DID - July 18, 2008 Issue

Vol. 7 No. 140

Senate Appropriations Committee Approves $2 Billion for FDA

The Senate Appropriations Committee unanimously passed an appropriations markup measure Thursday, providing the FDA with a $2.04 billion fiscal 2009 budget.

This amount is $324.6 million more than the agency initially received for fiscal 2008 and about $5.2 million more than the administration requested.

The measure includes $12.4 million for buildings and facilities, $10 million more than the administration requested. The measure will have no number until it is introduced in the full Senate.

“The Food and Drug Administration is a firewall for our citizens. It must not be allowed to fail,” Sen. Herb Kohl (D-Wis.), a member of the appropriations committee, said.

“The increase in the Food and Drug Administration budget means the agency has, for the first time, a budget of more than $2 billion,” Sen. Bob Bennett (R-Utah), another committee member, said. “The FDA is in the front line. It is also in the front line of research.”

No action is scheduled on the House measure for the agency’s 2009 budget, which passed the agriculture subcommittee June 19 (DID, June 20). It includes a total of about $2.1 billion for the FDA, $282 million more than requested by the administration.

Last month, HHS Secretary Mike Leavitt requested a $275 million increase for the FDA’s fiscal 2009 budget, which would enable it to hire 490 new full-time equivalent (FTE) staff.

The increase would enable the FDA to hire 160 FTE staff to ensure safer drugs, devices and biologics, 71 FTEs to modernize the agency’s science and workforce and 259 FTEs for increased food protection, according to the agency (DID, June 13). — Martin Gidron


Daiichi, Ranbaxy Confirm Merger as House Promises Investigations

Japanese drugmaker Daiichi Sankyo has reiterated that its merger agreement with India’s Ranbaxy Laboratories is binding despite allegations of fraud and conspiracy made by the U.S. Justice Department earlier this week.

The assurance comes as the House Committee on Energy and Commerce announced it will investigate whether the FDA knowingly allowed drugs suspected of being fraudulently approved and manufactured in violation of good manufacturing practices to be sold by Ranbaxy in the U.S.

Reps. John Dingell (D-Mich.), the committee’s chairman, and Bart Stupak (D-Mich.), chairman of its Subcommittee on Oversight and Investigations, promised the investigation after learning of information in a Justice motion filed July 3 in the U.S. District Court for the District of Maryland to subpoena certain Ranbaxy documents.

Justice, through the U.S. State Attorney’s Office for the District of Maryland and the Civil Division, Office of Consumer Litigation, maintains the company submitted false information about stability and bioequivalence to support ANDAs and for anti-retrovirals distributed by the President’s Emergency Plan for AIDS Relief, a five-year, $15 billion program aimed at combating HIV and other diseases in 114 countries.

The government is investigating whether Ranbaxy used active pharmaceutical ingredients (APIs) from unapproved sources, blended approved with unapproved APIs and put less API in drugs than approved by the FDA. It had subpoenaed certain documents, some of which the company had made available but some of which it refused to provide, claiming they were privileged.

In a July 14 response, Ranbaxy said it waived all privileges for the remaining information and it knows of no proof supporting allegations that it had committed fraud or conspiracy (DID, July 15 ).

Stupak is questioning whether the FDA adequately assured the quality of drugs marketed in the U.S. “We learned from investigating contaminated heparin that [preapproval] inspections were dispensed with in the case of the active pharmaceutical ingredient manufactured in China, which resulted in a public health disaster. Now it appears that such inspections in India — the second largest supplier of drugs to the United States — may be another example in which FDA found it inconvenient to assure the safety and effectiveness of drugs before approving them,” he said.

The representatives’ announcement and a copy of the subpoena motion can be viewed at energycommerce.house.gov/Press_110/110nr318.shtml . — Elizabeth Jones


Merck Set to Fund Vioxx Claims in August

Merck is planning to make its first installment payment of $500 million to the Vioxx product liability settlement fund Aug. 6 — two days after it waives its right to back out of the settlement agreement.

The company will make additional payments to the $4.85 billion fund as needed to pay claims. The company announced the Vioxx (rofecoxib) settlement last year (DID, Nov. 12, 2007).

More than 48,500 of about 50,000 people with eligible injuries have enrolled in the program, and most have submitted releases or other materials for verification, the company said.

Verification and corrections to documentation of these claims will continue, and the company expects at least 85 percent of plaintiffs with eligible myocardial infarction, ischemic stroke or death claims to be enrolled, which will exceed the minimum enrollment requirements set as a condition of the settlement, it said.

Merck has extended the deadline again for potential claimants to enroll. Individuals with lawsuits or tolling agreements pending as of Nov. 9, 2007, now have until Oct. 30 to enroll.

The deadline had been extended to June 30 to “allow claimants and their counsel additional time to complete the enrollment process and for the claims administrator and the company to continue to verify the completeness and compliance of enrollment materials received so far,” the company said.

Merck recently scored a victory in Vioxx litigation in New Jersey. The state’s Supreme Court ruled that people who took the drug without suffering any physical injury cannot force the company to pay for medical monitoring to ensure they never come down with any side effects (DID, June 5). — Christopher Hollis


Tekturna Remains Focus of Novartis’ Hypertension Portfolio

Novartis reported strong results for its blood pressure franchise Thursday, and the company plans an aggressive filing strategy for its first-in-class renin inhibitor Tekturna as it prepares to lose exclusivity for its blockbuster hypertension drug Diovan in 2012.

During the first half of this year, sales of the firm’s blood pressure medications increased 20 percent to $3.1 billion compared with the first six months of 2007. The growth excluded the effects of currency exchange rates.

Despite disappointing sales for Tekturna (aliskiren hemifumarate), which came in at $58 million during the first half of 2008, sales of Diovan (valsartan) increased 12 percent to $2.9 billion. Exforge (valsartan/amlodipine besylate), which is a combination of generic Norvasc (amlodipine besylate)and Diovan, had sales of $173 million.

The FDA approved Tekturna last year as a first-in-class renin inhibitor for the treatment of hypertension either on its own or in combination with other blood pressure medications (DID, March 7, 2007).

Diovan — approved for the treatment of heart failure, hypertension and post-myocardial infarction — is an angiotensin II receptor blocker. It acts on a different part of the renin-angiotensin system than Tekturna does.

Tekturna Filing Strategy

“Renin inhibition is going to be a major therapy for cardiovascular disease going forward,” Joseph Jimenez, CEO of Novartis’ pharmaceuticals division, said during the firm’s second-quarter earnings call.

The company recently said it intends to purchase a majority stake in Speedel, which licensed Tekturna to Novartis in 2002, showing the firm’s commitment to the drug, Jimenez said.

The company has an extensive postmarket clinical trial program for the drug. The ASPIRE HIGHER program is being expanded to 35,000 patients in 14 clinical trials, making it the largest cardio-renal outcomes program ever, Novartis said.

Although the company did not disclose specifics about filing plans for Tekturna, it is planning multiple combinations of the drug with other blood pressure treatments, including Diovan.

“We have several fixed-dose combinations under development — some are doubles, some are triples. We’re targeting one launch per year for the next few years,” Jimenez said. “You can assume that we’re going to have a pretty aggressive launch program.” 

The company launched Tekturna HCT (aliskiren hemifumarate/hydrochlorothiazide) during the first half of 2008, and Jimenez said the next filing would occur this year. The exact combination was not disclosed, but Jimenez confirmed that a combination with Diovan is planned.

Oncology Franchise

Novartis also reported strong results for its cancer drugs, sales of which increased 14 percent to $4 billion during the first half of 2008 as compared with a year ago.

Gleevec (imatinib mesylate), which is approved for multiple cancer indications, had sales of $1.8 billion for the first half of the year. Femara (letrozole), a treatment for hormone-sensitive breast cancer, had sales of $561 million. Zometa (zoledronic acid), an IV bisphosphonate used to treat patients with cancer that has spread to their bones, had sales of $677 million.

Novartis plans to file global applications seeking approval for Afinitor (everolimus) for the treatment of advanced metastatic renal cell cancer this year. The filings will be based on the RECORD-1 trial, which was halted early because of positive results, it said.

The company expects Afinitor to be approved next year. The drug, which is a mammalian target of rapamycin (mTOR) inhibitor, has the same active ingredient as Novartis’ Certican (everolimus), which was approved in Europe for organ rejection related to kidney and cardiac transplants. — Christopher Hollis


GSK Sued for Anti-Competitive Conduct

A welfare benefit plan has sued GlaxoSmithKline (GSK), alleging the company abused the citizen petition process to delay the introduction of a generic version of its blockbuster allergy drug Flonase.

The plaintiff, IBEW-NECA Local 505 Health & Welfare Plan, brought the suit in the U.S. District Court for the Eastern District of Pennsylvania accusing GSK of maintaining a monopoly for the drug’s market in the U.S. and overcharging the plan and indirect purchasers by delaying the launch of a generic version.

In October 2002, Roxane filed an ANDA seeking approval for a generic version of Flonase (fluticasone propionate) for which GSK had marketing exclusivity until May 2004.

Days prior to the expiration of exclusivity, GSK filed the first of several citizen petitions to delay generic competition for Flonase, according to court documents. The petition asked the FDA to refrain from approving any fluticasone propionate ANDA until the agency issued a final guidance to determine bioequivalence for nasal spray products. The agency replied that regulations did not require it to issue a final guidance prior to approving an ANDA.

In March 2005, GSK filed a petition for a stay of action for Flonase ANDA approvals, but the agency again denied the company’s request and approved Roxane’s application Feb. 22, 2006, about eight months after GSK filed a second supplement to its citizen petition.

Roxane began selling its generic product in March 2006, roughly 22 months after GSK’s market exclusivity ended, according to court documents.

In its suit, the plaintiff asks the court to find that GSK “used willful and exclusionary means as part of an overall scheme … to improperly maintain its monopoly power in the fluticasone propionate market” through filing useless citizen petitions. It also asks the court to rule that GSK engaged in “unfair, unconscionable, deceptive or fraudulent acts or practices in violation” of state consumer protection statutes.

The company defends its actions, maintaining that it always had urged “prompt completion of a guidance-development process to establish scientifically valid bioequivalence methods for approving generic copies of locally acting nasal sprays and to assure a level product-quality ‘playing field’ that assures generic copies will perform to the same standard as Flonase,” GSK told DID.

“We believe this was recognized when a judge granted GSK a temporary restraining order against a generic manufacturer, saying: ‘GSK has demonstrated some likelihood of success on the merits, that the balance of harms and the public interest clearly weigh in GSK’s favor, and that GSK will suffer immediate and irreparable injury unless the Defendants and the Defendant Intervenor (Roxane) are temporarily restrained as set forth in the order,’” the company added.

Flonase is an intranasal coricosteroid used to treat the nasal symptoms of indoor and outdoor allergies and year-round nonallergic nasal symptoms. Worldwide sales of Flonase were roughly $92 million in the first quarter of the year, according to GSK. — Elizabeth Jones


FDA Tells Wyeth to Stop Using BeneFIX Card

The FDA has told Wyeth Pharmaceuticals to stop using a BeneFIX flashcard suggesting, without sufficient evidence, that its hemophilia B drug is safer than CSL Behring’s Mononine.

A table on the front of the card compares BeneFIX (coagulation factor IX [recombinant]), Original BeneFIX and Mononine (coagulation factor IX [human]), implying both recombinant products are safer than the plasma-derived one, according to the agency’s June 30 letter to Wyeth, posted Thursday on the FDA’s website. All three drugs are approved to control or prevent hemorrhages in patients with hemophilia B.

The table’s claim of safety superiority — “Low diluent with recombinant safety” — is emphasized by statements on the back of the card, giving the impression the product has no viral risk compared with Mononine, which the card implies is virally unsafe, the letter says. But plasma-derived products are virally safe when made properly, and recombinant products may have viruses from using animal sources, according to the letter.

None of the six points made on the card supports the safety claims, including three that refer to the drugs’ prescribing information, the letter says. Such claims must be supported by “substantial evidence or substantial clinical experience,” the letter adds.

“The pharmacokinetic study using Original BeneFIX and Mononine, referred to in the prescribing information for BeneFIX, does not constitute substantial evidence or substantial clinical experience to support the superiority safety claim for BeneFIX because this study, like most clinical pharmacology studies, was not designed to statistically evaluate the safety profile of a drug or the comparative safety profiles of multiple drugs,” the letter says.

The agency told Wyeth to immediately cease using the card or similarly violative promotional materials for the drug and to inform the agency within 10 days of its plan to stop using them.

Wyeth did not respond to a request for comment by press time. The FDA’s letter can be viewed at www.fda.gov/cber/adpromo/benwye063008.htm — David Grant


Cardiologist Cited for Informed Consent Failures

A cardiologist conducting a clinical trial failed to get informed consent, enrolled the same patient twice and did not maintain acceptable case histories and drug disposition records, an FDA warning letter says.

Edward Mostel of Palm Beach Gardens Medical Center in Florida started two patients in the trial before they signed informed consent forms, according to the warning letter, which was sent May 16 and posted to the FDA website this month.

Mostel replied that the forms may have been misdated, but the agency rejects his assertion as unprovable and added that a third patient’s consent form was not signed or dated by him or any subinvestigator.

Mostel acknowledged that a patient had been enrolled in the study twice but blamed the mistake on a subinvestigator, the warning letter says. The agency also notes that Mostel was responsible for overseeing the study as its clinical investigator.

During its investigation, conducted Oct. 17–31, 2007, the FDA found that drug accountability records were missing for nine subjects between Oct. 13 and Dec. 5, 2005, according to the letter. Mostel responded that hospital records confirmed the subjects received the study drug according to protocol, but the agency’s letter says he provided no evidence to support that assertion.

Mostel did not maintain adequate and accurate case histories, the warning letter says, citing as examples the investigation’s findings that:

  • Source records failed to document the calculated serum creatinine clearance value for 50 subjects whose records were audited, in violation of the protocol. Mostel said this value was calculated but not documented, which the FDA called unacceptable;
  • Enrollment sheets for eight subjects failed to document whether they had met all inclusion criteria; and
  • Mostel did not sign and date completed electronic case report forms submitted to the sponsor for 12 subjects.

Mostel did not respond to a request for comment by press time. The warning letter can be viewed at www.fda.gov/foi/warning_letters/s6838c.htm. — Martin Gidron

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