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.