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.  

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

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

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!

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?

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 being 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