Drug Industry Daily - Feb. 23, 2011 Issue

Vol. 10 No. 38

DDMAC Praises Drugmakers for Ad Improvements, But Says More Work Needed

FDA officials have seen an improvement in the advertising and promotional materials released by drugmakers in the last year, but are warning that the industry still has significant work to do to meet all of the agency’s standards.

In a speech Tuesday at the DIA Marketing Pharmaceuticals workshop in Washington, D.C., Thomas Abrams, director of the FDA’s Division of Drug Marketing, Advertising and Communications (DDMAC), said the presentation of risk information in advertisements was a particular area of improvement for drugmakers.

“I think the main thing I’m seeing is more effort by companies interacting with DDMAC,” Abrams said. “They are more focused on trying to do it right.”

That sentiment was echoed by Lisa Stockbridge, branch chief of CBER’s Advertising and Promotional Labeling Branch.

“I think we’re seeing more voluntary compliance,” Stockbridge said. “We have pretty open contact with several companies. They call and ask questions ahead of time — it’s better actually.”

But not every company has changed, Abrams said, noting that he has seen a number of firms continue to try to push the boundaries of what the FDA considers acceptable.

“Trying to get to the line before you’re deemed misleading makes no sense to me,” Abrams said.  “If you do it, you can get a warning letter, and that’s not good for anybody.”

Indeed, an untitled letter the agency sent to Novartis earlier this month highlighted that danger, with the company being cited for an advertisement that subtly implied its influenza vaccine Fluvirin was indicated for use in a wider patient population than the FDA had approved (DID, Feb. 15).

The 52 warning and untitled letters issued by DDMAC in 2010 also was an all-time high for the agency, Abrams said, and more than double the amount issued in 2008.

Still, Abrams acknowledged the FDA has work to do to provide drugmakers with more information on how to avoid the agency’s ire.

While he declined to provide a date when the long-awaited guidance on social media would be released, he said industry could expect in the near future a guidance detailing the FDA’s process for reviewing television ads. — David Belian


FDA Comes Down Hard On Sanofi-Aventis for Data Reporting Lapses

Sanofi-Aventis U.S. instructed employees not to report certain postmarketing studies in its NDA annual report, a direct violation of FDA regulations, according to a warning letter recently posted online that outlines a number of data reporting problems.

“FDA regulations require that all IND and NDA clinical trial studies associated with an approved drug be reported in the NDA Annual Reports,” the FDA wrote in the warning letter dated Jan. 28 and posted online Tuesday. Drug studies cited by the FDA include those of the diabetes drug Apidra (insulin glulisine), Eloxatin (oxaliplatin), which is used to treat colon and rectal cancer, and the insomnia drug Ambien (zolpidem tartrate).

FDA also cited the Bridgewater, N.J.-based company for failing to file postmarketing adverse drug events as required. In some cases, Sanofi waited more than two years before filing reports with the FDA. The agency requires companies report such data 15 calendar days after initial receipt.

FDA found 185 15-day reports filed late from Jan. 1, 2009 to March 31, 2010, including the anticoagulant Lovenox (enoxaparin), the allergy medication Allegra D (fexofenadine HCl and pseudoephedrine HCl) and the antiarrhythmic Multaq (dronedarone HCl).

Reports for the diabetes drug glibenclamide were 824 and 810 days late, the agency said. The FDA also cited Sanofi for submitting 127 follow-up adverse event reports late, including Lovenox, which was 597 days past due.

The FDA wrote that Sanofi’s action plan didn’t adequately address procedural deficiencies. “The procedure lacks clear and concise work instructions for employees to promptly investigate and follow-up on reports not containing the minimum criteria for submission to FDA,” the letter states.

The agency also found Sanofi’s “Adverse Event Reporting Form” failed to correctly identify adverse outcomes required to determine the seriousness of an adverse event. Incorrectly identifying outcomes could lead to inaccurate data.

“You should conduct a thorough root-cause analysis of your reporting systems and procedures in order to identify all potential deficiencies which led to the reporting violations and amend your procedures and implement any necessary changes accordingly to ensure that the violations are not repeated,” the FDA wrote.

Furthermore, the FDA found Sanofi failed to report certain foreign postmarketing studies. “We are troubled that your firm did not disclose to FDA, until the 2010 inspection, that it did not report on foreign trial or studies prior to 2008,” the letter states.

Sanofi spokesman Jack Cox failed to elaborate on what the drugmaker had done to address the issues raised by the FDA. Instead, Cox told DID that patient safety is the company’s highest priority.

“We acknowledge the FDA’s observations and accept that we can and must strengthen procedures and systems for reporting,” Cox said. “Sanofi-Aventis is already working to address these observations and will continue to work with the FDA to ensure compliance with all reporting requirements.”

Sanofi is not the only drugmaker to get a sternly worded letter from the FDA over adverse event reporting. Last year, the agency issued Pfizer a warning letter for failing to promptly notify the agency of severe adverse events, and noted its lateness in reporting such events has been getting worse (DID, June 11, 2010).

A copy of the letter can be read at www.fdanews.com/ext/files/UCM243585.pdf. — David Pittman


Drugmakers Encourage FDA to Expand Codevelopment Guidance

Drugmakers have asked the FDA to broaden the scope of its draft guidance on codevelopment to allow use of drug combinations under a wider set of circumstances.

The responses come in comments on a December draft guidance on codevelopment of two or more investigational drugs. The deadline for comments was Feb. 14.

The guidance, which focuses on novel drugs, describes four criteria for deciding when combination treatments should be developed (DID, Dec. 15, 2010).

One criterion in particular, that the combination demonstrates “greater than additive activity,” compared with each drug used individually was questioned in many comments. Trade groups PhRMA and the Biotechnology Industry Organization (BIO) both suggest the requirement’s phrasing is unclear, with BIO adding that the requirement “seems unnecessary” and would likely cause confusion.

Another criterion, that the combination must be for the treatment of a serious disease or condition, has drawn protest. AstraZeneca points out that while “serious disease” is a broad term, it’s still unnecessarily limiting. “Surely any disease where there is a scientific rationale for combination development could meet the criteria for this guidance,” the company writes.

Many commenters suggest the phrasing of the remaining two criteria — “a compelling biological rationale for the use of combination” and “a compelling reason for why the agents cannot be developed individually” — is overly broad or confusing and needs clarification.

Industry stakeholders also take issue with the exclusive focus on unmarketed drugs. Pfizer and BIO both request clarification as to whether approved drugs would be considered novel if they were codeveloped for a new indication.

Pfizer also expresses concern about trial requirements, saying the “codevelopment study designs … will require considerable patient populations as well as multiple studies.” The company further adds that the Phase III trial parameters could lead to complex three- and four-arm trials.

The guidance, “Codevelopment of Two or More Unmarketed Investigational Drugs for Use in Combination,” is available at www.fdanews.com/ext/files/UCM236669.pdf. — Wilson Peden


Regeneron Submits BLA for VEGF Trap-Eye to Treat Wet AMD

Regeneron Pharmaceuticals has submitted a BLA to the FDA for VEGF Trap-Eye to treat the neovascular form of age-related macular degeneration (wet AMD), but competition may diminish the drug’s commercial success.

Regeneron also said Tuesday it had requested priority review.

The BLA is supported by data from two Phase III trials, VIEW 1 and VIEW 2, in which VEGF Trap-Eye (aflibercept ophthalmic solution) met primary endpoints of noninferiority compared to Genentech’s Lucentis (ranibizumab), the standard of care. Additionally, there was a relatively consistent and favorable safety profile reported in patients who received VEGF Trap-Eye and those receiving ranibizumab (DID, Nov. 23, 2010).

VEGF Trap-Eye may appeal to patients since it is dosed every two months, following three loading doses, compared to Lucentis, which is given monthly, according to Regeneron CEO Leonard Schleifer.

Analysts appear optimistic on the biologic’s chances for success before the FDA. “Today’s announced BLA filing for VEGF Trap-Eye in wet AMD comes about a month earlier than expected,” Baird analyst Christopher Raymond said in a note Tuesday. “With little in the way of major safety signals, we expect approval of this agent.”

Raymond also foresees the FDA granting priority review, which would give the candidate a late August user-fee action goal date and a possible late third quarter launch.

While Raymond expects VEGF Trap-Eye revenues to reach $426 million by 2014, he has concerns about the treatment’s commercial standing, based on physician cost sensitivity and results from the National Institutes of Health CATT study, which are expected in the first half of this year. The CATT study is a multicenter clinical trial comparing the relative safety and effectiveness of Genentech’s Lucentis (ranibizumab) and Avastin, which is closely related to Lucentis, but is considerably cheaper and used-off label for wet AMD.

Raymond warned, “we fear interchangeability between [Roche’s Avastin (bevacizumab)] and more expensive anti-VEGF therapies will become increasingly apparent,” thus, “VEGF Trap-Eye will be launching into a very price-sensitive market.”

Regeneron collaborated with Bayer HealthCare to develop VEGF Trap-Eye, which is also in development to treat central retinal vein occlusion, diabetic macular edema, myopic choroidal neovascularization, and other eye diseases and disorders. Bayer plans to submit a marketing authorization application for the wet AMD indication in Europe in the first half of the year. — Molly Cohen


Pharming, Santarus Begin Phase III Rhucin Trial, Anticipate FDA Action

Dutch drugmaker Pharming and its U.S. partner Santarus have begun a Phase IIIb study of Pharming’s investigational angioedema drug Rhucin in an attempt to stay one step ahead of FDA reviewers.

The companies previously conducted two randomized, placebo-controlled studies demonstrating the safety and efficacy of Rhucin (recombinant human C1 inhibitor), a treatment for acute attacks of angioedema in patients with hereditary angioedema, in dosage strengths of 50 U/kg and 100 U/kg.

The placebo-controlled, randomized study will enroll approximately 50 patients, Pharming and Santarus say, and should be completed in 12 to 18 months. The companies also expect a number of follow-on indications for the drug.

The primary reason for the new study is to gain more experience with patients at the lower dosing strength in anticipation of questions from the FDA, Debra Crawford, Santarus’ chief financial officer, told DID.

“We’re trying to be proactive,” she said, adding that Pharming filed a BLA in December.

Waiting for the FDA to return with questions can add months to the application process, Crawford said. By initiating the study now, the companies will be prepared in the event that the FDA requests more information about the lower dosage.

Crawford could not comment on the anticipated cost of the trial, as Pharming is responsible for all trial expenses. Santarus, which holds rights to commercialize the drug in the U.S., did not comment on the likelihood of recouping the cost in a faster approval for Rhucin. — Wilson Peden

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Reporters: David Belian, April Hollis, Virgil Dickson, Wilson Peden, Molly Cohen, David Pittman

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