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.