DID - March 13, 2009 Issue

Vol. 8 No. 50

Waxman’s Biogenerics Bill Limits Patent Infringement Damages

Brand manufacturers would only be entitled to a “reasonable” royalty when a biogeneric or biosimilar company’s product is found to have infringed on a company’s patents, according to a provision in Rep. Henry Waxman’s (D-Calif.) biogenerics bill.

House Energy and Commerce Committee Chairman Waxman and three other representatives introduced the bill this week (DID, March 12). H.R. 1427 has been referred to the Energy and Commerce and Judiciary committees. Sen. Charles Schumer (D-N.Y.) is taking the lead on companion legislation, which could be introduced as soon as March 17, according to a congressional staffer.

Under House legislation, brand companies would be required to respond to requests from generic companies for information on patents covering their biologic products. If the brand company doesn’t disclose the patent information to the generic company by the statutory deadline, an infringement action could not be initiated.

User fees for generic biologics and biosimilars would be established under the legislation, giving the FDA funding to review abbreviated biological product applications (ABPAs). FDA action on ABPAs would have to occur within 10 months of the application’s submission. Determinations of interchangeability with the brand product could be granted with the initial approval of the generic, or subsequent approval of a supplement.
When prioritizing ABPAs for review, the FDA must take into account the number of years before an innovator product’s exclusivity expires, the bill says. The longest period of exclusivity a non-orphan brand product could receive would be six years, including pediatric exclusivity. The exclusivity provisions for brands are:

  • Seven years of marketing exclusivity for orphan biologic products;
  • Five years of marketing exclusivity for new biologics that contain “major substances,” or very similar major substances, and that represent a major therapeutic advance. The provision would apply to biologics approved after the bill is enacted;
  • Three years of exclusivity for modifications to biologics that contain a major approved substance but only if the modification were approved after the bill was enacted;
  • Six months of additional exclusivity upon approval of applications that contain new clinical data — other than pharmacokinetic or pharmacodynamic data — or applications for a “significant new indication” or new patient subpopulation, excluding pediatrics; and
  • Six months of pediatric exclusivity.

The six extra months of exclusivity received for approval of supplements containing additional clinical data or significant new indications could be reduced by three months if the product had sales exceeding $1 billion. Only one six-month extension for an efficacy supplement or new indication may be obtained for each product, according to the bill.

There are eligibility criteria for biologics to receive five years of marketing exclusivity for new products. Products with proteins that differ in structure solely due to post-translational events, “infidelity of translation or transcription,” or minor difference in amino acid sequence would not be eligible for the five-year exclusivity, the bill says.

In addition, under certain circumstances, the five years of exclusivity will not apply to polysaccharide and polynucleotide biological products, glycosylated proteins and closely related, complex, partly definable biologics. By regulation, the FDA could also identify other biologic products that would not be eligible for five years of marketing exclusivity. 

The specific language in the bill on the exclusion criteria for five-year exclusivity comes from the FDA’s orphan drug regulations used to determine if a product is the same chemical as the protected orphan drug, according to Sandi Dennis, deputy general counsel of healthcare and regulatory affairs for the Biotechnology Industry Organization (BIO).

The language is very narrow and usually not found in legislation, Dennis told DID. She also noted that the three-year exclusivity for modified biologics is for products that represent a “significant therapeutic advance,” which also is not well defined and might lead sponsors to develop medicines that would not have exclusivity protection. Language in the bill regarding “major substances” also is not defined, she noted.

Permanent Injunctions, Citizen Petitions

There would be no 30-month stay of FDA approval once an innovator initiates patent litigation against a generic company under the legislation, allowing for an at-risk launch upon approval of an ABPA. 

Only a permanent injunction could stop the FDA from taking action on an ABPA when the innovator company has prevailed on the merits of its case filed against the agency, and when the company would suffer imminent and actual irreparable injury, threatening the “imminent destruction” of the brand company’s business.

Further, the interests of the brand company must overwhelmingly outweigh the public interest in obtaining prompt access to the biosimilar product, according to the bill.

The FDA could not delay approval of an ABPA based upon a citizen petition unless it determines that it is in the interest of public health. The FDA also must publish the reasons for such a delay on its website.

Final action on the citizen petition must occur within 180 days of its submission, and the FDA cannot delay that deadline in any circumstance, even on the basis of another petition, the bill states. If the 180-day period expires with no action, the petition is denied.

Each citizen petition must be accompanied by a statement that certifies that the petition is: truthful, contains all the information upon which it relies, and includes data known by the petitioner to be unfavorable to the petition. The statement also would certify that the petitioner took reasonable steps to find such unfavorable information and that disclosures of payments sent to the petitioner for filing the petition, the bill says.

In addition, if the FDA determines that the petition was submitted for the sole purpose of delaying agency action on the ABPA, the petition would be denied.

Competing follow-on biologics legislation is expected to be introduced in the House next week, a Republican spokeswoman for the Energy and Commerce panel confirmed. Rep. Anna Eshoo (D-Calif.) is taking the lead on the competing bill. The Waxman bill is available at energycommerce.house.gov/Press_111/20090311/hr1427.pdf: — Christopher Hollis


Pipeline Benefits Seen in Roche-Genentech Merger

Roche’s $46.8 billion acquisition of Genentech “will bear fruit in the next 10 to 20 years,” Roche Chairman Franz Humer says.

Genentech’s Avastin (bevacizumab), a treatment for metastatic colorectal and advanced lung cancer, its breast cancer drug Herceptin (trastuzumab) and Roche’s oral chemotherapy drug Xeloda (capecitabine) started as research projects 20 years ago, Humer says in a videotaped statement.

“Our investment to new technologies like RNAi, the way we are allowing diversity of approaches in research — that will create new products,” Humer says. “The merger will speed up our development programs; therefore it will allow us to approach clinical trials in an even more coordinated way on a global scale.”

Genentech’s pipeline faces potential problems. For example, about 60 percent of the value of Avastin is tied to a successful launch for breast cancer, which is expected to start generating revenue in 2012, according to an analysis by Greenhill, an investment banking company. The National Surgical Adjuvant Breast and Bowel Project (NSABP) is testing Avastin to treat colon cancer patients who have undergone surgery.

Roche believes that the NSABP trial may not be sufficient to obtain regulatory approval for Avastin in the colon cancer indication, and more data may be required, the Greenhill report adds. Other potential problems Greenhill pinpointed were: competition for Herceptin and the effect on sales of Genentech’s psoriasis drug Raptiva (efalizumab) after patients who took the drug died from the rare brain infection progressive multifocal leukoencephalopathy (DID, Feb. 20).

Roche has agreed to buy the 44 percent stake in Genentech that it did not already own for $95 a share, or $46.8 billion, which will make Genentech a wholly owned subsidiary of the Swiss pharmaceutical giant.

The combined company will be the seventh largest U.S. pharmaceuticals company in terms of market share, generating about $17 billion in annual revenues, according to a joint statement by Roche and Genentech. Drug research and early development will be conducted in South San Francisco, Calif., as will all U.S. commercial pharmaceutical operations, which will carry the Genentech brand name.

Roche said it expects the combination to generate annual pretax cost savings of $750 million to $850 million. The expiration date for the offer is March 25. — Martin Gidron


Sutent’s Significant Benefit May Lead Pfizer to Stop Late-Stage Trial

Pfizer’s Sutent showed a significant increase in progression-free survival for patients with pancreatic islet cell tumors, leading an independent data monitoring committee to recommend that a Phase III trial be halted to allow all patients to receive the drug.

The full data set from the clinical trial of Sutent (sunitinib malate) is being analyzed and more details will be presented at an upcoming scientific meeting, Pfizer says in a statement Thursday.

The pancreatic tumor study is the second Phase III Sutent trial Pfizer has stopped early because of positive results. In January 2005, a trial in gastrointestinal stromal tumor patients was unblinded early when a planned interim analysis showed a significantly longer time to tumor progression with Sutent compared with placebo.

Pfizer also is studying Sutent for the treatment of advanced breast, nonsmall cell lung,  colorectal, hepatocellular carcinoma and hormone-refractory prostate cancers in Phase III trials.

Last month, the UK’s National Institute for Health and Clinical Excellence (NICE) recommended Sutent as a first-line treatment for certain renal cancer patients, reversing an earlier decision on the drug.

In August 2008, NICE had determined that four products were not cost-effective for treating advanced or metastatic renal cell carcinoma: Sutent, Wyeth’s Torisel (temsirolimus), Genentech and Roche’s Avastin (bevacizumab) and Onyx Pharmaceuticals and Bayer HealthCare’s Nexavar (sorafenib tosylate) (DID, Feb. 6).

In the U.S., Sutent is approved to treat advanced renal cell carcinoma and second-line gastrointestinal stromal tumors. The product had global sales of about $847 million last year, according to Pfizer. — Elizabeth Jones


Matrix’s HIV Treatment Receives Tentative FDA Approval

India-based Matrix Laboratories has received tentative approval to market lopinavir/ritonavir tablets, a generic version of Abbott Laboratories’ HIV treatment Kaletra.

Matrix’s ANDA for lopinavir/ritonavir tablets (200 mg/50 mg) is the only one approved under the President’s Emergency Plan for AIDS Relief (PEPFAR), Mylan, which holds a 71.5 percent controlling interest in Matrix, says in a statement

“Matrix’s version of this product is heat-stable and affordable, making it practical for distribution and use in warm climates,” Mylan says in a statement. Vice Chairman and CEO Robert Coury says the goal is to provide HIV treatments worldwide.

Kaletra, which is known as Aluvia in developing countries, is used in combination with other medications to control HIV infection and is included in the class of antiretroviral drugs known as HIV protease inhibitors. The FDA approval for Matrix’s generic version follows last month’s clearance by the World Health Organization.

A WHO approval indicates that a drug meets international safety, efficacy and manufacturing quality standards and allows Matrix to sell the treatment in most countries outside the U.S. and Europe.

An HHS panel recommended last November that once-daily lopinavir, boosted by ritonavir be added to the list of preferred protease-inhibitor components, in revised guidelines on the use of antiretrovirals in HIV-1 infected patients (DID, Nov. 6, 2008). — Martin Gidron


Postmarket Reporting to Cost Companies More Than 7 Million Hours

Drugmakers, packers and distributors will spend approximately $47,000 and 7.8 million hours annually complying with new FDA regulations on reporting postmarket drug adverse events.

The most time-intensive requirement for applicants under the new provisions will be maintaining records of all adverse drug experience reports known to the applicant for 10 years, according to an FDA notice published in the Federal Register Friday. About 642 drugmakers, packers and distributors will spend about 6.4 million hours maintaining about 400,000 records annually, the agency says.

Providing periodic reports of adverse drug events also will take drugmakers, packers and distributors about 689,000 hours annually. Companies are required to report: serious, expected adverse events, and incidents that are not considered serious, an index of those reports, a narrative summary and analysis of adverse drug events and a history of actions taken because of adverse drug experiences.

FDA received no public comment during a 60-day period that ended Feb. 17.

A copy of the notice can be found at http://www.federalregister.gov/OFRUpload/OFRData/2009-05494_PI.pdf. — David Belian


Judge Rules for Dr. Reddy’s in AstraZeneca’s Prilosec Suit

A  federal judge dismissed AstraZeneca’s patent lawsuit alleging Dr. Reddy’s Laboratories infringed on its patents covering the nonprescription heartburn drug Prilosec.

AstraZeneca’s complaint alleges Dr. Reddy’s infringed on the ’424  and  ’960  patents covering Prilosec (omeprazole magnesium), which is distributed by Proctor & Gamble under a licensing agreement.

Dr. Reddy’s maintained it did not infringe on the patents because its proposed product doesn’t contain omeprazole sodium that is at least 70 percent crystalline in structure. Claims of both patents in the suit require that the active ingredient exhibit at least 70 percent crystalline structure. Furthermore, the product is not made using an environmentally friendly water-based process, a key aspect of AstraZeneca’s ’424 patent, according to court documents.

AstraZeneca tested a sample of Dr. Reddy’s product in November 2007 and found the company did not infringe the patents in suit. However, the plaintiff “insisted that it needed substantial additional discovery before it could decide whether to continue with the lawsuit,” according to court documents.

Judge Colleen McMahon expressed skepticism about the AstraZeneca case but didn’t cut off the discovery phase, according to court documents.

AstraZeneca asked Dr. Reddy’s to produce a witness to testify about the manufacturing process for the infringing product. AstraZeneca said the witness wasn’t prepared but didn’t ask the court to compel compliance. Instead, it continued arguments in Dr. Reddy’s move for summary judgment, which was filed last July. The decision last Tuesday grants Dr. Reddy’s motion.

AstraZenecaAB, et al. v Dr. Reddy’s Laboratories, Ltd. was filed in the U.S. District Court for the Southern District of New York. — Elizabeth Jones



The March 12 article “Rep. Waxman Introduces Biogenerics Legislation” that said, “The bill … gives innovators three years of additional exclusivity for new indications, similar to provisions in the Hatch-Waxman Act for small-molecule drugs” should have said, “The bill … gives innovators as much as a year of additional exclusivity for new indications and when pediatric studies are conducted.”

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