DID - Jan. 9, 2009 Issue

Vol. 8 No. 5

FDA Requests REMS for Long-Acting Injectable Formulation of Zyprexa

The FDA decided again to reject a long-acting injectable formulation of Eli Lilly’s Zyprexa and asked the company to establish a risk evaluation and mitigation strategy (REMS) for the drug, the company told DID.

The REMS is the only thing keeping the product from being approved, and no additional clinical trials are required, the company said Thursday. The surveillance program would address and quantify the drug’s risk for post-injection delirium and sedation, which can lead to comas.

One option the FDA can require as part of a REMS is a registry for patients, prescribers and pharmacists. Lilly is seeking to market the drug for the acute and maintenance treatment of schizophrenia in adults.  The company told DID it plans to submit the REMS soon.

The long-acting injectable formulation of the atypical antipsychotic, olanzapine pamoate, won support from the FDA’s Psychopharmacologic Drugs Advisory Committee last year (DID, Feb. 7, 2008). Shortly thereafter, the FDA issued a not-approvable letter for the drug, saying it needed more information on cases of excessive sedation, including an event that occurred shortly before the advisory committee meeting (DID, Feb. 29, 2008).

The new formulation of Zyprexa would be administered to patients only once every four weeks, which would be an advantage over Johnson & Johnson’s (J&J) long-acting atypical antipsychotic Risperdal Consta (risperidone), which is administered every two weeks.

If the FDA approves the new version of Zyprexa, it might not be the only long-acting antipsychotic on the market. J&J has its own once-monthly injectable product application pending at the FDA. The product, paliperidone palmitate, has the same active ingredient as J&J’s Invega (paliperidone) and was the subject of a complete response letter last year (DID, Aug. 27, 2008). — Christopher Hollis


Daschle Emphasizes Communication, Leadership as Key to Improving FDA

Former Sen. Tom Daschle (D-S.D.), nominated by President-elect Barack Obama to head HHS, told a Senate panel that he would concentrate on better communication between health agencies and strong leadership to help overcome problems at the FDA.

“Tearing down the stovepipes” between NIH, FDA, the Centers for Disease Control and Prevention and the Centers for Medicare & Medicaid Services is one of the problems to be addressed, Daschle said during confirmation hearings before the Senate’s Health, Education, Labor and Pensions (HELP) Committee.

Sen. Richard Burr (R-N.C.) described a lack of funding, declining morale and expanding mission at the FDA. Daschle said he would work toward getting adequate resources to the agency and installing leadership to boost morale.

HHS must live up to its responsibility to protect the American people through its regulation of food and drugs, especially in light of growing concern that the FDA may have lost the confidence of the public and Congress, Daschle said in prepared remarks.

Daschle plans to restore trust in the FDA as the leading science-based regulatory agency in the world and said he would work to remove politics from the practice of science. He also promised to ensure that agencies under his authority would comply with laws governing accountability and transparency.

Daschle pledged to respond quickly to inquiries and share information with the Senate HELP committee in response to a question from Sen. Mike Enzi (R-Wyo.), who said the committee has the ability to work in a bipartisan manner. — Elizabeth Jones


Advisory Committee Supports Ovation’s Anti-Epileptic Drug

The FDA’s Peripheral and Central Nervous System Drugs Advisory Committee voted unanimously to recommend that the FDA approve Ovation Pharmaceuticals’ anti-epileptic drug Sabril under a risk evaluation and mitigation strategy (REMS).

The panel supported approval of the drug as an adjunctive therapy to treat complex partial seizures in adults on Wednesday and agreed to recommend its use as a monotherapy for infantile spasms on Thursday.

An NDA for Sabril (vigabatrin) was originally submitted in 1994 by Merrell Dow, now Sanofi-Aventis (DID, Jan. 7). In 1998, the FDA became aware of a visual field defect associated with the drug, putting the product in its third approval cycle. Ovation later acquired the product and submitted another NDA in December 2007.

The company’s REMS would require vision tests for patients, Tim Cunniff, vice president of global regulatory affairs, told DID Thursday. The surveillance program also calls for a mandatory physician and patient registry, in which the doctor would have to sign a document stating that he or she understands the risks of the product.

Ovation’s REMS proposes to allow only board-certified neurologists to prescribe the drug, but committee members thought that was too restrictive and expressed support for expanding the prescribing base to physicians with experience in treating epilepsy.

The company also proposed a requirement for patients to have their vision tested when the drug is prescribed, in six months and again four to six months later. Cunniff told DID that committee members expressed support for testing that would begin three months after the baseline assessment.

In addition, the company proposed waiting 45 days before the REMS required doctors to reduce the amount of the drug given to patients who have not had their vision tested. But committee members wanted a longer grace period, Cunniff said. — Christopher Hollis


Rep. Pallone Keeps Helm of Health Subcommittee

Rep. Frank Pallone (D-N.J.) has promised to continue trying to arrive at a consensus on a generic biologics bill after he was reelected as head of the House Energy and Commerce Committee’s Subcommittee on Health.

The subcommittee has jurisdiction over Medicaid, the FDA, the NIH and the Centers for Disease Control and Prevention. It oversees public health and biomedical programs as well as drug and device safety.

In addition to working on a generic biologics bill, Pallone promised Thursday to advocate for the expansion of NIH medical research and to work on health information technology provisions for the overall economic recovery package to modernize the nation’s healthcare system, according to his statement. — Elizabeth Jones


Drugmakers May Spend Thousands of Hours Complying With Rule

Drugmakers will spend a total of more than 300,000 hours a year designing, testing and submitting prescription drug labeling for NDAs or BLAs under revised regulations, the FDA says.

The final rule, which took effect June 30, 2006, amended regulations governing the format and content of labeling for new and recently approved prescription drug and biologic products. An FDA notice of proposed collection of information, which was submitted to the Office of Management and Budget in compliance with 44 U.S.C. 3507, was published today in the Federal Register.

The final rule revised FDA regulations to help health practitioners access, read and use information in prescription drug labeling. The revisions required that the product labeling contain highlights of prescribing information and a table of contents for that information.

The FDA estimates in its OMB submission that 85 drugmakers will spend a total of 358,343 hours designing and creating prescription drug labeling; testing these labels to ensure they fit into carton-enclosed products, and submitting the labeling to the FDA for approval. About 107 NDAs and BLAs will be submitted annually, and each applicant will spend 3,349 hours ensuring the corresponding labeling complies with the rule, according to the announcement.

Drugs approved during the five-year period before — or pending on — the effective date of the final rule also are affected. The FDA estimates that 172 applicants will spend 196 hours to redesign, test and submit the labeling — a total of 67,424 hours.

Efficacy supplemental applications for older drugs submitted to the agency on or after the effective date of the final rule also are subject to its requirements. The FDA estimates 172 applicants will generate 186 efficacy supplements, and each company will spend roughly 196 hours to revise the labeling in the application. The total burden for companies will be 36,456 hours, according to the announcement.

Generic drugs also will be affected by the final rule. Roughly 42 generic applicants will submit labeling supplements annually. The time required for them to revise and submit their labeling will be about 27 hours per application, for a total of 9,072 hours, the announcement says.

Comments on “Requirements on Content and Format of Labeling for Human Prescription Drug and Biological Products” are due before Feb. 8 and may be submitted by email. The notice is available at www.fda.gov/OHRMS/DOCKETS/98fr/FDA-2008-N-0500-n.pdf. — Elizabeth Jones


Merck Applies to Expand Gardasil Vaccine Use to Males

In a bid to boost the billion-dollar market for its controversial Gardasil vaccine against human papillomavirus (HPV) infection for women and girls, Merck has submitted an sBLA to add use of the vaccine in men and boys.

HPV infection has been linked to cervical cancer, and the vaccine has been approved to prevent the disease in women. Gardasil sales were $1.5 billion in 2007 and $1.1 billion in the first nine months of 2008. Merck announces its fourth-quarter and full-year 2008 results Feb. 3, spokeswoman Amy Rose told DID.

The sBLA seeks approval to give the drug to boys and men age 9–26 because males can transmit the disease to females through sexual contact.

In a Phase III study to support approval for use in males, Gardasil (human papillomavirus quadrivalent [types 6, 11, 16 and 18] vaccine, recombinant) prevented 90 percent of the external genital lesions caused by HPV types 6, 11, 16 and 18 in males age 16–26, according to the company (DID, Nov. 14, 2008).

The randomized, placebo-controlled study enrolled young men who had not been infected with at least one of the four HPV types. Participants include approximately 3,400 heterosexual males age 16–23 and approximately 600 males age 16–26 who have sex with other men. The study is ongoing, and the company plans to submit additional data to regulatory agencies when it becomes available. The application was submitted last week.

The vaccine is indicated for use in girls and women age 9–26 for the prevention of cervical, vulvar and vaginal cancers caused by HPV types 16 and 18, genital warts caused by HPV types 6 and 11, and precancerous or dysplastic lesions caused by HPV types 6, 11, 16 and 18.

The FDA approved the use of Gardasil for prevention of vulvar and vaginal cancer last September, expanding the indication from cervical cancer prevention alone (DID, Sept. 15, 2008). — Martin Gidron


FDA: Particle Testing Procedures Coordinated by ICH

The U.S., European and Japanese Pharmacopoeias provide interchangeable methods of testing drugs for particulate contamination with subvisible particles, according to the FDA.

The International Conference on Harmonisation (ICH) has issued a final guidance harmonizing the methods for testing subvisible particles, such as the microscopic particle count test. The guidance provides the results of the ICH evaluation of the test with the aim of not making drug companies conduct redundant testing “in favor of a common testing strategy in each regulatory region,” the FDA said when it announced the availability of the guidance Thursday.

The U.S., European and Japanese pharmacopoeial texts can be used interchangeably in the ICH regions, as long as instrument calibration and system suitability measurements follow regional good manufacturing practice (GMP) requirements, according to the ICH guidance, which cites the organization’s steering committee and the expert working group on this subject. The only exception is for nominal 100-mL parenteral products. The Japanese criteria are more stringent for those products than the other two pharmacopoeias.

Also, when a drugmaker changes its methods to those specified in the pharmacopoeial texts that the ICH has verified, the company should handle any change in notification, variation or prior approval procedures in accordance with established regional regulatory mechanisms related to compendial changes, the ICH says.

A guidance on the entire process was issued in November 2007, and the FDA published it in the Federal Register the following February. The ICH has published the information on the subvisible particle test as a third annex to that guidance. It sent this annex to the FDA and the European Medicines Agency’s Committee for Medicinal Products for Human Use.

The information on pharmacopoeial texts for use in the ICH regions, designated as Quality Guideline Q4B, can be accessed from the ICH website at www.ich.org/cache/compo/363-272-1.html#Q4B. The deadline for sending comments to the ICH on the third annex is March. — Martin Gidron


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