DID - Nov. 3, 2009 Issue

Vol. 8 No. 214

FDA Seeks Comments on Genotoxicity Guidance Changes

Two parts of an International Conference on Harmonisation (ICH) 2008 draft guidance on genotoxicity testing standards need revision, the FDA proposes.

The agency is requesting comment on proposed revisions to the guidance and plans a meeting to solicit input from experts Jan. 25, according to a notice to be published in the Nov. 3 Federal Register. Comments on the proposed changes are due by Feb. 24.

The ICH draft guidance, called ICH S2 (R1), is geared toward helping drugmakers establish the best standard genetic toxicology battery to predict a drug’s potential risk to humans and giving researchers ways to interpret the data, the FDA says in a March 26, 2008, Federal Register notice. However, two parts of the guidance, ICH S2A and ICH S2B, were completed almost 15 years ago.

The meeting will address what constitutes an adequate genetic toxicology battery and whether a two-option system would provide comparable or superior patient protection to the current single-option test battery. One option is similar to the current ICH and CDER test battery, the notice says. The second option removes an in vitro mammalian cell test from the test battery and instead includes two in vivo endpoints that can be assessed in a single assay (DID, March 25, 2008).

The meeting also will focus on which tests are reasonable follow-ups to a positive in vitro cytogenetic assay or mouse lymphoma assay and whether an in vivo comet assay is a reasonable follow-up test.

In addition, the experts at the meeting will discuss a proposal in the guidance to lower the concentration at which drug substances should be tested in vitro if no toxicity is seen at lower concentrations. Current ICH safety guidances specify 10 millimolars and the proposal would lower that concentration to 1 millimolar. The workshop will address the scientific basis for lowering the concentration and the potential effect on patient safety.

The notice is available at www.fdanews.com/ext/files/2009-26397_PI.pdf. The 2008 draft guidance, “S2 (R1) Genotoxicity Testing and Data Interpretation for Pharmaceuticals Intended for Human Use,” is available at www.fdanews.com/ext/files/08-1076.pdf. — April Hollis


Byetta Gets Expanded Indication, New Labeling Warnings

Amylin Pharmaceuticals and Eli Lilly’s injectable Type 2 diabetes drug Byetta has received FDA approval for use as a standalone treatment, but the label also has been updated with warnings about pancreatitis and possible kidney function impairment.

The agency’s action expands the drug’s indication — Byetta (exenatide) had been approved to treat patients who were also taking other common diabetes medications and had not achieved adequate glycemic control. As a monotherapy, Byetta still must be combined with diet and exercise to improve glycemic control in adults with Type 2 diabetes, Amylin and Lilly say in a statement Monday.

Lilly and Amylin are preparing a “dear healthcare provider” letter about the pancreatitis risk. In August 2008, the FDA asked the companies to develop stronger warnings for Byetta after six cases of pancreatitis, including two deaths, were reported in patients taking the drug (DID, Aug. 19, 2008).

Language currently on the drug’s website asks patients to tell their healthcare providers if they have had pancreatitis, gallstones, a history of alcoholism or high blood triglyceride levels, and to call their healthcare providers right away if they have pain in their abdomen that is severe and persistent.

Also Monday, the FDA says it has received 78 reports from April 2005 through October 2008 of problems with kidney function — some from patients with pre-existing kidney disease or those with one or more risk factors for developing kidney problems who were taking Byetta, according to an agency statement.

“Healthcare professionals and patients taking Byetta should pay close attention to any signs or symptoms of kidney problems,” Amy Egan of CDER’s Division of Metabolism and Endocrinology Products says in the statement. Signs of impaired renal function may include fatigue, changes in appetite, changes in urine color, amount or frequency of urination, and unexplained swelling of the hands or feet.

The new label also expands on existing language regarding use of Byetta in patients with renal impairment — the website states that the drug should not be used in people who have severe kidney problems and should be used with caution in people who have had a kidney transplant.

In the third quarter, Lilly had $115.8 million in revenue from Byetta.

“While we don't provide specific revenue forecasts, the monotherapy indication is important,” Lilly spokeswoman Kindra Strupp told DID. “This provides an opportunity to use Byetta to treat patients with Type 2 diabetes earlier in the disease.” — Martin Berman-Gorvine


FDA Requests More Study Data on Toremifene

GTx has received a complete response letter on its toremifene NDA requesting additional trial data on the drug’s safety and efficacy.

Toremifene 80 mg is under review to reduce fractures in men with prostate cancer receiving androgen-deprivation therapy, GTx says in a statement Monday.

The FDA cited clinical deficiencies in the NDA and requested results of a second adequate and well-controlled Phase III trial demonstrating the safety and efficacy of toremifene citrate 80 mg, and data from an adequate, well-controlled clinical trial showing toremifene does not have a detrimental effect on time to disease progression or overall survival.

GTx has not yet learned why the FDA considers the original Phase III safety and efficacy trial insufficient, company spokesman McDavid Stilwell told DID Monday. He added that the company hopes data from the original trials can be used to satisfy the FDA’s second request.

The company remains committed to the toremifene development program and has requested a meeting with the FDA to discuss the next steps, Stilwell said. — April Hollis


Mylan Files Second Suit Against Pittsburgh Post-Gazette

Generic-drug maker Mylan has filed suit against the Pittsburgh Post-Gazette, two staff writers and unnamed third parties claiming defamation related to a series of articles on the company’s Morgantown, W.Va., plant.

The company says a July 26 story headline accused Mylan workers of overriding drug quality controls. The article contained “sensationalism, exaggeration and outright falsehood,” according to the Mylan complaint filed in Monongalia County, W.Va., Circuit Court.

The complaint in the defamation case alleges that the newspaper articles were intended “to instill apprehension in the minds of patients, shareholders and the general public ... that Mylan’s pharmaceuticals were unsafe.”

In a related case, the company alleged that the newspaper and its staff writers improperly obtained confidential corporate records and misconstrued them to paint an unfairly negative picture of Mylan’s practices. The drugmaker filed the case in the same court but it was transferred to U.S. District Court for the Northern District of West Virginia.

In both complaints, the company’s lawyers cited an FDA investigation following the newspaper articles that found no data deletion (DID, Aug. 14). Both lawsuits seek unspecified damages for Mylan.

The newspaper articles allege data deletion by Mylan workers and failure to heed alerts about deviation from specifications, Mylan says (DID, July 31). Mylan appears to have conducted an adequate investigation, FDA spokeswoman Crystal Rice told DID in August, adding that the agency’s investigation is closed and the agency plans no additional action.

“Mylan’s most recent attack on the Post-Gazette is, like Mylan’s earlier suit, meritless,” John Robinson Block, publisher and editor-in-chief of the Pittsburgh Post-Gazette, said in a statement emailed to DID. “The Post-Gazette’s coverage of Mylan’s own internal report was meticulously accurate, and we will defend ourselves vigorously.”

The FDA’s establishment inspection report on Mylan’s Morgantown plant is available at www.fdanews.com/ext/files/Mylan-Pharmaceuticals-Redacted.pdf.

The federal court case is Mylan Pharmaceuticals, Inc. et al. v. PG Publishing Company et al. The circuit court case filed Oct. 30 is Mylan Inc. and Mylan Pharmaceuticals Inc. v. PG Publishing Company d./b./a. Pittsburgh Post-Gazette, Patricia Sabatini, Len Boselovic and John and Jane Doe Defendants 1-10. — Martin Berman-Gorvine


GSK, Valeant File US, European Applications for Epilepsy Drug

GlaxoSmithKline (GSK) and Valeant Pharmaceuticals International have filed an NDA for their epilepsy treatment retigabine with the FDA and a marketing authorization application with the European Medicines Agency.

Retigabine is intended as an adjunctive therapy to treat adult epilepsy patients with partial-onset seizures, the companies say in a statement Monday.

Valeant, based in Aliso Viejo, Calif., received an upfront payment of $125 million last year from London-based GSK for collaborating on the development of retigabine (DID, Oct. 20, 2008). The drug works as both a neuronal potassium channel opener and a potentiator of gamma aminobutyric acid.

The regulatory filings took longer than expected, Michael Pearson, Valeant chairman and CEO, said in a conference call with investors Monday. Scientists from Valeant and GSK met with the FDA in August to discuss technical aspects of the NDA submission, Valeant says in a September statement.

In Phase III trials, retigabine reduced epileptic seizure rates compared with a placebo. The most common adverse reactions in all completed trials are dizziness, fatigue, confusion, vertigo, tremor, abnormal coordination, double vision, disturbance in attention, weakness and visual blurring.

In September, the companies began three Phase I studies of modified-release technologies for retigabine. Pearson said the goal is to choose one of them for further development next year. The current regulatory filings, submitted Oct. 30, apply to an immediate-release version of the drug. — Martin Berman-Gorvine


Takeda, Amylin Agree to Cooperate on Obesity Drugs

Takeda Pharmaceutical and Amylin Pharmaceuticals have entered into a development and commercialization agreement for drugs to treat obesity and related indications.

The agreement gives Amylin responsibility for developing products through Phase II clinical trials with the aim of winning regulatory approval in the U.S., the companies say in a statement Monday. Takeda will lead development activities beyond Phase II in the U.S. and all development activities outside the U.S.

Drugs from both companies’ obesity research programs will be included in the agreement, as well as products from Amylin’s pipeline, including its obesity treatment compounds pramlintide-metreleptin and davalintide, which are currently in Phase II development.

Amylin will receive a onetime upfront payment of $75 million from Takeda and will be eligible to receive additional milestone payments that could exceed $1 billion. In most cases, Amylin will be responsible for 20 percent of development costs associated with obtaining approval for products in the U.S. and Takeda will be responsible for 80 percent. Outside the U.S., Takeda will be responsible for all of the development costs associated with obtaining product approvals.

Takeda also will have full responsibility for the commercialization costs associated with the products, but Amylin will have the option to co-commercialize the first two approved products in the U.S. and any follow-on products containing the same active ingredients, the companies say.

The agreement will allow the companies to advance their obesity treatment drugs more quickly together than either company could do alone, Daniel Bradbury, Amylin’s president and CEO, says in the statement. — David Belian


EMEA Updates Postmarketing Advice on MA Transfers

Drugmakers seeking to transfer a European marketing authorization (MA) to a new company have received recommendations from the European Medicines Agency (EMEA) on presenting an application to the agency.

MA holders should submit the name of the medicinal product concerned, the authorization number and the date on which the authorization was granted, the EMEA says in a question-and-answer (Q&A) document posted on its website recently.

The names, addresses and email addresses of the companies making and receiving the transfer should be provided, as well as a document certifying that the complete and up-to-date file concerning the medicinal product, including any data related to its pediatric obligations, has been made available to the company taking on the product.

A document stating the date on which the parties complete the arrangements should be included, as well as proof that the company receiving the transfer is established within the European Economic Area. The EMEA also requires evidence that the receiving company has the capacity to perform all of the responsibilities required of an MA holder, including documents that:

  • Identify the qualified person responsible for pharmacovigilance;
  • Describe the scientific service in charge of information about the medicinal product;
  • Identify the person or company authorized for communication between the receiving company and the EMEA after the transfer has been authorized; and
  • Identify the contact details of the person responsible for quality defects and batch recall.

If the medicinal product involved in the transfer has not yet been marketed in the EU, this should be specified in a signed statement, the EMEA says. A letter signed by the company accepting the product transfer listing any remaining follow-up measures or specific obligations related to the product also should be provided.

Applicants also must provide a signed statement that no other changes have been made to the product information other than to the details of the MA holder, and providing an overview of any organizational activities that will be performed by the company transferring the product during the transition.

The EMEA Q&A on the transfer of an MA can be found at www.emea.europa.eu/htms/human/postguidance/q80.htm. — David Belian

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

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