FDA ups enforcement on marketed unapproved drugs, as KV draws seizure.

FDA is placing stronger emphasis on compliance enforcement on manufacturers that produce unapproved drugs, which account for approximately two percent of the 3.6 billion prescriptions filled in the United States annually, officials announced July 17.

And, just 13 days later on July 30, FDA made good on its promise, by initiating a seizure of about $24 million in unapproved medications from KV Pharmaceutical Co., St. Louis.

According to an agency announcement, the confiscation followed an investigation of several KV Pharmaceutical plants, where federal agents discovered cases of non-compliance with FDA regulation and illicit manufacturing of unapproved medicines, including wound, cold, gastrointestinal treatments and narcotics.

Earlier this year, FDA inspectors found KV in violation of its 2007 notice (72 FR 29517) prohibiting drug companies from manufacturing timed-release products containing guaifenesin. Improperly manufactured timed-release products can alter the product's release rate, rendering it ineffective and even unsafe. KV Pharmaceutical continued to produce timed-release drugs, as well as other unapproved drug products.

The agency is stepping up enforcement of its Marketed Unapproved Drug Initiative because these products frequently are unsafe, said Deborah Autor, director of the Center for Drugs Office of Compliance.

"There may not always be a documented safety risk; the absence of proof of a problem is not proof of the absence of a problem," Autor said.

FDA takes an average of seven months to issue warnings to drug makers for off-label marketing, and the drug makers take an average of four months to address violations, according to a recent Government Accountability Office report.

The report also determined that FDA has no one assigned to specifically monitor off-label violations. The agency's Division of Drug Marketing, Advertising and Communications, which has 44 employees reviewing DTC ads, primarily monitors off-label marketing.

Michael Levy, Director of New Drugs and Labeling Compliance in the Office of Compliance, noted that enforcement priorities for the initiative are as follows:

* Drugs with potential safety risks;

* Drugs that lack evidence of effectiveness;

* Fraudulent drugs;

* Unapproved drugs that directly compete with an unapproved drug;

* Drugs form manufacturers that are otherwise violating the FD&C Act; and

* Drugs with formulation changes made as a pretext to avoid enforcement.

Unapproved drugs frequently are ineffective, and "doctors and consumers cannot assume that marketed drugs have been found by FDA to be safe and effective," Autor said.

Unapproved drugs are a public health problem because of:

* Limited post-market surveillance and no periodic reporting;

* Challenges to the integrity of the drug approval system; and

* Potential for drug labeling deficiencies.

Autor stressed that all drugs must have FDA approval or comply with an OTC monograph, unless:

* There is a Drug Efficacy Study Implementation (DESI) pending;

* There is an OTC monograph pending;

* The drug is generally recognized as safe and effective (GRAS/E); or

* Is grandfathered.

To be GRAS/E, Autor said that a consensus is required "among experts that the product is safe and effective based on published scientific literature regarding the finished drug product of the same quality and quantity needed to approve a drug."

It is unlikely, she added, that any currently marketed prescription drug is GRAS/E.

To be grandfathered, a firm must document that its product is identical in formulation, strength, dosage form, route of administration, indications, intended patient population and other conditions of use to a drug marketed on the relevant date. Autor also noted that it is unlikely that any currently marketed prescription drug is grandfathered.

Levy said that recent enforcement actions for marketed unapproved drugs have included Carbinoxamine in June 2006, Quinine in December 2006, Ergotamine in March 2007 and Hydrocodone in September 2007.

Another enforcement action occurred, said Levy, in May 2007 for timed-release products containing Guaifenesin. This was done because the unapproved drug was competing with approved competitors, lacked evidence of effectiveness and showed signs of dose dumping.

The Hydrocodone action was implemented because there were seven approved versions, numerous adverse event reports associated with the unapproved versions of the drug, and because it was labeled for use in young children.

FDA is increasing awareness and understanding regarding marketed unapproved drugs with the recent appointment of an unapproved drugs coordinator. There have been approximately 100 calls to the new coordinator to date and "numerous NDA/ANDA applications," said Levy.

There also was an unapproved drugs workshop by FDA in January 2007 with over 400 attendees.

Ironically, earlier this year drug makers began lobbying Washington to push for looser government restrictions on off-label promotion. According to published reports, 10 manufacturers, including Pfizer, Bayer, AstraZeneca and Johnson & Johnson, formed a coalition to push for looser off-label restrictions with an eye toward submitting comments to FDA, which has been soliciting comments on its proposed off-label promotion guidelines.

Read more about the KV seizure and other GMP compliance news at http://www.fdainfo.com/vtonlinepages/VTOnl ine_7.31.08.htm To get the page weekly, call [phone], email: [e-mail].