with them to withdraw Distaval from the market. DCBAL refused, citing the doctor’s inability to reproduce a single birth defect in his lab animals. Also, 23 women who had taken Distaval in their pregnancies delivered normal babies.
It was David and Goliath all over again.
Frances Kelsey, a pharmacologist Ph.D. and a medical doctor, was a new face at the Federal Drug Administration, FDA, office in Chicago. Her first assignment: The New Drug Application, NDA, for Kevadon, the Merrell Company’s Thalidomide version. Still operating under the 1938 Food, Drug and Cosmetic Act, her job was to review the application. She had 60 days after the original filing to notify Merrell of a rejection. Or to approve the drug, she simply would do nothing and the approval was automatic. The original NDA reportedly requested that the Kevadon be approved for pain, nervousness, and nausea of pregnancy or morning sickness.
The 1938 Drug approval law established an imperfect system which also allowed drug companies to conduct clinical trials of new drugs, without approval or consent, or notification of any agency, by distributing them to practicing physicians who would then submit anecdotal reports that would be used to support the NDAs.
But Dr. Kelsey was not impressed with anecdotes. Known as a meticulous methodical worker she would later write that she found the NDA just too good, too subjective, with no actual scientific data. The application had glowing testimonials and summary statements saying animal studies showed no ill effects, but no actual data. Importantly, she also noted the animals studied were not sedated in the slightest. She quickly surmised the effects in drug in humans was obviously different than in animals.
She rejected the original application, citing lack of data. Then she rejected the second request. By February of 1961, she had rejected Merrell a total of five times. The firm was reportedly frustrated by Kelsey, and complained vehemently to her superiors.
In the meantime Merrell continued its clinical trials with gusto. The final numbers showed 1267 physicians had distributed 2.5 million tablets to unsuspecting patients of all types, including pregnant women with morning sickness, a total of 20,000 patients. There were 10 phocomelia births from the U.S. distribution, 7 more cases were eventually determined to be from overseas sources; pregnant women would borrow the medicine from a friend or neighbor who had gotten the drug overseas or in Canada.
Dr. Frances Kelsey, c. 1961
Bottle of Thalidomide used during U.S. clinical trials.
Merrell continued their pressure for an approval of their NDA. As another 60 day deadline approached, Kelsey read a December, 1960 British Medical Journal article that linked Thalidomide to a painful side affect, peripheral neuritis; and the pain didn’t go away when the drug was stopped. What’s more, the effect was known, but never reported by Grunenthal or, more importantly to her, by Merrell. Kelsey was reportedly furious and immediately rejected the NDA again, requesting more data and a list of all the physicians who had given the drug during the clinical trials.
The drug had actually been distributed by Merrell’s marketing division, not its research division, and records were not well kept. A rough estimate of the amount of Thalidomide distributed: Five tons. Two tons of which have never been located.
So it was the peripheral neuritis which prompted the final rejection by Dr. Kelsey, not the birth defects. She was quoted as saying she always had the feeling that Merrell was not being complete candid. And once she determined that the peripheral neuritis complication had been withheld by the drug company her rhetoric heated up. “We are much concerned,” she included in her last rejection,” that apparently evidence with respect to the occurrence of peripheral neuritis in England was known to you but not forthrightly disclosed in your latest application.”
Meanwhile, Dr. McBride was still pressuring his local distributor in Australia to stop selling Distaval. Two more babies with phocomelia had been born in September of 1961. The drug company refused, but it forwarded McBride’s data to Grunenthal, in Germany.
The end was near. Dr. Lenz presented his data to Grunenthal at about the same time the Australian data reached them. They sent out an advisory to practitioners notifying them of the recent data. The German newspaper Welt am Sonntag, within a few days, headlined “Malformations from tablets.” And within a few days Grunenthal issued a recall, taking Contergan off the shelf. Without comment, Richardson-Merrell withdrew its NDA.
Final counts of still births and miscarriages can never be known. Over twelve thousand severely deformed babies were born.
But, despite its sordid past there is a Thalidomide rennaisance. What?
It has the makings of a whole separate article; The rebirth of Thalidomide as a wonder drug, well proven this time, is being manufactured and used worldwide for a variety of illnesses.
Thalidomide’s mechanism of action is thought to be its inhibition of the release of growth factors for new blood vessel formation. That’s why the deformities occurred, the new limb buds on the fetus could not generate a blood supply to the extremities. Still nobody knows why animals had no observable effects from Thalidomide. No sedation, no deformities, nothing. Something is different with humans. Thalidomide has two isomers, mirror images, and it’s known one form is active and the other isn’t. Other than that, no one knows why.
It is still manufactured, sold, and prescribed legally in many countries. Why? Because the same characteristic that made it so teratogenic, the inhibition of new blood vessel formation, makes it remarkably effective in a variety of diseases: Leprosy, Myeloma, AIDS complications, Lupus, Rheumatoid Arthritis, Macular Degeneration, and a few other rare conditions. Patients bedridden by Leprosy reportedly get up and walk painlessly within a few hours of a Thalidomide injection. To some, it appears to be a wonder drug, finally.
Brazil has one of the highest incidence rates of Leprosy in the world. It has legally manufactured and used Thalidomide since 1965 when it was accidentally discovered to reduce symptoms of the ancient disease and promote cures. It has also caused 63 phocomelia cases since 1965.
The most enigmatic question about Thalidomide remains.
Senior Correspondent Jones interviewing former Merrell National Labs executive Claude Griffin, Ph.D., in Texas. Above: Looking at the August 10, 1962 Thalidomide edition of Life magazine.
The reader may have guessed what it is, but first an interview with Claude Griffin, former Richardson-Merrell Vice-President for Global Affairs. Dr. Griffin had joined Merrell in 1970, and he knew most of the top executives who had been with the firm during the Thalidomide scandal.
Using several sources, I had tracked him down and he agreed to be interviewed for Health WorldNet. We met at his comfortable golf course home in north central Texas. He told me his biggest success in his job as vice-president for new drug development was Seldane, the world’s first non-sedating antihistamine.
Griffin: “It was the world’s first billion dollar drug. It helped a lot of people and made their lives a lot easier to live.” He also supervised the development of the first nicotine gum product and worked with several Nobel laureates.
Jones: “In your final position at Merrell you were Vice President of global operations, which included a lot of responsibilities I suppose. What was your greatest success in this management role?”
Griffin: “It wasn’t just me, it was all of us in the business of developing and marketing new drugs. The old way of evaluating drugs by using the anecdotal information obtained by ‘the old boy’ network of practicing physicians doing clinical trials was in need of change when I got to Merrell. Especially after the MER 29 mess.”
MER 29 was Merrell’s drug, developed in the late 1950s, it was the world’s first effective cholesterol lowering agent. It had the disastrous side affect of causing cataracts and Merrell executives were criminally charged with covering up evidence and coercing lab workers into falsifying data.
He talked a little about his company’s Thalidomide trials.
Griffin: “That whole way of doing things had to change. So we did. I had some creative differences with some people in new drug development. But after they retired I was able to bring our company around to a more scientific approach to evaluating our data.” The clinical trials without patient consent or knowledge also stopped by virtue of the 1959 Food and Drug act which required consent and put the burden on the drug companies to show safety and effectiveness.
Griffin: “And when we got microcomputers everything became so much easier. Instead of going through stacks of raw data looking for a trend, I could do it in a few seconds. We could finally show statistical significance. Use statistics and science.”He also gave me some information that I had not run across in my research for this article.
Griffin: “We did do our own animal testing on Thalidomide, thousands of tests, all kinds at different stages of gestation. And there wasn’t one single mutation or defect. Not a single one. I wish I knew why. To this day I don’t know why.”
And regarding the U.S. clinical trials he was emphatic.
Griffin: “All our clinical trials in those days distributed the drugs either with a written warning on the container, or an advisory to the physician not to use on women of childbearing age. It was standard operating procedure.”
The Bottom Line
The Thalidomide story points out the obvious. There are always two sides to a story. It appears that thalidomide has finally found its true calling.
However, the final enigma has never been answered, as far as this writer can determine. And that is: How and why was Thalidomide thought up, developed, and synthesized as a Sarin antidote in the first place? Out of all the possibilities in the world, why Thalidomide. No documents have ever been recovered, no lab notes, no files, nothing regarding what Ambrose and Schrader had been thinking.
None of the chemists and pharmacologists I interviewed for this story had the slightest clue. Thalidomide can be made in various ways. One of the easiest is to alter the substance called Glutamine, which occurs naturally in the body. Glutamine, itself, has nothing to do with acetylcholine function. Ambrose and Schrader never spoke publicly about their experiments and took whatever secrets they had to their final resting places, in 1990.
- Glauberman S, The Real Thalidomide Baby: The Evolution Of The FDA In The Shadow of Thalidomide, 1960 - 1997, Harvard Law School, Food and Drug Law, Winter 1997
- Lutz K, From Tragedy to Triumph: The Approval of Thalidomide, Harvard Law School, 1962
- Levy A, Nazis developed Thalidomide and tested it on concentration camp prisoners, author claims, MailOnline, February 08, 2009
- Frances Oldham Kelsey, WikiBooks
- von Moos R, Thalidomide: from tragedy to promise, Swiss Med Weekly, 2003, 133: 77-87
- The Thalidomide Trust
- Thalidomide UK Agency
- Nobody’s Perfect
Senior Correspondent Jones practiced emergency medicine in Southern California for 30 years and now writes for HealthWorldNet.com. He has also published several scientific papers as well as his novel A Murder in West Covina, Chronicle of the Finch-Tregoff case.
Saturday, May 18, 2013
In the United States, at least 9% of school-aged children have been diagnosed with ADHD, and are taking pharmaceutical medications. In France, the percentage of kids diagnosed and medicated for ADHD is less than .5%. How come the epidemic of ADHD—which has become firmly established in the United States—has almost completely passed over children in France?
Is ADHD a biological-neurological disorder? Surprisingly, the answer to this question depends on whether you live in France or in the United States. In the United States, child psychiatrists consider ADHD to be a biological disorder with biological causes. The preferred treatment is also biological--psycho stimulant medications such as Ritalin and Adderall.
French child psychiatrists don't use the same system of classification of childhood emotional problems as American psychiatrists. They do not use the Diagnostic and Statistical Manual of Mental Disorders or DSM.
According to Sociologist Manuel Vallee, the French Federation of Psychiatry developed an alternative classification system as a resistance to the influence of the DSM-3. This alternative was the CFTMEA (Classification Française des Troubles Mentaux de L'Enfant et de L'Adolescent), first released in 1983, and updated in 1988 and 2000. The focus of CFTMEA is on identifying and addressing the underlying psychosocial causes of children's symptoms, not on finding the best pharmacological bandaids with which to mask symptoms.
To the extent that French clinicians are successful at finding and repairing what has gone awry in the child's social context, fewer children qualify for the ADHD diagnosis. Moreover, the definition of ADHD is not as broad as in the American system, which, in my view, tends to "pathologize" much of what is normal childhood behavior. The DSM specifically does not consider underlying causes. It thus leads clinicians to give the ADHD diagnosis to a much larger number of symptomatic children, while also encouraging them to treat those children with pharmaceuticals.
- AstraZeneca hit by steep drop in profits (25 Apr 13)
- 'Anxiety drugs making Swedish fish go rogue' (15 Feb 13)
- Wallenbergs give new life to Södertälje research (25 Jan 13)
Friday, May 17, 2013
A Federal Court judge has refused drug company Merck's $540,000 settlement with Australians who claim its drug Vioxx caused them a heart attack, labelling the deal an "obvious injustice".
More than 1700 people joined a class action against the Australian arm of the international pharmaceutical company, claiming their heart trouble stemmed from taking its arthritis drug.
The parties reached a $540,000 settlement last month, subject to Federal Court approval, which would have resulted in the proceedings being dismissed and the matter finalised, meaning no future claims could have been brought against Merck over the drug.
Justice Christopher Jessup refused to approve the settlement on Friday, having last month expressed concern about its fairness.
The court had heard successful applicants would receive a maximum of $2000 if they were alive, and their estate would get $1500 if they were dead.
If the total payout for living claimants was to exceed $497,500, that figure would be divided equally among them.
The maximum payout for dead claimants would be $45,000.
It was estimated that only 200 to 300 claimants would meet the eligibility criteria, which required them to prove they suffered a heart attack after taking Vioxx for a certain period.
The lead plaintiff, Victorian grandfather Graeme Peterson, was awarded $330,000 in 2010 after Justice Jessup found Vioxx caused him to have a heart attack.
That decision was overturned on appeal to the Full Court but the judgment still allowed others to continue legal action over Vioxx.
Justice Jessup said the settlement had "very obvious advantages" for Mr Peterson, who would be relieved of hefty legal costs he owes to Merck after losing his case.
He said the claimants' law firm Slater and Gordon, who have spent millions of dollars on the case but will not receive any payment for their services, also "have a very real interest in securing the settlement".
But the settlement did not make an "important discrimination" between group members like Mr Peterson who had other risk factors when they had their heart attack, and those who had no other risk factors other than taking Vioxx, he said.
"For a group member who might, consistently with the reasons of the Full Court, anticipate a favourable judgment, the settlement would represent an obvious injustice," Justice Jessup said.
"(Mr Peterson) has taken upon himself the burden of conducting a representative proceeding.
"(It would) make it both unfair and unreasonable of him now, in effect, to walk away from the claims of those group members on the strength only of being able to settle the claims of the less deserving group members."
Claimant Trevor Whitehead, who objected to the settlement, said he was pleased there was potential for a better outcome.
"This case is complex and the settlement offer will also need to be complex in nature if the individual class members have any chance of receiving a fair and reasonable settlement for themselves," he told AAP.
The judgment means the parties can either try to renegotiate a new deal or take the case back to trial with a new lead plaintiff.
A Slater and Gordon spokesman said the firm was considering the judgment and would get instructions about options for the future of the proceedings.
Comment was sought from Merck.
Thursday, May 16, 2013
Pharma must provide convincing evidence of drug value
(Reuters) - Germany's largest drugmaker Bayer said it agreed to buy privately held Steigerwald Arzneimittelwerk GmbH, a maker of herbal treatments.
Bayer said on Thursday that Steigerwald, based in Darmstadt, Germany, generated sales of 61.3 million euros ($78.8 million) in 2012 with 180 staff. It did not disclose financial terms of the takeover.
Wednesday, May 15, 2013
For almost a decade, the United States has been standing in the way of an idea that could lead to cures for some of the world's most devastating illnesses. The class of maladies is known as neglected diseases, and they almost exclusively affect those in the developing world. The same idea, if realized, might also be used in more affluent nations to goad the pharmaceutical industry into producing critical innovations that the free market has yet to produce - things like new antibiotics, which are likely to be used judiciously, and are unlikely to be wildly profitable.
But the idea, which advocates have outlined as a treaty, and which will have its fate decided next week at the World Health Organization (WHO) where it has languished for years amid bureaucratic tumult, is "good enough to be dangerous," in the words of one person close to the negotiations. It has thus drawn the fierce opposition of those who benefit most from the status quo, the pharmaceutical giants and the nations that claim them.
"It's a precedent. It's a competing paradigm," Jamie Love, 63, the director of Knowledge Ecology International, a progressive group agitating in favor of the idea, told me. "And the Obama administration, instead of wrapping its arms around it and trying to breathe some life into the future so we don't have $200,000 drugs, is killing it."
When I met Love in February at his office in Washington, D.C., he had just returned from Geneva, where the World Health Organization (WHO) is based, and he planned to be on a return flight shortly. Coach class, he assured me. Love has a boyish face with pale blue eyes and an inscrutable energy about him. The energy, according to those who know him, is nothing new. As a young man, he dropped out of college in Washington and moved to Alaska, where he became a longshoreman and cannery worker and opened two small NGOs. The work drew the attention and support of Ralph Nader, and, in 1980, Love moved to Boston on a fellowship to Harvard's Kennedy School. He added a second Master's degree from Princeton, where he studied with Joseph Stiglitz.
"Part of the problem is that nobody understands what we're talking about," Love told me in his office, a small loft beneath a gabled roof on Connecticut Avenue. "There's really only twenty or thirty of us who understand what we're trying to do with this."
Bill Gates, speaking to the Royal Academy of Engineers in London last March, managed to capture the problem that Love's idea would be leveled against: "Our priorities are tilted by marketplace imperatives," Gates said. "The malaria vaccine, in humanist terms, is the biggest need, but it gets virtually no funding. If you are working on male baldness or the other things you get an order of magnitude more researching funding because of the voice in the marketplace."
This fact -- that research-based pharmaceutical companies focus on the most lucrative products, rather than the most needed -- is particularly damning for the global poor, whose diseases will never be profitable enough to attract the industry. The WHO has recognized 17 such diseases, known as either type III or neglected tropical diseases (NTDs). Almost all of them edge on biblical in both scope and horror.
"The needs are pervasive because these diseases have been so understudied," said Peter Hotez, the founding dean of the National School of Tropical Medicine at Baylor University. "Look at a disease like hook worm infection. Well we now know that single dose mebemindizole doesn't work against Nacator americanus, which is the major hookworm. Why is that? We really don't know," Hotez said. "The WHO I think did us a disservice a few years back when they coined the term 'tool ready' versus 'tool deficient' diseases. All neglected tropical diseases are tool ready, and those same diseases are tool deficient," Hotez said, meaning drugs exist to fight all of the conditions, but many are met by severe resistance and others are poorly adapted for low-resource settings.
The WHO list of NTDs includes Chagas disease, which has a burden of disease five times that of malaria in Latin America, and Dengue fever, which 40 percent of the world's population remains at risk of acquiring. It also includes river blindness, which affects 20 million people in sub-Saharan Africa and leads to infections that itch so severely -- as worms die in the flesh -- that sufferers turn to nails, scalding water, and other violent means to numb the sensation. The existing drug for the disease, Ivermectin, requires six doses over three years to be effective, a regiment that would be difficult to deliver in affluent countries with robust health systems, and is nearly impossible to accomplish in rural Africa.
Neglected diseases, even when coupled with type II diseases, things like malaria and tuberculosis that primarily affect the global poor, receive less than two percent of the $160 billion spent on medical research and development (R&D) each year.
The idea, which has gained the support of a range of academics and economists from around the world, as well as Doctors Without Borders/Médecins Sans Frontières (MSF), Oxfam, Health Action International (HAI), and DNDi, aims to develop new cures for those diseases, and to manufacture the drugs and vaccines at prices affordable to the global poor.
It hinges on the incredible discrepancy between the cost of developing a drug or vaccine -- an expensive and risky enterprise -- and the actual cost of manufacturing a drug, which is often astoundingly cheap.
"Once you sort of turn that corner and you realize that intellectual property rights are really man made policies ... then it just opens your mind up."
"So there is the idea that there are gaps in research," Love told me in February, "and the second idea is that linking the cost of R&D to the price of the drug through the grant of a monopoly is inherently problematic, and the problems are diverse." The existing system relies on the promise of drug sales under patent to incentivize innovation -- an effective monopoly on production, typically lasting more than a decade. That system leads drug makers to set prices at whatever level they think the market can bear, regardless of the cost of manufacture or even the cost of development. The point was driven home last year, when Memorial Sloan-Kettering Cancer Center, in New York, refused a new colorectal cancer drug priced at over $130,000 per year. The drug maker, Sanofi, promptly cut the price in half.
The point is also particularly egregious in the case of lifesaving antiretroviral drugs (ARVs) for those suffering from HIV/AIDS. The fight to make those medications accessible to the global poor was another battle in which Jamie Love was intimately involved.
"If you're looking for sort of the intellectual driver for the idea, it's undoubtedly Jamie," said Robert Weissman, who now runs the storied advocacy group Public Citizen. Weissman was alongside Love in 2001 when Love made the most important play of his career: He asked Yusef Hamied, a chemist and the director of the Indian pharmaceutical manufacturer Cipla, for a rock-bottom price to produce a cocktail of ARVs. At the time, the pill regiments were selling for over $10,000 per year under patent-protected prices. Hamied said that Cipla could produce the drugs for a dollar a day per person.
"Jamie got that it had to be a dollar a day, that it wasn't $400 a year, that the price of a dollar a day would move the whole debate," Weissman said.
Hamied's offer made headlines around the world. It set a floor in the market and lead the prices for name brand drugs to fall precipitously.
"Before all this, we had a meeting with the U.S. Trade Representative and we were talking about how keeping these prices and patents in place was costing millions and millions of lives in Africa," Weissman recalled, referring to Love and himself. "And the Trade Rep. said to us -- I'll never forget this -- 'I don't work for millions of people in Africa.'"
The $10,000 that pharmaceutical companies were willing to charge for ARVs -- and that their US government was willing to defend as reasonable at the WTO -- was egregious in part because the drugs can be produced so cheaply, as Cipla proved. But the prices were also impossible to justify because the development cost for the first generation of ARVs was close to nothing for private industry. The drugs, known as dideoxynucleotides, were almost all developed in the 1960s at Wayne State University under National Institutes for Health (NIH) grants to research cancer therapies. And, in the 1980s, it was again NIH researchers who thought to test the compounds against the AIDS virus.
Love traces the genesis of the idea to a similar situation, this one involving cancer drugs. In the early 1990's, Love began investigating Taxol for Senator Ron Wyden of Oregon. The drug is used to treat breast and ovarian cancer, and was developed by the NIH and produced for less than a dollar per milligram for clinical trials. Bristol-Meyers Squibb, once effectively given the patent, sold the drug for $4.87 per milligram, roughly moving the price from $100 per dose to $850 per dose.
"I do a lot of historical research on the things I do. I like to go back and look at earlier disputes and case studies on particular drugs or legislation or just try to figure out how we got where we are," Love said. One of the cases Love climbed into involved Cisplatin, the drug that saved Lance Armstrong's life. The drug was also developed within NIH and effectively handed to Bristol-Meyers.
"In the old days, the government would grant five year monopolies on government-funded inventions that were done by NIH or universities or something, but if you wanted more than five years, you could ask the government to extend the monopoly," Love said.
In the Cisplatin case, when Bristol-Meyers wanted to extend the patent, the government negotiated a 30 percent drop in the drug's price, and for Bristol-Meyers to contribute $40 million in grants to research of the NIH's choosing.
The case fundamentally changed how Love thought about intellectual property.
"Once you sort of turn that corner and you realize that intellectual property rights are really man made policies and they're designed to do something, and there's other ways to induce that same thing that can compete those ideas, then it just opens your mind up."
Love's idea suggests the use of cash prizes -- rather than patents -- to incentivize research; say, $2 billion for an effective therapeutic drug for Chagas disease. A cure, once developed, proven, and awarded a prize, would then exist as open-access intellectual property, with manufacturers around the world competing to produce the drug in the most cost effective manner. Implementing the idea, Love said, "is effectively leveraging the power of the free market twice, once to produce the thing you want and then again to manufacture it as economically as possible." The concept is known as delinking.
The prospect also has interesting second-order effects. "The numbers have to be big enough," Love said. "You can't replace monopolies that involve billions of dollars with prizes that involve thousands of dollars, but it's financially easy to do that because the savings from delinking are so big." Because drug makers are no longer dependent on sales, delinking would relieve huge strains on budgets beyond research and development; the industry only spends about 16 cents on the dollar for R&D. Massive ad campaigns, for instance, would become obsolete in such a system, because the innovator's profits are no longer tethered to sales, the same for gifts and meals to woo physicians.
Love's concept of delinking is outlined in a proposal for an R&D treaty, which remains in limbo at the WHO in Geneva. It will have its fate decided in late May, at the annual World Health Assembly (WHA), the democratic forum of members states that governs the WHO.
The proposal adds a second, equally powerful idea to Love's, one inspired by open-source software models.
A post-doctoral student in Edinburgh, Scotland, who had been tracking the project's open lab books online, produced a compound that Todd's own lab couldn't figure out how to synthesize.
Historically, basic research and drug innovation has been in done in silos, with little communication across companies and labs. That isolation guarantees that researchers repeat failures that have already occurred elsewhere, a problem that becomes glaring in the case of neglected diseases, where the total research investment is a fraction of what it is for profitable diseases. The lack of information sharing also guarantees that some labs remain stymied by problems that researchers in other places may know how to solve.
"The existing funding structures are competitive, national grant based," said John Wilbanks, who works at the non-profit Sage Bionetworks and is a fellow at the Kauffman Foundation. "So, for most people, the rational economic decision is not to share, not to collaborate, in order to obtain additional taxpayer grants to continue the research and to keep employment."
Wilbanks's background is largely in tech, and the group he works for is building a platform for computational biology akin to GitHub, a system that lets computer programmers track their contributions to open-source code.
"The fear is that by spending my time working on your project, for which I don't have a system to get credit that the existing system recognizes, I will be less competitive over time than someone who participates in the traditional system of information hoarding and publication," Wilbanks said. "We're trying to fix that problem through openness, similar to the R&D treaty."
To combat the problem, the R&D treaty would create an observatory, an open platform for researchers in disparate corners of the globe to pool data and coordinate their work. Grants given to fund their studies would come with provisions requiring that the research exist on that public, cloud-based observatory.
Such an open system also means that help can come from unexpected places. Mathew Todd, a chemistry professor and researcher in Sydney, is currently running an open-source malaria project. He explained how a post-doctoral student in Edinburgh, Scotland, who had been tracking the project's open lab books online, produced a compound that his own lab couldn't figure out how to synthesize.
"The chemistry wasn't working out, and we were being open with this," Todd said. "And he looked at it and said, 'Well I can make that.' And so he went off and made it, and we were interacting with him by Twitter, sort of following his progress and he was posting his experimental data to our lab books online, and he made it."
"It's that kind of example where you think, 'Well if everything's open and it's clear what needs to be done and anybody can chip in, then that means you're going to attract the expertise you need without actually knowing who those people are," Todd said.
Todd told me he's put forward a proposal to host a panel focused on the future of intellectual property and drug development at the February meeting of the American Association for the Advancements of the Sciences. "I think the time is right to have that discussion about whether the patents are working, and whether they're necessary for drug discovery," Todd said. "I want to hear on from people from on both sides. I think we just have to have that conversation."
Last November, the Obama administration made its most strident effort to date to stall the idea. Because successive U.S, administrations have stonewalled the process so effectively, negotiations on actual language for an R&D treaty have never begun. That hasn't prevented the intellectual scaffolding beneath the idea from developing, though.
To fund the system -- research grants and an observatory to produce and coordinate the foundational science, and prizes to incentivize the pharmaceutical industry to spring off of that basic research -- the treaty would commit member states to spending 0.01 percent of GDP on neglected diseases each year. The U.S. already spends at that level, and would have no further financial obligations. No other country comes close.
Nonetheless, the idea of binding financial commitments by way of treaty has been a centerpiece of US opposition.
"They are using a process argument, saying we are against the form, but in fact what they are opposing is the content of the negotiations," said Judit Rius, the U.S. manager of Doctors Without Borders/Médecins Sans Frontières Essential Medicines Campaign. "When governments get serious about an issue, they agree to binding global norms and they agree to be held accountable. And that's what we want," Rius said. "What the U.S. is really opposing is a conversation about the how this funding should be spent. They are protecting the current business model, the status quo innovation models."
At the November meeting, the U.S. hammered through a resolution effectively neutering the idea in a late night vote. It was held four hours after simultaneous translation of the debate ceased, with only 25 of the original 194 member state representatives remaining in the negotiating hall.
"At least with the Bush guys you could have a conversation with them about this kind of stuff."
"I've never seen something like that happen in an international negotiation," Carolos Correa, the representative from Argentina, told me. "The meeting should have been terminated, because clearly some of the delegations were not able to follow the debate. In these cases, the governments generally say, 'Well this is not possible to go on, so we'll finish and inform the assembly there was no conclusion.'"
According to delegates present at the meeting, which took place behind closed doors, it was clear from the outset that the U.S. had no intention of negotiating in good faith. "The U.S. was delaying the issue and opposing it totally," one negotiator said. "Very little real negotiation, they were very radical. They were even insisting on some ideas that were not totally correct."
The resolution that emerged from the November session will be taken up in late May, at the annual meeting of the World Health Assembly. If the measure is adopted, further consideration of the idea will be pushed until at least 2016. The resolution also includes the unusual provision of being sealed, barring any further discussion at the WHA.
The document also suggests the creation of a pilot program and an observatory to monitor research, but does so without allocating funds, and with such vague language as to render the resolution moot.
The U.S. has promised to bury the resolution altogether if other countries try to reopen negotiations in May.
"We saw in January that the U.S. negotiator said publically what we had been told he was saying in November behind closed doors, which is that, 'If you change even one comma, we'll kill it altogether," Rius said.
Early in the November meeting, the U.S. moved to quiet a Colombian negotiator. Nils Daulaire, the lead U.S. representative in Geneva, has made a habit of using backchannels to sideline other delegates voicing positions he does not share.
The negotiator in question declined several requests for comment for this piece.
"She was very well prepared, and she was taking the floor several times during the first day," another delegate told me. "And I saw that the U.S. delegation was a little bit nervous, because usually Colombia -- in the last years -- they never take the floor on these issues and they always support the U.S. position. Around four o'clock on the afternoon of the first day, she was called outside the room, and one hour after she came back to the room and she never took the floor again in the next two and a half days. She stayed until two o'clock in the morning the last day, but she never took the floor again."
In March, when I spoke with Daulaire, an assistant secretary for global affairs at the Department of Health and Human Services (HHS), I asked what had provoked his complaint. His response took the kind of emphatic tone that conveys both displeasure and the desire to say a great deal more: "I'm not familiar with any formal diplomatic complaint against the Colombian representative," he said. "I don't know where that comes from." Daulaire struck the same tone later in our conversation, when I asked at what level within the Obama administration the U.S. position had been crafted. "I do not discuss internal administration processes," he said.
Daulaire has a round nose and soft chestnut hair with a beard and glasses, lending the overall affect of a college dean. He is -- according to his official biography -- the speaker of seven languages, and a graduate of both Harvard College and Harvard Medical School. He is known as exceedingly ambitious, and is rumored to have put himself forward to replace Eric Goosby as U.S. AIDS Coordinator. The position is one of the most vaulted in the field of global health.
"He is very trenchant in his views, and I'm not sure whether that is because he's hearing that from the industry or whether he's hearing that from the administration, but he's looking at where the political wind is going," one source with intimate knowledge of the debate said.
Daulaire's efforts to derail the November meeting started more than a month before he and his staff arrived in Geneva. His office sent representatives to a WHO regional meeting in Angola to discourage support for the treaty amongst African states, and Daulaire himself made bilateral calls to number of negotiators and ministers of health. On the calls, he asked whether the officials were prepared, at the November meeting, to commit their governments to financing the treaty. None of the officials Daulaire called have the power to make such a commitment, nor does Daulaire himself. Moreover, the treaty he asked them to commit to financing has not yet been written, largely because of Daulaire's own intransigence.
"Nils says, 'The U.S. is the biggest funder of R&D, and we don't think anyone else is going to put up the money,'" one civil society member said. "But the bizarre thing about that is when developing countries said, 'We will put some money up, whether we will reach sort of figure that the experts came up with, we might not but we're prepared to do it incrementally,' he just said, 'No I don't believe you, let's just take the whole thing off the table.' It's very strange to me that the U.S., being the largest funder, is actively undermining putting pressure on other countries to step up to the plate."
"I was sort of looking forward to working with the guy," Jamie Love said of Daulaire. "Everybody knew that he was close to the industry, but that's not necessarily a bad thing. But he really changed when he got the job [at HHS]. At least with the Bush guys you could have a conversation with them about this kind of stuff."
Daulaire's deputy at HHS, Holly Wong, previously worked for the drug industry's main lobby group, PhRMA, and as director of public affairs at Schering-Plough Pharmaceuticals. The company was acquired by Merck in 2009.
Before his appointment to HHS, Daulaire ran a nonprofit called the Global Health Council (GHC) for close to a decade. The group was based in White River Junction, Vermont, where Daulaire lived. The organization had an annual budget of close to $7 million, although it didn't actually provide any health services. After Daulaire left, the organization was handed off to Jeff Sturchio, a former Vice President at Merck. Sturchio drove the group into the ground in less than three years. "It was really a lobby group," one observer said, speaking of the GHC. "At the World Health Assembly meetings they would rent huge halls in the Intercontinental with very expensive food and drinks," another recalled.
The GHC's main function appears to have been providing briefings for incoming members of Congress and new presidential administrations. "I don't think anyone has filled that role," Jonathan Quick, who is trying to revive the GHC, told me. Quick spent eight years working at the WHO as the Director of Essential Drugs and Medicines Policy.
Quick and several others in the global health space pushed back against questions about GHC's lobbying, arguing that the organization served as a kind of hub for advocates of greater U.S. involvement in global health. I asked Quick about his thoughts on the U.S. opposition to the R&D treaty, and whether he, having worked at the WHO, had misgivings about U.S. negotiators having such strong ties to the pharmaceutical industry.
"The U.S. is interesting, having seen it from the WHO side," Quick said. "Most countries when they come to the World Health Assembly lead with their health policies. And they bring to the WHA the values and policies they have at home. There are a few countries where that's difficult, because there are such strong commercial interests that there's a tension. That's always been a very difficult challenge for people representing the U.S. in the international health sphere."