fda report on avandia implications and a critique of the critique

8/14/2019 FDA Report on Avandia Implications and a Critique of the Critique

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Thinking about Life Sciences

http://blog.aesisgroup.com

Thursday, July 26, 2007

FDA Report on Avandia: Implications and a "critique" of the critique

According to the N ew York Times from today (Wednesday 7/ 25), the FD A issued its formal report on theAvandia controversy that appears to substantiate the safety concerns raised by Dr. Steve Nissen and others andapparently also sharply criticizes the manufacturer on a number of points. As I did earlier with Strykers hipresurfacing announcement The Many Surprising Implications of Hip Resurfacing Implants, this posting willdo a sentence-by-sentence deconstruction (or reading between the lines) of Gardiner Harris N ew York Timesarticle F.D.A. Review Criticizes D iabetes D rug and Maker.

The text in bold-italics below is from the N ew York Times article; the indented text is the commentary whichreferences several of the points made previously regarding drug safety and FDA reform. In a sense, thediscussion below provides a contextual backdrop to the broader array of policy issues outlined in these previousarticles. Please note that the discussion below pertains to the N ew York Times article and not to the FDA reportper se. That being said, some of the implications and takeaways have general value.

P atients who tak e A vandia , a popular but controversial dia betes medicine made by G lax oSmithKline, a re far morelik ely to suffer a nd die from heart problems than those who tak e A ctos, a similar pi ll made by Tak eda, according tofederal drug reviewers.

Kudos to the FD A for intervening which speaks to the core safety mission of the agency.However, the operative term here is federal drug reviewers and one of the major points of

this blog (see FDA: Tortoise, Hare or Something Else has been that safety should be almosta preview (e.g. pre-market) issue rather than a review situation.

A vandia is particularly dangerous to patients who also take insulin. By contrast, A ctos can be taken safely withinsulin, according to the review.

Part of a more robust pre-market safety regime will be to analyze (even if it means moreexpensive animal models or computer simulations) drug interactions. Drug interactions suchas this are particularly hard to spot during voluntary post-market surveillance studies. Thishas to be done proactively. Of course, it is easy to be an arm-chair general and say I toldyou so but the point is not so much any specific Avandia-insulin interaction but rather torealize on a conceptual level that post-market surveillance is only a blunt and relatively

unreliable instrument with which to analyze potential drug-interactions.

T he findings lik ely spell the end of A vandias status a s one of the nations most popular drugs for treat ing diabeticswho are not dependent on insulin. L ast year, more than a million pa tients in the U nited S tates took A vandia , a nd asimilar number took A ctos.

When it comes to approving drugs, safety is secondary to efficacy as efficacy is the keydeterminant (after routine safety test are done) that creates billions in the stock market.Investors are becoming increasingly aware that billions can be lost as a result of a safety issue.The question is then: why isnt safety given the absolute top priority from the beginning that itrequires?

ing about Life Sciences: FDA Report on Avandia: Implications and a... http://blog.aesisgroup.com//2007/07/26/fda-report-on-avandia-jus

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A vandias 2006 global sales were nearly $3.4 billion."

Avandia is a blockbuster drug which, by definition, is given to broad populations of patients.That makes it appealing from a business perspective but also just on a statistical basis alone makes it highly risky from a safety perspective. That realization has not yet percolated intothe types of innovative, proactive safety studies that should be part of pre-market studies.SeeFDA Reform Redux: On Business Models, Regulatory Reform and Safety for more on therelationship between the pharmaceutical blockbuster business model and safety risk.

The report and [sic] charges that GlaxoSmithKline sought to intimidate a doctor who publicly warned aboutA vandias risk s in 1 99 9 could lead to a cascade of lawsuits against G lax oSmithKline. Indeed, F .D .A . reviewerswere sharply critical of the quality of the studies G lax oSmithKline has undertak en to test t he safety of A vandia,dismissing the present and future results of an ongoing 4,000-patient trial as unreliable and invalid.

As outlined in the blog posting Avandia, the Drug Safety Debate and How to Get a NobelPrize, scientists risk their careers if they focus their research inquiries on the unglamorousarea of drug safety. They are certainly not considered to be heroes by many, though looking atthe big picture, maybe they should be.

T he report by medical and sa fety reviewers within the F ood a nd D rug A dministration also provides ammunition tocritics on C apitol H ill a nd elsewhere who claim tha t top F .D .A . officials ha ve been far too slow to a ck nowledge

A vandias risk s. G lax oSmithKline suggested a year ago that the agency add a note to the drugs label aboutA vandias growing hear t r isk s, the report states.

There is certainly great furor around potential FDA Reform and it will likely (as indicated byyour own reader poll in You voted on the FDA. See the results here ... likely going to bemore along the lines of a paradigm shift at the FD A rather than a tweaking of the system.

A t another point in the report, an F .D .A . safety reviewer, D avid G raham, concluded that a safety alert released bytop F .D .A . officials on M ay 21 falsely reassured pa tients that a t least one large A vandia study showed that the drugwas safe. T hat study, D r. G raham concluded, provided no such reassurance.

As Ive emphasized before, I dont believe there is malicious intent, yet, a systematic bias

which does not put safety as absolutely primary (and efficacy as a luxury item thats good tohave but not essential) will result in inappropriate (and potentially false) interpretations of thedata.

These conclusions come in a 436-page compendium of reviews released in advance of an advisory committee hearing tobe held on M onday to d iscuss A vandias effects on the heart. T he F .D .A . intends to ask the committee of independentexperts whether A vandia should continue to be sold. I t is far from clear, F .D .A . safety reviewers concluded in thereport, whether tak ing A vandia , a lso k nown a s rosiglitazone, is worth the risk .

While the risks are far from clear, olitics (and life in general) often function on a backlashbasis. I would think that the results of Mondays hearings will be similarly condemnatory.

A critical question to be resolved in determining appropriate regulatory action is whether the anticipated therapeuticbenefit of rosiglitazone outweighs the demonstra ted cardiovascular r isk , one F .D .A . reviewer concluded.

Everything in medicine is about risk-benefit ratio. And likewise, the entire point of the FDAreform proposals outlined in the several blog postings here is that the safety-efficacy ratio alsoneeds to be aligned more towards the safety side of the equation. That is what our society isdemanding, that is what will need to and what will happen.

I n 2 00 0, the F .D .A . ask ed W arner-Lambert to remove Rezulin from the mark et because that drug caused moreliver problems tha n either A ctos or A vandia , both of which were approved for sale in 19 99 and provided similarbenefits.


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These FDA reform are not about lambasting the FDA or stripping away its powers but rathershifting its powers away from making efficacy the primary arbiter of drug approval buttowards safety and, in that regard, requiring more safety evaluations and more innovativeapproaches to safety studies a part of the pre-market evaluation.

A vandias heart risk s are lik ely to injure far more patients than Rezulins ra re but serious effects on the liver. M ostdiabetics die of heart disease.

Again: in my opinion, it would seem that the likelihood of Avandia being taken off the market

is very high - if not explicitly by the FDA then at least over the long-run.

I hope that this critique of the critique put some of the ideas about drug safety and FDA reform in aconcrete context. For more on this important topic, see:

You voted on the FDA. See the results here ...

Boston Scientific, Medtronic settle some defibrillator suits; is the device safety storm over?

Avandia, the Drug Safety Debate and How to Get a Nobel Prize

FD A Reform R edux: On Business Models, Regulatory Reform a nd Safety

FDA: Tortoise, Hare or Something Else

Drug / Device Safety Debate to Yield Big Changes, Grow More Controversial

Itll be interesting to see how things play out over the coming week

Ogan Gurel, MD [email protected]:/ / blog.aesisgroup.com/

Drug safety FDA reform Avandia Diabetes Risk-Benefit ratio efficacy Aesis Research Group Ogan Gurel MD


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fda report on avandia implications and a critique of the critique

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