March 2006

VACCINE PRODUCTION

Vaccines and More Fight Avian Influenza, Rotavirus

From research and development to fill-and-finish, the pharmaceutical industry is applying creative strategies to stop the spread of deadly viruses and ensure a global supply of influenza vaccines.

Such developments come as scientists and government officials call for better preparedness and a boost in dedicated spending. According to recent reports, so far Congress has provided only $3.3 billion out of the $7.1 billion requested by President Bush (see D. McNeil Jr., "States and Cities Lag in Bird Flu Readiness," The NY Times, Feb. 6 and M. Fox, "Congress Urged to Spend More Money on Flu," Reuters/USA Today, Jan. 31).

Strides and struggles

Researchers in industry and academia have made great strides in vaccine development to combat seasonal influenza and a possible avian pandemic caused by the H5N1 virus.

In January, Sanofi Pasteur, the vaccine business of the Sanofi-Aventis Group (Swiftwater, PA, en.sanofi-aventis.com) shipped to the National Institutes of Health (NIH)15,000 doses of its investigational doses of vaccine to protect against H5N1 influenza strain. The doses will be used in NIH clinical studies to determine the optimal formulation of the vaccine. Sanofi's formulation is prepared with various levels of antigen as well as an adjuvant, aluminum hydroxide. The company also completed production of additional bulk-concentrate of the H5N1 vaccine antigen, valued at $50 million, for the US government stockpile and in support of the US Department of Defense requirements.

FDA last week approved a Centers for Disease Control and Prevention (CDC) laboratory test to diagnose H5 strains of influenza in patients suspected to be infected with the virus. The test provides preliminary results on suspected H5 influenza samples within four hours once a sample arrives at the laboratory and testing begins.

ProImmune (Oxford, UK, www.proImmune.com) also announced it has developed a screening technology to help identify specific antigens on viruses such as H5N1 and enable rapid analysis of proteins derived from a pathogen for potential immunogencity. The company plans to begin a pilot study.

Sales for MedImmune's (Gaithersburg, MD, www.medimmune.com) "FluMist" reportedly dropped 56% last year compared with sales in 2004. As observed in a Feb. 3 Washington Post article, the vaccine's poor performance may be the result of its requirement to remain frozen and the fact that it is approved only for healthy people from 5 to 49 years of age. The company is currently testing a new formulation that requires refrigeration in hopes of meeting approval for the 2007–2008 influenza season.

Also eyeing the 2007–2008 flu season is Australia's major biopharmaceutical company, CSL Ltd. (Melbourne, www.csl.com.au). The company plans to initiate a human clinical study of its vaccine this year and announced plans to submit a biologics license application to US Food and Drug Administration within 12 months. Contingent on FDA approval, CSL hopes to supply 20 million doses of its vaccine in the United States. The company also plans to double its existing vaccine manufacturing capacity to 40 million doses annually following an $80 million investment.

BD Medical (Franklin Lakes, NJ, www.bd.com), the medical technology segment of BD, and GlaxoSmithKline (London, UK, www.gsk.com) have partnered to launch the industry's first prefilled-syringe flu vaccines using BD's "Hypak" platform and design. GSK previously announced plans to acquire "Fluviral" maker ID Biomedical Corp. in hopes of having the vaccine approved for the 2007 flu season. GSK announced plans to increase production of its "Relenza" seasonal flu vaccine as well as invest in a vaccine against the H5N1 strain, with clinical trials possibly this year.

On Feb. 17, FDA's Vaccines and Related Biological Products Advisory Committee planned to discuss influenza strains to be included in the vaccine for the 2006–2007 season.

Preventing rotavirus gastroenteritis

In January, FDA approved "RotaTeq," an oral liquid vaccine developed by Merck & Co. (White House Station, NJ, www.merck.com) to prevent rotavirus gastroenteritis in infants.

RotaTeq is the only vaccine approved in the United States that can help protect against rotavirus, which, according to the CDC, is the most common cause of severe diarrhea among children, resulting in the hospitalization of nearly 55,000 children each year in the United States and the death of more than 600,000 children annually worldwide.

A different vaccine against rotavirus previously approved in 1998 was withdrawn because of its association with an increased risk of intussusception, a rare, life-threatening blockage or twisting of the intestine.

Although a safety study involving 70,000 children did not associate Merck's RotaTeq with an increased risk of intussusception, the company plans to conduct additional post-licensure safety studies. CDC also will conduct a large study through its Vaccine Safety Datalink Program to detect any association of intussusception with RotaTeq.

Cell-grown vaccine protects against avian flu virus

Meanwhile, researchers continue to seek faster and more effective processes for developing vaccines against H5N1.

University of Pittsburgh Medical Center (Pittsburgh, PA, www.upmc.com) researchers have genetically engineered an avian flu vaccine from the critical components of the H5N1 virus, and shown that the vaccine completely protected mice and chickens from infection.

Researchers grew the vaccine in cell cultures, developing the recombinant vector vaccine in 36 days. In contrast, conventional vaccines prepared in fertilized chicken eggs require a minimum of several months to develop.

According a university press release, the vaccine was constructed by genetically engineering adenovirus, a common cold virus, to express either all or parts of an avian influenza protein called hemagglutinin on its surface. Hemagglutinin allows the virus to attach to the cell that is being infected and is, therefore, vital to the influenza virus's ability to cause illness and death.

The investigators constructed several adenovirus vectors, containing either the full genetic sequence of the HA protein or sequences for subunits of of the protein. Collaborating with investigators from the CDC, the researchers tested the ability of their vaccines to protect mice from infection by wild-type H5N1 by comparing its performance with an adenovirus vector containing no H5N1 genes (i.e., an empty vector). The H5N1-exposed mice were studied for any signs of illness, and their blood was checked for antiviral antibodies and other markers of H5N1-specific immunity.

All of the mice immunized with the empty-vector vaccine experienced substantial weight-loss after exposure to wild-type H5N1, and all were dead within six to nine days of avian flu exposure. In contrast, most of the mice immunized with the adenovirus containing all or part of the hemagglutinin protein showed only mild and short-lived weight loss and survived H5N1 infection. Six days after infection, researchers could not detect any infectious H5N1 in the organs of mice immunized with the full-length HA vaccine. Moreover, when they looked at the cellular immune response to vaccination, they found that all of the animals immunized with full-length hemagglutinin or the subunit vaccines developed strong cellular immune responses, and the full-length hemagglutinin-immunized mice developed strong T-cell responses to both of the hemagglutinin subunits.

The fact that two types of immunity were produced (antibodies that block hemagglutinin and a strong T-cell response) could mean that that even if the H5N1 virus mutates, the vaccine may still be effective against it, said the researchers.

The vaccine was then tested in chickens, which have almost a 100% mortality rate after H5N1 exposure. Chickens were inoculated either intranasally or subcutaneously with either the hemagglutinin-containing vaccine or the empty-vector vaccine. The chickens were challenged with a dose of whole H5N1 virus 10,000 times greater than the dose given to the mice and significantly greater than the dose farm chickens are likely to be exposed to during a natural outbreak. All of the chickens that were immunized subcutaneously survived exposure to H5N1, developed strong HA-specific antibody responses, and showed no clinical signs of disease. Half of the chickens immunized intranasally died, and all of the chickens immunized with the empty vector died within two days of H5N1 exposure.

Researchers suggest their adenovirus-based vaccine could complement traditional inactivated influenza vaccines by immunizing chickens against H5N1. The widespread inoculation of susceptible poultry populations could help prevent the spread of the virus. In addition, if there were a disruption in the traditional vaccine production pipeline, a recombinant vaccine could be an alternative for human immunization.

Purdue University researchers, partnering with the CDC also published promising results of an adenoviral-vector-based pandemic influenza vaccine study conducted in mice (The Lancet, Feb. 2). The recombinant human Ad vector expressing H5 carried the full length coding region of the H5 gene of the virus. The egg-independent vaccine does not involve an adjuvant and induced both humoral and cell-mediated immune responses against avian H5N1 influenza viruses.

Eggs from transgenic hens express interferon beta-1a protein

Researchers at Oxford BioMedica (Oxford, UK, www.oxfordbiomedica.co.uk), Viragen Ltd. (Plantation, FL, www.viragen.com), and Roslin Institute (Edinburgh, Scotland, www.roslin.ac.uk) have expressed interferon beta-1a in the whites of eggs laid by transgenic hens. Interferon-beta 1a is a key component of the human immune system and is the active ingredient in several multiple sclerosis therapies.

The project is a based on Viragen's "OVA" avian transgenic biomanufacturing system and Oxford BioMedica's "LentiVector" gene delivery system. According to the companies, avian transgenic technology aims to develop flocks of specially produced transgenic hens that have been engineered to lay "virtually unlimited" numbers of eggs expressing high volumes of target protein in the egg whites. Researchers hope the technology will serve as an efficient and economical alternative to standard biomanufacturing techniques.

These results are the first in a series of anticipated proof-of-principle milestones with an avian-expressed version of interferon beta.

In a company press statement, Karen Jervis, Viragen's vice-president and managing director, said, "We will continue to collect eggs from these hens and subsequent generations to confirm quality and quantity of the protein. In addition, we will be analyzing the carbohydrate profile of the product, which may represent another key advantage to OVA-expressed proteins. Certain biotech drugs require post-translational modifications in order that the drug retains its full efficacy and is well tolerated when used as a human therapeutic. Although we must confirm the nature of the modifications conferred by the OVA system, we are hopeful that avian transgenic production may be able to retain these beneficial modifications, which may in turn translate to a lower cost of goods and a more economical process."

–Maribel Rios

Dow AgroSciences Receives Regulatory Approval for Plant-Made Vaccine

Dow AgroSciences LLC (Indianapolis, IN, www.dowagro.com), a wholly owned subsidiary of The Dow Chemical Company (Midland, MI, www.dow.com), has received regulatory approval for a plant-cell-culture-derived vaccine from the US Department of Agriculture Center for Veterinary Biologics. The vaccine is produced from the "Dow-AgroSciences Concert Plant-Cell-Produced System" that uses plant cells instead of whole plants in a biocontained environment to produce vaccines. With the approval, Dow AgroSciences says that it can focus its efforts on developing vaccines for animal health and that using this technology for human vaccines is a possibility.

–Patricia Van Arnum

BUDGET

$1.95-Billion FDA Budget Request Fouses on High-Priority Programs

The US Food and Drug Administration's (Rockville, MD, www.fda.gov) budget request for the 2007 fiscal year, released Feb. 6, totals $1.95 billion, an increase of $70.8 million (3.8%) from fiscal 2006.

All of that increase is earmarked for high-priority programs, including:

• $55.3 million for pandemic protection, increased $30.5 million (123%);

• $178.2 million for food defense, increased $19.9 million (13%);

• $5.9 million for the newly funded Critical Path Initiative;

• $38.5 million for drug-safety oversight, up $4.0 (10%);

• $9.0 million for human-tissues safety, increased $2.5 million (28%); and

• $7.4 million needed to fund activities that will trigger collection of user fees for medical devices and animal drugs.

In addition to these increases, the agency is budgeting $20.3 million for cost of living increases and $14.3 million more for infrastructure (to cover rent paid to the General Services Administration and the agency's consolidation on its new White Oak, Maryland campus).

To cover the costs, the agency plans to reduce spending for existing programs by $52.3 million, defer $3.0 million in facilities and maintenance expenses, and increase user fee revenues by $19 million (to $364.3 million).

Reductions in existing programs

The agency's 81-page "Performance Budget Overview" describes the reductions, referred to as "budget offsets" for "strategic redeployment," this way:

"To fund these initiatives and essential infrastructure requirements at FDA, our budget reflects a strategic redeployment of resources from lower-priority programs to the priority initiatives that we have proposed for FY 2007. Our strategic redeployment will achieve program savings of $52,277,000, and thereby enable the Agency to fund new high priority initiatives."

All told, FDA will eliminate or change the duties of 189 employees to cover the budget gap. The Food part of FDA will bear the largest portion of these redeployments, some $22.6 million worth. On the Drug side of the house, the $14.9 million in reductions are allocated as follows:

The Generic Pharmaceutical Association (GPhA, Arlington, VA, www.gphaonline.org) reacted immediately to the program changes, voicing "extreme disappointment." The GPhA statement charges that the FDA's Office of Generic Drugs (OGD) has been "flat-funded at best, even though its workload has increased by a staggering 36%. OGD currently has a backlog of more than 800 generic drug applications, a number that will only grow."

User fee changes

The great majority of user-fee revenues should come from Prescription Drug User Fee Act (PDUFA) charges for human drug approvals, budgeted at $320.6 million, up $15.3 million (4.8%).

In addition, FDA is asking for authority to impose two new classes of user fees: the larger (budgeted to bring in an additional $22 million in FY 2007), would be levied for re-inspecting human-drug plants that have failed current good manufacturing practice inspections; the fee is estimated to exactly balance the direct costs of re-inspection. The smaller new fee (anticipated to produce $3.5 million) would pay direct costs required to issue some 37,000 annual food and animal-feed export certificates.

–Douglas McCormick

MANUFACTURING

Noninjectable Insulins Win Approval: Pfizer in the US, Generex in South America

With a Feb. 1 US Food and Drug Administration (Rockville, MD, www.fda.gov) approval, Pfizer's (New York, NY, www.pfizer.com) "Exubera" (insulin human [rDNA origin]) inhalation powder to treat adults with type 1 and type 2 diabetes became the first inhaled insulin okayed for marketing in the United States, but the second marketed worldwide. Last November, Generex's (Toronto, ON, Canada, www.generex.com) oral insulin "Oral-lyn" went on the market in Ecuador for the treatment of patients with Type-2 diabetes, and is in clinical trials in Europe.

United States approval

Exubera was found to be an effective substitute to injectable insulin and can be taken with oral insulin. Plans are underway to make the drug available by mid-year.

Said Hank McKinnell, chairman and chief executive officer of Pfizer in a release, "Exubera meets a critical medical need by offering a highly effective and needle-free alternative to diabetes pills and insulin injections to manage this complicated, debilitating disease."

According to Pfizer, Exubera is a rapid-acting, dry-powder human insulin that is inhaled through the mouth into the lungs before eating, using the handheld Exubera inhaler. Weighing four ounces, the inhaler produces a cloud of insulin powder, which is designed to pass rapidly into the bloodstream to regulate the body's blood sugar levels.

"During clinical trials, Exubera was studied in more than 2500 adults with type 1 or type 2 diabetes for an average duration of 20 months. In clinical trials, many patients using Exubera reported greater treatment satisfaction than patients taking insulin by injection," Pfizer said.

The drug does have a few drawbacks. Smokers or people who quit smoking within six months cannot use the drug. Anyone suffering from chronic or poorly controlled lung disease also is not a candidate from treatment. Side effects reported include low blood sugar levels and a mild cough after inhalation.

Going global

Meanwhile, biotech company Generex is planning on releasing Oral-lyn in the rest of South America by the end of the year. Unlike Exubera, Oral-lyn is delivered to the mouth for absorption through the buccal mucosa. The drug, which is delivered through the company's "RapidMist" inhalation system, is expected to have sales close to $300 million, according to Generex.

The company has met with Health Canada officials to discuss filing a new drug submission to market and distribute Oral-lyn in Canada. There is no word yet as to when or if the Generex will file for a US new drug application for FDA approval.

–George Koroneos

FDA Releases Guides to Dissolution Testing and Quality Overall Summary

On Jan. 31, the US Food and Drug Administration (Rockville, MD, www.fda.gov) released two sets of documents: From the Office of Generic Drugs came the "Model Quality Overall Summary," a 36-page illustration of what the newly instituted Quality Overall Summary (QOS) for generic products should look like. And from the Office of Testing and Research came "Mechanical Qualification of Dissolution App. 1 & 2," an eight-page guide to the set-up, mechanical calibration, and operation checks for dissolution testing devices, along with sample calibration-reporting sheets.

REGULATIONS

FDA unveils new prescription drug information format

In an effort to manage the risks of medication use and reduce medical errors, the US Food and Drug Administration (Rockville, MD, www.fda.gov) has revised the prescription drug information format, commonly known as the package insert. The new label design is the first revision in 25 years.

The format will require that the prescription information for new and recently approved products meet specific graphical requirements and includes the reorganization of critical information. Significant changes include:

• a "highlights" section that summarizes the most important prescribing information about benefits and risks;

• a table of contents that facilitates reference to detailed safety and efficacy information;

• the date of initial product approval, which makes it easier to determine how long a product has been on the market;

• a toll-free number and Internet reporting instructions to encourage more widespread reporting of suspected side effects.

The agency is encouraging pharmaceutical manufacturers to consider complying with the new labeling requirements on a voluntary basis at first. All drugs approved within the past five years are included and will be converted gradually to the new format.

–Maribel Rios