DID - March 11, 2009 Issue

Vol. 8 No. 48

Competing FOB Legislation May Be Introduced This Week

Reps. Henry Waxman (D-Calif.) and Anna Eshoo (D-Calif.) may introduce competing follow-on biologic (FOB) bills in the House this week.

Waxman’s legislation could move through the House Energy and Commerce Committee because he chairs it, Ann Witt, Waxman’s health counsel, said Tuesday on a panel at the Center for Business Intelligence conference. Waxman introduced FOB legislation in 2007 — the Access to Life-Saving Medicine Act, H.R. 1038 — that never reached the House floor. His new bill includes data exclusivity provisions, according to Witt.

Eshoo also has plans to introduce a bill this week, as she did a year ago when she and House Energy and Commerce Committee ranking member Joe Barton (R-Texas) introduced the Pathway for Biosimilars Act, H.R. 5629.

Both bills in the previous Congress permitted the FDA to approve a biosimilar product as interchangeable with the reference product. Furthermore, the first interchangeable version of a biologic product approved would receive a two-year period of marketing exclusivity (DID, March 17, 2008).

The Eshoo-Barton bill included 12 years of exclusivity for innovators as did a 2007 Senate compromise bill — the Biologics Price Competition and Innovation Act, S. 1695. It had the support of Sens. Hillary Clinton (D-N.Y.) and Edward Kennedy (D-Mass.) and was referred to the Senate Health, Education, Labor, and Pensions (HELP) Committee, where it died (DID, June 28, 2007).

The 2008 Eshoo-Barton bill was referred to the Subcommittee on Courts, the Internet, and Intellectual Property, but it never passed out of committee.

Hurdles to Senate Passage

It may not be as easy this year compared with last year for the Senate to pass FOB legislation, according to the conference panel’s moderator, Steve Grossman, president of the HPS Group, a health policy and regulatory consulting firm in Silver Spring, Md.

Clinton, who championed S. 1695 when she was a member of the HELP committee, has become secretary of state, so a consensus might be more difficult, Witt said.

Furthermore, the composition of the committee has changed, and new leaders have come to the forefront, including Sen. Sherrod Brown (D-Ohio). When S. 1695 was being debated in the committee, Brown drafted an amendment that would have shortened the exclusivity period to seven years. But Sens. Clinton, Michael Enzi (R-Wyo.) and Orrin Hatch (R-Utah) were unwilling to budge from 12 years. Brown withdrew the amendment without a vote.

President Barack Obama might boost the chance that Congress will approve some form of FOB legislation, Witt said. Obama’s recently proposed fiscal 2010 budget called for the development of FOBs (DID, Feb. 27). — Elizabeth Jones


Canada to Issue Completed Biosimilar Draft Guidance

Canadian health regulators plan to issue a new draft guidance this month creating a pathway for approval of biosimilars even though no procedures have been established to help manufacturers follow the recommendations, according to an industry expert.

Health Canada began work on biosimilars, also known as subsequent-entry biologics (SEBs), in January 2008, when it issued the “Draft Guidance for Sponsors: Information and Submission Requirements for Subsequent Entry Biologics.” The new draft guidance was delayed when the Canadian Parliament was dissolved late last year, forcing the country to start again.

Canadian authorities are playing “catch up” in trying to develop regulations for SEBs, according to Brian Finlay, a former project manager for the Laboratory Center for Disease Control in Ottawa.
The issuance of the new draft guidance means the process is back on track, Finlay said Tuesday at the Center for Business Intelligence conference on biosimilars. Once the new draft guidance is released, a two-month period of public comment will commence, followed by the issuance of the finalized document sometime this spring, he added.

Next, Health Canada will develop regulations governing SEBs, and a full regulatory framework is expected within 18 months to two years. Health Canada says it plans to publish additional guidance on specific product classes.

Further complicating the situation is Health Canada’s claim that it has the authority to approve an SEB under the country’s existing Food and Drug Act, which faces an overhaul in Parliament this year.

Original Draft Guidance

Finlay expects the new draft will be little changed from the original one. In the first draft, an SEB sponsor has to show that its proposed product is similar to an approved biologic, relying in part on publicly available safety and efficacy data. Interchangeable and substitution characteristics would not be required automatically but would be judged on a case-by-case basis, according to the original guidance.

The first draft guidance also said an SEB would not be approved automatically for all the same indications as the reference product, and data would be required to support each indication in most cases. An SEB would have a different product monograph from that of the reference product.

To approve an SEB, Health Canada would require studies demonstrating similarity to reference biologics with respect to safety, efficacy and quality, the first draft says.
Makers of SEBs would have to demonstrate quality by showing comparability to the reference product through analytical and biological characterization methods.

If a sponsor cannot demonstrate comparability, it should file the application as a full new drug submission with a complete clinical data package, Health Canada says in the first guidance. For proposed SEBs where comparability has been shown, clinical data would be required for each indication sought (DID, March 21, 2008). — Elizabeth Jones


Warning Letter Cites Computerized Production Systems for Fabrazyme

Genzyme did not update its computerized manufacturing system for Fabrazyme, a treatment for Fabry disease, and ran an aseptic filling line at an unvalidated line speed, according to an FDA warning letter.

“Your firm failed to maintain computerized systems in a validated state,” the FDA tells Genzyme. “For example, the [redacted] console, used for formulation for the elution buffer for Fabrazyme [agalsidase beta], has not been updated since 1999. The specific gravity value entered into this system in 1999 is incorrect.”

The FDA is concerned that there may be other discrepancies in the system, which contains formulas and recipes for buffers, the warning letter says.

The letter cites operations at Genzyme’s plant in Allston, Mass., which manufactures several of the company’s best-selling biologics — Gaucher’s disease treatment Cerezyme (imiglucerase), Myozyme (alglucosidase alfa) for Pompe disease and Fabrazyme. Fill and finish activities for the biologics Aldurazyme (laronidase) and Thyrogen (thyrotropin alfa) also are conducted at the plant, according to an SEC filing.

Genzyme announced the Feb. 27 letter last week. The letter resulted from an inspection performed from last September through October. It was accompanied by a compete response letter for Lumizyme (alglucosidase alfa), a version of Myozyme made on a larger production scale (DID, March 4).

The FDA will not approve Lumizyme until the warning letter is resolved, the company says in the filing. Genzyme expects to reach an agreement with the agency on requirements that need to be fulfilled in the complete response letter by the end of March, and it hopes to have both the warning letter and complete response letter resolved within three to six months, it told DID last week.

Form 483

At the end of the inspection of the Allston facility, the FDA issued the company a Form 483 with 16 inspectional observations, the company said.

In response to observations regarding the use of an aseptic filling line at an unvalidated line speed, the company told the FDA that it would validate the filling line last December, the warning letter says. But in response to another Form 483 observation, the company committed to validating that filling line during the third quarter of 2009.

Genzyme also failed to validate its use of cryoshippers, which are used to transport master cell banks and working cell banks between production facilities, the letter says.

At the time of the inspection, maintenance on the cryoshippers was not performed. Further, the shelf life of the shippers is five years yet some of the shippers have been in use since late 2002 or early 2003, the FDA says.

The company told the agency it would no longer transport cell banks with the cryoshippers from its plant in Framingham, Mass., to the site in Allston without validating their use, according to the letter. But the FDA is asking whether Genzyme also ceased using the shippers to transport cell banks from Framingham to San Diego and to Belgium.

The FDA letter notes inadequate monitoring of bioburden levels after hold times of intermediates or pooled buffers during the purification of Cerezyme, Fabrazyme and Myozyme.

Bioburden issues were noted in a prior warning letter citing Genzyme’s plant in Lyons, France, which is where acute organ rejection treatment Thymoglobulin (anti-thymocyte globulin [rabbit]) is made in bulk (DID, Oct. 5, 2007). That warning letter has been resolved, the company told DID.  

Internal surfaces and manual valves on stainless steel chromatography columns used during purification processes were not maintained — specifically, maintenance was not performed on the interior of columns to prevent metal contamination in cell cultures, the letter says.

Airflow pattern testing in Genzyme’s HVAC system used for a filling suite was inadequate, the FDA says. The tests did not completely demonstrate airflow movement away from work surfaces while personnel activities and manual simulations of aseptic fillings were under way, the letter says.

The warning letter, which was posted on the FDA’s website Tuesday, is available at www.fda.gov/foi/warning_letters/s7123c.pdf. — Christopher Hollis


Falsified Patient Record Allegations May Disqualify Researcher

The FDA has warned a clinical investigator he may be disqualified from conducting studies after his alleged falsification of patient records and other violations of regulations.

Manuel Macapinlac of Forest Hills, N.Y., was sent a “notice of initiation of disqualification proceeding and opportunity to explain” letter citing his conduct in three drug clinical trials, at least two of which involved investigational cancer treatments.

Macapinlac acknowledged to FDA investigators that he “had lost control over the studies,” was unable to effectively manage them and was unaware of their status during his leaves, according to the letter dated Feb. 23 and posted on the FDA website this week.

During an investigation conducted in 2007, the FDA says it discovered that Macapinlac’s records for one of the studies “contained multiple diary entries for the same subjects on the same dates.” Two subjects had two sets of diaries containing different information for the same dates, the letter says. Other patient diaries did not cover the appropriate period of time.

Moreover, the case report forms (CRFs) “excluded some of the data from one or more sets of patient diaries,” including such information as visits to medical facilities, pain levels for the subjects, interruptions of daily activities by pain and data describing patient compliance with prescribed doses of medication, regimens and any concomitant medications.

Evaluations Questioned

The FDA may disqualify clinical investigators who repeatedly or deliberately failed to comply with regulations or repeatedly or deliberately submitted false information to the sponsor or to the  FDA, according to the Office of Regulatory Affairs website. A disqualified or totally restricted clinical investigator is not eligible to receive investigational drugs, biologics or devices.

The FDA found that in several instances in one of the studies, Macapinlac was on leave when patient visits and evaluations were recorded. The study coordinator signed the records, but the initials “M.M.” had been added. Similarly, his signature or initials appeared on patient enrollment forms completed when he was on leave, the letter says.

Macapinlac told the FDA investigators that although he did not authorize anyone to initial the patient evaluations on his behalf, he noticed that someone had done so. But he acknowledged he failed to recognize the problem, report it in a timely fashion and correct the problem or take steps to prevent its recurrence. In addition, documents show that laboratory reports for eight of the 12 subjects in the same study had date discrepancies, significantly delayed reviews or no review at all, the FDA says.

Macapinlac told the FDA that when he wasn’t at the hospital, he remotely accessed the subjects’ electronic medical records to review their laboratory results, but the hospital’s electronic records did not support his assertion. In some cases, the electronic records indicated that no one at the investigative site reviewed the subjects’ records on the dates documented in the laboratory reports, the FDA letter says.

Supervision Failures

The letter also cites Macapinlac for not personally conducting or supervising the clinical trials, which contributed to the unauthorized use of his initials and the failure to review patients’ lab reports. The supervisory failure also resulted in the study coordinators filing several progress reports that contained “no documentation regarding who had performed the subject’s evaluation, including the physical exam, during study visits” — despite instructions from the sponsor’s monitors. 

Macapinlac also failed to conduct the studies or ensure that they were conducted according to plan, and he did not maintain adequate and accurate patient case histories and drug disposition records, according to the FDA. Examples include:

  • Four versions of the CRF for a patient’s general medical history on the first visit, each one “adding a new disease or condition”;
  • A protocol violation in which a subject was enrolled who had not had at least two painful crises within 12 months of the screening visit; and
  • Another violation of protocol in which a subject was enrolled despite inadequate hematologic and other physiological organ function.

Macapinlac has the option of entering into a consent agreement or explaining why he should not be disqualified as a clinical investigator, either in writing or at an informal conference with the FDA. If these options fail or he does not respond, he will be offered an FDA regulatory hearing. He also may be subject to judicial proceedings or administrative sanctions.

Macapinlac did not respond to a request for comment by press time. The FDA’s letter can be viewed at www.fda.gov/foi/nidpoe/n58l.htm. —  Martin Gidron


Federal Court Delays Teva Distribution of Generic Raloxifene

Eli Lilly has won a temporary restraining order barring Teva Pharmaceuticals USA from introducing a generic Evista osteoporosis drug pending resolution of a patent lawsuit.

“Teva’s launch will remove Lilly’s marketing exclusivity with respect to Evista, which will result in a rapid loss of market share that will be difficult if not impossible for Lilly to recover even if the court were to later rule in favor of Lilly and Teva’s generic raloxifene product was removed from the market,” Judge Sarah Evans Barker of the U.S. District Court for the Southern District of Indiana wrote in her opinion.

Eli Lilly and Company v. Teva Pharmaceuticals USA, Inc. alleges Teva would infringe on three patents for Evista (raloxifene HCl): ’086, which expires in July 2012; ’050, expiring in March 2014, and ’811, in March 2017. Teva, on the other hand, would only be delayed in entering the market with its generic raloxifene until the court can hear Lilly’s case, Evans Barker said. Lilly filed its lawsuit in 2003.

Monday marked the end of the 30-month statutory stay the FDA had imposed on Teva’s ANDA for generic raloxifene, and the company said the agency “was prepared to approve Teva’s production forthwith,” according to the judge.

“Teva has conceded infringement of two of the patents at issue … but challenges their validity and enforceability on grounds of obviousness, lack of enablement and inequitable conduct,” the judge wrote, adding that the restraining order “can  succeed on evidence that would not necessarily support a judgment of validity at trial.”

“We believe Teva’s challenges to Lilly’s Evista patent are without merit and we expect to prevail in this litigation,” Robert Armitage, senior vice president and general counsel for Lilly, says in a statement. “We have taken and will continue to take all appropriate actions needed to protect our intellectual property rights as they relate to Evista.”

“Teva does not comment on ongoing litigation,” spokeswoman Denise Bradley told DID. — Martin Gidron

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