DID - Oct. 16, 2009 Issue

Vol. 8 No. 202

FDA Postmarket Pilot Finds Safety Signals in Four of Five Drugs

An FDA pilot program to evaluate safety signals of approved new molecular entities (NMEs) more intensely than through CDER’s routine process is likely to continue in some form because it identified safety issues that routine evaluation did not.

The FDA identified safety signals in four of five NMEs examined in its New Molecular Entity Postmarketing Safety Evaluation Pilot Program, which has led to labeling changes to add risk information and prevent medication errors, according to the report posted on the FDA’s website Thursday.

The pilot was conducted primarily by about 50 staff from CDER’s Office of Drug Evaluation I (ODE I) and Office of Surveillance and Epidemiology (OSE) and began in early 2007. Products were chosen based on their indication, length of time on the market and number of postmarketing cases in the adverse events reporting system (AERS).

In contrast to CDER’s routine postmarketing evaluation process — which includes review of mandatory reports of serious and unexpected events, applicants’ periodic safety reports, healthcare professionals’ and consumers’ reports of serious problems, and reviews of data from clinical trials and drugs in the same pharmacologic class — the pilot’s evaluation also included data-mining analysis of AERS data, analyses of product use and medication errors, reviews of risk management and reviews of postmarketing clinical trial and epidemiologic studies.

For example, the pilot studied Eli Lilly’s antidepressant Cymbalta (duloxetine HCl) from January through March 2007. The evaluation led the FDA to ask Lilly to add information to the drug’s label on the risk of bleeding, hyponatremia (low serum sodium levels) and falling, and potentially serious urinary hesitation and retention (DID, Sept. 8, 2008). In addition, the company made changes to the product’s container labels and labeling to prevent medication errors.

The program also examined Otsuka and Bristol-Myers Squibb’s (BMS) antidepressant Abilify (apiprazole) from January through March 2008, identifying several potential safety concerns requiring further review, including:

  • Liver toxicity;
  • Extrapyramidal symptoms (a type of movement disorder);
  • Torsades de pointes (a type of ventricular tachycardia);
  • Bone marrow failure;
  • Hemolytic anemia;
  • Pancytopenia; and
  • Exacerbation of psychosis when clinically stable patients were switched to Abilify from another antipsychotic medication. 

The FDA discussed the signals with Otsuka and BMS but did not require labeling changes (DID, Feb. 6). “We will work with FDA to ensure safety information about Abilify continues to be appropriately communicated,” BMS and Otsuka spokeswoman Sonia Choi told DID.

The pilot identified no specific safety issues for CV Therapeutics’ angina medication Ranexa (ranolazine).

Adverse events requiring further action were found for Teva Neuroscience’s Azilect (rasagiline mesylate) and Ipsen’s Apokyn (apomorphine HCl), both of which are indicated to treat Parkinson’s disease, according to the report.

CDER approved 10 NMEs through the end of May, compared with 17 approvals from Jan. 1 through Nov. 30, 2008.

The pilot project was “extremely useful and productive,” but discovering the safety signals required a lot of effort and considerable resources from ODE I and OSE, the report says. “It is clear that such NME evaluations will still require a significant amount of time when complex safety issues are discovered requiring hands-on review of individual cases,” the report says.

A chart with details of the pilot and reviewed drugs is below, and the report can be seen at www.fdanews.com/ext/files/ucm185252.pdf. — Martin Berman-Gorvine

NME Pilot Product Details and Resources Used to Complete Pilot Evaluations


Months Since Approval

Patients on Prescriptions
(in millions)

Crude No. of AERS Reports

Hours Spent on NME Evaluation

Safety Issues Identified for Follow-Up

Cymbalta (duloxetine)






Ranexa (ranolazine)






Apokyn (apomorphine)


 < .003




Abilify (aripiprazole)






Azilect (rasagiline)






Source: CDER


Senate Panel Approves Bill to Ban Pay-for-Delay Deals

The Senate Judiciary Committee approved a bill designed to eliminate patent settlements between brand- and generic-drug makers to delay introduction of the less expensive medicines.

Sen. Herb Kohl’s (D-Wis.) Preserve Access to Affordable Generics Act, S. 369, includes a provision that permits such settlements if drugmakers can offer “clear and convincing evidence” in court that the agreements are pro-competitive (DID, Sept. 28).

The committee’s 12–7 vote Thursday to send it to the Senate floor was largely along party lines. Sen. Arlen Specter (D-Pa.) joined all Republicans except Sen. Chuck Grassley (R-Iowa) in voting against the bill.

Kohl introduced his legislation Feb. 2 but faced opposition from fellow senators who believed it went too far (DID, Feb. 4). The bill originally would have banned all pay-for-delay agreements between innovators and generic-drug makers.

Sen. Tom Coburn (R-Okla.) expressed concern Thursday that the clear and convincing evidence standard was too high. He suggested that a “preponderance of evidence” standard would be more appropriate. He offered and withdrew an amendment to change the evidentiary standard language.

Kohl disagreed with Coburn, arguing that the preponderance of evidence standard would permit agreements of questionable competitive effects.

While praising Kohl’s efforts to eliminate deals to delay consumer access to less expensive drugs, Sen. Orrin Hatch (R-Utah) said he the bill is “not there yet” and would have the effect of prohibiting pro-consumer agreements. He said he hopes to continue work on developing a bipartisan agreement.

FTC Chairman Jon Leibowitz, who has spoken against pay-for-delay settlements, praised the committee’s vote. “We estimate that stopping these pay-for-delay settlements will save consumers about $3.5 billion per year and advance the cause of affordable health care for all Americans,” he says in a statement.

Rep. Bobby Rush (D-Ill.) introduced similar legislation in the House. The Protecting Consumer Access to Generic Drugs Act of 2009, H.R. 1706, was incorporated in the House Energy and Commerce Committee’s version of the healthcare overhaul bill passed this summer (DID, Aug. 4).

Kohl’s bill is available at frwebgate.access.gpo.gov/cgi-bin/getdoc.cgi?dbname=111_cong_bills&docid=f:s369is.txt.pdf. Rush’s bill is available at frwebgate.access.gpo.gov/cgi-bin/getdoc.cgi?dbname=111_cong_bills&docid=f:h1706ih.txt.pdf. — Elizabeth Jones


Roche Pipeline Holds Several Pending Applications in US and Abroad

Roche’s drug pipeline includes several pending applications and labeling expansion requests in the U.S., EU and Japan.

The company is expecting an FDA decision by Nov. 17 on two sBLAs submitted by Roche subsidiary Genentech and Biogen Idec for Rituxan (rituximab) plus standard chemotherapy in chronic lymphocytic leukemia, Roche spokeswoman Amy Berry told DID. The applications were granted priority review in July, the company says in a statement Thursday accompanying its third-quarter earnings report.

Roche expects a decision Oct. 16 on its sBLA for earlier use of Rituxan in rheumatoid arthritis patients, Roche spokeswoman Nikki Levy told DID Thursday. The drug is approved after inadequate response to tumor necrosis factor therapy. If the application is approved, the drug could be used after treatment with a disease-modifying drug, Levy said.

The company also plans to apply for expanded labeling for Rituxan in the U.S. and EU after a Phase III study found Rituxan maintenance therapy can significantly increase the time to disease progression in newly treated, advanced follicular lymphoma patients.

Additionally, Roche plans an sBLA submission for Lucentis (ranibizumab) after two Phase III studies announced in July showed improved vision in patients with swelling in the retina due to branch retinal vein and central retinal vein occlusion.

The company should hear from the FDA by Jan. 8, 2010, on its resubmission for rheumatoid arthritis treatment Actemra (tocilizumab), Roche spokeswoman Lindsay Rocco told DID. This follows the FDA’s complete response in September 2008 and subsequent discussions with Roche (DID, Dec. 5, 2008). The agency designated a six-month review timeline for the resubmission, filed in July, Roche says.

The company also has pending applications in Japan for approval of Mircera (methoxy polyethylene glycol-epoetin beta) for renal anemia and Tarceva (erlotinib) to treat pancreatic cancer. Applications in the EU were filed to expand the authorization for Herceptin (trastuzumab) to include treatment of advanced HER2-positive stomach cancer and to expand authorization for rheumatoid arthritis drug RoActemra (tocilizumab) to include inhibition of the progression of joint damage and improvement of physical function.

The company also notes two studies published in September found increased survival rates in patients with avian flu and severe seasonal flu who were treated with Tamiflu (oseltamivir).

Separately, Baxter announced earnings Thursday and says it expects a U.S. regulatory filing in the first half of 2010 for a seasonal influenza vaccine. The company expects final study results from a Phase III study by the end of the year, according to its statement Thursday. — April Hollis


Mylan Gets Approval to Market Generic Topamax Capsules

Mylan has received approval from the FDA for a generic version of Ortho-McNeil Janssen’s anticonvulsant Topamax Sprinkle Capsules.

The drug, which will be marketed as Topiramate Capsules (Sprinkle), will be available in 15- and 25-mg doses and has already been launched by the company, Mylan says in a statement Thursday.

The company had received tentative approval for the formulation in 2007 and earlier this year received approval to market the non-capsule form of topiramate in 25-, 50-, 100- and 200-mg forms (DID, Sept. 12, 2007).

The 15- and 25-mg strengths of the drug had U.S. sales of about $58 million for the 12 months ended June 30, Mylan says. The company currently has 121 ANDAs pending FDA approval representing $85.7 billion in annual brand sales, 34 of which represent potential first-to-file opportunities. — David Belian


Teva Answers Gilead, Emory’s Amended Patent Complaint

Teva Pharmaceuticals USA, which wants FDA approval for generic versions of Gilead Sciences’ Truvada and Atripla, is seeking a declaratory judgment that patents covering the two HIV treatments are invalid.

The ’245 and ’396 patents owned by Emory University and licensed to Gilead are invalid due to obviousness-type double patenting, Teva maintains in court documents filed recently in the U.S. District Court for the Southern District of New York.

Teva maintains that FDA approval for generic versions of Truvada (emtricitabine/tenofovir disoproxil fumarate) and Atripla (efavirenz/emtricitabine/tenofovir disoproxil fumarate) wouldn’t infringe claims of the Gilead patents, which are assigned to Emory.

Teva informed the companies in March that it intended to make generic Atripla before the expiration of the patents, according to court documents. Gilead and Emory added accusations in their Sept. 25 complaint that Teva infringed the patents through its proposed generic version of Atripla.

The case Gilead Sciences, Inc. and Emory University v. Teva Pharmaceuticals USA, Inc., et al. originally was filed in December 2008. — Elizabeth Jones


Sanofi-Aventis Anti-Emetic Drug Gains New Indication

Sanofi-Aventis’ anti-emetic drug Anzemet has gained a new indication — the treatment of postoperative nausea or vomiting.

Anzemet (dolasetron mesylate) has approval for the prevention of nausea and vomiting associated with initial and repeat courses of emetogenic cancer chemotherapy, including high-dose cisplatin, and the prevention of postoperative nausea and vomiting. The revised label was approved Oct. 6 and posted to the FDA website this week.

The new label is available at www.accessdata.fda.gov/drugsatfda_docs/label/2009/020624s020lbl.pdf. — Martin Berman-Gorvine

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Reporters: Martin Berman-Gorvine, David Belian, Elizabeth Jones, April Hollis

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