Get Your Resume Out of the Pile

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

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

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

The FDA has released its long awaited update and replacement to the outdated 1988 guidance on clinical monitoring.  The draft guidance for industry on Oversight of Clinical Investigations - A Risk Based Approach to Monitoring is early evidence that the findings and recommendations of the Clinical Trials Transformation Initiative (CTTI), FDA's public-private partnership with Duke University among others, are beginning to take hold in practice in the clinical trials domain.

According to a CTTI survey, clinical trial sponsors are successfully employing a range of monitoring modalities, such as centralized monitoring by biostatistical and data management personnel, targeted on-site visits to higher risk sites as well as frequent on site visits to all sites by clinical monitoring personnel.  Yet historically, industry sponsors have rarely relied on any mechanism other than comprehensive all-site monitoring performing 100% source data verification, every four to six weeks.  It is a well-understood, costly and time consuming method of monitoring that the industry perceives is preferred by FDA.  Yet, given the vast changes in the clinical trial landscape in the decades since the FDA's previous 1988 guidance and the regulations covering sponsor obligations, including the increase in the number and complexity of clinical trials, investigator experience, changes in ethical oversight, treatment options, and geographical dispersion of clinical trial sites, the FDA now calls on the industry to employ new and more effective methods for monitoring clinical trials.  

This is big news.  As in the recent final rule on safety reporting, which requires sponsors to make judgments about whether a single case is instructive enough to warrant reporting to the authorities, FDA here is encouraging sponsors to reduce their reliance on a one-size-fits-all, on-site, 100% source data verification comprehensive monitoring approach in favor of a more diversified, horses-for-courses approach, building monitoring plans and employing monitoring modalities based on multiple factors such as:

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

·           disease state of patient population

·           sponsor experience with investigator and investigator experience with research

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

·           availability of EDC to facilitate centralized monitoring

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

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

·           withdrawing the extremely outdated 1988 guidance

·           ensuring that BIMO guidance manuals are compatible with the recommendations

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

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

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

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

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

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?

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

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

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

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.

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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.

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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

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

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

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

A little something for your Friday...

Informed Consent May Be Compromised & Medical Device reform

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

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.