June 2006

REGULATIONS

FDA Withdraws Jan.17 Rule Relaxing Phase I GMP Standards

In a May 2 Federal Register notice (1), the US Food and Drug Administration (Rockville, MD, www.fda.gov) withdrew its Jan. 17 direct final rule, "Current Good Manufacturing Practice (CGMP) Regulation and Investigational New Drugs" (2), which would have exempted the manufacturing of drugs for Phase I clinical trials from most provisions of 21 CFR 211.

The withdrawal effectively reinstates the agency's fifteen-year-old Guideline on the Preparation of Investigational New Drug Products (Human and Animal), which required investigational new drug application adherence to commercial-scale CGMP standards.

Under the Agency's direct final rule procedure, "the receipt of any significant adverse comment will result in the withdrawal of the direct final rule," according to the May 2 notice. Many of the comments submitted to FDA were, in fact, highly critical.

Some commentators, such as the Pharmaceutical Research and Manufacturers of America (PhRMA, Washington, DC, www.phrma.org) Vice-President Alice E. Till, Parenteral Drug Association (Bethesda, MD, www.pda.org) President Robert B. Myers, and Biotechnology Industry Organization (BIO, Washington, DC, www.bio.org) Managing Director Sara Radcliffe, expressed broad support while suggesting changes (some of them extensive) in the details. Most comments are available on FDA's Web site, at www.fda.gov/ohrms/dockets/dockets/05n0285/05n0285.htm.

In her Mar. 7 letter, Till said, "PhRMA strongly supports the development of this FDA guideline, as we believe there is currently a general consensus within Industry that there should be an incremental application of CGMP expectations throughout clinical development as a product approaches commercialization."

Others, like Peter Lurie and Sidney M. Wolfe of Public Citizen's Health Research Group (Washington, DC, www.citizen.org) and Barbara Immel of Immel Resources (Petaluma, CA, www.immel.com), voiced strong opposition, triggering the automatic withdrawal.

"We can see no reason," wrote Lurie and Wolfe, "why subjects in Phase I clinical trials should be any less deserving of FDA protection than those in later phases of development (or, subsequently, marketing). From the perspective of any patient injured by a GMP-violating drug in a Phase I study, it will be cold comfort that the FDA deemed following accepted standards too cumbersome. If some company or academic laboratory cannot follow GMPs, they should probably not be in the practice of preparing drugs for administration to humans."

Immel had similar concerns. "I am opposed to this rule," she wrote, "and believe that a guidance document, which is not legally binding, should not be used to replace an existing regulation that provides the minimum requirements for the safe manufacture of drugs or biologics for human beings. I believe that this rule may place patients in Phase I in jeopardy."

References

1. US Food and Drug Administration, "Current Good Manufacturing Practice Regulation and Investigational New Drugs; Withdrawal," Fed. Regist. 71 (84), 25747 (May 2, 2006).

2. FDA, "Current Good Manufacturing Practice Regulation and Investigational New Drugs," Fed. Regist. 71 (10), 2458–2462 (Jan. 17, 2006).

–Douglas McCormick

DRUG APPROVAL

Sandoz Wins EU Approval, US Progress for Biogeneric Product

Sandoz (Holzkirchen, Germany, www.sandoz.com), the generics division of Novartis (Basel, Switzerland, www.novartis.com), received European marketing authorization for its recombinant human growth hormone, "Omnitrope" (somatropin), making it the first biogeneric product approved under the biosimilar pathway of the European Commission.

"As more biotechnology-based products come off patent, biosimilars will play an increasingly important role by providing lower-cost, safe, and effective versions of patent-expired biological medicines," said Andreas Rummelt, Sandoz CEO, in a company statement.

Omnitrope is the first of several biosimilar products Sandoz is pursuing. Sandoz expects to begin marketing Omnitrope in Germany and Austria. The product is currently on the market in Australia, where it was launched in November 2005.

Sandoz also is seeking approval for Omnitrope in the United States and gained a step-wise victory in its ongoing litigation with the US Food and Drug Administration (Rockville, MD, www.fda.gov) over its Omnitrope application.

Sandoz recently reported that the US District Court for the District of Columbia granted a summary judgment that upholds the statutory deadline for FDA action on a pending new drug application, thereby requiring FDA to issue a decision on Sandoz's application for Omnitrope, which was filed in July 2003. Sandoz had filed a lawsuit against FDA in September 2005, seeking a ruling on its Omnitrope application.

A second biogeneric for recombinant human growth hormone is under European regulatory review. In February, the European Medicines Agency's Committee on Medicinal Products for Human Use issued a positive recommendation for "Valtropin" (somatropin), a biosimilar product made by BioPartners GmbH (Baar, Switzerland, www.biopartners.com).

–Patricia Van Arnum

Merck To Acquire Biologics Companies GlycoFi and Abmaxis

Merck & Co Inc. (Whitehouse Station, NJ, www.merck.com) agreed to acquire two biologics companies: GlycoFi Inc. (Lebanon, NH, www.glycofi.com), a specialist in yeast glycoengineering, for $400 million, and the biopharmaceutical company Abmaxis Inc. (Santa Clara, CA, www.abmaxis.com) for $80 million.

GlycoFi has a position in yeast-based protein optimization technology that may be used for developing, producing, and commercializing biotherapeutics. Glycoengineering provides the ability to make proteins such as monoclonal antibodies with prespecified and defined human carbohydrate chains. Merck says the ability to make such proteins in yeast has advantages of speed, costs, and quality over current methods of producing monoclonal antibodies and other protein-based therapeutics.

Abmaxis is a privately held biopharmaceutical company focused on the discovery and optimization of monoclonal antibodies. Its antibody engineering technology platform, "Aisim" (Abamaxis in-silico immunization) enables structure-centric computational design followed by experimental selection of human or humanized monoclonal antibodies.

Both deals are expected to close in the second quarter.

–Patricia Van Arnum

ACQUISITION/RESTRUCTURING

Novartis Creates New Vaccines Division Following Close of Chiron Deal

Novartis AG (Basel, Switzerland, www.novartis.com) closed on its $5.4-billion acquisition of Chiron Corporation (Emeryville, CA, www.chiron.com), paving the way for a new Novartis vaccines and diagnostics division.

Chiron shareholders approved the merger at a special shareholders' meeting, with the deal officially closing on April 20. Annual cost synergies of $200 million are anticipated within three years after closing, with 50% expected to be achieved in the first 18 months.

With the Chiron acquisition now complete, Novartis is creating Novartis Vaccines and Diagnostics, consisting of two businesses: Novartis Vaccines and a diagnostics business that will retain the Chiron name.

"We are committed to investing the significant skills and capital needed to build a global leader in the increasingly important vaccines and diagnostics markets and contribute to meeting emerging public health needs," said Joerg Reinhardt, CEO of Novartis Vaccines and Diagnostics, in a company statement.

Novartis will continue Chiron's current manufacturing-remediation program. Novartis says it will focus on continued improvements in quality assurance and make the necessary investments to upgrade manufacturing capabilities while exploring new technologies to increase the capacity and reliability of the manufacturing process.

Chiron had quality issues at its manufacturing facilities in Liverpool, England that produced its "Fluvirin" influenza virus vaccine. Its license to manufacture the vaccine was suspended temporarily beginning in 2004 and later reinstated in 2005. It also had to reduce supply expectations in 2005 for its "Begrivac" influenza virus vaccine because of quality issues at its manufacturing facility in Marburg, Germany.

Chiron is supplying the US government with prepandemic influenza vaccine for a stockpile against the H5N1 avian influenza strain. Chiron won a $62.5-million contract in October 2005 and is manufacturing the product at its Liverpool facility.

In finalizing the Chiron deal, Novartis also reported that Chiron's biopharmaceutical business will be integrated into Novartis Pharmaceuticals. Chiron's early-stage research will be incorporated into the Novartis Institutes for Biomedical Research, which will maintain Chiron's existing research center in Emeryville, California.

–Patricia Van Arnum

WARNING LETTER

Pliva

On April 28, the US Food and Drug Administration's Center for Drug Evaluation and Research (Rockville, MD, www.fda.gov/cder) issued a Warning Letter (www.fda.gov/cder/warn/2006/320-06-02.pdf) to Pliva Hrvatska d.o.o., a subsidiary of Pliva d.d. (Zagreb, Croatia, www.pliva.com). The six-page letter, which FDA posted on May 5, refers to a variety of shortcomings noted during inspections conducted Jan. 23 through Feb. 8, 2006, as well as in August 2002:

1. maintenance of facilities used to manufacture injectable drugs (21 CFR 211.58), including water dripping from a light fixture in a Class C injectable production area and torn flexible piping;
2. cleaning and maintenance of equipment (21 CFR 211.67.a), including failure to demonstrate the effectiveness of disinfectants used and equipment observed in-use with alarm lights lit;
3. instrument calibration (21 CFR 211.160.b.4), including failure to calibrate equipment used during sterilization;
4. justification of deviations from written specifications (21 CFR 211.160.a), specifically inconsistencies in standards used to evaluate cleaning swabs and solvent tests;
5. establishing scientifically sound and appropriate test procedures for identity, strength, quality, and purity (21 CFR 211.160.b), including errors in hold-time studies and microbiological tests;
6. adhering to test procedures (21 CFR 211.160.a);
7. laboratory record keeping (21 CFR 211.194.a);
8. investigation of unexplained discrepancies in tests of batches or components (21 CFR 211.192), including delays as long as several months in studying a two-hour process stoppage, use of an incorrect program in testing, and an equipment failure.

In a May 8 statement, Pliva said that it was "addressing this issue very seriously and is in the process of implementing a corrective action plan, which was submitted to the FDA in April and which, except as stated in the warning letter, has been accepted by the FDA."

According to the statement, Pliva does not expect any disruption in delivery of finished dosage forms and active pharmaceutical ingredients to Pliva Inc. (its US subsidiary) or other customers. Though the company anticipates that FDA will not approve any of Pliva's pending abbreviated new drug applications until the issues are resolved, the company "does not currently expect this to have any material impact on the company's financial outlook for 2006."

–Douglas McCormick

Thermo Electron and Fisher Scientific to Merge

On May 8, Thermo Electron Corporation (Waltham, MA, www.thermo.com) and Fisher Scientific International Inc. (Hampton, NH, www.fisherscientific.com) announced they will merge in a tax-free, stock-for-stock exchange. The new $9-billion company will be named Thermo Fisher Scientific Inc. and will provide laboratory products and services for the life-, laboratory-, and health-sciences industries. The transaction is expected to close in the fourth quarter of 2006 (see further coverage in this month's "Outsourcing Outlook" column).

VACCINES

HHS Awards $1 Billion in Contracts to Speed Cell-Based Vaccine Development

The US Department of Health and Human Services (HHS, Washington, DC, www.hhs.gov) will distribute more than $1 billion in contracts to accelerate the development of cell-based production technologies for influenza vaccines. This technique uses cell cultures rather than chicken eggs (as do most vaccine manufacturing techniques) for primary production, which greatly shortens the production time (see Pharmaceutical Technology's April 2006 Special Report, "Process Considerations for Cell-Based Influenza Vaccines").

The funds, which were part of President Bush's $3.3-billion plan to protect the United States against pandemics, were divided into five contracts that will be distributed over the next five years:

• GlaxoSmithKline (GSK, Philadelphia, PA, www.gsk.com) will receive $274.75 million to carry out clinical programs to support the filing of a biologics license application for a cell culture-based trivalent seasonal flu vaccine. GSK also will complete Phase II studies of an H5N1 cell culture-based pandemic influenza vaccine.

• MedImmune (Gaithersburg, MD, www.medimmune.com), maker of the "FluMist" intranasal flu vaccine, was awarded $169.46 million to develop a live, attenuated, needle-free flu vaccine using cell-based technology. The company is currently in Phase III trials with a cold-adapted trivalent influenza vaccine, a next-generation form of FluMist.

• HHS committed $220 million to Novartis (East Hanover, NJ, www.novartis.com) to support cell-based vaccine development and facility and equipment design and validation. The company also plans to invest additional resources into its US vaccine manufacturing facility.

• DVC LLC, a CSC Company (Frederick, MD, www.dynport.com) will use its $242.5-million award to collaborate with Baxter Healthcare Corporation (Deerfield, IL, www.baxter.com) to develop a cell culture-derived, split-virus vaccine for seasonal flu and a modified whole-virus vaccine to protect against H5N1 avian flu. DVC will manage the project and clinical trials, and Baxter will manufacture the vaccines and serve as the FDA license-holder.

• As part of its $298-million award, Solvay Pharmaceuticals (Marietta, GA, www.solvaypharmaceuticals-us.com) plans to establish a state-of-the-art, cell-based manufacturing facility in the United States.

–Kaylynn Chiarello-Ebner

RESTRUCTURING

CDER Reorganizes

The US Food and Drug Administration's Center for Drug Evaluation and Research (CDER) (Rockville, MD, www.fda.gov/cder) formally put into action its reorganization plan, effective May 15.

Per the goals announced in last fall's State of CDER address, the reorganization is intended to support FDA's Critical Path Initiative. Among the changes are creating the Office of Translational Sciences to include the Office of Clinical Pharmacology and the Office of Biostatistics; elevating the Office of Surveillance and Epidemiology (formerly the Office of Drug Safety) to report to the center director; appointing an associate center director for safety policy and communication to focus on broad drug-safety policy and safety communication; moving the pediatric drug development review staff to the Office of New Drugs; and realigning the Division of Scientific Investigations from the Office of Medical Policy to the Office of Compliance.

US Food and Drug Administration, Center for Drug Evaluation and Research reorganization, effective May 15, 2006

In an official memorandum, CDER Director Steven Galson said, "I am confident that these changes will lead to greater improvements in regulatory and drug development science and in how we evaluate and ensure the safety and efficacy of the products we regulate, and will result in greater protections for patients and consumers who depend on us every day."

–Kaylynn Chiarello-Ebner

COLLABORATION

Device Companies Unite for a Better Inhaler

Bang & Olufsen Medicom (Copenhagen, Denmark, www.medicom.bang-olufsen.com), a drug-delivery device solutions provider, and Bespak (Milton Keynes, UK, www.bespak.com), a medical-devices and inhalation-valve technologies company, established an exclusive partnership to codevelop and comarket the "Assist Actuated Inhaler," a single-increment, dose-counting inhaler. The integrated device features an assisted firing mechanism for easier patient use, according to a company release.

The partnership has been formed to develop a next-generation "press and breathe" inhaler aimed at the expanding asthma and chronic obstructive pulmonary disease market. The two companies will share responsibility for the development, manufacture, and promotion of the device.

Bang & Olufsen Medicom's CEO Henrik Kagenow stated in a release, "We are excited it will be the first patient-compliance device on the market with a dose counter that meets FDA requirements."

According to the company, the functionality of the device has been thoroughly validated and is ready for incorporation into a metered-dose inhaler program. Bespak and Bang & Olufsen Medicom are currently seeking alliances with pharmaceutical companies interested in providing new inhaler solutions for patients.

–George Koroneos