Pfizer, Drug Pricing, Conflict of Interest

The photo was taken last December in New Dehli.

Lately this blog has been beating up on Pfizer, here and here. They are big, they can take it. Here is some more. Fierce Pharma today links to a Telegraph report covering Pfizer CEO Jeffrey Kindler's rehabilitation tour, first last week in the UK and now in the US. This year Pfizer has not once but twice made huge court settlements: one for the Trovan case discussed previously, and the other for $2.3 Bn to settle the ongoing investigation of its off-label marketing practices, the largest settlement of its kind, in the same month that Lilly settled its Zyprexa woes for $1.4 Bn. Like those television preachers who, after getting caught with their hands in the till - or worse, quickly come back on stage with a tearful repentance speech and then start lecturing everybody on how they should behave, now we have the spectacle of one of the largest drug companies telling us all that we should follow the rules - or else.

And it is the 'or else' that matters here. We don't need to spend much time adjusting our expectations of Pfizer or its kind. Kindler makes clear in his remarks the real motivation behind all this soul-searching: change or face increased regulation. Kindler is not the only one worried about this. Merck's chief exec was on the stump about this very same issue last spring. At least he is on to something that would actually improve big pharma's image as well as improving people lives, and that is pricing. Drugs cost too much in this country, even after factoring in the high development costs and low ROI. Nearly every other major government and quite a few minor ones control drug prices, but not the US. People on fixed incomes have to decide whether they are going to buy their medicines or pay the heating bill. That should not be. Apparently Congress thinks so too, but do they think so enough to do something about it?

The Pharmalot blog seems to have relevant content a lot of the time. Today they link to a new report out from Seton Hall University on managing conflict of interest in clinical trials. Some of the report's suggestions seem unwieldy, such as not allowing payment for screening activities - who will bear those costs if not the sponsor? And what incentive will investigators have to find patients for trials, a task that has become increasingly difficult in this country? If you go to this link, be sure to note the comments section at the bottom.

And if you've made it this far, how about a little shameless self-promotion? I will be presenting at this meeting Partnerships in Clinical Trials in Orlando, April 2010. Hope to see you there!

Fall Term Catchup

The picture is of the Capitola, California beach on a beautiful fall day last week, the last warm day before temperatures dropped. The fall term is nearly over (yay) and my inbox is stuffed with items I've been marking to blog but somehow never found the time. So here is a whole bunch of them in one go.

First up: a nice piece on direct-to-consumer advertising from Slate. My students know I love to take off on big pharma's fatal attraction for DTC advertising and how it can be directly linked to the problems of Merck's Vioxx. While the Slate writer makes a nice, facile point with his analogy of running shoe ads, there is still a fine line between educating and developing the marketplace versus creating one out of whole cloth.

This piece from MicroArray blog points out an issue that I see within the scope of Anhvita, and that is the propensity of trained monitoring staff within India to 'job jump'. This is creating a work force with great breadth but insufficient depth, and is also contributing to a loss of continuity for sponsors which could directly and adversely effect safety reporting, among other things. We need to create a cultural shift that encourages professional staff to develop all their skills, instead of leaping to the next attractive salary and perks package.

Here is an update to an item I posted a while back about the Pfizer-Trovan-Nigeria case. In case you thought justice was imminent after the US 2nd Circuit Court of Appeals' decision last summer to let the case finally be heard in the US courts and Pfizer's subsequent $75M settlement - think again. Pfizer did indeed fund the settlement, all but $30M of which is going to line lawyers' and Nigerian government officials' pockets, but they also appealed the decision to the Supreme Court. The Supremes have asked the Obama Justice department to render its legal opinion, so we may see a ruling this term. Meanwhile, Pfizer is continuing its one-company crusade to lose the hearts and minds of the prescription-buying public - who is not inclined to cut the pharma industry a break in the best of times - by requiring victims in the case to submit DNA in order to receive compensation. It's all here. One of the salient facts of the case is that there were no medical records left behind from the two week study conducted at Kano in 1996, so it isn't immediately clear exactly what the DNA samples are supposed to be compared to. If the whole thing is not a ploy to avoid paying out compensation to the victims, then Pfizer certainly seems comfortable with giving that very impression.

And speaking of fall days, this one is over. More next time.

Farewell, Joey

This blog has at times attempted to be quite high-minded and instructive, other times more introspective. Today it is going to become sentimental in an adolescent way because today I am going to mourn the loss of my cat, Joey, pictured here about 7 years ago.

This picture does not really do him justice. His fur was a beautiful, soft, shiny silver that caught the light like water. He had long legs and a small head like a cheetah, and though he was at least 14 years old, he looked as beautiful the last time I saw him as he does in this picture, and indeed the first day.

Joey was not really meant to be mine. The first time I saw him he was running down the street at top speed with his ears laid back, with two neighborhood dogs hot on his heels. The dogs didn't catch him, they almost never do, and the cat disappeared into a hedge. I saw him again a couple of days later; he was on our front porch peering in our window and meowing at the top of his lungs. After a day or two of this I was a goner. I wanted to put food out for him but I knew that would be delaying the inevitable, and I told Rob as much. We already had two cats that I had before we were married. It was early enough in our marriage that Rob probably had a hard time saying no to me. He has since got past that.

With what seemed to be Rob's blessing I brought the cat inside. He had a cut over his eye and his paw pads were bloody from his high speed chases on the asphalt. We cleaned him up, fed him, and took him to the vet to make sure he didn't introduce any new feline diseases to the population. He slept for two days straight.

At first things seemed to go well. He looked like another silver cat I used to have named Chloe, so Rob named him Joey. Joey was about a year old when we took him in and very playful. Rob used to entertain both himself and Joey for hours poking his finger out from under the sofa blanket or seat cushions. The cat was endlessly fascinated with this game, which we called blanket thing.

Joey was fearless, often tempting fate in a way most cats are too cautious to try. We had an older cat named Ben who had developed some curmudgeonly tendencies by this time, and didn't cotton much to the younger cat crowd, preferring to sit in meatloaf position on the sofa with his eyes half-closed. Joey used to take a bead on a dozing Ben from across the room, run across at top speed and do a drive-by pounce on Ben, making at least 3 passes each time. The first pass he would get away with the sneak attack, but by the second Ben was ready and he would deliver a perfectly timed blow to Joey's head just as he came into striking range that would send the younger cat reeling. Just to make sure it was not a fluke, Joey would make one more run at Ben, get sent packing, and call it a day.

Joey was also the most friendly and curious cat toward dogs I've ever known. He always wanted to engage them, surprising since he first came to me because he was running away from dogs. Once he greeted a friend's dog who had come visiting. A skirmish ensued and the next thing I knew we were picking silver fur out of the dog's teeth.

Joey was an easy cat to live with in many ways - clean, low maintenance, no vet bills - except one important one: he developed a habit of marking the belongings of people he liked, and since he liked almost everyone, there was a lot of marking. No one was spared, although I seemed to get tagged the least, and nothing we did seemed to discourage him, despite seeking advice from every source we could find, knowledgeable and otherwise. Over time Rob developed a deep loathing of Joey which he attributed to the marking problem, but the visceral, almost pre-verbal nature of his animosity for this very small animal seemed to me disproportionate to the crime. Many, many times I offered to find another home for Joey but Rob wouldn't take me up on it, insisting for some reason to put up with it. It became one of our rare points of contention, the kind of issue that can be a pressure valve in a marriage: you bicker about these little things to let off steam from daily life.

As Rob's animosity increased, Joey found himself restricted to smaller and smaller sections of the house. Recently he spent most of his time in my office curled up on my desk chair. Whenever I worked at my desk he jumped onto my lap and settled there, purring and gently working his paws. I was the only one who showed Joey any affection at all, yet as though he remembered all those games of blanket thing, Joey never stopped trying to get Rob to pet him or play with him, which of course did not happen.

Earlier this week we noticed that no one had seen Joey for at least a day. We looked everywhere, in all the closets and under all the beds. Joey was nowhere to be found. The only thing we could think of was that the door was left open when Rob was bringing stuff in from the car and Joey got out while I was at work. An indoor cat with a curious nature, an open door had always presented a flight opportunity and we were usually careful. But on that day, not careful enough. Since then I've looked around the neighborhood for him, waiting for the dogs to chase him down the street, but he is gone. It looks like Rob got his wish.

I am sad that it ended this way. It hurts to think of him out there alone, frightened and hungry, his beautiful soft fur matted and dirty. I hope someone has taken him in as I did all those years ago and that he is sitting on her lap right now, purring softly and working his paws.

Home

A blogger called Jung At Heart that I follow with some regularity did a post on home this week that got me thinking abut what defines home. (No I don't knit, but a couple of my blogger friends do.) I am still on summer break from teaching and need to start thinking about my curriculum for the fall classes. But since I have nothing relevant to post on clinical research ethics or the like, I will muse for a bit on the idea of home.


In our house, my husband and I have tried to establish a no-shoes policy. We have a large basket near the front door for shoes. The policy hasn't seemed to take hold for a variety of reasons: my feet are usually cold, so I keep them covered; Rob takes his shoes off and deposits them under the living room table - within clear view of the shoe basket - approximately 4 seconds before he hikes his feet up on the sofa. Our kids mostly leave theirs on because we rarely enforce the no-shoe rule.

Near the end of last term, I had a little gathering at my house for some of my students, most of whom come from India. Each of them left their shoes on my front porch as they stepped inside, just as they would do in their own homes.





A couple of months ago I was in Bangalore working with my business partner. I stayed in a lovely apartment that she provided. When I arrived and she went into this apartment with me, we kept our shoes on. As I settled in by myself after she left, I put my shoes by the door, like most Indian households do. When in Rome, and so on. A few hours later when my partner came back to collect me for dinner, she walked in and without the slightest pause, ditched her shoes by the door where mine were. I interpreted this to mean that this space was now, at least for the next few days, home to me, and she treated it as my home instead of an unoccupied space.

My Jungian blogging friend posted the following questions as a springboard to understand the definition of home. Let's see what we can learn, shall we?



Where is home for you?

These days my definition of home has expanded beyond a physical space and a building, and I find I feel much more at home within myself as I get older. Having said that, home is very much the space I share with my husband.




What is the difference between home and house for you?

When I was a child my parents loved to go house-hunting and to look at model homes. I hated this. I couldn't see the point of looking at a house that no one lived in. The difference between a house and a home was whether or not someone lived there, and more to the point, whether or not I lived there. Not only was I not interested, it scared me to look at houses. I was always afraid we would move into one of them, and none of them was home.


Are you at home now?

Indeed yes.



Have you always felt at home?




I have often felt not at home even in my own home, usually having to do with who else I might have been sharing my home with. Recently we converted one of our bedrooms into a music room - fresh paint on the walls, brought in all the various instruments from various parts of the house, set up the electronic keyboard that I use for a piano (which I bought specifically because it has a true piano-like action to the keyboard). This opened up a room that I had previously not stepped into for several years, and gave me access to a little bit more of my house.



What makes a place a home for you?

I think it must have less to do with the physical space itself and more to do with my state of mind, and who lives in it with me. I lived entirely alone for maybe 16 years of my adult life, usually in smallish apartments, places I generally felt at home. Having my stuff in the home helps - my pictures, books, animals - but I don't necessarily have to make all the choices about how the house looks. For instance, for the music room above, Rob chose the color on his own pretty much sight unseen by me. The same thing when we had the exterior painted last year; he chose the color, which was a different tone than we had before. While I actually preferred the older color, I didn't prefer it enough to make myself part of the decision making process.

How has where you lived impacted you?

I lived for the first 20 months in an orphanage. I lived with other relatives for about 18 months when I was 5-6. In my childhood through college I lived in 10 different houses; as an adult or well over three quarters of my life, only another 5. I would say that where I have lived as a child has impacted most substantially my choices of where and how I live as an adult.

Do you think you can go home again?

No. I think you move on from each home and there is only forward movement, never backward.



How did you find your home?

We went house-hunting - which I still hate - on a Sunday afternoon. When we walked into the house we now own, which was I think the second one we saw that day, Rob said this is the one. We made the offer the next day and had it accepted by the end of that week. It has three 60 foot tall liquid amber trees in the front yard, hardwood floors, and lots of windows. I dislike dark rooms. We are hip-deep in fallen leaves every November and December. The house is small, only 1500 square feet. But we have great weather. My friend Mary says that's why we pay prices this high for houses this small.

What is your ideal home?

A little less cluttered than my homes tend to me, especially living with cave-bear Rob.

Transitions

Long time no blog, as they say. Usual excuses about being too busy, traveling etc. But the real reason is that things have been in such flux the last weeks that I haven't had the singleness of purpose to write. I've been too busy trying to stay present with all the changes. Some are seasonal and mundane: end of school term, posting of grades and the full-on arrival of summer (which in the SF bay area feels like spring just about everywhere else - as my friend Mary says, there is a reason why we pay prices this high for houses this small). Some are big and all-consuming, like travel in June to start my new business - more on that shortly.

Some of the most mind-spinning transitions have been in the lives of others, the kind you can only stand by and watch in helpless awe. One friend recently had surgery to remove cancerous lesions from his tongue, acquired most likely from radiation therapy for his previous three bouts with lymphoma. My oldest friend's 18 year old daughter has been fighting against a tumor wrapped around her thalamus. Last week they were told all options are exhausted and they are looking at about 6 weeks. Another friend died about 5 weeks ago after her breast cancer returned and metastasized into her bones. My father will undergo an open heart valve replacement procedure next week, a risky move in an 89 year old, to say the least.

But I am back. Here are a couple of links of note this week. ClinPage has a write up on some survey results taken by J&J in the wake of their rather public flogging in 2006 at the hands of the BBC. The piece in question is in my opinion poorly reported, long on sensation and speculation but short on balance and does nothing to actually educate the viewer about clinical trials. Nevertheless, J&J reacted and put together a group to look at the problems identified in their consent forms and to make some suggestions, and unveiled the results at June DIA meeting in San Diego. I hope this is the beginning of a trend in the industry. Consent forms have become too long and too filled with language intended to protect the sponsor and investigator, to limit their liability instead of to inform the subject.

The first thing we do, to paraphrase the Bard, is get the lawyers out of the process. The next thing is to stop worrying about people writing headlines. We should simplify the consent process to include the most important elements - research, risk and voluntariness - in the first page and stop trying to rewrite the entire protocol in the rest of the consent.

I also came across this blog whose author draws a comparison between Sasha Baron Cohen's new film Bruno and the research consent process. Worth a look.

Now for the news. With my partner in India I have opened a new clinical trials consulting business: Anhvita BioPahrma Consulting. Our aim is to connect the right clinical services in India and other emerging markets to sponsors in the US and Europe. It is all about bridging gaps and that is what 'Anhvita' means in Sanskrit. We are also developing professional training components for clinical research professionals in India and elsewhere to increase the emerging markets' capacity to handle the burgeoning clinical trial market, which hit US$50 bn last year and is growing. Watch this space for more information as we explore this market together.

And that's the way it is. RIP Walter Cronkite, narrator of all the nation's major events during my youth.

Air France and Coast Fallout

AccessCR links to a piece from Epoch Times about fraudulent trials producing clinical data for some of the more popular asthma drugs out there, like Serevent, Singulair, Flovent, etc., etc., according to charges brought by a former sub-investigator on the trials named Dr. Robert Davidson. According to the piece,"Davidson charges that during aggressive recruitment schemes in the late 1990s, patients with abnormal EKGs, multiple risk factors for coronary artery disease, arrhythmias, pulmonary embolisms, rheumatic fever histories, acute illnesses, and even pituitary tumors were enrolled with impunity in trials that earned investigators as much as $10,000 per patient."

The article quotes FDA inspection reports that cite dry-labbed patient diary cards, investigators who were advised not to state the risks to potential subjects, investigators pressuring patients to participate against their wishes, patients enrolled in clear violation of entry criteria, and on and on. I searched the FDA's warning letter listings but was unable to turn up the documents, so I will have to take Epoch Times at their word. FDA has since mandated new safety warnings in the labels of several of these drugs.

Yikes. I often use the analogy with my students of plane crashes. Transportation safety people study plane crashes because in doing so they learn to make air travel safer than by studying the hundreds of thousands of flights that go off unremarkably every year. However focusing on air crashes, especially in today's intense news cycle, can make them seem a lot more common than they are, and the public can lose sight of the fact that airplanes simply do not fall out of the sky without warning or reason, although after what happened to Air France this week, that possibility seems frighteningly more likely than it should. In teaching future clinical research professionals, we focus on the bad things, like Robert Fiddes, or the Jesse Gelsinger case, so we can learn what to be on guard for, and it can seem like there are only bad things and bad actors. This story adds fuel to that fire.

AccessCR is a nice resource out of Australia whose biweekly email updates should be of interest to clinical research professionals. It is free. According to their website they offer international perspectives on regulatory issues, public perceptions, trials discontinued for whatever region and regional news from the hot emerging markets as well as the more tired old ones, and industry news, all conveyed with a bit of unmistakable Aussie flair. I read it as soon as it comes out.

In other news, there were signs this week of fallout in the US IRB space from the Coast affair. Over a small technicality, all of a sponsor's study screening activities in entire state were brought to a screeching halt. I can't share much detail without disclosing potentially proprietary information, but it seems very clear - at least to me - that the IRB over-reacted to their own mistake in approving a consent several months ago without certain technical elements having to do with state privacy laws and went into box-checking mode, rescinding their previous approval and shutting down patient screening activities until those elements - none of which had anything to do with safety or procedures or even confidentiality of patient information - were added. The best part was that, again according to state law, which the IRB was unable to cite upon request, these elements needed to be presented in the consent document in - wait for it - 14 point font. Yes. Patient screening activities suspended not for safety concerns, but for font size. I fear that we are in store for much more of this kind of over-reaction and box-checking mentality from US IRBs if they even think that what happened to Coast could happen to them as well. And why couldn't it? In a Kafka-esque world such as Coast found themselves, anything is possible.

At this time in late May the jacarandas are in full bloom in my neighborhood. I love the rich color of the blossoms and the painterly carpet of lavender they lay down underneath the tree. I suspect the owners of the trees don't love them so well as I do when they have to clean up.

As the spring term winds down there is also less news in clinical research and ethics related topics this week. I did note one rather old item from a blog called Reason Online that discussed a case from the 90s about a woman who submitted a blood sample to be tested for the gene BCRA1, mutations of which can indicate high risk of breast and other cancers. If found positive, this survivor of one episode of breast cancer already planned to have her remaining breast removed as a preventative measure, and the problem arose when the physicians refused to give her the results, claiming such knowledge could be 'dangerous if revealed at the wrong time'. The patient claimed that by giving her blood sample she had entered into a kind of contract with the physician, including the connotation that she wanted the answer no matter what it was, and he was obligated to provide the result.

It turns out the physician was not just being recalcitrant or merely paternalistic. At the time of this incident in 1996, several prestigious bioethics boards including the University of Southern California's Pacific Center for Health Policy and the Law, Medicine, and Ethics Program at the Boston University Schools of Medicine and Public Health recommended that the BCRA1 test only be used in a research setting and the results not be provided to patients, the idea being that if there is no known prevention for a disease, what does it benefit the patient to know that they are more likely to get it? Happily, in the end the women received her test result which turned out to be negative.

Prestigious or not, the Mayo Clinic begged to differ with regard to prevention, publishing in the New England Journal of Medicine that year that prophylactic mastectomy before the appearance of breast cancer was about 90% effective in reducing the risk in moderate to high risk women. And leaving aside for a moment the question of prevention, is it really a valid view in a society that values individual responsibility and autonomy to withhold important medical information from a patient is who otherwise able to make her own decisions? The blog post goes on to review the evolution of bioethics in this country, tracing through the Tuskegee syphilis study and discussing the ethics of in vitro fertilization and other aspects of reproductive medicine.

And finally we have a picture from a gathering of some of my students who have just completed my course on clinical trials in emerging markets, taken in my living room last weekend. Some of them were being a bit goofy. Chalk it up to spring time.

Cheerios, American Idol, and Clinical Trials

The photo this week is a detail from some ruins in the Qutub Minar complex in Delhi, taken one fine Sunday afternoon on an outing with colleagues during my only visit to that city (so far) last December.

Slate magazine had a rare non-negative piece on clinical research last week, here. The author explains the concept of surrogate endpoints used in research - the idea that a lab value or other short term markers are predictive of long term health outcomes - by drawing comparison to reality TV shows like The Apprentice, The Bachelor, or American Idol (which at this writing had its season finale last night. I wouldn't know, I didn't see it, but my Facebook friends can't seem to stop talking about it. Apparently the outcome was unexpected). The stated premise of these shows is that the person who is last to be fired by Donald Trump, or gets picked by the bachelor after a series of improbably lavish - and frankly smoking hot - dates, or wins the most TV audience SMS votes after the singing competition, is reasonably predicted to be Fortune 500-successful in business, or live happily ever after with the handsome prince, or jumpstart a recording career.

The parallel to the use of surrogate markers in clinical trials is an apt one. CD4+ T cell counts are "highly prognostic for progression to AIDS", and so it was reasoned that by developing treatments that raise CD4 counts, you could by extension delay the progression of HIV to full-blown AIDS. AZT was approved based on CD4 count data. In postmenopausal osteoporosis drug development, we ran 3 year long vertebral fracture intervention trials correlating bone mineral density data to fracture rates, so that in subsequent trials we could use BMD only as the marker for fracture reduction, resulting in shorter, safer (because vertebral fracture was no longer the endpoint) and less expensive trials.

However, the author of the Slate article points out that just as winning the highest number of text votes is not necessarily a guarantee that those same people and all their friends will buy your new record, medical surrogate markers as endpoints in clinical trials are not always predictive of long term benefit. He points out the widespread belief amongst physicians and parents in the effectiveness of stimulant medications in kids with ADHD based on the federally funded Multimodal Treatment Study run by the National Institute for Mental Health in the 90's - and resultant blockbuster sales of drugs like Ritalin. Long term follow up of the subjects from that study shows that ultimately the drug-treated kids fared no better than the controls, due perhaps to the 'real world' effect after the idealized environment of the clinical trial, lack of compliance with the regimen after the close monitoring is over, or simply a weak - or even nonexistent - relationship of the surrogate marker to the actual desired health outcome. Does this mean that surrogate markers are not to be used? Of course not, if we waited for final outcomes in the big diseases of interest to an aging population, like heart disease and diabetes, it would prohibitively delay medical progress and make it far too costly. The takeaway message of the author and I agree is for patients and prescribers to have their awareness goggles strapped on tightly when writing or filling any prescription, to stop believing that a pill fixes all and that a government approval for sale also confers some kind of divine or mystical exemption from any further thought about the matter.

Meanwhile, Jim Edwards at BNET Pharma has an interesting item yesterday about Big Pharma blogging and twittering. Apparently twittering wins out over blogging - AstraZenaca's twitter stream was highly active as of a few hours ago ("AZ just had a peanut-butter-banana sandwich for lunch and is stuffed!"), but GSK's new blog is only the 4th ever for a big pharma company, and two of those four are already dead from inactivity. It's not hard to imagine why. Blogging and big pharma don't seem well-suited to one another (check out GSK's little item explaining how patents actually benefit patients because without adequate patent protection there would be less innovation. The argument is true yet it still comes off vaguely smarmy and self-serving in the context of a big pharma blog.) And from a legal standpoint, it is simply easier to stay out of trouble in 140 characters than in the free form, boundary-less world of blogging*.

*Disclaimer: The views of 2Decades-and-counting are her own and not necessarily representative of her employer, family, friends, or dog.

This just in: A colleague just sent me a copy of an FDA warning letter to General Mills food company for labeling problems, false claims and promotion, and misbranding of - wait for it - Cheerios breakfast cereal. I was sure it was a joke until I found the letter on FDA's website. It's all here. General Mills' response is here.

Informed Consent, Helsinki and Conflict of Interest

The Pfizer Trovan Case, Still

The New England Journal of Medicine has a piece this week on the problems of informed consent in the increasingly globalized environment of clinical trials (h/t D. Karpf). The article specifically unpacks the ethical rationale for the January 2009 opinion in the case of Abdullahi v Pfizer by the U.S Court of Appeals for the Second Circuit which covers New York, Connecticut and Vermont (and is the current home of Judge Sonia Sotomayor, thought by many at this writing to be on Obama's shortlist for Justice Souter's recently vacated Supreme Court seat). The case is brought by the families of young victims from the now-notorious 1996 Pfizer Trovan trial in Kano, Nigeria.


The facts of the case are these: during an outbreak of meningitis, Pfizer brought non-local physicians to the Kano Infectious Diseases Hospital to conduct a trial of its antibiotic Trovan against a low dose of US-marketed Rocephin. The study participants were 200 sick children, half of whom received Trovan; the oral formulation of Trovan had not been previously tested in a pediatric setting. The dosing portion of the trial lasted two weeks at which point the Pfizer team decamped, leaving no continuing safety monitoring or care. Eleven children died, five randomized to Trovan and six to Rocephin; other children became blind, deaf, paralyzed or brain-damaged, according to case documents. The families allege these results were directly related to the trial. The families specifically allege that Pfizer and the Nigerian government, working together, failed to secure informed consent of either the juvenile participants or their parents and 'failed to disclose or explain the experimental nature of the study or the serious risks involved' and failed to inform them of the availability of effective alternative treatment that was available at the hospital from Medicins sans Frontieres.


Pfizer managed for several years to avoid having the case heard at trial by successfully arguing that there exists no international norm requiring physicians to obtain informed consent, thus eliminating all question as to why the public holds the pharmaceutical industry in such contempt. My GCP students could tell you after the first class meeting, and it turns out the Second Circuit agrees, that there most certainly is an international norm for requiring informed consent, in fact there are several. The Appeals Court reversed the trial court's dismissal of the US lawsuit (once the case finally made it to trial following a report by the Nigerian Ministry of Health concluding the study had violated Nigerian law), and sent the case back to trial, citing the following codes: The Nuremberg Code of 1947, the International Covenant on Civil and Political Rights of 1976, the Declaration of Helsinki (more on this in a minute), and CIOMS' International Ethical Guidelines for Biomedical Research Involving Human Subjects. All of these state, in one way or another, that the investigator must obtain voluntary, freely-given informed consent before subjecting a human to experimental treatment.


The court found these norms not only international, but universal, and specific. It noted that while 'promoting the global use of essential medicines can help reduce the spread of contagious disease,' to conduct clinical trials in 'other countries' without informed consent 'fosters distrust and resistance... to critical public health initiatives in which pharmaceutical companies play a key role'. You don't say. Evidence of this mistrust was found right back in Kano, where the local population boycotted international pharmaceutical companies' efforts to provide polio vaccinations during the 2004 epidemic, dealing a serious blow to worldwide efforts at polio eradication.



Whither the FDA and Helsinki?

I also came across a comment published earlier this year in The Lancet worrying about the abandonment by the FDA late last year of the Declaration of Helsinki as the basis for acceptance of foreign data in US marketing applications. The PDF download is here. The new basis for acceptance is the ICH Good Clinical Practice Guideline. The authors are not impressed with the FDA's rationale for this switch, stating that the ICH GCP guideline lacks 'moral authority' due to the fact that its signatories are fewer and more, well, Western, and that the guideline focuses on regulatory harmonization than on clinical trial conduct.


Anybody who has been paying attention for the past decade knows that the issue here really is the use of placebo controls in clinical trials: Helsinki has steadily moved away from their acceptability, with most emerging nations' health authorities following suit, while the FDA maintains that placebo controls are necessary for scientific rigor and can be made safe for patients if designed correctly and monitored appropriately. I am pretty sure we are not going to settle this question here, but I was struck by the authors' assertion that the GCP guideline lacks moral authority. This comes as a bit of a surprise to all of us who teach GCP around the world and to the many industrialized nations of the world for whom the ICH guideline is the accepted standard for clinical trial conduct and is the model for the GCP regulations of many emerging nations.



Here is Somebody You Don't Want to Be

Getting caught, with good reason, in the never-ending swirl surrounding the use of anti-psychotics in pediatric patients is this University of Texas researcher. She initially attracted the white hot light of US Senator Chuck Grassley's scrutiny by reporting having received $600 from pharma companies, but neglecting to mention the $230,000 paid to her by GSK. The real problem is not about the financial disclosure or lack thereof. The real problem is the fact that this physician was paid these fees apparently for co-authoring the 1998 sponsor-ghostwritten report on the Paxil pediatric study #329 which stated that Paxil was both safe and effective in children when in fact, as it turns out from internal emails, the company already knew at the time the study was negative. Dr Wagner was also paid for speaking appearances on behalf of the drug and the study in a variety of venues, some posh. The Alliance for Human Research Protection has a complete rundown, here, including the internal company memos. Ouch.


Last night my GCP class discussed the idea of rules, of breaking the rules, and the concept of the slippery slope. I feel better about the future on this industry when I know it is going to be in the hands of people who get that concept.


Here is what happens when we don't get it. I recommend reading this on an empty stomach.

Getting Informed Consent Wrong: Count the Ways

The Washington Examiner has an item that reveals the U.S. Dept of Veterans Affairs has been injecting drug-addicted veterans with cocaine under 'extremely controlled conditions' in taxpayer-funded clinical studies. All 40 subjects, most of whom are veterans according to the article, were recruited specifically because they were addicted to drugs into this trial conducted at the San Antonio and Kansas City VA facilities. The VA also handed over abstracts and other documents that indicated decades of using hundreds of human volunteers, presumably veterans since that is the patient database of the VA, frequently administering controlled substances such as crack and intravenous cocaine, morphine, and other opiates to patients who were already addicted to these substances. The VA's acting director of research and development, Timothy O'Leary (wait, isn't that the guy...oh no that was Timothy Leary. Without the "O") said that these taxpayer-funded studies - did I mention these are taxpayer-funded studies? - were 'desperately needed to find ways to treat addiction'. Critics call attention to the problem of informed consent, an essential element of which is the right and opportunity and freedom to refuse to participate in research. How exactly does an addict say no to the possibility of receiving for free his drug of choice? And how do the VA and other government agencies justify using tax dollars to pay for it?

FierceBiotech also has a round up from the Partnerships with CROs meeting in Orlando last week. One item they noted is the apparent tension between sponsors and CROs around who is responsible for data quality. Better communication of expectations roles and responsibilities is probably going to be a key area for clinical teams to work on with their CRO partners, especially for studies in the emerging markets.

Congressional Sting Bites IRB - Who Benefits?

In March of this year, independent Coast IRB discovered what appeared to be a fraudulent clinical trial that had been submitted in 2008 for review by the IRB. According to Reuters, upon receipt of proof of the fraud, Coast ordered a halt to the clinical trial, alerted the appropriate state and federal authorities and instituted internal measures to prevent a recurrence. And that, Coast thought, was that.

Not so fast. Within days it was revealed that not only was Coast in fact the intended target of a fraud, but said fraud was perpetrated by the United States government in the form of the Government Accountability Office, whose website banner contains the words 'integrity' and 'reliability' to go along with 'accountability'. So instead of being the victim of a crime, Coast found itself in the dock before the U. S. House Subcommittee on Oversight and Investigations of the House Committee on Energy and Commerce on March 26th, answering charges that it had failed in its duty to protect human subjects from potential harm in clinical research.

As it turns out, the GAO created a fake protocol for a fake device, which they falsely claimed was FDA approved for sale, manufactured by a fake company in Virginia, developed a fake curriculum vitae for a fake investigator and submitted these documents to 3 different IRBs to induce them to perform reviews. The purpose of this elaborate sting was to "gather evidence to form the basis for arguments critical of the FDA and in favor of greater regulatory oversight" (Reuters, 11Mar09). Other components of the sting that did not involve Coast IRB were: establishing a fake IRB and advertising its services on the web, inducing a company to seek approval to add a site to an existing approved ongoing study (not to approve new research, which according to the regulations receives a different level of scrutiny than ongoing research); and submitting the fake name and qualifications of a fake IRB to the Dept. of Health and Human Services to receive an assurance approval number and be listed on HHS's directory of IRBs that review federally funded research.

Following review by 3 different IRBs of the fake device protocol and other documents, according to the GAO's report, 2 of the IRBs returned such extensive feedback that the GAO determined they 'did not have the technical expertise' to respond, and withdrew its applications. By contrast Coast IRB conditionally approved the protocol after a full board review, and contacted the 'sponsor' via the email address set up by GAO and sought at least two different interactions: one for proof of the medical qualifications of the proposed investigator, which the GAO provided by supplying a forged medical license number from the Commonwealth of Virginia. In another request Coast asked the 'sponsor' to modify the informed consent to make the language understandable at the 5th grade reading level. The GAO modified the informed consent as requested and resubmitted it, whereupon full board approval was granted.

I have requested of the GAO copies of the fake protocol and other submission documents for use in developing a teaching module on this episode, and so that we private citizens in the business can determine for ouselves whether the IRB met its obligations. I have yet to receive a reply.


After the truth of the scam came out at the Subcommittee hearing on March 26th, the FDA, in a response that can be filed under Closing the Barn Door After the Cows Have Gone, issued a warning letter to Coast IRB finding fault with them for not, among other things, determining that risks to subjects had been minimized, for not determining whether the FDA approval of the fake device was valid, failure to ensure that basic elements of informed consent were included in the consent form, and failure to determine whether the proposed research is acceptable under applicable regulations and law.

Nobody in Congress or the FDA seems to be the least bit concerned about the acceptability of perpretating a fraud upon a private organization without any prior suspicion of wrongdoing, of Kafka-esque harassment and eventual ruination of said company without due process, potentially in violation of several federal and state wire fraud and mail fraud laws, as well as state laws against false credentialing. According to Reuters, under the auspices of the Department of Jutice or pursuant to a court order, these practices would have been lawful. However this operation was performed at the behest of the legislative branch, not the judicial or executive.


On April 14th, Coast agreed with the FDA to submit itself to severe restrictions in its operations and to completely revamp its procedures to ensure full compliance with FDA regulations. However as of April 29th Coast has raised the white flag and will close its operations for good after transitioning all its active research projetcs to another IRB. The entire staff has been or will be laid off.


I am as concerned about patient safety as the next person and have a long track record of teaching students that no matter what their role in clinical research may be, however great or small, their first duty is to ensure patient safety above all else, including timelines, profit, and cost. So I question just who has benefitted by this targetting of a specific IRB - who had never received an FDA warning letter before - when it would have been so much simpler, and at the same time legal, to simply audit their files and determine through above-board means whether or not they were meeting their obligations to patients under the regulations. I do not see how patients are better protected when the government itself perpetrates fraud to create a new problem, when many profressionals believe the real problem lies in the fact that there are simply not enough good IRBs to cover all the research being conducted. Taking a potentially good IRB, at least once they had developed a procedure for identifying fraud, out of the equation does not seem to me to be the answer.

Risotto as a Metaphor for Life

I made my first risotto last night, pictured here, with green garlic and leek from the farm coop. The recipe is here. Making risotto is not quite as fearsome as one often hears, but you do have to commit to about 30 minutes of very frequent stirring once you start. And you do need to mise en place. Seriously. You don't have time to chop, wash or prepare anything once the first cup of broth goes in, or at least I didn't. I served the risotto with some fresh red snapper sauteed in a little butter, seasoned only with salt and pepper. Hard to go too far wrong. Everybody took seconds.

I had a conversation this week with someone who told me about Janus the god of beginnings and endings, whose face looks both forward and backward. She related this to people entering middle age and coming to realize that not only do people die, but I will too, and looking to make sense of what has come before to make the best of what comes next. That sounds like a good idea.


I got to thinking about the nature of motivations. If I want to make a big change what is my motivation? To explore new challenges? To have more control of my future? To engage my brain a little more? Does destiny have a role? Or is it just about luck, and are they actually different?

I know I am supposed to blog about my visit in Germany with family. There is so much to tell there, it is hard to get started. Soon, soon...

Life as a locavore

Here is the bag of vegetables from my farm coop last week: beets, leeks, carrots, artichokes, chard, fava beans, broccoli, apples and green garlic. This was the third week of the season, our first in a farm coop and I am starting to get the rhythm of it: pick up a huge bag of produce on Thursday after work, cook like a fiend for the next several days trying to use as many ingredients as possible each night, start casting about for unsuspecting neighbors to palm off any remaining veggies that I either couldn't figure out what to do with or we didn't like, clean out the fridge by Thursday and start the process all over again. One change is already in place: we are eating out a lot less. Which is kind of a bummer because I liked going to the local Indian restaurant on Thursday night after everything was done - Thursday is kind of like a Friday for me because I work from home on Fridays - but now I think about all this minutes-from-the-ground produce aging in my refrigerator, and so I cook instead. Lucky for me, the Minimalist (Mark Bittman of the New York Times) has been writing about the same foods so I've had a new source of recipes. Last night I made his carrot, spinach and rice stew, adding green garlic and cup-up chicken thighs, and heated up some roti for bread - absolutely delicious.

A couple of weeks ago Passover sort of snuck up on us, like everything seems to these days. All of a sudden I realized we hadn't planned anything, so I hastily prepared the ceremonial foods (from my farm coop bag, natch) and invited one of Rob's constantly hungry riding partners and managed with some help from Sean to get the entire meal on the table in about 2 hours - blazing speed for a Seder. I used Sydnee's homemade Seder plate, here.

Closing the Loop

The picture is of a colleague named Paul Loveday. I met Paul in 2007 at a conference in San Francisco. He was the founder and CEO of ClinStar, a CRO in Russia. At 6'10" Paul, a former NBA basketball player, was hard to miss in any room. During a coffee break on the first day of the conference, he loped up to where I was sitting, dropped to one knee (he was still tall even when kneeling) and said "Should I know you?"

There was no earthly reason why he should have. I said, "Do you mean in the metaphysical sense?", he laughed and from there an easy acquaintanceship was struck. I believe I only saw Paul 3 times during the 17 months that I knew him, yet I felt as though I knew him quite well - well enough to ask him to guest lecture twice to my UC class on emerging markets, by phone, all the way from Moscow at 6 AM his time, for 90 minutes at a stretch. Paul had a presence that made whoever he was speaking to feel as though they were the only person in the room. I would not be surprised if there were literally hundreds of people who only met him 3 times, and yet felt they knew him and he them.

The last time I saw Paul was in July of 2008. I was about to speak at a conference on emerging markets in Washington DC - the same conference where I had met Paul the year before - and he said he was planning to heckle me during my talk. I said "Bring it, Paul, bring the heat" and he laughed. His colleague had invited me to go with them for dinner the previous evening but I had declined in favor of previous plans.

The last time I heard Paul's voice was on November 10th, 2008. He called into my class on emerging markets from his office in Moscow and held forth on the benefits and challenges of doing clinical trials in Russia and Ukraine - preferably using his CRO - and somehow managed to make each student in the class feel as though he was standing in the room talking instead of thousands of miles away over a phone line.

In January as I was planning speakers for the spring offering of the emerging markets course and wondering if asking Paul to lecture again was going to the well too many times, I received an email out of the blue from his business development colleague Erin, with whom I had also become friendly. She wrote me that Paul had died suddenly in St Petersburg, 17 days after I last heard his voice.

The loop finally closed when I saw Erin at a two day meeting in San Francisco a couple of weeks ago. Together with the new president of ClinStar, Erin and I mourned. She told me that during the time she worked with Paul, she had often spent long stretches of time with him doing business development, broken by long stretches of time that she did not see him at all when he was in Russia running the business. She said she hadn't really accepted that he is gone, she just thought of him as still in Russia. She kept referring to him in the present tense; we both did. We talked about how their business would go on. We talked about dreading the next summer emerging markets conference without Paul. Erin told me that her sense was that Paul was getting ready to take on his next great challenge - she wasn't sure what it was but now we will never know.

*************

While I was still at this same meeting, I got a call from my mother with the news that my father has severe aortic stenosis with a not very good prognosis due to his age and other factors. He is not a good candidate for surgical valve replacement, which gives him a life expectancy of months, not years. He may be a candidate for a clinical trial, in which case the way I have spent my adult life earning a living may actually let me help my parents out by cutting through some of the barriers. My mother has a vague mistrust of experimental therapy (despite my careful explanations - what is that saying about a prophet not being welcome in her own hometown?); my father is all in for any reasonable chance to go on living as long as he can. I am walking a fine line of gathering information and pushing to keep the doors open and trying to keep the ball rolling for the trial which is very complicated, while still respecting my parents' autonomy. I take a deep breath whenever my phone rings and I see my mother's caller ID, wondering which call will be the one I'm dreading.

*************

I met with an old acquaintance this week whom I had not seen for several years after a falling out. It was surprisingly easy to make the small talk, but difficult to broach the subject of the disagreement. Once I had finally said my piece, she said "Fair enough. Water under the bridge?"

That was all. And it occurs to me that yes, the water is long gone under the bridge, but the bridge is no longer there either.

**************

Finally I am off to Germany next week to close another loop long left open. No doubt that trip will generate future blogging. Another day.

Focuses for the Upcoming Term

This tide marsh is located behind the building I where I work Monday through Thursday, on the east side of the San Francisco bay. It is close enough to walk to, and it has long flat dirt paths to run on when I feel energetic. On a clear day, such as we had this week, you can identify individual buildings in the downtown San Francisco skyline. Most days there is a haze on the water that precludes even seeing the mountains of the peninsula on the other side. I like to go out there during the day to clear my head or to think. Sometimes if I don't have early morning calls I stop by the marsh before heading into the office to watch the great white herons, snowy egrets, mallard ducks and other shorebirds make their living. I find the movement of the tides calming. The water of the bay has a different personality every day; sometimes calm, flat and glassy, sometimes grey and choppy. But the water in the marsh, seen here at high tide, is always smooth and tranquil.

The focus of this week has been building my network of experts in the field of clinical trials in emerging markets. I'm starting to do some research into the area of informed consent in emerging markets: what does signing a form mean to the patient, why are we shoving 15+ page consents down people's throats, and why do the ethics committees let us? I will be contacting my Indian, Eastern European and other connections in the developing world (although they don't know it yet) in the coming weeks to get their perspectives for the next iteration of the emerging markets course, to be offered in the spring term.

The winter term at UC Santa Cruz starts for me next week. It's been about an 8 week break since the fall term ended. Good Clinical Practices, my flagship class, begins Wednesday evening Jan 21 from 6-9pm, and runs for 10 weeks. I've improved (I hope) the curriculum for this term, updating some older information and including references to recent events in the NY Times, NPR, and other sources.

Looking for a Silver Lining

My notes for this week's entry carried a theme of relationship. As I get older I've learned to recognize that companies don't do business with each other - people and relationships do. Sometimes when I go back to a company that I enjoyed working with before, I find that the next experience can be markedly different - and sometimes poorer - and it is all because of the people. More and more in recent years I've invested in relationships with the people with whom I do business, relationships that in my younger days I would have taken for granted, because I find it is those relationships that not only make the job more enjoyable, but also get you through the tough times. I have been in the clinical research business a long time - there is not much exciting about doing new studies anymore. On the other hand, building relationships and networks with great people makes doing the same job more interesting.

None of us is irreplaceable; whenever someone leaves, it almost always creates an opportunity for someone else to grow into their own potential. And I have always believed that people should do what they need to do and are never indebted to their employer or me or anyone else. Still it is hard to say goodbye sometimes.