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.