Drug Industry Daily - May 31, 2011 Issue

Vol. 10 No. 106

Acting Solicitor General Asks High Court to Grant Certiorari in Prandin Patent Case

Siding with a generic-drug maker, acting Solicitor General Neal Katyal urged the Supreme Court to hear a dispute over Novo Nordisk changing patent claims to thwart generic competition.

In the case, Novo Nordisk sought to change its patent for Type 2 diabetes drug Prandin (repaglinide) to cover approved uses not originally listed in its ’358 patent for the drug.

Caraco Pharmaceutical Laboratories had filed an ANDA to market Prandin for those uncovered uses. After Novo Nordisk’s patent was changed, the FDA reversed its decision and rejected Caraco’s label.

Caraco sued in Michigan federal court, and a judge ruled in its favor. However, the U.S. Court of Appeals for the Federal Circuit reversed the decision, saying the Hatch-Waxman Act didn’t prevent Novo Nordisk from changing its patent-use codes (DID, April 19, 2010).

“Congress enacted the counterclaim provision at issue here to combat precisely that sort of manipulation,” Katyal wrote in a brief filed Thursday. “The court’s ruling significantly impairs ANDA applicants’ ability to secure FDA approval for their products, and hence deprives consumers of the full benefit of generic competition.”

The Supreme Court had previously asked for his opinion in its consideration of whether to hear the case or not (DID, March 30).

Katyal wrote the Federal Circuit erred in three ways in its decision.

The court wrongly applied Hatch-Waxman’s counterclaims mechanism, saying it’s available only when an Orange Book-listed patent doesn’t claim “any” approved method of using an approved drug, Katyal said. Caraco sought to use repaglinide as a monotherapy, which wasn’t covered under Novo Nordisk’s ’358 patent.

The Federal Circuit also held that patent information open to change is limited to number and expiration date. Lastly, Katyal wrote the court’s interpretation undermines Hatch-Waxman’s efforts to place a judicial check on brand-drug maker’s “exaggerated claims of patent protection.”  

In a brief asking the Supreme Court to deny certiorari, Novo Nordisk says this issue hasn’t occurred before and likely won’t in the future. The high court must deny the case because it won’t have lasting impact beyond the involved parties.

The company also argues there’s no federal jurisdiction because Caraco changed its ANDA from Paragraph IV to Section VIII statement, the former only bearing federal jurisdiction.

The Generic Pharmaceutical Association, which has been a vocal proponent of the court’s hearing the case, hailed Katyal’s brief, saying the Federal Circuit’s ruling would eliminate an important check on brand-drug makers (DID, April 18).

“If the Federal Circuit’s ruling stands, Novo’s actions will become a playbook for all brands and cost consumers millions of dollars by delaying the introduction of affordable, lifesaving generic drugs,” Executive Director Bob Billings said Thursday.

Apotex, Mylan Pharmaceuticals and Teva Pharmaceuticals have all filed amicus briefs supporting Supreme Court review and sided with Caraco.

“If the decision in this case stands, brand-name drug manufacturers will be able to abuse the Orange Book listing system with impunity because the FDA does not review the accuracy of those listings,” Mylan wrote. “With no agency oversight and no judicial review, branded-drug companies can and will deter and delay legitimate, non-infringing generic competition.”

View a copy of Katyal’s brief here www.sblog.s3.amazonaws.com/wp-content/uploads/2011/05/No__10-844_Caraco_v__Novo_Nordisk_working_final-cvsg.pdf. — David Pittman


FDA Seeking Comment on Burden of cGMP-Related Recordkeeping

About 100 drugmakers will need to create up to 25 standard operating procedures (SOPs) for current good manufacturing practices (cGMPs), resulting in a total of 2,500 new records, the FDA predicts in a request for comment on proposed cGMP information collection provisions.

The task of creating the 25 SOPs, which mainly affects startup companies and those expanding into new manufacturing areas, will require approximately 20 hours per recordkeeper, for a total of 50,000 hours, the agency says.

In addition to the need for new SOPs, the FDA describes specific cGMP recordkeeping requirements that drugmakers must follow in order to ensure the manufacture of safe and effective drug products.

For example, filters for liquid filtration used in the production, processing or packaging of human injectable drugs must not release fibers into the products. The agency also requires manufacturers to identify major equipment using a distinctive identification number or code and record that information in the batch production record. In all, the proposal identifies more than 20 cGMP information collection requirements.

Overall, FDA estimates the annual recordkeeping burden related to cGMPs at 848,625 hours.

The agency outlined its projections in a Federal Register notice published today. The notice affects only manufacturers of finished pharmaceuticals.

The FDA is especially interested in receiving input on the following issues:

  • Whether the proposed collection of information is necessary for it to carry out its duties, including whether the information will have practical value;
  • Whether the estimated burden of the provisions is accurate;
  • Ways to improve the quality, utility and clarity of the information collected; and
  • Ways to minimize the burden of information collection on drugmakers, including through the use of automated collection and other IT techniques.

Interested parties will have 60 days to comment on the proposal. — Meg Bryant


Inspections Now Available in Searchable FDA Database

The FDA has launched a searchable database that catalogs its inspections as part of the agency’s ongoing efforts to improve transparency.

The site, announced by the FDA Thursday, allows the public to search inspections from October 2008 through September 2010, but will be updated annually.

The database sorts inspections by company name and address, final inspection date, and FDA district office and project area.

The only mention of outcome is whether the inspection required no action, voluntary action or official action. It doesn’t list the Form 483 from the visit, if one was given.

The site shows 1,465 of the 3,015 inspections conducted by CDER and CBER in the two-year span — 48.6 percent — required some sort of follow-up action.

The FDA said it hopes providing the information will shed more light on company practices that could jeopardize public health and others that have satisfactory inspections.

The database is part of the second phase of the agency’s three-pronged Transparency Initiative (DID, Jan. 13, 2010).

The comment period recently closed for the third phase, which addresses ways the agency can become more transparent to industry (DID, March 23). Drugmakers requested more direct communication between the FDA and sponsors.

“By the end of 2011, FDA will also begin to disclose additional information about FDA evaluations of filers, expand disclosure of Untitled Letters, and in appropriate situations, support industry efforts during a food recall to inform consumers of products that are not subject to the recall,” the agency said.

The inspection database is available at www.accessdata.fda.gov/scripts/inspsearch/. — David Pittman


DDMAC Flashes Warning at Noven for Pexeva Marketing Materials

The FDA’s Division of Drug Marketing, Advertising and Communications (DDMAC) recently warned Noven Pharmaceuticals for a flash card that discusses its antidepressant Pexeva.

The flash card is false or misleading because it broadens the drug’s approved indication, presents unsubstantiated effectiveness claims, overstates its efficacy and omits and minimizes important risk information, according to the May 24 letter.

The card shows a smiling woman sheltered by a Pexeva (paroxetine mesylate) umbrella from the mood disorders the drugs is indicated to treat shaped as color-coded rainclouds with similarly-coded raindrops representing select symptoms of the disorders. The drug is indicated to treat major depressive disorder (MDD), obsessive compulsive disorder (OCD), panic disorder (PD) and generalized anxiety disorder (GAD).

DDMAC takes issue with several aspects of the flash card, starting with the picture of the MDD cloud and the GAD cloud shown combining to produce a new, unnamed cloud raining down the symptoms of irritability, sleep disturbance and fatigue.

“The totality of this presentation misleadingly implies that Pexeva is effective in treating patients with co-morbid MDD and GAD, when this has not been demonstrated by substantial evidence or substantial clinical experience,” DDMAC says.

The agency says Pexeva is indicated to treat MDD and GAD individually, but not concurrently.

The card also cites a study to support its claim that “as many as 75 percent of patients with MDD also exhibit a range of anxiety symptoms or distinct disorders,” but DDMAC says that study was cross-sectional, not based on random sampling and its purpose was to directly compare the clinical features of depression for patients entering clinical trials at primary and specialty care settings, not to identify anxiety disorders distinct from MDD.

DDMAC also says the card’s presentation implies Pexeva is efficacious in treating the individual symptoms depicted as rain drops. The agency says it is not aware of substantial evidence showing patients treated with Pexeva will experience improvement in these individual symptoms since the clinical trials section of the drug’s prescribing information says “the effectiveness of paroxetine in the treatment of OCD, MDD, GAD and PD was demonstrated based on the total scores of the respective scales evaluated for each mood disorder which do not measure the impact of treatment on these individual symptoms.”

The card also omits and minimizes material risks associated with Pexeva, DDMAC says. It completely omits the warning for potentially-fatal serotonin syndrome and NMS-like reactions as well as precautions related to the activation of mania/hypomania, seizures, adverse events from discontinuing Pexeva, akathisia, hyponatremia and abnormal bleeding.

The card also fails to include a warning that families and caregivers should be closely observing the patient for signs of clinical worsening, suicidality and changes in behavior and that it is not for pediatric use. 

Lastly, it claims improvement in sleep, but fails to mention Pexeva is associated with a 13 percent incidence of insomnia in MDD patients and overall minimizes the risk of insomnia associated with Pexeva.

DDMAC requests Noven immediately ends dissemination of the “violative” promotional materials and submit a written response by June 7 regarding its intent.

However, the flash card was discontinued and taken out of sales force use in March, Noven Vice President of Corporate Affairs Joe Jones told DID. The decision to end its use was related to a shift in company focus to another product.

Jones says the card was submitted to DDMAC for review about a year ago at the time of first use, as is required by the FDA, and the agency was not aware the materials were no longer in use.

The DDMAC letter is available at www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/EnforcementActivitiesbyFDA/WarningLettersandNoticeofViolationLetterstoPharmaceuticalCompanies/UCM256863.pdf. — Molly Cohen


NIH Halts Study of Abbott’s Niaspan as Data Showed No CV Risk Reduction

A trial conducted by the National Institutes of Health (NIH) studying the effects of a high-dose version of Abbott’s Niaspan in combination with a statin on patients with heart and vascular diseases was ended 18 months earlier than planned after data showed the combination did not reduce the risk of cardiovascular (CV) events.

The Atherothrombosis Intervention in Metabolic Syndrome with Low HDL/High Triglyceride and Impact on Global Health Outcomes (AIM-HIGH) trial was studying whether raising high-density lipoprotein (HDL) levels in patients with a history of CV disease and well-controlled low-density lipoprotein (LDL) could lower the rate of major adverse cardiovascular events (MACE).

All 3,414 study participants were given standard therapy with simvastatin 40 mg per day and were also randomly assigned to receive Niaspan (niacin extended-release) 1,500 to 2,000 mg per day or placebo. During the first year, the simvastatin dose could be adjusted or a second LDL cholesterol-lowering drug, Merck’s Zetia (ezetimibe) 10 mg could be added to achieve the target LDL cholesterol goal.

The trial was started in September 2005 and was scheduled to finish in 2012, but it was stopped early “due to the lack of incremental benefit on cardiovascular risk reduction in the extended-release niacin plus simvastatin treatment group,” the FDA says. NIH sponsored the trial along with Abbott.

Additionally, a small and unexplained increase in the rate of ischemic stroke was noted in the Niaspan group. Nine of the ischemic strokes in that group occurred in participants who had stopped taking their niacin for at least two months and up to four years before their stroke. “Therefore, it is unclear what role, if any, niacin contributed to this imbalance in ischemic stroke,” the FDA says.

All study participants will be scheduled for clinic visits within the next two-and-a-half months and will be followed for an additional 12 to 18 months.

The FDA has made no new conclusions regarding the use of niacin but will conduct a review of the study’s data when it is released, which should be in the fall.

For now, the FDA says healthcare professionals should consider the available clinical information on Niaspan and statins when prescribing cholesterol-lowering medication. The agency also recommends patients should not stop taking their current medications without talking to their healthcare professional.

Abbott plans to reflect the relevant study findings in the label after finalization of the AIM-HIGH study results and appropriate review.

“There are a number of unanswered questions that remain, based on these interim study results. Some of these issues may become clearer when the study database closes this fall and a comprehensive analysis of the complete database can be conducted,” the company added.

Niaspan is also available in combination with simvastatin under the name Simcor and in combination with lovastatin under the name Advicor (DID, Feb. 19, 2008). — Molly Cohen

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