2 Decades & Counting

Get Your Resume Out of the Pile

2011-11-09T10:39:00.000-08:00

Forbes has an article on commonly used but tired resume words, such as 'experienced', 'team player', 'seasoned' and 'customer focused'. These words ascribe a quality label to yourself without quantifying your experience. 'Experience' can mean having done something once or 5000 times. So use that precious resume real estate to paint a picture for the reader of how you obtained your experience. "Experienced clinical project manager" becomes "Led five large multinational oncology trials to on-time, on-budget conclusion with high quality submission-ready clinical data". This statement tells much more about your skills than merely that you were in the room when these trials occurred.

'Team player' is another well-worn resume term that can mean anything from 'plays well with others' to 'world's greatest cupcake maker for team meetings'. Show your potential manager how you work in teams, using statements like "Led (or participated in) a cross-functional clinical team of CRAs, data managers, regulatory advisers in developing a project plan template for managing a cardiovascular clinical development program.

"Dynamic" is a hard quality to describe and is usually better left for the interview itself. Dynamism on paper is not quite the same thing as in person. Use your resume to quantify your skills and accomplishments and save your personality for the interview.

Read the article for yourself, follow the links below for other great sometimes free resume advice, courtesy of Lifehacker.

Vizualize.me Creates an Infographic Resume for You in One Click

Give Your Resume an Edge by Making It More Modern

Top 10 Ways to Rock Your Resumé

New German Law Raises the Bar for Drugs Entering the Market

2011-10-05T11:48:00.000-07:00

A new law on the books in Germany since the beginning of this year seeks to incentivize innovation by pharmaceutical companies, by structuring pricing models based whether a new drug represents an improvement over existing therapies or not. This creates in effect a two step process to access the sizable German market; first regulatory approval and then, an assessment of efficacy data by a separate German pricing committee. If that pricing committee determines that the new drug offers not benefit over existing therapies, the drug may enter the market under a fixed price regime. If the new drug does offer improvement, then the payers and manufacturer may negotiate a price.

According to the blog The Language of Science, some manufacturers are choosing not to enter the German market at all rather than accept fixed price restrictions on new non-inferior products. In September, Boehringer Ingelheim and Lilly opted not to launch their new oral anti-diabetes drug Trajenta in Germany after the federal commission relegated it to the fixed price model. It is interesting to note that the decision was made by comparing Trajenta to a generic diabetes drug, not to other gliptins in Trajenta's class. Also in September, Novartis pulled their new anti-hypertensive product Rasilamlo after they could not provide differentiating data to the pricing committee's satisfaction.

The German government has presented this law as an incentive to manufacturers to find and develop novel innovative therapies over "me-too" products, perhaps not surprisingly the industry does not see it this way, as their actions of withdrawing products rather than submit to fixed pricing seem to indicate. Given that Germany is the largest market within the EU, it will be very interesting to watch whether other EU members follow suit in creating a pricing scheme based on benefit. It will not happen in the US any time soon, because the market, not the government controls pricing in the US marketplace.

Clinical Trials in India

2011-09-26T08:45:00.000-07:00

I am thrilled to have a guest commentary this week on Carl Anderson's wonderful GXP Perspectives blog on recent changes in the clinical trials landscape in India. New rules and guidances emerging in recent months are all pointing - I believe - to an even stronger clinical trials enterprise in a country whose credentials are already very good. Please go on over to Carl's blog and take a look, make a comment. I'd love to get your thoughts.

Thanks very much indeed to Carl for his support.

FDA's New Guidance on Clinical Monitoring Arrives

2011-09-18T14:21:00.000-07:00

The FDA has released its long awaited update and replacementto the outdated 1988 guidance on clinical monitoring. The draft guidancefor industry on Oversightof Clinical Investigations - A Risk Based Approach to Monitoring isearly evidence that the findings and recommendations of the Clinical Trials TransformationInitiative (CTTI), FDA's public-private partnership with DukeUniversity among others, are beginning to take hold in practice in the clinicaltrials domain.

According to a CTTI survey, clinical trial sponsors aresuccessfully employing a range of monitoring modalities, such as centralizedmonitoring by biostatistical and data management personnel, targeted on-sitevisits to higher risk sites as well as frequent on site visits to all sites byclinical monitoring personnel. Yet historically, industry sponsors haverarely relied on any mechanism other than comprehensiveall-site monitoring performing 100% source data verification, everyfour to six weeks. It is a well-understood, costly and time consumingmethod of monitoring that the industry perceives is preferredby FDA. Yet, given the vast changes in the clinical trial landscape inthe decades since the FDA's previous 1988 guidance and the regulations coveringsponsor obligations, including the increase in the number and complexity ofclinical trials, investigator experience, changes in ethical oversight,treatment options, and geographical dispersion of clinical trial sites, the FDAnow calls on the industry to employ new and more effective methods formonitoring clinical trials.

This is big news. As in the recent finalrule on safety reporting, which requires sponsors to make judgments aboutwhether a single case is instructive enough to warrant reporting to theauthorities, FDA here is encouraging sponsors to reduce their reliance on aone-size-fits-all, on-site, 100% source data verification comprehensivemonitoring approach in favor of a more diversified, horses-for-coursesapproach, building monitoring plans and employing monitoring modalities basedon multiple factors such as:

· type or study and endpoints (whether objectivelyor subjectively derived)

· disease state of patient population

· sponsor experience with investigator andinvestigator experience with research

· complexity of protocol, such as adaptivedesigns, stratified designs, complex dose titrations, etc.

· availability of EDC to facilitate centralizedmonitoring

Throughout the guidance, the FDA continually refers to theprevalence of electronic data capture (EDC) that allows for centralized andrisk-based monitoring. It appears that their expectation is that EDCusage is now or very soon will be the norm rather than the exception. This is certainly one of the most important advancements in clinical trialstechnology that allows for alternatives to comprehensive on-site 100%monitoring and indicates that despite its earlier struggles for acceptanceduring the 1990s, remote data capture is here to stay at last.

While this is a draft guidance, the FDA is putting teethinto it by:

· withdrawing the extremely outdated 1988 guidance

· ensuring that BIMO guidance manuals arecompatible with the recommendations

· ensuring affected areas of FDA are aware of thegoals of the guidance

· will consider establishing processes within CDERfor sponsors to voluntarily submit feedback on proposed monitoring plans.

It will be interesting to watch how sponsors and CROsimplement this new guidance. Having traditionally supported comprehensive,frequent on-site monitoring methodology, CROs will have to develop new pricingmodels other than X monitors spending Y days onsite every Z weeks. Sponsors by their turn will have to revise their SOPs and employdifferent kinds of training to use centralized electronic monitoringmethods efficiently.

This post was published at the Clinical Leader site. I am grateful to Rob Wright, Chief Editor of Life Science Leader magazine for his support.

Follow up on All Things Makena

2011-04-04T09:45:00.000-07:00

BioCentury TV covers the wild week that was KV Pharmaceutical's, after the FDA nixed their plans for exclusive marketing of a form of progesterone that had previously been used widely and cheaply for decades by women to prevent premature birth. See the video report here and read the PDF followup here.

Followup to the Makena/KV Pharma Saga

2011-03-30T11:17:00.000-07:00

Sometimes the little guy wins. Sometimes it pays to stand up and fight back. That's what has happened in the case of KV Pharmaceutical and its Makena, a form of progesterone indicated for preventing premature birth and approved by the FDA recently under the Orphan Drug Act. This blog has addressed this twice recently, here and here (scroll down). The injectable form of the drug, for which no one holds a patent including KV, has been available for decades from compounding pharmacists at a cost of $10-20 per week for weekly injections during critical weeks of gestation. Under the Orphan Drug Act, KV Pharma was able to augment the available clinical research with some additional clinical data and obtain approval for sale under accelerated review, and receive considerable government assistance (read: tax breaks), plus 7 years' market exclusivity, for a product on which they don't hold a patent and in which their development investment was relatively low. Meanwhile, KVeliminated the competition - the compounding pharmacists - by sending them letters stating that under the terms of their approval, the FDA would no longer 'exercise enforcement discretion with regard to compounded versions of Makena." KV priced the product at a whopping $1500 per weekly injection - and neither the FDA nor any other arm of the US government controls drug pricing in this country - made some weak noises about providing assistance to certain women, and thought that was the end of that.

Not so fast, say the patients and their physicians. Public response to this story has been swift and loud. A sampling of coverage of the outcry is at the bottom of this post. Patients and physicians were outraged at KV's wantonness in so drastically inflating the price by a hundred fold, and their rationalization that weekly dosing would still cost less than a stay in the NICU fell on unsympathetic ears.

Not so fast, also says the FDA. In a statement released today on FDA's web site, the FDA makes it clear that while it cannot tell KV how much to charge for their product, it indeed can exercise its enforcement discretion and will not come after pharmacists that "compound hydroxyprogesterone caproate based on a valid prescription...unless the compounded products are unsafe of substandard quality", or not compounded according to proper technique.

According to FiercePharma, KV has yet to comment on the FDA's statement and it is not yet clear what effect if any this will have on pricing.

http://www.fiercepharma.com/story/payers-may-balk-makena-pricing-kv-says/2011-03-23
http://www.fiercepharma.com/story/senators-demand-ftc-probe-kvs-makena-pricing/2011-03-21
http://www.fiercepharma.com/story/kvs-makena-delivers-1500-sticker-shock-docs/2011-03-10

KV Pharma and the Drug Price Wars

2011-03-27T12:52:00.000-07:00

At the bottom of my last post I looked at the recent case of KV Pharma and its new drug Makena, which was approved last month by the FDA under the Orphan Drug Act for prevention of premature birth. Makena is a form of progesterone that has been available for decades at a cost of $10-20 per week from compounding pharmacies, but now KV Pharma, which went to the trouble of registering their version of the product has a 7 year monopoly on sales of the product (thanks to the Orphan Drug Act), which they have priced at $1500 per injection. The drug is dosed weekly from weeks 16 through 20 of gestation. The penalties associated with trying to provide the compound the old way should give any pharmacist reason to think twice.

Two US Senators (Amy Klobuchar, D-Minn and Sherrod Brown, D-Ohio) have asked the Federal Trade Commission to look into the pricing matter and investigate whether the $1500/injection price tag constitutes anti-competitive behavior. The senators also charge that KV Pharma's patient assistance program is insufficient. You can see the press release and letter, which uses words like 'price gouging', here.

As is often the case, Pharmalot is all over this. This week they asked for an explanation from Jamie Love of Knowledge Ecology International. Love points out a number of issues stemming from the use of the Orphan Drug Act to secure this approval along with its exclusivity. The Orphan Drug Act was originally enacted to incentivize manufacturers to make otherwise unprofitable medicines available for diseases that strike relatively few patients. In the case of Makena, the compound was already available to pregnant women since the 1950's. So even though KV Pharmaceuticals did perform clinical trials, and the rest of the research was done by the NIH (see here for the full list of trials), and KV does not hold the patent on the progesterone compound (hydroxyprogesterone capoate, apparently no one does according to the Orange Book), they still receive the seven-year market exclusivity under the law. The Pharmalot Q&A with Love is here, which includes links back to their earlier coverage of the story. Love's blog noting how the Orphan Drug Act could be improved is here.

What Price Drug Development?

2011-03-10T19:34:00.000-08:00

UPDATE 3/18/2011 - see links to Tufts Center response and PharmaExec's op-ed at the end of of the post.

There have been several pieces in the trade and popular press this week about the cost of clinical development of new drugs. This discussion is really about drugs, not devices, as not only the costs but the way devices are researched, evaluated and cleared can be quite different. Here is a rundown:

Slate published a piece by Timothy Noah on March 3rd called The Make Believe Billion, which takes a critical (does that surprise you?) look at Big Pharma's oft-quoted and not-often challenged claim that it costs $800 million (in 2000 dollars) and takes 12 years to bring a new drug to the patient. These figures, adjusted upwards for inflation, are used by the Big Pharma lobby with roaring success to justify the high cost of brand-name prescription medicines. The two numbers come from this 2003 study published in the Journal of Health Economics. The lead author is economist Joseph DiMasi who was working for the Tufts University Center for Drug Development, an academic, non-profit study group that welcomes corporate sponsorship. Because of the Tufts connection of DiMasi, most of the time that you see the $800M/12 year figures cited, the source of the data is often cited as the Tufts Center.

The Slate piece discovers a new challenge to the $800M claim in a study (PDF) published last month in the London School of Economics' BioSocieties journal by Princeton's Donald Light and University of Victoria's Rebecca Warburton. Following along in the vein of The $800 Million Pill by Merrill Goozner, the Light study takes apart the source data the Tufts group used to develop their results, citing various problems.

First, the Light paper challenges the sampling of data used to feed the model. In the Tufts study, financial information was requested from 24 companies, 10 of whom ultimately submitted data via confidential survey. Because the data were collected in a confidential form, they are unverifiable by independent means, say the Light group. And because the results are based on data submitted by self-selected companies that agreed to share their data, there is no true random sampling from a larger population of data. The Tufts study does not describe any efforts to verify the reported data, so there is no way to determines whether the R&D costs are uniformly reported from sponsor to sponsor. Additionally it is not clear whether or how much of the data reported are R&D costs for self-originated new chemical entities (NCEs), which according tot he same Tufts group are 4.4 times more costly to develop than in-licensed NCEs, which are in turn 3.4 times more costly than non-NCE variations on existing drugs. Only 35% of new drugs developed during the reporting period (1990-2000) were NCEs, and even fewer were self-originated, or developed in-house.

The second challenge of the Light paper comes from the exclusion of discovery costs reported as part of the R&D figures used for the $800M calculation. The reasons for this are multiple: discovery costs are much harder to tease out as discrete portions of R&D budgets because there are no recognizable chunks of work like phase 1, 2 or 3; often several compounds or targets are researched together under one budget line item; basic research is often carried out by entities other than pharma companies, like universities or the government; and sometimes new therapies are discovered quite by accident, like penicillin. To solve this problem, the Tufts group simply factored in an average cost of $121 million and 52 months of development time, without any data to support the figures.

Thirdly, the Light group argue against the Tufts claim that tax breaks and taxpayer subsidies for pharma companies should not be discounted from the total R&D cost. The Light paper argues that this might be reasonable if R&D were depreciated over time like over long-term investments, but they are not: R&D costs are deducted from profits each year that they are incurred. This effectively creates a 100% tax deduction every year. According to a 1993 US Office of Technology review of pharma research costs, the net savings was nearly 50%, and this was at a time when the top marginal tax rate was 46%. Now that the top rate is 35%, the Tax Policy Center puts the average tax savings on R&D per year at about 39%, yet these discounts do not appear in the Tufts study.

The fourth large challenge to the Tufts study is in the assumption that half of R&D costs are accounted for by the 'cost of capital', in other words, returns that did not materialize from investing that same money in the market instead of using it for research, assuming an 11% return in the period under study. Calculating the cost of capital is a common method for corporations to decide whether to pursue new projects, but the Light authors claim it is a bit ingenuous for the pharma industry to then claim that the cost of capital, what the pharma company would have made on the market instead of a new drug, should be considered part of the cost of R&D, especially when developing a new drug is the business of the pharma company, not to invest money. And when that cost of capital calculation ends up as half of the claimed $800 million R&D costs.

There are some other challenges in the Light paper too, about inflation of individual per-patient trial costs, exaggerated time for total development (52 months preclinical, 72 months for trials and 18 months for review, or 11.8 years), and the claim that only 1 in 10,000 compounds ever make it to the marketplace, the use of median costs instead of means to counter the shifting effect of outlier data points, i.e., more expensive or large trials. When all is said and done, the Light group claim that the average cost of the "D" part of bringing a drug to market is more like $59 million based on the 2000 data in the Tufts study. In today's dollars that would be $75 million average, or $55 million median.

Not so fast, says research scientist Derek Lowe in his blog In the Pipeline. He challenges that it is a lot harder than people think to come up with compounds and targets that actually have some potential clinical benefit while remaining safe enough for human use, and that you can't simply not count discovery research costs simply because they are harder to identify. From my own perspective on the clinical side of things, during the time represented by the Tufts study, we were routinely running $20 million/year clinical budgets to develop an antiretroviral medication for CMV, and the study sizes were relatively low, just a few thousand patients. The clinical development period of that product was around 5 years if memory serves, and of course it was an accelerated program since it was largely developed for HIV+, full-blown AIDS patients.

Later this week we saw two other articles make the rounds: one from CenterWatch that pleaded the pharma manufacturers case that if only they could get longer data exclusivity, companies would be able to innovate again and patients would live longer. Extending data exclusivity to 12 years would net the pharma companies 5% additional profits, resulting in 228 new drugs over the next 50 years and increasing the average person's lifespan by...wait for it...1.7 months. The article is here.

And lastly, today's paper had a piece that got some pretty strong reactions from all sides, where KV Pharma announced that injections of their drug Makena, which now cost $10-$20 per dose, next week will cost $1500, the total cost to the patient ranging from $27,000 depending on length of gestation. The company's CEO defends the price increase by pointing out that PICU care can cost $51,000 or more, and Makena can defray some of that cost. The reason for the change? Makena is a newly approved form of progesterone that until now was provided by compounding labs for literally a few cents worth of chemicals. Compounding will no longer be legal now that an approved version is available. KV Pharma has had all kinds of problems recently, having entered into a consent decree for making and distributing adulterated and unapproved drugs, pleading guilty to two criminal fraud for failing to report oversize tablets to the FDA, but all that seems to be in the past now. Their stock is up from $1.50 in early February to close at $12.64 today.

3/18/2011 - Tufts Center response is here; an op-ed on the PharmaExec blog is here.

Vulnerability and Informed Consent

2011-03-02T18:03:00.000-08:00

I spent most of today discussing ethics in clinical trials at a conference produced by Leo Intelligence in San Diego with a fascinating group of people from IRBs, sponsor companies, and CROs. It was a really good small meeting, and I hope they put it on again next year and give it a chance to grow.

In the morning we reviewed how the relentless drive for new, willing, and preferably treatment naive patients is pushing clinical research out to farther and farther away places, countries that may have weak, stressed or crumbling health care delivery systems that struggle to serve their citizens' basic medical needs. We discussed some of the major ethical policy issues of international clinical research, especially in developing countries, such as placebo controls, clinical trials as treatment or even marketing, and vulnerability and consent. (The slide set for this talk can be found here.) Some countries have legislated and developed and invested, such as India and Brazil (and other South American countries), many countries of the post-WWII east. Some countries have grown a clinical research enterprise out of the opportunism of a health crisis, such as Russia and the Ukraine following the Chernobyl disaster. Even in these countries we see challenges in obtaining truly informed, voluntarily given consent. Cultural differences can take the standard western idea of consent and stand it on its head.

For example, the Belmont Report's first principal of respect for persons, usually defined as the autonomy of the individual, is considered a universal ethical truth, one which even the ethical relativists can accept as valid for all. Except that in many non-Western cultures where the collective is valued above individual - where "the needs of the many outweigh the needs of the few, or the one" - the idea of a patient making a decision to participate in a clinical trial based on her self-interest quite stretches the imagination.

Now consider this same patient, who has little experience making a decision that is not at least informed by or simply made outright for her by another member of her family, and add to that the fact that she cannot read; not her own language and certainly not English. Then add finally the factor that her physician is an even more powerful figure in her life than her husband or father, and whatever he (or she) says has the weight of the voice of God himself. Now the idea of slapping a 19 page consent form in front of that patient, getting her signature or mark, and going to sleep at night believing that we have met our obligation to obtain true, voluntary informed consent to participate in a study is truly laughable.

And yet that's what we do.

And this is not all. This afternoon's keynote speaker was Andy Mikulak, of Max's Ring of Fire, who gave a patient's perspective of participating in clinical trials. Andy is not a researcher, or IRB member. He is a father, and his son Max taught Andy much about participating in clinical trials - right up until the time he died of neuroblastoma at age 7. Since Max's death Andy has coped with his grief by becoming a patient advocate and raising money and awareness for pediatric cancer research. Check out the website and click on a couple of videos. Your eyes will not stay dry.

Andy gave a short talk intended to explain to us why patients go into clinical trials, and what we could do to make the experience better and more useful for patients. He said patients go into trials to live, to survive, and sometimes because they cannot get treatment for their serious disease any other way. He suggested to researchers that if they meet their patients' needs, their own needs for data and results will be met. He also admonished us for making informed consent forms too complicated. He said that he and other patient families routinely seek out other patients for 'true' information' about trials, because the sponsor/IRB provided documents are written "to protect the institution first, and inform the patient second". He said the language used in consents did not meet his needs or those of other patient families: the language was too obtuse and not intended to inform. There is too much protectionist, defensive language. And this is not a guy who cannot read beyond the 6th grade level; Andy had no problem discussing the preclinical data of various chemo agents his son was treated with, so the issue was not the level of the language, but that the language was not intended to inform.

This got a big response from the IRB members in the room, whose nominal role is protect patients, yet some IRBs seem to be a driving force behind the ever-lengthening consents in recent decades. When I have asked them why, the most prevalent reason seems to be: "we want to anticipate patient questions so in case they don't know what to ask, it's all there in the document." Fair enough; many patients don't know what to ask or are too timid to ask. But why then do we not train and then empower the investigator to provide information, to anticipate questions and prompt for them? Have we completely abandoned the investigator's role in providing risks and other information to patients? (For information about the learned intermediary and its rise and fall in the pharmaceutical world, as well as clues as to how we became so protectionist, see Perez v Wyeth Labs.) It seems that instead of using the consent form as the documentation of the consent conversation, and the basis for discussion, we are allowing the form to replace the process almost entirely.

And in the end, studies show that many patients - western and non-western alike - do not understand that they are involved in a study, that they have right to withdraw, what the risks are and that they may receive treatment with a comparator (or placebo). So clearly the answer isn't to be found by adding more pages to the consent form other than to make the institution's lawyers feel better.

The plane is boarding. Next post, some thoughts about where the low hanging fruit might be found; how we can minimize the mistakes that we make and better protect the patients we study.

Pfizer Settles Trovan Lawsuits

2011-02-22T09:56:00.000-08:00

Here at Two Decades & Counting we've been following the legal battles over the Trovan investigations in Nigeria in 1996. You can review the case and its ramifications in the US legal system here, here, here, and here. Today Pfizer announced they had settled "lawsuits stemming from" the case for undisclosed sums, with deleterious effects on Pfizer's stock price.

Upcoming Clinical Research Conferences & Events

2011-02-19T12:23:00.000-08:00

In about 10 days I will be in San Diego for the first Ethics in Clinical Trials conference.

Current deals (I think these are still good - call 720-212-0440):

· 4 for 3: Send 4 delegates for the price of 3

· 10% off: Mention booking code leoE11

· Free Pre-Conference Workshop: preE11 (Led by me, a discussion of emerging region clinical trial ethics)

Call: 720-212-0440 or click www.ethicsintrials.com.

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

Later in March I will be at Partnerships in Clinical Trials in Phoenix - March 30-April 1. I am chairing a market insight round table discussion on Strategies for Indian Clinical Trials on Thursday Mar 31, at 11:00 AM. Click here to register, or here for pricing.

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

Finally, I will be in a panel discussion at MAGI's Clinical Research Conference in Philadelphia, May 22-25.

I have attended and presented at the western edition of this conference a couple of years running; this will be the first time I travel east for MAGI. I am delighted to join again with Joan Chambers of CenterWatch, Nye Pelton of Eli Lilly and Marlene Llopiz of Venn Life Sciences to discuss the current state of globalization of clinical trials.

According to the conference organizers, two-thirds of attendees will have 5+ years of experience. About 48% of attendees will be from sites, 27% from sponsors, and 25% from CROs and other service providers.

The conference website is here. A friend-of-speaker discount can save you $100 - code Q367.

Click here to register. Enter the above discount code when prompted. (Does not apply retroactively or to already-reduced group rates.)

FDA News Roundup

2011-02-12T12:33:00.000-08:00

The FDA was in the news a lot this week, an especially noticeable series of events if you have multiple searches returning FDA news each day as I have. Reviewing my Twitter feed alone (follow me!), I linked to six separate news items about the FDA the last four days:

Feb 11 - FDA to contract out more foreign inspections from FiercePharma
Feb 11 - An evidence-free and detail-light op-ed in The Hill's Congress Blog written by Newt Gingrich*, GOP 2012 presidential hopeful; Andrew C. von Eschenbach, former FDA commissioner appointed by Bush 41; and Wayne Oliver, former Georgia Pharmacy Association lobbyist and current head of Gingrich's Center for Health Transformation, a "think-tank" for health care and FDA reform.
Feb 10 - An op-ed by Rep Joe Pitts (R-PA) claiming that the new proposed FDA medical device regulations are driving innovation and jobs to the EU.
Feb 10 - FiercePharma again, this time linking to an NYTimes op-ed by Ian D. Spatz, former Merck exec, writing about how direct-to-consumer ads are an important public educational tool that can reduce side effects.
Feb 9 - a press release from the House Appropriations committee with proposed budget cuts of $220M from FDA's budget for 2011, around 7% of its requested $3.2B in 2010.
Feb 9 - A Wall Street Journal article noting FDA's concern over six different companies not completing their follow up commitment studies they promised to conduct following accelerated approval of their products.

Bringing all these stories together into some sort of context I leave to others. One does note that the "over-regulation is hurting business" meme was in heavy rotation this week.

*Newt has been after the FDA for a long time. In 1994 as Speaker of the House, he advocated "nuking" the FDA altogether and replacing it with a combination of third party reviewers and corporate tax incentives. (Authentic Leadership: Rediscovering the Secrets to Creating Lasting Value, William W. George; Jossey-Bass, 2003)

Offshoring Science

2011-02-09T15:19:00.000-08:00

The current issue of IRB: Ethics and Human Research from The Hastings Center has a review of a book I wish I had written, entitled When Experiments Travel: Clinical Trials and the Global Search for Human Subjects, by Adriana Petryna. Petryna's profile page lists her as an anthropology professor at the University of Pennsylvania.

The review by Alex John London, professor of philosophy at Carnegie Mellon takes us through Petryna's review of the rise of globalization of clinical trials and discussion of the both the dangers and promise of researchers looking offshore to find trial subjects. Both London and Petryna point out that because of the power of clinical trials to shape opinions and behaviors of both patients and physicians, not to mention regulators and political forces, researchers must be all the more careful not to place clinical trials of minimally effective experimental remedies into host populations that lack access to the best proven care (to quote the Declaration of Helsinki) or to use willing and unwitting patients to generate information that may have little relevance to the planned consumers of a therapy that will not be made available to the host population.

London seems to derive from his reading something we often talk about in discussion of research ethics, or the lack thereof; namely the highly rare occurrence of one individual intentionally setting out to commit ethically problematic behavior. Far more commonly, ethical difficulties are the result of a cascade of poor decisions, delegations and skipped steps. Just as airplane crashes are most commonly the result of an accumulation of errors rather than one failed part or decision, so too with researchers and their ethical behaviors.

The IRB publication is available with a paid subscription, but Hastings have made this review available for free on their website, here. You may have to create an account to see the whole thing. It's worth it.

Ethics in Clinical Trials Conference Now Open

2011-02-01T11:46:00.000-08:00

We are about one month away from a conference I am really excited about. Ethics in Clinical Trials will be held on March 2-3 in San Diego at the Hilton San Diego Resort and Spa. Looks like a lovely place to escape winter for those of you buried under records snows in the US. Click on the conference website above for the details. Here are a couple of promotions the organizers are generously offering:

4 for 3: Send 4 delegates for the price of 3
10% off: Mention booking code leoE11
Free Pre-Conference Workshop (led by your 2Decades blogger) : preE11

Or just contact the conference organizers, Leo Intelligence at +1-720-212-0440

If you come to the conference please be sure to come up and say hello - I'd love to meet you in person.

FDA Approves Depressant Drug For The Annoyingly Cheerful

2011-01-27T18:06:00.000-08:00

A little something for your Friday...

Informed Consent May Be Compromised & Medical Device reform

2011-01-25T13:13:00.000-08:00

In a study published today in IRB: Ethics and Human Research (free abstract, $ subscription for full article), concluded that unrealistic optimism is prevalent among some clinical study subjects and that it "has the potential to compromise informed consent". Seventy-two early phase cancer study subjects completed questionnaires designed to assess their level of understanding of the study's purpose as well as to detect signs of unrealistic optimism. Unrealistic optimism is defined as "specific to a situation and consider (sic) a form of bias...and is distinct from "dispositional optimism, which is a general outlook on life and is neither realistic nor unrealistic". Questions to reveal unrealistic optimism revolved around the likelihood of particular individual outcomes as compared with other study participants, or the participant's tendency to give greater weight to possible benefits than possible risks. According to the study's findings, 72 percent of the subjects accurately understood the objectives of the cancer trial in terms of potential benefits to future cancer patients rather than directly to themselves, which means that 28% of respondents did not clearly separate those facts. The researchers' concluded that we need to improve the informed consent process by "paying more attention to how patients apply the consent information to themselves". Reporting on the trial is found online at Medical News Today.

In other news, last week the FDA announced proposed changes to improve the agency's 510(k) program for approving medical devices for sale. Some of the recommendations include:

consolidate the terms “indication for use” and “intended use” into a single term, “intended use”;
expand its statutory authority to consider off-label use when determining the intended use of a device;
issue guidance on when a device should no longer be available for use as a predicate;
issue a regulation on its rescission authority;
issue guidance to create a “Class IIb”; and
seek greater authorities to require postmarket surveillance studies as a condition of clearance for certain devices.

The full report is here (PDF). FierceMedicalDevices reported generally favorable reception of this news by the industry. We have a long way to go until any of the report's recommendations become regulation, but now at least we have some ideas of which way the agency's thinking is going. At the same time, the Wall Street Journal carried an op-ed by President Obama discussing the balance between regulator and free market. It all makes for very interesting reading.

Thalidomide and Public Perception

2011-01-11T18:23:00.000-08:00

Thalidomide's left and right enantiomers

Yesterday on Slate.com, a piece was posted entitled Thalidomide's comeback: Who'd have thought the drug would have a second life? The piece first briefly - very briefly - reviews thalidomide's dark past as a sedative and treatment for morning sickness - not a great idea for a drug with a powerful teratogenic profile - in the 1950's and 60's and the resultant extreme fetal damage followed by the drug's banishment into the wilderness for a biblical 40 or so years of wandering. The piece relates the oft-told - and some say apocryphal - story of the FDA's heroic stopping of the the drug on US shores before it could become approved and wreak its havoc here. In the late 1990's the drug was resurrected and rehabilitated, first as a treatment for a complication of a form of leprosy (free; registration required), then in 2006 as first line treatment for multiple myeloma. Researchers studied the cancer indications initially because of thalidomide's inhibition of blood vessel development, although now scientists are downplaying that hypothesis and looking at the drug's ability to boost the body's malignancy-hunting immune cells, which is leading to possible indications such as lupus and others. As a condition of approval, FDA required thalidomide's new owner Cellgene to develop an education program for prescriber, pharmacist and patient so that everyone understood the risks and took the proper precautions. (I have a copy - I knew Cellgene's local sales rep a few years ago.) The post author then questions why, in the face of such compelling safety concerns, the FDA would "give it another chance", and notes that the target population, at least those with multiple myeloma, is most likely to be people who are of an age to remember thalidomide and its damage.

What I find interesting about stories like these is the premise that the drug itself is somehow an actor, a party to the conflict, that there is such thing as a "good" or "bad" drug, and that a "bad" drug should somehow be punished by never being used for any good purpose. Drugs aren't bad or good; they are just chemical compounds with learn-able and predictable behaviors. Develop a chemical compound that interacts badly with the human body's own chemistry and bad things will happen. Develop a compound that heals or helps the body perform its homeostasis chores and, as long as you know or can predict what the side effects are and manage them, good things will happen. The question really should not be: why did the FDA give thalidomide another chance; it should be why not? More people are suffering from cancers and other life-ending diseases than ever before. Why would we not want to use all the tools in our toolbox? An ax can be used to cut down firewood or to damage the backyard fence. We don't cut our firewood with a butter knife simply because an ax has potential for damage. We learn the productive uses for the ax while protecting ourselves by keeping it is a safe place and making sure we know how to use it. Likewise, we can learn how to predict the behavior of chemical compounds and then target them at the stuff making us sick. Or use them to help keep us well.

Thalidomide is not a "bad" drug any more than is acetaminophen. The box of cold medicine I bought yesterday over the counter loudly advised me to review the new warnings that if I take too much acetaminophen in a 24 hour period I could suffer life-threatening kidney damage. There was no prescription required, no pharmacist advising me of the risk and verifying that I understood it. Thalidomide on the other hand is carefully prescribed for people with a specific condition and who are inform why it should not, must not, be used by pregnant women or women who might become pregnant - which is not a very big subset of multiple myeloma patients in any case; procreation is just not their main concern. The number of people who buy cold medicine each year must be orders of magnitude than the number of people who are prescribed thalidomide, and the potential for kidney damage from overdose of acetaminophen seems to be far greater than the danger of another wave of thalidomide-induced birth defects. Yet we're not reading blog posts about the dangers of OTC cold medicines.

What people really should be thinking about is not "bad" drugs, but the fact that any drug from aspirin on up can have bad side effects, even when used as directed. One of the reasons it takes so long for a new drug to make it through the research cycle is that it takes a long time to identify potential side effects and learn how to adjust dosing to minimize them. People sometimes think that once a drug is approved it must be completely safe, and they get upset and look to haul someone into court for damages if they suffer an adverse effect - check out the comments to Slate's thalidomide post to get a flavor of this. But that's not what approval means. Approval simply means that the risk:benefit ratio appears to favor the benefit side; it never means that the risk has been completely eliminated.

Whether the FDA really did sniff out the problems from the data alone or whether the submission was passively awaiting review when the feathers hit the fan in Europe as some regulatory old timers have suggested, is something we will probably never know for sure. The bottom line is that a drug that was not safe for the indication sought in the application, that of morning sickness, was kept off the US market and a new a high standard for safety evaluations of every drug that came after it was set. Even the law governing drug evaluations was changed in the wake of the thalidomide disaster; the 1962 Kefauver-Harris amendments changed the Food Drug and Cosmetic Act - the law that gives the FDA its teeth - so that drug manufacturers would have to demonstrate both safety and efficacy to win US marketing approval. It is really hard to come up with a cure or treatment for a disease and it should be.

Patient Participation in Clinical Trials: Is There a Country Difference?

2010-12-21T18:20:00.000-08:00

In the December 2010 issue of PLoS One, a diverse group of authors from Brazil, Singapore, India and the US published a paper entitled: So Different, yet So Similar: Meta-Analysis and Policy Modeling of Willingness to Participate in Clinical Trials among Brazilians and Indians. Their objective was to conduct a systematic review and meta analysis (SRMA) of the literature to determine a model for predicting willingness of Brazilian patients to participate in clinical trials,and then compare the findings regarding Indian patients' willingness to participate in clinical trials. The results if validated could be useful for sponsors and CROs planning studies to avoid wasting time and money in the wrong country and to better design protections for vulnerable patients.

The findings are based on a rather small sample of only five papers, narrowed down via various factors from 28119 (that's the systematic review part), and the authors grouped their results into two broad groups: factors favoring participation in clinical trials and factors presenting a barrier to that same end. Interestingly, and again based on a relatively small sample, the researchers found that the most commonly cited reason for participating in clinical trials among Brazilian patients was altruism, at 55%. Personal health benefits (30%), convenience (11%), and monetary reimbursement (6%) completed the list of favoring factors. The barrier factors amongst Brazilian patients were: fear of adverse events (12%), mistrust (6%), lack of knowledge (4%) and inconvenience (2%).

By modeling this information to a previous systematic review of literature pertaining to Indian patients, the authors discovered a significant difference in Indian patients' motivations to participate in clinical trials. The leading factors for Indian patients were: personal health benefits (48%), altruism (43%), monetary reimbursement (31%), and trust in their physician (8%). Convenience did not factor at all for Indian patients according to these findings. The factors representing barriers to participation for Indian patients were: fear of side effects (27%), mistrust of drug companies or researchers (26%), dependency issues (19%), loss of confidentiality (17%), and inconvenience (11%).

The authors also conclude from their research that Brazilian patients are more likely to participate in clinical trials than their Indian counterparts. I think we can also draw from this the inherent vulnerability of clinical trial participants, especially in the developing and emerging regions,and use the factors favoring and inhibiting participation to help protect and reassure patients as they come into trials.

WikiLeaks and Trovan

2010-12-11T15:28:00.000-08:00

If you thought the WikiLeaks story had nothing for you, think again. Today's New York Times discusses a State Department cable, made available via recent the WikiLeaks dump, alleging Pfizer's attempt to disrupt the Nigerian lawsuit following several deaths after the experimental use of Trovan in Kano in 1996. According to the Times story, the State department accused Pfizer of hiring investigators " 'to uncover corruption links' to Nigeria’s former attorney general and apply pressure to drop lawsuits against the company." Nigeria's former attorney general, Michael K. Aondoakaa, was quoted in the piece saying he knew nothing of any Pfizer attempt to investigate him. Pfizer denied the allegations as "simply preposterous". This is just the latest in the continuing saga of Trovan in Nigeria, which we have talked about here and here.

Happy Thanksgiving!

2010-11-24T17:47:00.000-08:00

To all my US readers, as well as to those who have to work tomorrow, Happy Thanksgiving! Enjoy the holiday and try not to overeat.

Has Clinical Trial Globalization Run Its Course?

2010-11-17T19:44:00.000-08:00

A few weeks ago I had the good fortune to participate in a very interesting panel on just that topic at MAGI's Clinical Research Conference in San Francisco. The session was chaired by Joan Chambers, COO of CenterWatch, and my panel mates were Kamran Ansari of Sanofi-Aventis and Nye Pelton of Eli Lilly. I jumped at the chance to be on this panel because I have noticed that the recent, breathless you-heard-it-here-first pronouncements coming out of the CRO industry hearkening a great tidal wave of clinical studies to places like India, South America, Russia and Central European countries have not quite panned out. The studies are still going to those places but not exactly in the free-for-all we were led to expect. Does this signal that globalization has peaked, and if not, what adjustments should we make in our expectations, especially those of us with a strong international expertise component in our business models?

My view is that we are experiencing a pause in the marketplace, if not quite a correction, and we will start to see increased movement again quite soon. I think the pause occurred for a couple of reasons: one) performance did not quite measure up to the claims of some providers, and two) the worldwide financial meltdown took an awful lot of business with it in the form of reigned in development programs and planned studies that never got started to save precious cash. Let's look at the first reason, since this is not an economics blog.

In the first half of the 'aughts' or the decade just ended, I attended a lot of informational meetings and conferences on emerging markets and heard many vendors explain how they had so harmonized their processes, so locked in the regulatory pathways in each country that sponsors could entrust their studies to these vendors safe in the knowledge that the conduct and resulting data would be of the highest quality and the entire experience would be as painless as if the study were bring run in the US or EU. Which is many things but painless is not one of them. And which inevitably turns out not to be true anyway. Sponsors experienced some significant buyer's remorse when they discovered that their project manager was not the person who came to do the bid defense; that the data, ethics, and medical practice standards could be very different in actual countries of conduct and required an experienced hand in the design phase of the protocol, not just the conduct and reporting phases; that their data were being collected many time zones away by people who the sponsor had never clapped eyes on. Instead of finding the experience painless, many sponsors felt unease with the entire process even when the data and trial results proved to be of high quality - they didn't quite trust what they saw because they didn't know who was running the trial - there was no relationship. Vendors who were paying attention have now retooled their presentations to highlight the relationship side of the business.

Even the FDA has got on the bandwagon of mistrust. A recent Pink Sheet ($) dated October 4, 2010 published findings by CDER's Office of Biostatistics that showed in 13 of 16 large multinational cardiovascular outcome trials, the measured drug efficacy was lower in the US than outside. Four drugs studied in these trials were not approved specifically because of this 'regional heterogeneity' and nine of the drugs were deemed approvable but required more data. Anecdotally I have seen this type of regional difference myself and have always interpreted it as proof of the quality of the conduct, the high acceptability of the data. FDA says not so fast. Some regional differences in treatment effect may be expected, but too much can arouse concern. The Pink Sheet report cites examples such as the extended release version of metaprolol (AstraZeneca) whose 'effect on mortality was virtually all outside the US"; AZ's ticagralor which demonstrated no effect in US patients, only exUS; and whether anti-epilepsy drugs bring an increased risk of suicidality, where studies showed that outside the US, suicidality was higher. Bridging studies, even PK/PD or surrogate studies may be indicated to explain regional differences that are not entirely due to chance.

In discussion amongst our panel and with the attendees, it seemed that at least based on the interest in the room, globalization is not dead yet. We all agreed that training, relationship, close monitoring, realistic expectations and appropriate study design are all important factors in running successful, evaluable international clinical trials.

photo credit: J. Mardell, 2010

Conducting Clinical Research

2010-11-09T14:09:00.000-08:00

Time to play catch up with the blogging as the year begins to wind down. The fall term at UC Santa Cruz will finish next week and I have no more conferences booked till January.

A couple of weeks ago I attended and presented at MAGI West Conference on Clinical Research in San Francisco. The event was neatly sandwiched in between the end of baseball pennant series' and the World Series, in which my beloved San Francisco Giants prevailed for the first time in, well, my whole life. San Francisco was a very orange place to be during these days, and as a lifelong baseball fan left heartbroken by my team twice before in my adult life, it was a glorious time to be in the city.

But this blog is not about baseball. The MAGI conference was well attended by over 500 people, many more than had attended the same event last year in San Diego (on the last day of the baseball 2009 regular season, in case anyone is keeping track). MAGI (Model Agreements and Guidelines International) so far is offered on either coast - in the east in spring and the west in the fall - and I think it is rapidly becoming one of the must-attend meetings on the yearly calendar for clinical research professionals, especially as the scope of the conference gradually expands from its origins in contracts and agreements to its current goal of "establishing best practices for clinical research operations, business and regulatory compliance". The quality of speakers that I heard was uniformly quite high with little variation, although a couple stood out in both directions. As the conference becomes larger it is also becoming an important networking opportunity and my LinkedIn connections have expanded significantly as a result of the acquaintances I made and renewed during the two days I attended.

One of the people I reconnected with in San Francisco is Dr Judy Stone of Maryland, the author of "Conducting Clinical Research", a newly revised quite complete how-to guide primarily written for investigators and would-be investigators to help them understand their role in the clinical research enterprise, particularly as relates to pharmaceutical industry-sponsored research, which is ultimately for profit. Dr Stone has done her homework and produced an excellent reference that, while geared toward investigators, also offers new insights to the sponsor and CRO sides of the industry for those who might have a look. It is always a good idea to remember to see things from the investigator's perspective, and Dr Stone has done this very well. I plan to recommend this volume to my GCP students as adjunct reading material starting in the next term.

At the conference I was fortunate to participate on a panel entitled "Are Sponsors Re-evaluating Globalization of Clinical Sites?", moderated by Joan Chambers of Centerwatch. In my next post I will review some of the key points of the discussion with the panel and audience.

I close this post with the acknowledgement that our world became a great deal poorer last week when our friend Kate Allen died of gastric cancer. She was 44. She was a good teammate, colleague and friend, and she left many friends and loved ones behind who will miss her for the rest for our lives.

Guatlemalan Syphilis Trials and the Nuremburg Code

2010-10-03T10:22:00.000-07:00

The New York Times has a piece this week revealing that “from 1946 to 1948, American public health doctors deliberately infected nearly 700 Gautemalans – prison inmates, mental patients and soldiers – with venereal diseases in what was meant as an effort to test the effectiveness of penicillin.”

Susan M. Reverby is a professor at Wellesley College and a medical historian who has previously written two books on the Tuskegee syphilis trial, discovered records of these experiments in the archives of the University of Pittsburgh as she was preparing a research paper. The archives also revealed that NIH funds were used to pay syphilis-infected prostitutes to sleep with prisoners in order to infect them. If that method didn’t work, patients were infected by experimenters pouring live bacteria over abrasions on their scraped up body parts or injected directly into the spine.

The connection to Tuskegee is not accidental. The Guatemalan experiments were led by one John C. Cutler, a public health service doctor who was to become instrumental in the Tuskegee experiments later on, and it was his unpublished Guatemala work that Reverby discovered at Pitt. Reverby told the Times that she had previously presented her findings at a conference last January but received no reaction. In June she submitted a manuscript for a future issue of the Journal of Policy History to Dr David J. Sencer , former director of the CDC (a body that has its own not completely benign role in the Tuskegee affair), and he requested a government investigation.

All of this was going on at the same time military and civilian lawyers at Nuremburg were mounting a vigorous prosecution of Nazi physicians in the Doctors’ Trial following WWII. From this prosecution came the Nuremburg Code from whose appearance many ethicists date the modern era of human subjects protection, a code which included such protections as voluntary consent, a favorable risk/benefit analysis, avoidance of needless suffering, appropriate prior animal data, the right to withdraw, and so on. US public health doctors were conducting VD trials on presumably unconsented (or at least not fully informed) subjects at the same time physicians were being hanged in Germany for doing the same things. The theme connecting these events is this: lack of respect for person, the unwillingness of the experimenters to see research subjects as full human beings deserving of protection and respect.

In the wake of these revelations, Secretary of State Clinton and HHS Secretary Sebelius have issued an apology to Guatemalans, the subjects and their descendents, and of course it is not their fault. We do not need to waste time looking for conspiracies in the US government. FDA regulations, the Common Rule, the Declaration of Helsinki and ICH and WHO-CIOMS guidelines for GCP are all designed to protect future human subjects. Our job is to make sure that we educate our successors so that things like this never happen again.

Should FDA split safety ops from CDER?

2010-09-28T12:27:00.000-07:00

This is a topic that comes up early in my GCP class at UC Santa Cruz Extension, when we do an overview of the FDA's operations and PDUFA as they pertain to good clinical practice. PDUFA has over the years enabled a a more efficient and predictable pathway through the US regulatory review process. Improvements are not without cost, and the consequences here have been felt on the continuing review of the safety of marketed medicines as budget has shifted to meet the Congressionally mandated trigger for user fees, and one option long under study has been to move safety evaluations altogether away from the evaluation of new drugs.

Bloomberg today has looked at the data since 1995 (PDUFA was first enacted in 1992) and reports that over half of the 21 drugs approved since 1995 have since been withdrawn from the market behind cardiovascular problems. Armed with these findings, Sen Chuck Grassley (R-Iowa) is developing a bill with Rep. Rosa DeLauro (D-CT) to create a new Office of Surveillance and Epidemiology whose function - and one presumes budget - would be completely separate from CDER and its budgetary constraints, and its heavy reliance on voluntary post-marketing adverse event reporting. FiercePharma has it all here, along with an interesting link to a story about Sen Grassley's plans to move from the Senate Finance Committee to Judicial. You read it here second.

Next week I will be attending and speaking at this meeting, Managing Relationships with CROs in London, and then a couple of days off.

FDA's HSP/BIMO Progress Report

2010-09-27T13:49:00.000-07:00

The FDA has released a progress report on its Human Subjects Protection/Bioresearch Monitoring Initiative (HSP/BIMO). In the 18 months since launch several new regulations and guidelines have been produced, including:

IRB registration;
Expanded access to investigational drugs;
A new informed consent essential element notifying subjects of study registry on the clinicaltrials.gov system;
The final guidance on 1572s;
New guidance on investigator responsibilities;

And a whole bunch more. Included in the report is an update from the FDA/Duke University Clinical Trials Transformation Initiative (CTTI), which includes among many other things a joint initiative between FDA and EMA for good clinical practice. The EMA/FDA GCP terms of engagement and procedures document is here. The HSP/BIMO report is here.

FDA Limits Action Against HIV Investigator

2010-09-13T13:10:00.000-07:00

A story linked via FierceBioTech today from an article published last week in the Chicago Tribune describes the apparently light touch the FDA is using to discipline an investigator whose clinic allegedly submitted fictitious data in a clinical drug trial. Standard procedure in such cases is usually either disqualification from running clinical trials altogether or restriction of the number of trials an investigator may conduct or the number of patients they may enroll. This investigator, whose writings about HIV are easily searchable on the Web, apparently escaped all such restrictions and instead is allowed to continue clincal trial operations under the supervision of an outside medical monitor for the next three years and is required to submit annual reports to the FDA in that same three year period. This seemingly light slap runs counter to the message being sent to drug manufacturers themselves for whom the agency is stepping up its oversight with warning letters, product recalls and threats of prosecution, according to the Fierce story.

Switching gears entirely, here is a link to the OHRP's 2010 International Compilation of Human Research Protections. This is an absolutely invaluable resource covering the key organizations, legislation, regulation and guidelines pertaining to human subjects protection of 96 countries, updated every year with clickable links. Every clinical research professional planning studies anywhere in the world including the emerging regions should make this document their first stop.

Roche Jobs Shift to China

2010-09-09T11:26:00.000-07:00

As a former Roche employee (and holder of a pension) my eye is always drawn to stories about changes at that company. Last week they announced a major cost cutting effort in the US and Europe, letting slip an internal memo naming the employees responsible for each sector. This week they are announcing a hiring boon in China, increasing headcount there by as many as 750 jobs. This appears to be the sharp end of the stick in China that we have been watching for, as the Chinese government invests in its drug development capacity and more large sponsors move in to establish operations. The Fierce article notes that Eli Lilly announced thousands of layoffs last year while staffing up in China. I think this puts India under some pressure, as clinical trial application approval times there have slipped into 120 days and more, a not very welcoming gesture to sponsors interested in running clinical trials there and have the means to ensure patient safety and ethical conduct.

FDA's Marketing Crackdown

2010-09-08T16:58:00.000-07:00

There has been a lot of news about the FDA cracking down on drug makers advertising direct to consumers, which is either a) poor ethical behavior or b) an indispensable way to educate the marketplace, depending on your biases. I tend to lean toward the former. Anyway FiercePharma has been following this issue closely, and has an item here worth checking out.

I read this blog from Steven Grossman called FDA Matters, which I found via GxP Perspectives. The whole FDA is covered not just drugs, so I pick and choose the articles within my wheelhouse. Take a look.

I have a few more speaking engagements coming this year: Managing CRO Partnerships in London October 4-5, and MAGI West in San Francisco October 24-27. See the sidebar for links and details.

Also I will be moderating a panel at Astia's Silicon Valley Doing It Right session in San Francisco November 5. Astia is a program that provides resources and training for women entrepreneurs in life sciences, technology and clean tech.

The fall term starts at UC Santa Cruz extension today; 10 weeks of GCP class. It's not too late to sign up.

We've Hit the Big Time!

2010-09-08T14:52:00.000-07:00

Two Decades just got listed on this posting at GxP Perspectives as a blog "well worth checking out". Thanks Carl!

New Powers for the FDA?

2010-08-07T16:09:00.000-07:00

Fierce Pharma had a piece yesterday revealing a new measure introduced in the House recently in the wake of the J&J recall hearings by Rep. Edolphus Towns (D-NY), calling for the FDA to have power to initiate its own recall rather than having to wait for the drug maker to do it. Senator Michael Bennet (D-CO) has produced a bill of his own in the Senate that echoes the House bill's call for more power, including more agency oversight of foreign drug manufacturing. In either case the legislation has a long way to go and can expect significant heel-digging by PhRMA. It's all here.

More Student Advice

2010-07-10T13:22:00.000-07:00

A lucky former student recently asked some advice on how to give notice at a job she loves, for a job she hopes will propel her career to new levels. Here is my response.

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Congratulations! This is a very exciting time in your career, and I am gratified to be along for the ride.

I completely understand and empathize with the misgivings around giving notice to an organization that you have enjoyed working for, and where you got your early development opportunities. I have been there myself and it can weigh heavily on your heart. Here are a couple of thoughts that have helped me over the years.

1. Any good manager will understand your reasoning in leaving for a good opportunity, especially if that manager cannot create the same opportunity for you herself. No good manager would think of holding an employee back or resenting her for taking the next move in her career. A good manager needs to think about the team's best interests too, and realizes that letting you go in anything other than a head-up way would send a poor message to the remaining team members, and that would eventually undermine team cohesion.

2. Of course the above would not necessarily be true if an employee has been dishonest with her manager, or leaves before 'giving back' after having been trained. Managers don't appreciate promising employees who leave too soon. But this isn't the case with you; two-plus years in an organization is about the norm these days.

3. Leaving your current organization will create an opening for someone else to step up and show what they can do. In my early days as a manager I really worried if one of my stars left, but I came to see that there were always others waiting in the wings, ready to step in. Your departure may even create a job that someone from the outside can fill, giving someone a badly needed first chance as you got two years ago.

With all that said, my advice for you when the time comes is to tell your manager what you told me: that you value the opportunity your current job gave you and that you have enjoyed the organization and feel that you made a significant contribution, and now it is time to take the next step in your career. Be forthright and honest, describing why the next opportunity develops your career in the way you wish it to go. Offer to help train your replacement and be diligent in handing off your duties. For the reasons I stated above, your manager should accept your resignation graciously and send you on your way with her very best wishes and with the relationship very much intact.

On the remote chance that this does not go well, that there is resentment or ill feelings left behind, you need to know that you did everything right. That ultimately you cannot control what other people think or do, you can only control your own behavior. If you handle this professionally and honestly, you need not fear reprisals or burned bridges. As you say this is a small community and our colleagues have good instincts about these things; they will be able to judge for themselves that you handled yourself correctly in this episode. Remember that only you are in control of your own reputation and brand; no one can successfully pass untruths about you for very long. If you handle yourself professionally the ship will right itself - it always does.

Big Pharma Wants to Buy You Lunch

2010-06-30T19:53:00.000-07:00

Jessica Wapner of Slate explains how the pendulum may have swung a bit too far in this piece on the value of industry sponsored medical education, here.

The latest in the Pfizer/Trovan saga comes down from the US Supreme Court today. The Supremes have kicked the entire mess back to the lower courts by ruling today that it won't stop Nigerians from suing Pfizer in the US. Technically they didn't rule so much as declined to hear Pfizer's appeal of the lower court ruling from last summer. We have run down this story a couple of times on this blog, here and here. Pharmalot's take is here.

Career Question

2010-06-25T14:16:00.000-07:00

A former student wrote to tell me she had a chance to take a year long consulting job at a very big stable company, although it would mean leaving her current job that she had held as a headcount for a long time, and she asked my advice. Here is an excerpt of my reply.

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The question you are asking yourself is exactly the right one: do I leave something comfortable and reasonably secure for the possibility of an even better job, knowing that I am stepping into the unknown and could eventually lose more than I gain?

In rock climbing, going from handhold to handhold is one thing. But sometimes the next hold is far enough away that you actually have to jump to it, meaning you have to let go of the rock for a split second to get where you want to go, risking a serious fall. This is called a 'commitment move', and that is a good analogy of where you find yourself right now.

Sometimes we think in terms of 'secure' versus 'not', as though having a headcount job now means that job or the next one will be there as long as we want it. But that is often not true: the job that seems solid now can disappear in a flash if the company goes into protect mode. No company, even the good ones, is so loyal to its employees that it will sacrifice its financial health to keep its employees secure. If there is a choice between the company or the employees, the company will survive. They can always get new employees; it is a buyer's market. So the choice is not as black and white as secure versus the unknown. There is risk in staying, too. That might make it easier to think about.

In addition to your taste for risk, think about your long-term career goals. Where do you see yourself in 2 years, 5 years? What job would you like to be doing, and does your current position provide you with a path to that goal? Have you had that conversation with your manager? Does going to a large company as a consultant take you closer to that goal? Are you okay with being content, or do you want to check out the grass on the other side of the fence?

And a final thought: your current position is in a smaller organization. Where you are thinking of going is the very definition of a giant organization, and it is quite different to work in that culture. That is part of its security, but it can come at the cost of some autonomy in the job role: every decision gets processed through a long chain before it can be acted on, and that can be frustrating. You may not know how you feel about that until you've worked in it for a while, but it is something to think about nevertheless.

This is all more than you really asked - you happened to catch me in a moment of transparency. To sum up: For the most part, clinical consultants in the Bay Area do pretty well, and taking a full time contractor role at a bigger company is about as safe as it gets in the consulting world. Most people are betting that the job market in our industry will continue to improve slowly over the coming year - the number of deals announced this week alone seems to support that - and in the unlikely event that your contract is not renewed after the year, your resume would probably be richer for having spent the year there getting the big company experience.

Updates to 1572 Guidance

2010-06-11T11:27:00.000-07:00

The FDA has finally released a final FAQ, representing their 'current thinking' on 1572s. The guidance in the form of question and answer runs for 17 pages and covers, among other things, how to fill it out, who should be listed in item #6, whether it is required to be submitted to the FDA, and under what circumstances an investigator needs to sign a new one. Makes for surprisingly interesting reading.

In this FAQ the 1572 is describes as having two purposes: one) to provide the sponsor with information about the investigator's qualifications and the suitability of the site for clinical trial purposes, and two) tho inform the investigator of his/her obligations and to obtain the investigator's commitment to discharge those obligations according to the regulations. This clearly defines the document as a two-way communication tool in addition to a statement of undertaking. The parties involved in the communication flow are the sponsor and the investigator. Notice that the FDA is not among those sharing in this conversation. The guidance makes it clear that sponsors are not required to submit the 1572 to the IND, although it acknowledges that most sponsors do because it is a convenient collection tool for all the information that sponsors must submit to the FDA under 21 CFR 312.23(a)(6)(iii)(b). This is a small but potentially important distinction: the 1572 itself is not required to be submitted, just the information contained. A sponsor could submit that information on a separate sheet of paper and be fully in compliance. Most regulatory folks both of sponsors and CROs have always insisted that the 1572 itself must be submitted, yet I never found a regulations supporting the policy. It's nice to know what the requirement actually is.

Study Coordinators Now Should be Listed Routinely

Former FDAer and blogger Carl Anderson has an excellent run-down on one of the other new provisions of the guidance, namely that study coordinators should now be listed on the 1572:

“Generally, a research coordinator has a greater role in performing critical study functions and making direct and significant contributions to the study data. For example, a research coordinator often recruits subjects, collects and evaluates study data, and maintains study records. Therefore, the research coordinator should usually be listed in Section #6 of the 1572.”

This represents a major shift from the draft 1572 guidance dated July 2008, where it was recommended that study coordinators be listed if performing "critical study functions". The change appears to acknowledge not only that study coordinators play a consistently critical role in study conduct, but also that they take a significant role in recruiting subjects.

Notice also the non-committal use of words like "should" and "generally", but don't be mistaken: The FDA considers their guidances and FAQ's to be a close to regulation as you can get without going through the full process, so as Carl says, might be a good idea to update your 1572s to include study coordinators.

Sign It Once and Done

However after you get all your 1572s updated to reflect this guidance, the FDA says you shouldn't be revising them and having the investigator re-sign them any time something changes during a study, like new sub-investigators or a change in lab. The guidance says that 1572 needs to be completed and signed by the principal investigator on only two occasions: when participating in a new protocol under the IND or when he is being added to an existing protocol under an IND (question 7, page 6). One hopes that this will cut down on some of the paper chase that goes on throughout long studies when people think they have to update the 1572 every time some item on it changes. The FDA says we can simply include these changes during routine informational updates to the IND.

Use of Foreign Investigators

The FAQ also has a lot of guidance on the requirements of foreign investigators vis-a-vis the 1572, use of foreign data in support of submissions, foreign investigators obligations with respect to local versus US laws, and so one. I did not know for example that multinational studies may include domestic sites under the IND and foreign sites not under the IND. In that case the non-US investigators would not be required to sign the 1572, which is sometimes a sticking point with them as they don't wish to be obligated to US law, and the sponsor could use similar rather than exactly identical protocols to allow for differences in medical practice yet still result in pool-able data. If this is a change it is a good one.

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How about a photo? Here is one from a recent project management workshop that we led in Bombay.

It was mango season.

Partnerships with CROs Wrap-up

2010-04-13T18:38:00.000-07:00

Day 2 of the Partnerships meeting in Orlando is over and while there is a day 3 tomorrow, I go home in the morning. I was lucky enough to be on two panels discussing clinical trials in emerging markets. Here are my highlights.

Day 1 - The morning was all pre-conference workshops so the mass of conference attendees were not evident yet. My panel of 4 experts on the emerging regions - Mark Lanfear, Julie Margules, Nagaraja Srivatsan and me - gave a 4 hour workshop in the morning with maybe 45 people in attendance, many of whom stayed for the whole 4 hour period. We divided up the world by regions and shared some of our experiences. Good discussion ensued. The session was blogged by Keith Russell, link here. Lunch was a meeting of the Partnerships Emerging Markets Advisory Board.

In the afternoon there were some additional sessions of contracts, RFPs, and phase 1 study design concerns, followed by the keynote speaker Ethan Zohn and a reception in the exhibit hall, lots of networking.

Day 2 - The keynote speakers were Dr Jack Dean, chairman of Partnerships and then Sen. Tom Daschle who gave an excellent talk about the policy points of Health Care Reform. He summarizes the debate in language refreshingly devoid of political heat )although I may not be unbiased as I supported the need for health care and insurance reform and thought the resulting law does not go far as it should). He said the key points of the debate were/are: 1. the role of government; 2. the complexity of a $2.5 trillion problem; and 3. the size and nature of the pie - how big will it be, and how big will be the slice that goes to each party? Daschle then described the solution - or at least as defined by the new law - as threefold: insurance reform, payment reform and access reform. Of the three, the insurance component has the most detail in the new law, phasing in a series of reforms in two year increments until 2018. Many of the most needed elements come in this year: no exclusions for pre-existing conditions in children, no recisions, no lifetime or annual limits, a small business tax credit, and rebates for seniors caught in the Rx drug gap in Medicare. Payment and delivery reforms have less detail, but they are intended to shift the reward from volume to value, incentivize wellness, end fee for service, encourage electronic medical records (1 out of every $5 spent in health care goes to administration, paper records), encourage the use of best practices and evidence based medicine.

In the afternoon I attended a talk by Michael Marcarelli of the FDA. He was refreshingly engaging and disarming about the business of compliance monitoring and reminded us all about the sponsor's responsibility to provide oversight for and service providers, including providing training for investigators and CROs. He made an odd anachronistic comment when answering a question near the end when he noted with apparent surprise that so many site monitors these days do not have medical degrees, and 'sometimes they (sponsors) even send Gal Friday to monitor'. I don't know where he has been all this time, but the industry realized literally decades ago that CRAs/monitors need not be medically qualified and even then most monitors in this country were nurses, never doctors. And the 'Gal Friday' comment was plain offensive.

Finally it was our turn again and this time my two colleagues - Larry Fiori and Graciela Racaro - and I shared a relatively brief 45 minutes sharing what are the different considerations when doing studies in the global space, particularly the newer countries. This session was blogged by Foreign Exchange Translations, here.

Questions

2010-02-16T15:18:00.000-08:00

A former GCP student sent me this question today: "Can you tell me if it is OK for a principal investigator to have his signature Xeroxed onto the ICF for the subject to sign? This doesn’t seem appropriate to me, but I am having trouble finding anything that says otherwise. Also, can they sign the ICF in advance of the subject signature, or should it always be after the subject consents to be in the study."

Every class term starts with my passionate admonishment that GCP is more than just knowing the rules, in fact knowing the rules is only a small part of the task. To understand the rules, we have to think through why those rules exist. Reading this students' question gave me an unsettling feeling that I am not being very effective at getting this point across.

Whether there is or is not a regulation about pre-signing informed consent forms, whether in ink or by photocopying, stamping, or smoke signals, is entirely beside the point. The point is not the signature at all. The point is what the signature represents. (*Extra credit: is the investigator's signature even required under US regulations?) My students have all been taught that the signature represents that the investigator's obligations to the patient with respect to the nature of the study, risks and discomforts, alternative treatments, right to withdraw and all the other elements of consent have been met. Therefore, of course it is unacceptable to pre-sign the form, Xerox a signature onto the form or whatever else this investigator has thought up.

*Answer: No, only the patient's (21CFR 50.27(a)). Under ICH guidelines the consent should be signed by the patient and by the person who conducted the informed consent discussion (ICH E6 4.8.8).

New Year, New Challenges

2010-01-25T13:24:00.000-08:00

The new year has hit the ground running hard and many colleagues are just trying to hang on. The good news is that though we are still in the midst of some hard times, we are starting to see an upturn in movement of money, new clinical programs under development, and jobs. Enrollment is up in the UC Santa Cruz certificate programs where I have taught for the last 10 years and in honer of the winter term just getting underway, I posted a picture from my most recent trip to India of a woman walking her children to the school bus in Bangalore.

The conference season is in full swing. I just came back from the Indian Society for Clinical Research's excellent 3rd annual national conference at the Hotel Leela Kempinski in Bangalore. Attended by 500 participants from all over India and beyond, the conference featured many of the most influential people in the Indian clinical research field as well as many young CRAs and project managers, and it was a fantastic opportunity to listen and learn from the people who know the region best.

This week I will be attending and presenting at Outsourcing in Clinical Trials West Coast in San Francisco, on the topic of Offshoring to Emerging Countries: Navigating Uncertain Waters. I gave a similar talk last week as an advance for the Partnerships in Clinical Trials event to be held in Orlando in April. I'm told a podcast of last week's talk is forthcoming and I will make it available to anyone who contacts me for it. This week I am also presenting in a webinar entitled Biotech and the Global Marketplace for the US Commercial Service. My task is to discuss clinical trials in emerging markets and opportunities for US biotech companies to enter into co-development projects with sister companies in these regions.

My partner and I were recently featured in a blog post over at goBalto.com about the Indian clinical trial market- see it here.

I receive regular updates from Audrey Erbes, who is a faculty colleague of mine at UC Santa Cruz extension and teaches in the biosciences certificate program. I took her 2 day course on business development and highly recommend it. Here is her excellent blog where she freely shares huge amounts of information from her network including job postings with students and colleagues alike. Highly worth subscribing to in your reader.

2010 represents my 30th year in the clinical research field. Next year I will have to rename my blog to '3 Decades, Full Stop'.

Pfizer, Drug Pricing, Conflict of Interest

2009-12-02T13:50:00.000-08:00

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

2009-11-17T16:46:00.000-08:00

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

2009-08-13T15:00:00.000-07:00

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

2009-08-06T15:07:00.000-07:00

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

2009-07-06T14:35:00.001-07:00

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

2009-06-04T14:53:00.000-07:00

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.

2009-05-29T10:42:00.000-07:00

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

2009-05-21T09:52:00.000-07:00

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

2009-05-14T12:08:00.000-07:00

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

2009-05-05T15:09:00.000-07:00

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?

2009-04-30T12:09:00.000-07:00

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

2009-04-29T03:30:00.000-07:00

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

2009-04-20T16:13:00.000-07:00

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

2009-03-06T17:34:00.000-08:00

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

2009-01-15T17:43:00.000-08:00

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

2009-01-12T14:06:00.000-08:00

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.

Looking to 2009

2008-12-31T15:52:00.000-08:00

The 2008 holidays are winding to a close and I've been thinking about the coming year for a few weeks now. Here are some lessons I take into 2009:

Lesson #1: Contracts come and go; relationships are as permanent as you make them. Any successes in my working life this year have been achieved entirely through investing in relationships, in some cases for years. This is a source of joy for me, as I am reminded this year more than many that when I am in my rocking chair looking back over my life, it is the people I will remember, not the goals and milestones hit or missed. Banking on my credibility with staff, management, partners and others is scary but ultimately very rewarding.

Lesson #2: Surround yourself with smart people and then listen to them. Kind of a corollary to lesson 1, could be restated as 'know your limitations and fill them'. 2009 will see me focusing on networking far more than previous years.

Lesson #3: The future is a little farther away than it was a year ago. For the last 10 years I had planned to retire from full time clinical research by my mid 50's, now just about 3 years away. The global recession thinks otherwise, and I am gradually accepting the fact that I will be working longer. On the plus side, thanks largely to heeding some very good advice (see lesson 2 above), we are down slightly less than the market at large, above water on our home and carrying no consumer debt, and the college expenses will probably wind down by 2012 or thereabouts. In my worklife I am focusing on developing greater expertise and networks within the field of clinical research in emerging markets. I shared some of that expertise at a couple of conferences in 2008 and hope to develop more such opportunities in the coming year.

Focuses for 2009:

build credibility
invest in relationships
simplify wherever possible - the common sense approach is usually the right one
rebuild capital through wise investments and sound spending

2009 looks to be a challenging year in all arenas, but we will get through it. See you in the trenches.

2008-12-27T17:23:00.001-08:00

Welcome to my new blog for the other part of my life, the one where I earn a living. Here is where I will post thoughts for courses, notes for colleagues and other random thoughts. I also like photography and cooking, so occasionally I will post pictures I take. Of food I cook.