Jazz Buys Compliance Trouble With FazaClo Acquisition

The schizophrenia drug’s previous owner, Azur Pharma, produced a patient brochure that drew a warning letter FDA’s Office of Prescription Drug Promotion.

Jazz Pharmaceuticals PLC acquired a compliance problem with its new product, the schizophrenia drug FazaClo (clozapine), thanks to a patient brochure produced by the drug’s previous owner, the Irish drug maker Azur Pharma Ltd.

“The warning letter basically addresses a FazaClo promotional piece that is no longer in use,” Bill Craumer, Jazz director of investor relations, said in an interview. He added that the brochure was developed by Azur, from which Jazz acquired FazaClo earlier this year, and “we discontinued it eight to nine months ago because it did not meet our standards” (Also see "Jazz Cools On Women’s Health, Sells Unit To Meda" - Pink Sheet, 7 Sep, 2012.).

Jazz will continue to review its promotional materials for compliance and will respond to a Sept. 18 warning letter from FDA’s Office of Prescription Drug Promotion (OPDP) by the Oct. 2 deadline, Craumer said.

He further noted that FazaClo comes in two versions, an LD and an HD version, and the former “isn’t a strategic product” for the company, as a generic version was approved within the past month. Jazz’s FazaClo revenues were $17.5 million in the first half of 2012.

Déjà Vu All Over

For Jazz, there must have been a feeling of déjà vu in the missive from OPDP, as it is the second FDA warning letter the company has received in two years for making promotional efficacy claims about individual symptoms of the broader disease states a drug is approved for.

OPDP objects to the brochure’s claim that FazaClo “can be highly effective in relieving distressing symptoms such as agitation, unusual thoughts, hearing voices … lack of motivation, and lack of interest in social activities … over a period of time, symptoms like voices or unusual thoughts usually diminish or disappear … [and] you may experience renewed interest in attending school, or holding a job; and you may want to join in more social activities with your family and friends,”

According to OPDP, there is not evidence to back up these assertions, so they overstate the drug’s efficacy. The problem is that the symptoms allegedly improved by FazaClo were part of composite endpoints, the “Brief Psychiatric Rating” and “Clinical Global Impression” scales used in the pivotal clinical trial. Being composite, the endpoints don’t “demonstrate an effect on an individual component of these scales.”

Two years ago OPDP’s predecessor, the Division of Drug Marketing, Advertising and Communications (DDMAC), sent Jazz a warning letter citing a patient brochure for Luvox CR (fluvoxamine maleate). The issue then was similar: efficacy claims about individual symptoms of the broader disease states the drug is approved for, social anxiety disorder and obsessive compulsive disorder (Also see "Luvox CR Symptom Benefit Claims Draw DDMAC Warning" - Pink Sheet, 26 Jul, 2010.).

Jazz isn’t the only drug manufacturer for which the warning letter should sound familiar alarm bells. OPDP/DDMAC has been cracking down on claims about individual symptom relief for a while, such as in a 2010 “notice of violation” letter to Shire PLC for claims about the symptom relief potential of its attention deficit/hyperactivity disorder drug Intuniv (guanfacine) (Also see "Short Attention Span? Shire Cited Again For Out-Of-Bounds ADHD Promotion" - Pink Sheet, 1 Jul, 2010.).

A Multi-Category Offender

OPDP also found the FazaClo brochure lacking in that it omits or minimizes risk information, wrongly broadens the drug’s indication and makes unjustified superiority claims.

The risk information was very inadequate, being presented only on page 8 of the 12-page brochure, OPDP says. There are several more problems in this category, such as the fact the brochure doesn’t talk at all about any of the contraindications and common adverse reactions, and neglects to mention “warnings such as QT interval prolongation, neuroleptic malignant syndrome (NMS), tardive dyskinesia (TD), hyperglycemia and diabetes mellitus; and precautions, such as interference with cognitive and motor performance.”

Even where the brochure does include risk information, it leaves out key facts; for example, it “discloses some information regarding the Boxed Warning for agranulocytosis on page 8 [but] fails to include the important material fact that agranulocytosis is a potentially life-threatening adverse reaction [emphasis OPDP’s].” References to the risk section on page 8 of the brochure and to the full prescribing information do not mitigate these problems, OPDP says.

The brochure broadens the indication of FazaClo in that “it suggests that FazaClo is indicated for the overall treatment of schizoaffective disorder,” when in fact it “is only indicated for reducing the risk of recurrent suicidal behavior in patients with schizoaffective disorder, not for overall treatment of the disorder itself [emphasis FDA’s].”

The brochure also “misleadingly implies that FazaClo is useful in a broader range of conditions or patients than has been demonstrated by substantial evidence or substantial clinical experience,” when it is actually approved for the management of treatment-resistant schizophrenia.

Furthermore, a claim in the brochure that “researchers say that clozapine, the active ingredient in FazaClo, is the most effective medication for reducing or eliminating symptoms in patients who have not had success with other products,” is an unsubstantiated superiority claim because it hasn’t been tested and found “more effective than all other products for treatment-resistant schizophrenia,” FDA says.

OPDP says the facts are “that clozapine has been demonstrated to be more effective than chlorpromazine and is the only product currently approved to treat severely ill schizophrenic patients who fail to respond adequately to standard drug treatment for schizophrenia.”

The brochure also unjustifiably insinuates a better risk profile for FazaClo than for other schizophrenia treatments, claiming that it “generally produces little or none of the restlessness, stiffness, shakiness, or tremor you may have experienced with other medications,” which the agency says there is not evidence for.

Finally, the agency objects to the brochure’s claims that the drug is “a new road to recovery” and other implications “that the outcome of treatment with FazaClo is the complete resolution of symptoms in patients with treatment-resistant schizophrenia.” Again there was not evidence for this, and given that the clinical trial was only six weeks long it couldn’t show long-term efficacy.