Drug Industry Daily - Jan. 27, 2010 Issue

Vol. 9 No. 18

Potential Budget Freeze Could Exacerbate FDA’s Challenges

The FDA’s challenges in conducting foreign inspections and expediently reviewing new drugs could be intensified if the agency is affected by a three-year budget freeze expected to be announced by President Barack Obama in his State of the Union address tonight. 

“I would think it would [affect the agency’s ability to maintain drug safety],” Ira Loss, senior health analyst with Washington Analysis, told DID Tuesday.

The effect on the agency would depend on the way the budget freeze is administered, Loss said. If it is not a “hard freeze” on all spending, certain parts of the budget could be reallocated and the FDA could actually see an increase in funding, he said.

“If the function has to do with job creation, then I doubt they’ll be frozen or be cut, but if the function does not have to do with job creation, then my guess is that it’s vulnerable,” Loss said.

The FDA received a 23 percent increase in appropriations to $3.2 billion for fiscal 2010 (DID, Oct. 12, 2009). CDER received $880 million, 13 percent more than last year, no less than $51.5 million of which must be made available for the Office of Generic Drugs. CBER received $305 million, a 12.5 percent increase.

The increased funding has given the agency enough money to be effective, even if its budget is frozen, Scott Gottlieb, a resident fellow at the American Enterprise Institute and former FDA deputy commissioner, told DID.

“On the drug side, FDA has received substantial increases over the last several years. Their challenge now is spending the money they have and ramping up their hiring,” Gottlieb said. — David Belian


FDA Outlines Approval Process for Drugs With Abuse Potential

Drugmakers developing potentially addictive drugs should include assessments of that potential in NDAs, the FDA says in a new draft guidance.

The NDAs should include a section with a summary, interpretation and discussion of abuse potential data, and a proposal and rationale for putting the drug in a particular schedule of the Controlled Substances Act (CSA), the draft, released Tuesday, says. Comments are due by March 28.

The CSA schedule determines requirements for the product’s manufacture, labeling, promotion, marketing and prescribing, the FDA says, and failure to meet those requirements can result in criminal penalties, including fines of up to $10 million for a first offense.

Products that may be abused are those affecting a user’s mood or central nervous system, and those that are chemically or pharmacologically similar to drugs with known abuse potential, including opioids, stimulants, depressants, cannabinoids and hallucinogens, the draft says.

The draft also outlined requirements in applications for new molecular entities, for which all primary data related to abuse potential should be organized into eight specific subheadings.

The applications also should include pertinent preclinical, pharmacological, chemistry, biochemical, drug formulation, and human laboratory and clinical study data. Proposed labeling that describes the drug’s potential for abuse and dependence also should be included, the agency says.

The draft “Guidance for Industry on Assessment of Abuse Potential of Drugs” can be found at www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/UCM198650.pdf. — David Belian


Appeals Court Upholds Boehringer Mirapex Patent

A federal appeals court has upheld a Boehringer Ingelheim patent for its Parkinson’s disease drug Mirapex, overturning a lower court decision.

The U.S. Court of Appeals for the Federal Circuit ruled that the ’812 patent, which has delayed Mylan’s plans to market a generic version of Mirapex (pramipexole dihydrochloride), is valid because it is covered by the safe harbor provision of Section 121 of the patent law. The patent expires Oct. 8, according to the FDA Orange Book.

The safe harbor protects a patent applicant from losing rights when an application is divided, according to the majority opinion. The appellate court says the most straightforward reading of Section 121 is that its safe harbor “applies even when the PTO issues a restriction requirement that leads to more than two separate applications.”

Boehringer sued Mylan in the U.S. District Court for the District of Delaware after Mylan filed an ANDA to make generic Mirapex in 2005. Mylan challenged the validity of the ’812 patent in 2006 on the basis of nonstatuatory double patenting — specifically saying the claims of the ’812 patent were anticipated by an earlier ’086 patent (DID, June 30, 2008).

The District Court ruled that Section 121 protection did not apply to the case and therefore the patent was invalid, according to court documents in Boehringer Ingelheim International GMBH and Boehringer Ingelheim Pharmaceuticals, Inc. v. Barr Laboratories, Inc., et al.

Barr was a defendant in an earlier lawsuit that was combined with the Mylan suit. However, Barr and Boehringer settled, allowing Barr to launch its generic Mirapex Jan. 2, according to Boehringer. — Owen Skoler


FDA Approves First High-Strength Morphine After Crackdown

Boehringer Ingleheim’s Roxane Laboratories is the first company to get approval for a morphine product, following the FDA’s crackdown last year on companies marketing unapproved formulations of it.

As part of its unapproved drugs initiative, the agency approved Roxane’s morphine sulfate oral solution in 100 mg per 5 mL or 20 mg per 1 mL. Intended for opioid-tolerant patients, it is the first FDA-approved morphine sulfate oral solution available at the high dose, Douglas Throckmorton, deputy director for CDER, said Tuesday at a media briefing.

The initiative, which was implemented in 2006 and prioritizes products with safety risks or that lack effectiveness, removes unapproved drugs from the market and brings them into the approval process. For example, the agency has approved several pain medicines through the initiative, including hydromorphone, morphine sulfate tablets and oxycodone, Michael Levy, director of CDER’s Division of New Drugs and Labeling Compliance, said at the briefing.

The FDA sent warning letters last year to six companies, including Roxane, for marketing unapproved versions of morphine sulfate solution. The companies were given two months to halt production and three months to stop shipping existing product (DID, April 1, 2009).

The agency is encouraging the other companies to seek approval, Throckmorton said. If they don’t submit information for approval, they will face enforcement action, he added. — Owen Skoler


Sunrise Pharmaceutical Warned After Using Excess API

Sunrise Pharmaceutical received a warning letter after manufacturing some of its products with excess active pharmaceutical ingredient (API) without justification in its batch records.

The Rahway, N.J., company said it used the excess amounts for some stomach, cough and gout drugs to make up for process loss, but none of those losses were documented, according to the Jan. 14 warning letter. A process is not in an adequate state of control when excess API is routinely used, the letter says.

Sunrise also failed to investigate and perform corrective actions for out-of-specification (OOS) humidity levels observed for the controlled room temperature stability chamber on several occasions.

During the inspection, which took place June 19 through July 17, the quality unit presented inspectors with backdated service requests to investigators as evidence of proper OOS result handling; however, no actual service requests were initiated, the letter says.

Sunrise also was cited for blending a validation lot for an additional 10 minutes — without review and approval by the quality unit — after the lot failed blend uniformity testing. Although the company told inspectors it would retrain employees, the FDA is concerned because the same commitment was made in the past for other deficiencies, the letter says.

Sunrise takes the warning letter seriously and is working to address the concerns, Himanshu Brahmbhatt, the company’s director of sales and marketing, told DID. The warning letter is available at www.fdanews.com/ext/files/Sunrise-Pharmaceutical-Inc.pdf. — April Hollis


FDA Recommends New Dissolution Test Method to Meet GMPs

A final FDA good manufacturing practice (GMP) guidance recommends a new method for testing drugs’ dissolution rates.

Drugmakers are encouraged to calibrate test equipment listed in the U.S. Pharmacopeia (USP) Chapter <711> by using an enhanced mechanical calibration (MC) method, the guidance, scheduled for the Jan. 27 Federal Register, says.

An enhanced MC procedure should be used because the USP method may give results that can be too variable. Whatever calibration procedures are used, they must control several significant sources of variation, including dissolved gases, vibration and vessel dimensions, which can significantly affect test results, the guidance says.

Drugmakers also should specify the frequency for performing each calibration step, taking those sources of variation into account.

The guidance is available at www.fdanews.com/ext/files/8782fnl.pdf. An example of an enhanced MC procedure used by CDER is available at www.fda.gov/downloads/AboutFDA/CentersOffices/CDER/UCM142492.pdf. — April Hollis

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