Tag Archives: Roche

Isotretinoin – Caught Between Help and Hype

The James Marshall Accutane trial has been highly anticipated – at least by some, including:

  • Rabid fans of the actor who at one time was dubbed “The next James Dean.”
  • Lawyers hungry to cast more chum upon the churning Accutane waters.
  • And dermatologists, who must balance yet another risk/benefit ratio: the risk of being named in a multimillion dollar lawsuit vs. the benefit of isotretinoin to young people with disfiguring acne.

Marshall – who goes by his legal name James Greenblatt in the case filed in New Jersey Superior Court – was the free-wheeling biker in “Twin Peaks,” and Pfc. Louden Downey in the Academy Award-winning film “A Few Good Men.” He used isotretinoin and developed an inflammatory bowel disease that required a colectomy. Mr. Greenblatt claimed this resulted in incontinence, derailing his acting career. The suit, scheduled to go to trial today, had an all-star cast of witnesses: Brian Denehy, Martin Sheen, and Rob Reiner.

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We might be able to handle the truth about isotretinoin -- if we could only decide just what it is. Photo by Flickr Creative Commons user rot ist die farbe der hoffnung

When I called the court this morning to confirm the case, court administrator Rob Helsabeck told me it had been indefinitely adjourned. “No continuance date has been set,” he said. “I don’t know the details, but I heard that there is ongoing discussion between Roche and Mr. Greenblatt’s attorneys.”

Will Roche settle, sacrificing a few million to keep a high-profile case low-profile?

Or, perhaps science will prevail?

And that leads us to the science…

Flckr Creative Commons user cemre - before and after isotretinoin

Accutane was practically birthed with a bad reputation. In 1982, it went to market with fewer than 100 cases under its clinical belt, Dr. Hilary Baldwin said at the summer meeting of the American Academy of Dermatology.

Its teratogenic dangers were already well-established, and the prescribing information made it abundantly clear that it could cause thalidomide-like birth defects. But it wasn’t long before — like an eighth-grade girl caught kissing in the bathroom —  Accutane began to acquire a long list of horror stories.

Alopecia. Aggression. Violence. Depression. Suicide.

And, beginning in 1986, ulcerative colitis and Crohn’s disease. Subsequent reports led to a 1988 modification of the package insert, warning of a possible association with inflammatory bowel disorders, and urging patients to be on the lookout for GI pain, rectal bleeding, and diarrhea.

“In 2007, the lawyers got hold of this by the neck,” said Dr. Baldwin, a dermatologist in Brooklyn, N.Y. “Since then, more than 5,000 suits have been filed.

Seven of those have gone to trial, and Roche lost every one of them, with a total settlement amount of $45 million. Three, however, have been overturned on appeal – one just last week, with  Roche recovering more than $10 million.

It’s a victory for the company to be sure, but 45 more cases are lined up in the New Jersey Superior Court case docket. One of Roche’s biggest legal handicaps, Dr. Baldwin said, is that it has been unable to fully tell its side of the story.  “You certainly don’t want to make light of the poor young person who has developed this terrible disorder, and yes, it’s sad that someone would get IBD after treating their acne. But the jury only hears the numerator – they were never able to hear the denominator, that 18 million people have taken isotretinoin” and only a tiny minority developed IBD.

“The picture gets even cloudier when you consider that a time of peak onset for IBDs is 15-30 years – also the prime time for isotretinoin treatment.”

Two clinical reviews, one conducted in 2006 and one in 2009, found no statistically significant association between the drug and either ulcerative colitis or inflammatory bowel disease. The 2006 case-control study found 85 cases of IBD concurrent with isotretinoin use – a rate of 14 per year. “Interestingly, the expected results from this age population would have been about 59 new cases per year, so you could look at it that isotretinoin was actually protective of developing IBD,” Dr. Baldwin said.

According to a probability scale used in the study, four cases (5%) scored in the “highly probable” range for isotretinoin as the cause of IBD, 58 cases (68%) were “probable,” 23 cases (27%) were “possible,” and no cases were “doubtful,” – a conclusion that would leave most doctors unconvinced of a direct causality.

Lawyers have a different interpretation. “Study confirms 100% of IBD cases may have been caused by Accutane,”
trumpets the website of The Orlando firm, P.C., of Athens, Ga.

So who’s right?

The answer is still fuzzy, Dr. Baldwin said. Things looked pretty good for isotretinin through 2009, when a Canadian study looked at 12 years of data on 1 million Manitoba residents. There were no significant associations between the drug and the disease in the case-control analysis.

But earlier this year, an American team came up with a slightly different conclusion. Looking at about 15 million people in 12 health care claims databases, the authors concluded that 24 cases and 36 controls had been exposed to isotretinoin. Cases were 4.5 times more likely than controls to develop ulcerative colitis, but there was no link between the drug and Crohn’s disease.

“With our two most vigorous studies showing conflicting data, we are left not knowing what to do,” Dr. Baldwin said.

In the meantime, she said, the best physicians can do is strongly warn patients (and their parents) to be on the lookout for GI symptoms, and to report them immediately. The warning must be repeated at every follow-up visit and the medication discontinued if anything untoward develops.

The reality? As Oscar Wilde said,  “The truth is rarely pure – and never simple.”

— Michele Sullivan (@MGSullivan on Twitter)

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Filed under Dermatology, Family Medicine, Gastroenterology, IMNG, Internal Medicine, Pediatrics, Primary care, Psychiatry, The Mole

Tocilizumab Approval Causes Buzz

One year after asking the Roche group to submit additional data for its monoclonal antibody tocilizumab, the FDA has approved the biologic agent for the treatment of moderate to severe rheumatoid arthritis (see story).

Although the drug, to be marketed under the name Actemra, is entering a somewhat crowded biologics market—it is joining abatacept, adalimumab, anakinra, etanercept, infliximab, and rituximab —it is the first and so far only interleukin-6 (IL-6) receptor inhibitor to be approved for the indication, and clinicians are cautiously optimistic that it will improve the lives of patients who have not responded to therapy with methotrexate alone or in combination with other disease modifying antirheumatic drugs (DMARDS).

 In fact, tocilizumab has been approved specifically for those adult patients who have failed methotrexate and one or more tumor necrosis factor antagonist, according to an announcement released today by the drug’s manufacturer, Roche Holding AG. 

The FDA approval is a much-anticipated development, according to Dr. Larry Greenbaum, a rheumatologist in private practice in Indianapolis. “It’s very exciting. Actually, one of the drug representatives has been stopping by my office for the last year or two, dropping hints about this product, although the company has not been allowed to “detail” the drug before release. And of course, there have been many drug company ads creating a crescendo of drum beats before the official release date,” he said in an interview.

The novelty of tocilizumab lends to the excitement. “There are multiple anti-TNF medications currently, and the reps for those drugs are trying very hard to convince clinicians to choose one medication over another, even though they are probably more similar than different,” Dr. Greenbaum commented. As an IL-6 blocker, tocilizumab IS different, which is why the industry is buzzing, he noted.

The new-drug hype notwithstanding, there are still a number of questions to be answered before clinicians can consider the potential clinical impact of tocilizumab, according to Dr. Greenbaum. “The main questions for me are: Is this medication any safer or more dangerous than the current biologic drugs? Is this medication more or less affordable (or accessible) than the current biologics? Where does this medication belong in the treatment algorithm?

“Undoubtedly, the company is going to try and convince doctors to use this medication immediately after methotrexate failure, but they will first have to convince doctors (and insurers) that this strategy is warranted,” Dr. Greenbaum said.

Of particular concern are the side effects. Biologic agents are powerhouse drugs, and powerhouse drugs often have the potential for causing serious adverse effects. Among the serious tocilizumab-related adverse events that have been reported in pivotal clinical trials include infections that lead to hospitalization or death, including tuberculosis, bacterial, invasive fungal, viral and other infections; gastrointestinal perforations; hypersensitivity reactions; and cellulitis. In March 2009, Roche’s Chugai Pharmaceuticals reported that among nearly 5,000 rheumatoid arthritis patients in Japan who had been treated with tocilizumab between April 2008 and February 2009, 15 deaths occurred and the possibility of a link to the drug could not be denied, although the exact causes of the deaths were unknown, according to a press release issued by the company.

Some of the common side effects associated with tocilizumab include upper respiratory infections, including pneumonia, inflammation of the nose and throat, headache, high blood pressure, increased liver enzymes, increased cholesterol levels, neutrophil decreases, and platelet decreases, according to the company.

The drug’s approval comes with a Risk Evaluation and Mitigation Strategy (REMS), which includes a medication guide, communication plan, and timetable for submission of assessments. The drug itself will be available the week of January 18, 2010.

—Diana Mahoney (on Twitter @dmpm1)

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Filed under Allergy and Immunology, Internal Medicine, Rheumatology