FDA’s newly confirmed commissioner, Margaret Hamburg, M.D., presented her proposed regulatory updates and outlined a number of enforcement initiative improvements at the Food and Drug Law Institute on August 6, 2009.  Commissioner Hamburg avowed, “The FDA is always looking for novel ways to prevent illness and promote health (1).”

Commissioner Hamburg’s Observations

In her first weeks in office she completed her initial review of the agency.  She met with over 150 consumer and patient organizations concluding that there is support for a strong FDA that protects the safety of the food supply and facilitates access to safe and effective medical products¹.  While the FDA has effective enforcement actions in place, they can be hampered by delays.  She noted that serious violations have gone unaddressed for far too long (1).  However Dr. Hamburg added, “I have been impressed by the commitment to compliance that many companies have made – both in terms of their corporate culture and their investment in compliance systems” (1).

The commissioner’s goal is to improve the enforcement by resolving problems early in order to intercept unsafe or fraudulent products by making sure companies are held legally responsible (1).Commissioner Hamburg is asking the FDA to be vigilant with regular inspections and follow-ups (1).  Transparency is also essential for increasing public confidence, encouraging compliance, and educating patients and consumers about potential risks (1).  “We must publicize our enforcement actions – and the rationale for those actions – widely and effectively” stated Dr. Hamburg (1).

Proposed Enhanced Enforcement Actions

Commissioner Hamburg’s goal is to focus the FDA on protecting the public by enhancing enforcement actions that are already in place.  She has outlined the following six steps to sharpen the enforcement effectiveness:

1.      Inspection Follow-up Deadline: Following a manufacture’s on-site inspection, the company may receive a list of issues that require follow-up.  The FDA will establish a deadline for the company to respond to significant FDA inspection findings.  The newly proposed deadline will require a company to follow up on inspection issues within approximately 15 days.  Failure to comply within the deadline will lead to more severe enforcement actions (1).

2.      Streamlined Warning Letter Process: Warning letters are issued to drug and device manufactures and are designed to address significant violations of the Title 21 Code of Federal Regulations (CFR) and the Food, Drug and Cosmetics Act.   Warning letters currently require many layers of review and supervision from the Office of the Chief Counsel.  This has resulted in warning letters being issued sometimes up to 6 months after an inspection. The new warning letter process will bypass the Office of Chief Counsel review unless the warning letter content involves a complicated legal issue or sets a regulatory precedent.  This will streamline the warning letter process (1).

3.       Regulatory Partner Collaboration: When public health is at risk from adulterated pharmaceutical or contaminated food the FDA must work quickly with state and local agencies.  The upcoming policy update will engage FDA’s regulatory partners to develop effective risk control by enhancing communication among different branches of government (1).

4.      Set Timelines for Subsequent Follow-Up Inspections: The FDA will prioritize enforcement for all follow-ups on corrective actions taken by non-compliant companies subsequent to a warning letter or product recall (1).

5.       End the Multiple Warning Letters Enforcement Method: The FDA must take swifter regulatory action and discontinue the practice of sending multiple warning letters for serious violations. More severe enforcement actions, such as injunctions or seizures, will be initiated in lieu of multiple warning letters (1).

6.      Close-Out Letter: After a company has corrected the issues listed in the warning letter, it will receive a close-out letter.  The receipt of the close-out letter will be published on the FDA website to motivate companies to quickly address their issues (1).

Inspections and Product Recalls

What should biotech companies be looking for with the newly proposed FDA regulations?  Although Commissioner Hamburg’s proposals have not been written into regulations, we can expect to see more inspections for pharmaceutical and medical device manufacturers. 

Mark Roh, Pacific Region Food and Drug Director of the FDA, spoke at the RAPS Pacific Region FDA update in August 2009 to inform regulators regarding current congressional inspection perspectives (2).  Both congress and public advocacy groups are concerned about the increasing number of product recalls.  This overwhelming list of product recalls covers everything from product failure to incorrect labeling.  To view the FDA recall list go to: http://www.fda.gov/safety/recalls/default.htm.

What is Congress Thinking?

Congress is considering legislating mandated inspection frequencies for drugs and device manufacturers.  The current FDA practice employs a high risk model approach and more frequently inspects products deemed to be of higher risk.  Congress would like to increase accountability with mandated inspection frequency because many legislators are concerned about the increase of recalls in the past few years (2).  Some of these recalled products were not consistent with FDA’s current high risk model (2).  The proposed inspection frequency would be once every two years and not more often than one inspection per year depending upon what is being manufactured (2).  According to Mark Roh consumers are very active in influencing congressional decisions (2).

Lack of Immediate Employee Resources

FDA is concerned about the proposed mandated inspection frequency because the lack of available resources.  FDA’s hiring of full time employees dropped off rapidly in 2003.  Although the FDA received hiring authority in the fall of 2008, they have yet recovered their 2003 staff levels.  The FDA compliance security officers (CSOs) have an increasing amount of companies and products to inspect with less staff to carry out these inspections which can take up to 3 days to complete.  In spite of recent and continued hiring of CSOs, 40% of all CSOs have been with the FDA for less than two years and 16% of CSOs are eligible to retire (2).  Mark Roh commented that it takes time to train qualified people and “not many people get out of college with a bachelors in FDA (2).”

Most Common Inspection Violations

An FDA inspection is concluded with a list of observations documented on the FDA form 483.  These are items the investigator notes as a deviation from the current Good Manufacturing Procedures (cGMPs).  Mark Roh’s list of the most common drug cGMP 483 observations are: 1) Responsibilities and procedures of the Quality Control department are not in writing or the written procedures are not followed; 2) Manufacturing control procedures are not established; and 3) There are inadequate specifications, written procedures and failure analysis policies (2).  Roh also listed the three most common device manufacturing inspection flaws as: 1) Deficiencies in the complaint file system; 2) Inadequate corrective and protective action procedures; and 3) Absence of written adverse event reporting procedures (2). 

We can certainly expect an increased number of FDA inspections in the coming months and even more as the newly hired FDA inspectors are trained.  The best place for a biotech company to start is to ensure they have written documentation of their operating procedures followed by a robust corrective action policy.  It’s a clear message from Commissioner Hamburg to the non-compliant companies that the agency is going to be more aggressive.   Finally, Dr. Hamburg aims to restore and maintain public trust in the FDA. 

1.      Effective Enforcement and Benefits to Public Health, Margaret Hamburg, M.D., FDA Commissioner speaking at the Food and Drug Law Institute, August 10, 2009.  View a transcript of Commissioner Hamburg’s speech at: http://www.fda.gov/NewsEvents/Speeches/ucm175983.htm  

2.      Regulatory Affairs Professional Society Pacific Region FDA Update, Mark Roh, Office of Regulatory Affairs Deputy Regional Director of FDA’s Pacific Division, August 21, 2009.

The FDA is always challenged to ensure that food, drugs, cosmetics, medical devices, animal feed, and veterinary drugs are safe.  This included drugs and devices imported into the US market. They also regulate microwave ovens and other radiation emitting products.  In 2008 the FDA employed 10,501 full-time employees (1).  The number of full-time positions within FDA's foods program would increase to 2,810 in this fiscal year, 2009 (2).  In addition to approving drugs and biologics for prescription pharmaceutical use the FDA also inspects food, drug, and medical device manufacturing.  The public sees the FDA as one of the most important consumer advocate and public health agency in the America but it budget is far less than the Centers for Disease Control and Prevention (3).  For more information about the FDA, the best place to start is FDA home page: http://www.fda.gov/default.htm.

Political Points of View

As the political climate in Washington D.C. changes from a republican to democrat, we can anticipate change within the federal government.  We can expect to see change in the FDA’s policy point of view.  The FDA policy point of view is influenced by the chief counsel’s office and the agencies legal point of view. 

Republican chief counsel administrators have traditionally taken a more narrow view of the legal construction authority by looking at the plain language of the statues.  In contrast, Democratic administrations have taken more expansive views of the FDA’s legal authority and are more likely to use full legal authority.  A new administration changes how the statues are interpreted long before policies are adapted. 

There are internal points of view which prevail within the agency.  Trends can become established over time irrespective of the political climate and are debated over time among the agency scientists and physicians. Let’s look at the antibiotic trend to allow a pharmaceutical company to compare a new antibiotic with an older approved antibiotic by just proving it’s not inferior to the older antibiotic by a reasonable margin.  The new antibiotic is not compared to a placebo due to the difficulty of duplicating actual infections of antibiotic trials under exact conditions.  In contrast, some skin and sinusitis infections may be better off compared to a placebo.  These medical issues are debated within the agency and the evolving trends influence policy development.

FDA Leaders

President Obama appointed Margaret Hamburg, M.D., as the new FDA administrator.  Dr. Hamburg was the former New York City health commissioner appointed in the early nineties by Mayor Dinkins and was known for developing New York City’s tuberculosis control program and increasing childhood immunization (3).  According to Jeffery Levi, executive director of Trust for America’s Health, Dr. Hamburg revived a demoralized and cash poor New York agency and could do the same at the FDA (3).  In the late nineties, Hamburg joined the DHHS to develop a pandemic flu response the bioterrorism initiative (3). 

Joshua Sharfstein, M.D. a Harvard Medical School graduate is the FDA’s principal deputy commissioner.  Sharfstein served as Baltimore’s health commission and served as an advisor for the often harsh critic of pharmaceutical manufactures, Representative Henry Waxman (Democrat).  Dr. Sharfstein made headlines for pushing the FDA to warn against over-the counter use of cough and cold medications for young children (4).  In contrast, Sharfstein sided with the pharmaceutical industry on vaccine safety, warning that vaccines are an essential part of public health (5).

Food Safety Scandals

Food safety scandals remain on the consumer’s mind – especially when there are deaths resulting from tainted food.  Pistachios, peanut butter, spinach, lettuce, and pet food have all made the headlines in the past few years.  The FDA admits it needs more funding to increase its inspection capacity.  The FDA, on the other hand, has only 1,307 inspectors who rarely get a firsthand look at the produce they are supposed to keep safe (6). This lack of oversight has been responsible for massive food-poisoning recalls.  In contrast the United States Department of Agriculture (USDA) which oversees the meat and dairy industries has 7,800 inspectors.

Both republican and democrat parties agree that food safety is in need of an overall.  Food safety in America can take many directions.  Many call for more FDA inspections while others prefer to remain inspected by state agencies.  Although it’s a goal of the Obama administration to food safety a priority by setting high standards and holding the industry accountable, The Obama administration’s goals are to set high standards for food safety and hold the industry accountable (6).  Plans for achieving improved food safety standards are in the developmental stages.  President Obama announced the creation of a new Food Safety Working Group (7).  The Food Safety Working Group’s goal is to determine how our food safety laws need to be overhauled (7).  This is an ambitious goal since the food safety laws were written way back when Teddy Roosevelt was the president (7). 

There is some talk about separating the FDA into two separate agencies (8).  A report from the Robert Wood Johnson Foundation suggests that the FDA should appoint someone with authority over all the FDA’s food safety programs and work with congress to establish a Food Safety Administration within the DHHS (8).  The other part of the FDA would be devoted to drugs, biologics, and medical devices. This may be a good idea in theory but it may not be cost effective. 

Risks of Long Term Prescription Use

After the Vioxx scandal, it has been proposed that the FDA should be looking for latent risks associated with drugs.  The FDA drug approval process and evaluation does a good job determining if a drug has an immediate risk to the organs or has a potential to cause toxicity, allergic reaction, or anaphylaxis.  Does prolonged administration of a drug over many years leave the patient at a higher risk for an event they may have had without using the drug? Even though the FDA approval process is persistent in determining a drug’s potential for carcinogenicity and teratogenicty, other long term risks may not be determined until a patient population has used the drug for a number of years.

There is a growing controversy that the FDA should be looking at cardiovascular risk with some of the long term diabetes medications.  Answering these types of questions requires very long large clinical trials to show a small potential risk.  How much revenue should a pharmaceutical or medical device company invest to detect potential for long term risk? 

The FDA requires quarterly reports of all serious, drug related, unexpected adverse events related to drug product for three years after they are marketed.  Unexpected adverse events are those events that do not appear in the label as expected side effects.  After the three year quarterly reporting period, the manufacture must submit annual adverse event summaries. 

So this becomes a philosophical debate.  Many physicians practice medicine assuming that all drugs have some risks associated with their long term.  Physicians must make reasonable risk balancing assessments when deciding to prescribe these drugs.

Failure to Warn

In March of 2009, the Supreme Court ruled in favor of a woman who had here arm amputated after an improper injection of an anti-nausea medication, Phenergan.  The drug was administered directly into an artery which can lead to gangrene and not into a vein.   Although the drug contained four separate warnings concerning injection directly into the artery, including a statement in boldface capital letters that reads: "INTRA-ARTERIAL INJECTION [CAN] RESULT IN GANGRENE OF THE AFFECTED EXTREMITY"(9). The lawyers for the patient argued that the warning wasn’t sufficient, and that Wyeth should have contraindicated intravenous use even though FDA had never required such a change (9).  FDA also specifically required that Wyeth retain the language about arterial injection in a label review a year before this incident (9). 

This case, Wyeth vs. Levine, sparked a controversy about FDA labeling policy.   Justice Stevens who spoke for the majority stated that “powerful evidence that Congress did not intend FDA oversight to be the exclusive means of ensuing drug safety and effectiveness” (10).  Justice Stevens also commented that the FDA has “limited resources” for overseeing more than 11,000 drugs on the market, and that “state tort suites uncover unknown drug hazards and provide incentives for drug manufactures to disclose safety risks promptly” (10).  The FDA does not tell a company that they are restricted from adding more warnings.  Companies may expect to see more “failure to warn” cases and cannot rely on federal regulation to protect them from lawsuits brought under state protection laws. 

Warning Letters from the FDA

The best way to watch trends within the FDA is to follow the warning letters issued to pharmaceutical companies, clinical trial investigators, and institutional review boards.  Warning letters are issued to drug and device manufactures and are designed to address significant violations of the Title 21 Code of Federal Regulations (CFR) and the Food, Drug and Cosmetics Act.   According to the FDA Regulatory Procedures Manual warning letters are issued when: voluntary action can be expected by the industry in response to the warning letter, the FDA policy is clear and unambiguous, failure to correct necessitates further enforcement action, and when deemed appropriate.  Warning letters are public documents and they can viewed at: http://www.fda.gov/foi/warning.htm.

Recent warning letters and interviews with FDA inspectors reveal trends focusing accountability on upper management (11).  The agency is likely to maintain its enforcement focus with senior management and business owners for poor oversight.  Over the past 18 months, warning letters did not mention anyone below the director or vice-president level (12).

FDA continued to scrutinize direct to consumer advertising and marketing this past year.  Prescription drug advertisements directed toward consumers cannot be false, misleading or omit material facts, and must present fair balance between effectiveness and risk information.  Promotional detailing aids and promotional materials aimed at healthcare professionals drew the most enforcement letters (13).  Other interesting FDA letters were directed to the manufactures of Adderall XR® for a YouTube video and for oral statements made by a sales representative for Seroquel® (13).   The FDA’s Division of Drug Marketing, Advertising, and Communications (DDMAC) paid less attention to “reminder items” such as pens, mugs, and desk top toys and were more focused on internet website materials (13).

DDMAC’s routine surveillance of company sponsored links on internet search engines included information on drugs that were not approved by the FDA (14).  DDMAC also found that drug manufactures website links had made suggestions for the efficacy of 48 different drugs without communicating any risk information about their use (14).  Promotional advertising to the public must contain risk information to avoid misleading the consumer about a drug or medical devices potential side effects.

Legacy Medical Devices

There are changes on the horizon for the medical device industry.  Medical devices that have been on the market prior to the enactment of the medical device law in 1976 are known at legacy devices.  Many of these medical devices were marketed with minimal testing.  FDA was required to re-classify these legacy devices but never completed the process and there are 27 different devices remaining on the re-evaluate list (15).  The types of medical devices that will be re-evaluated for potential reclassification are artificial lung membranes, external defibrillators, and some pacemaker components (15).  Industry groups predict that the FDA will not find these devices hazardous enough to provoke additional clinical testing (15).  Most of these devices have been on the market for so long their risk to cause potential adverse events has already been observed.

Electronic Signatures and Documents – Part 11

Electronic signatures and documents are covered under the 21 CFR Part 11.  The often referred part 11 was not regulated with a heavy hand by the FDA.  The FDA promises to publish additional guidances in this area.  Industry experts recommend that drug and device manufactures examine the long term date integrity and quality of the electronic data storage including: CDs, DVDs, and back up hard drives (16).

Congressional Bills

A sure way to follow FDA trends is to keep track of what bills will be introduced in the upcoming congressional session.  I keep my browser bookmarked to: http://www.acrpnet.org/MainMenuCategory/PublicPolicy/BillstoWatch.aspx.  I found the bills list below queued up for this session of 111^th session of congress.   We see the first two are focused on biosimilars and the remaining three concern clinical trials. 

·   Senate 1695 - Kennedy-Clinton-Schumer-Enzi-Hatch Biogenerics Bill
Description: To establish pathway for biosimilar biological products licensure and promote innovation in the life sciences.

·   House 5629 - Pathway for Biologics Act of 2008
Description: To amend the Public Health Service Act and establish a pathway for licensure of biosimilar biological products.

·    Senate 242 - Pharmaceutical Market Access and Drug Safety Act of 2007

    Description: To amend the Federal Food, Drug, and Cosmetic Act with respect to the importation of prescription drugs, and for other purposes.

·    House 248 - Resolution Honoring the Contributions of Patient Participants in Clinical Trials

   Description: A resolution in the House of Representatives to honor the contributions of patients who participate in clinical trials.

·   Senate 2029 - Physician Payments Sunshine Act

    Description: To create a reporting process for drug and medical device manufacturers reveal all payments and gifts of value which they make to physicians to the DHHS. 

The FDA’s clinical trial concerns have been focused on financial and vested interests of investigators and clinical trial sponsors.  Human subject protection depends upon the transparency of financial interest disclosure.  We may see more vigilant oversight concerning financial conflicts of interest on the part of sponsors and investigators.

Biosimilars – Generic Biologics

Bringing generic biologics to the market has been in the work for quite some time.  Biosimilars are sometimes referred to as follow-on biologics because they are generic versions of biological treatment products.  While generic versions of small molecules are very common, biological products are more complicated to make and often require elaborate fermentation and purifications processes.  The biosimilar manufacture does not have access the original cell type or molecular clone used to develop the marketed biologic therapeutic drug.  The real development caveat is to overcome the breakdown products which may cause adverse effects in the patient treated with the biosimilar product.

In spite of the manufacturing risks associated with biosimilars, law makers are determined to bring these products to the market in an attempt to lower the cost of medications.  Many of the pioneer biologic treatment products have soon to be expired patents.  The combined momentum to lower national health care costs along with the current bills in congress we are most likely to see some type of biosimilar reform and legislation. 

Stem Cells

President Obama reversed the strict limits placed on federal funding of stem-cell research by the Bush Administration. On March 19^th from the White House East Room, president Obama proclaimed, “Today, with the executive order I am about to sign, we will bring the change that so many scientists and researchers, doctors and innovators, patients and loved ones have hoped for, and fought for, these past eight years: We will lift the ban on federal funding for promising embryonic stem cell research” (17).  This will allow scientists to study hundreds of cell lines that were limited under the Bush era.  Scientists can now apply for NIH grants to study an expanded number of human embryonic stem cells which may lead to a greater understanding of stem cell biology and potential stem cell therapies.

The U.S. lost many good stem cell biologists as a result of the stem cell restrictions.  Significant basic science investigation at university medical centers depends on NIH grants to fund their research.  This early research is bridged into collaborations with industry to develop potential treatments.  The Bush stem cell ban interrupted these early stage collaborations and slowed the American progress of stem cell development.  We can expect to see significant growth in elucidating some of the science behind stem cells biology. 

The first-ever therapy using human embryonic stem cells enter a clinical trial early this year (18).  As stem cell therapies develop into medical treatments we can expect to see evolving regulations concerning their use.

Watching the Trends

There are a number of ways to watch for trends in the FDA.  The first place to look is the FDA website.  Warning letters show us what the FDA has been watching while congressional bills show us what legislation determines FDA policy.  We can anticipate developing points of view within the agency by examining the political background of the newly appointed department leaders. Congress can modify or undue what the agency has done.  When the agency acts, congress can react favorably or unfavorably. 

It is interesting to ponder how policy changes within the FDA will impact the pharmaceutical industry and eventually influence our healthcare.  Biosimilars have the potential to lower the cost of prescription biological treatments but may also impair innovation of new treatments.  Will it become financially difficult for the biologic developer to invent new prescription treatments with the new biogenetic legislation?  We can watch the developments of these changes in the more distant future and see how they impact our healthcare system and food supply.

Author: Trina Slabiak, RAC

1.       FDA website: http://www.cfsan.fda.gov/fdaoview.html

2.       FDA Web Site: http://www.fda.gov/default.htm

3.       Ex-New York Health Commissioner is FDA Pick, Gardner Harris; New York Times: March 11, 2009.

4.       Obama Appointee Sharfstein to be Acting FDA Chief, Lisa Richwine, Reporter; Reuters: March 27, 2009.

5.       Advocates for new FDA chief overlook independence, Alicia Mundy; Wall Street Journal Health Blog: December 18, 2008.  View at: http://blogs.wsj.com/health/2008/12/18/advocates-for-new-fda-chief-overlook-independence-from-industry/

6.       FDA Neglects Food Safety; St. Petersburg Times - A Times Editorial: April 26, 2009. View at: http://www.tampabay.com/opinion/editorials/article995147.ece     

7.       100 days later, Nation Waits for FDA Overhaul, Tom Costello, NBC News Correspondent; NBC News: April 25, 2009.  View at: http://www.msnbc.msn.com/id/30388073/    

8.       Full Plate for Obama’s New FDA Administrator, Marion Nestle, Nutrition and Public Policy Expert; San Francisco Chronicle: April 12, 2009. 

9.       Wyeth Loses Preemption Battle, George Koroneos, Online Content & News Editor; PharmExec Direct Marketing Edition: March 4, 2009.  View at: http://pharmexec.findpharma.com/pharmexec/Regulatory/Wyeth-Loses-Preemption-Battle/ArticleStandard/Article/detail/584710

10.   Justices Rule Against Drug Company in Injury Case, Robert Barnes, Staff Writer; Washington Post: March 5, 2009.  

11.   Compliance Report: FDA Enforcement Trends 2008-2009, Cerulean Associates LLC, Williamsburg, Virginia: March 2008 (download from www.ceruleanllc.com/reports).

12.   Effective Compliance and Quality Systems Oversight for Senior Executives, John Avellanet; Cerulean Associates LLC: October 2008 (download from www.ceruleanllc.com/seminars).

13.   2008 Year in Review: FDA Warning Letters and Untitled Letters Issued by DDMAC and APLB, Nikki Reeves, Christina Markus, Elaine Tseng, and Ami Patel; King and Spalding Client Alert: March 2009.

14.   Big Pharma Firms Warned Over Internet Drug Ads, Lynne Taylor; Pharma Times: April 7, 2009. View at: http://www.pharmatimes.com/WorldNews/article.aspx?id=15639  

15.   FDA to Check Safety of Old Devices, Gardner Harris; New York Times Business Section: April 8, 2009. View at: http://www.nytimes.com/2009/04/09/business/09device.html?partner=rss&emc=rss

16.   Understanding and Implementing the Revised FDA Part 11 and EU Annex 11, John Avellant; Cerulean Associates LLC: September 2008.

17.   Signing of Stem Cell Executive Order and Scientific Integrity Presidential; THE WHITE HOUSE Office of the Press Secretary.  Remarks of President Barack Obama – As Prepared for Delivery on March 9, 2009.

18.   In the News, Regulatory Affairs Professional Society (RAPS).  View at: http://www.raps.org/personifyebusiness/MediaCenter/IntheNews/tabid/342/Default.aspx#more   

April 2009- Novozymes and Millipore launched the first product from their alliance to supply animal-free cell culture supplements for bioprocessing. CellPrimeTM rTransferrin AF is the first animal-free alternative to serum-derived human or bovine transferrin for industrial cell culture and upstream biopharmaceutical applications.

CellPrime™ is a range of animal-free cell culture supplements that enable customers to utilize defined, animal-free supplements in their biopharmaceutical production processes. The new rTransferrin AF offers superior benefits over current plasma-derived alternatives, including facilitating effective iron uptake into cells for optimal cell culture and is now commercially available in scalable manufacturing quantities.

“We are pleased with the launch of our first commercial product and with the tremendous progress we have made in the first year of the alliance,” said Caspar Foghsgaard, Senior Manager, Novozymes Biopharma. “Both Novozymes and Millipore share a vision for providing biopharmaceutical manufacturers with a broad range animal-free supplements for industrial cell culture applications. The launch of animal-free transferrin for industrial scale production represents the first step toward that shared vision.”

“The expansion of our animal-free cell culture supplements offering is a critical part of our Bioprocess Division’s long-term strategy,” said Andrew Bulpin, Vice President of Millipore’s Upstream Bioprocessing Business Unit. “By working with an industry leader like Novozymes, we can complement our applications expertise to bring new, innovative products to the market that improve productivity and reduce the risk to our customers.”

Millipore is a Life Science leader providing cutting-edge technologies, tools, and services for bioscience research and biopharmaceutical manufacturing. For more information visit www.millipore.com.

Source: Novozymes Press Release

The advantages of this vaccine, in particular the convenience and the ease of administration, should help improve the coverage rate in Europe. This new vaccine for seasonal influenza will be marketed as Intanza® or IDflu®.

Intanza® / IDflu® vaccine is now approved in the European Union territory for the prevention of seasonal influenza in both the adult (aged 18 and over) and elderly (aged 60 and over) populations.

“This is the first major market license for Intanza® / IDflu® and a key step towards recognition of the ID route as a promising alternative for influenza vaccine administration,” said Wayne Pisano, President and CEO of Sanofi Pasteur.

The approval of Intanza® / IDflu® vaccine follows the positive opinion from the European Medicines Agency (EMEA) granted in December 2008, based on a review of data from clinical trials, involving more than 7,000 adults (aged 18 and over) or elderly participants (aged 60 and over). These trials evaluated the safety and ability to generate an immune response which meets all required EMEA criteria (1,2).

This innovative easy-to-use, pre-filled ID microinjection vaccine was developed with the objective of improving the standard of care for the prevention of seasonal influenza infection. “In clinical trials, Intanza® / IDflu® was highly accepted by adult and elderly people who received it while providing an effective and safe protection against influenza. Moreover, it was reported to facilitate influenza antigen administration and was appreciated for this by health care professionals,” added Pisano. “As for patients, the comfort benefits offered by Intanza® / IDflu® have the potential to improve the

coverage rate and consequently to help to protect more people and save more lives,” concluded Pisano.

About the intra-dermal route for vaccination

Vaccination via the ID route involves the administration of the antigen into the dermal layer of the skin. Due to the high concentration of specialized immune cells in this skin layer and their ability to effectively stimulate an immune response, ID vaccination provides direct and efficient access to the immune system.

This new convenient and user-friendly microinjection system, developed in collaboration with sanofi pasteur’s partner, BD (Becton, Dickinson and Company) provides a simple, safe and reliable (3,4) intradermal influenza immunization. The fine needle of the micro-injection system has a length of only 1.5 mm, ten times smaller than standard needles for the traditional intramuscular route.

Intanza® / IDflu® unique design and technology allows for a minimally invasive vaccination and ensures that the antigen is accurately and consistently deposited in the dermal layer of the skin (3).

As the world leader in research, development and manufacturing of influenza vaccines, sanofi-pasteur is working to develop new and improved influenza vaccines to save lives. With the production of more than 170 million doses of seasonal influenza vaccine in 2008, Sanofi Pasteur confirmed its global influenza vaccine market leadership.

* Intanza® and IDflu® are registered trademarks of sanofi pasteur’s novel microinjection system influenza vaccine in EU and other countries.

Seasonal Influenza Overview

Influenza is a disease caused by a highly infectious virus that spreads easily from person to person, primarily when an infected individual coughs or sneezes. According to the World Health Organization (WHO), 5-15% of the population is affected with upper respiratory tract infections in annual influenza epidemics. Hospitalization and deaths mainly occur in high-risk groups (elderly, people with chronic conditions/illness).

Although difficult to assess, these annual epidemics are thought to result in between

three and five million cases of severe illness and between 250,000 and 500,000 deaths every year around the world (5). Most deaths currently associated with influenza in industrialized countries occur among those over 65 years of age. The efficacy of vaccination in reducing the burden of the disease, as well as the economic burden of treating influenza, is well established.

About sanofi-aventis

Sanofi-aventis, a leading global pharmaceutical company, discovers, develops and distributes therapeutic solutions to improve the lives of everyone. Sanofi-aventis is listed in Paris and in NewYork. Sanofi Pasteur, the vaccines division of sanofi-aventis Group, provided more than 1.6 billion doses of vaccine in 2008, making it possible to immunize more than 500 million people across the globe. A world leader in the vaccine industry, Sanofi Pasteur offers the broadest range of vaccines protecting against 20 infectious diseases. The company's heritage, to create vaccines that protect life, dates back more than a century. Sanofi Pasteur is the largest company entirely dedicated to vaccines. Every day, the company invests more than EUR1 million in research and development. For more information, please visit: www.sanofipasteur.com or www.sanofipasteur.us

References:

1. Leroux-Roels I, Vets E, et al Vaccine 2008; 26:6614-19. Seasonal influenza vaccine delivered by intradermal

microinjection: a randomized controlled safety and immunogenicity trial in adults

2. Holland D, Booy R, et al JID 2008; 198:650-58. Intradermal influenza vaccine administered using a new microinjection

system produces superior immunogenicity in elderly adults: a randomized controlled trial

3. Laurent PE, et al Vaccine 2007; 25:8833-42. Evaluation of the clinical performance of a new intradermal vaccine

administration technique and associated delivery system

4. Laurent A, et al Vaccine 2007;25:6423–6430. Echographic measurement of skin thickness in adults by high frequency

ultrasound to assess the appropriate microneedle length for intradermal delivery of vaccines

5. http://www.who.int/vaccine_research/diseases/ari/en/print.html

Source: Sanofi-aventis Press Release

Establishes Leadership in Human, Animal, and Consumer Health, including Primary and Specialty Care; in Vaccines, Biologics and Small Molecules; and Across Developed and Emerging Markets

Unique and Flexible Business Model Features Focus and Agility of Smaller Enterprises Backed by Resources and Scale of Global Company

Combination Strengthens Platform for Improved, Consistent, and Stable Earnings Growth and Sustainable Shareholder Value

New Company Will Promote Health and Wellness and Respond More Effectively to Unmet Needs of Patients, Physicians, and Customers Around the World

NEW YORK, NY and MADISON, NJ--January 26, 2009 - Pfizer and Wyeth announced that they have entered into a definitive merger agreement under which Pfizer will acquire Wyeth in a cash-and-stock transaction currently valued at $50.19 per share, or a total of approximately $68 billion. The Boards of Directors of both companies have approved the combination.

The combined company will create one of the most diversified companies in the global health care industry. Operating through patient-centric businesses that match the speed and agility of small, focused enterprises with the benefits of a global organization's scale and resources, the company will respond more quickly and effectively to meet changing health care needs. The combined company will have product offerings in numerous growing therapeutic areas, a strong product pipeline, leading scientific and manufacturing capabilities, and a premier global footprint in health care.

With its broad and diversified global product portfolio and reduced dependence on small molecules, the new company will be positioned for improved, consistent, and stable top-line and EPS growth and sustainable shareholder value in the short and long term. It is expected that no drug will account for more than 10 percent of the combined company's revenue in 2012.

Financial Highlights

Under the terms of the transaction, each outstanding share of Wyeth common stock will be converted into the right to receive $33 in cash and 0.985 of a share of Pfizer common stock, subject to the terms of the merger agreement. Based on the closing price of Pfizer stock as of January 23, 2009, the stock component is valued at $17.19 per share. The transaction provides immediate value to Wyeth shareholders through the cash component, as well as continued participation in the future prospects expected to result from the combination through their ownership of approximately 16 percent of Pfizer's shares.

The deal is expected to be accretive to Pfizer's adjusted diluted earnings per share in the second full year after closing(1). The transaction is anticipated to yield cost savings of approximately $4 billion to be fully realized by the third year after closing. Savings are expected in selling, informational and administrative functions, research and development, and manufacturing.

The transaction will be financed through a combination of cash, debt and stock. A consortium of banks has provided commitments for a total of $22.5 billion in debt.

In connection with the proposed transaction between Pfizer and Wyeth, the Board of Directors of Pfizer has determined that, effective with the dividend to be paid in the second quarter of 2009, it will reduce Pfizer's quarterly dividend per share to $0.16, which continues to be competitive with other industry participants. Pfizer believes the transaction offers significant opportunities to enhance long-term shareholder value.

Strategic Overview

Jeffrey B. Kindler, Chairman and Chief Executive Officer of Pfizer, said: "The combination of Pfizer and Wyeth provides a powerful opportunity to transform our industry. It will produce the world's premier biopharmaceutical company whose distinct blend of diversification, flexibility, and scale positions it for success in a dynamic global health care environment. The new company will be an industry leader in human, animal and consumer health. With our combined biopharmaceuticals business, it will lead in primary and specialty care as well as in small and large molecules. Its geographic presence in most of the world's developed and developing countries will be unrivaled."

Bernard Poussot, Chairman, President and Chief Executive Officer of Wyeth, said, "Wyeth's commitment to scientific innovation has enabled us to build a diversified biopharmaceutical company with leadership in attractive growth areas such as vaccines, nutritionals and biologics. For example, Wyeth developed Prevnar, the first pneumococcal vaccine for infants. In addition, because we were early to see the potential of biotechnology to create life-changing medicines, we now have a strong franchise which includes Enbrel, the number one biotechnology product in the world. With our business focused on prevention and wellness, Wyeth is well positioned in today's rapidly changing health care environment. Our employees should be enormously proud of what we have built and confident that combining with Pfizer will accelerate our pursuit of innovative new medicines to meet critical unmet patient needs. Wyeth and Pfizer are highly complementary businesses, and together we can build the best diversified health care company in the world. We believe we can better execute our strategy and can accomplish far more together in the years ahead than either company could have achieved on its own."

Mr. Kindler continued, "With this combination, Pfizer will offer patients around the world a uniquely broad and diversified portfolio of biopharmaceutical innovations through business units--each one focused on different customer needs and backed by the resources of a premier global organization. By combining the spirit of small, agile enterprises with our combined scale, Pfizer will advance its mission of working together toward a healthier world."

Over the last two years, Pfizer has become a leaner, more disciplined, and far stronger company that is now capable of - and has demonstrated - superior and consistent execution of its strategies and commitments. As separately announced today, for example, Pfizer achieved its 2008 objectives despite the challenging economy, including meeting or exceeding its financial guidance and cost-reduction target.

With this essential foundation established, the combination with Wyeth meaningfully advances in a single transaction each of the strategic priorities that Pfizer has identified and pursued over the last two years, including:

    *  Enhancing the in-line and pipeline patent-protected portfolio in key "Invest to Win"  disease areas, such as Alzheimer's disease, inflammation, oncology, pain and psychosis;

    *  Becoming a top-tier player in biotherapeutics and vaccines;

    * Accelerating growth in emerging markets;

    * Creating new opportunities for established products;

    *  Investing in complementary businesses; and

    * Creating a lower, more flexible cost base.

Mr. Kindler added, "Over the last several years, Wyeth's leadership and its employees have done an outstanding job creating a strong, diversified biopharmaceutical company. The people, products, and technologies that Wyeth brings to the new company will enhance our scientific capabilities and drive further commercial innovation to improve the health of the patients we serve. The compelling combination of Pfizer and Wyeth allows us to advance our newly strengthened organization to the next level by harnessing the talents of the best people from both companies. This will enable us to accelerate significantly our progress along 'Our Path Forward' as we pursue our mission of applying innovative science to improve world health."

Global Biopharmaceutical Leadership and Business Diversification

The combination of Pfizer and Wyeth will create the world's premier biopharmaceutical company with a broad range of therapeutic solutions for many health challenges and preventive care.

For Patients Today - A Broad Portfolio of Health Care Solutions and Treatments

The combined company will offer customers and patients a broad range of products for every stage of life--with top tier portfolios in key therapeutic areas such as cardiovascular, oncology, women's health, central nervous system, and infectious disease and a diverse product portfolio that includes 17 products with more than $1 billion each in annual revenue. Pfizer will be the second largest specialty care provider, with products including the world's leading biologic, Enbrel; Prevnar, the world's largest-selling vaccine; Sutent for cancer; Geodon for schizophrenia; and Zyvox for infection. The transaction also builds upon Pfizer's position as a global leader in animal health, with strong product lines in attractive segments, for companion animals, biologics and anti-infectives.

For Patients Tomorrow - A Diverse Range of Technology and Research Platforms

The new company will have more resources to invest in research and development than any other biopharmaceutical company and access to all leading scientific technology platforms, including vaccines, small and large molecules, nutritionals and consumer products.

The combination also brings together a robust pipeline of biopharmaceutical research and development projects, including programs in diabetes, inflammation/immunology, oncology and pain, as well as significant opportunities in Wyeth's Alzheimer's disease pipeline, which has a number of compounds in development, including phase three biotech compound Bapineuzumab. These will be added to the exciting agents currently in early and later stage development at Pfizer for Alzheimer's disease, illustrating the breadth and depth the new company will be able to use in targeting the diseases that most affect patients.

The new company will have an enhanced ability to innovate, operating as focused business units tailored to patients and other customers. Each business unit will oversee product development from clinical trials to commercialization. This approach will allow for rapid decision-making and a more efficient use of resources and, as a result, will enhance the company's ability to invest in long-term opportunities. The combination will also provide additional high quality and high volume manufacturing capabilities, including Wyeth's Grange Castle, Ireland facility, the largest integrated biotechnology manufacturing facility in the world.

For Patients Everywhere - A Strong Global Presence

Geographically, the combination will enhance Pfizer's and Wyeth's compelling portfolios in important growth areas. Based on IMS data, the combined company will be number one in terms of biopharmaceutical revenues in the United States with an approximately 12% market share; in Europe with an approximately 10% share; in Asia (ex-Japan) with an approximately 7% share; in Japan with a 6% share; and in Latin America with a 6% share.

Pfizer and Wyeth's combined presence will be significant in high-growth emerging markets, such as Latin America, the Middle East and China, where Wyeth has an impressive presence in infant nutritionals and Pfizer is a recognized leader in pharmaceuticals. This enhanced geographic position will further strengthen the combined company's business, provide increased exposure to high-growth, less-developed and under-penetrated markets, and provide compelling opportunities for expense savings.

Conditions

The proposed transaction is subject to customary closing conditions, including approval by the stockholders of Wyeth, notification and clearance under certain antitrust statutes. In addition, the proposed transaction is subject to Pfizer's financing sources not declining to provide the financing due to a material adverse change with respect to Pfizer or Pfizer failing to maintain credit ratings of A2/A long-term stable/stable and A1/P1 short term affirmed. There are no other financing conditions to closing in the merger agreement. Pfizer and Wyeth expect the transaction to close at the end of the third quarter or during the fourth quarter 2009.

Advisors

Pfizer's lead financial advisors are Bank of America Merrill Lynch, Goldman Sachs and J.P. Morgan. Barclays and Citigroup are acting as financial advisors. Its legal advisor is Cadwalader, Wickersham & Taft LLP. Wyeth's financial advisors are Morgan Stanley and Evercore Partners and its legal advisor is Simpson Thacher & Bartlett LLP. In addition, Wachtell, Lipton, Rosen & Katz served as counsel to Wyeth's Board of Directors.

ABOUT PFIZER

Pfizer Inc, founded in 1849, is dedicated to better health and greater access to health care for people and their valued animals. Every day, approximately 81,900 colleagues in more than 150 countries work to discover, develop, manufacture and deliver quality, safe and effective prescription medicines to patients.

ABOUT WYETH

Wyeth is one of the world's largest research-driven pharmaceutical and health care products companies. It is a leader in the discovery, development, manufacturing and marketing of pharmaceuticals, vaccines, biotechnology products, nutritionals and non-prescription medicines that improve the quality of life for people worldwide. The Company's major divisions include Wyeth Pharmaceuticals, Wyeth Consumer Healthcare and Fort Dodge Animal Health.

Source: Pfizer Press  Release

* To date there are no approved vaccines to prevent CMV infections

* The vaccine is expected to enter phase II clinical trials in 2009

Basel, December 29, 2008 - Novartis has strengthened its vaccines pipeline through an exclusive agreement to license AlphaVax' investigational Cytomegalovirus (CMV) vaccine program. This CMV agreement adds to Novartis' promising early stage pipeline of novel vaccines, which focuses on significant unmet needs for the prevention of fatal diseases such as meningococcal infections and other hospital and community acquired infections. These include vaccines to prevent Helicobacter pylori infections, a major cause of gastritis that can lead to gastric cancer, and a Group B Streptococcus vaccine candidate with potential to protect against 85 percent of neonatal sepsis and meningitis.

"We are happy to gain access to a promising vaccine candidate for the prevention of cytomegalovirus infections, which are particularly problematic during pregnancy as they can cause permanent disability in newborns", said Dr. Andrin Oswald, CEO of Novartis Vaccines and Diagnostics.

AlphaVax is responsible for finalization of phase I clinical trials, and will provide the clinical trial material for the phase II trials. Novartis will be responsible for the development of the CMV program for phase II clinical trials onwards as well as for registration and world-wide commercialization. The AlphaVax vaccine candidate is based on an alphavirus replicon particle encoding CMV phosphoprotein 65, IE1 (immediate early protein 1) and soluble gB protein.

Novartis signed a definitive agreement to acquire rights to AlphaVax' investigational CMV program for an upfront payment of USD 20 million, which also grants rights of first negotiation to AlphaVax' preclinical respiratory syncytial virus (RSV) program. In addition Novartis has an option to make an equity investment at the end of phase II clinical trials for 4 million shares. Under the terms of the agreement AlphaVax will be eligible for milestones and royalties.

About Novartis

Novartis AG provides healthcare solutions that address the evolving needs of patients and societies. Focused solely on healthcare, Novartis offers a diversified portfolio to best meet these needs: innovative medicines, cost-saving generic pharmaceuticals, preventive vaccines, diagnostic tools and consumer health products. Novartis is the only company with leading positions in these areas. In 2007, the Group's continuing operations (excluding divestments in 2007) achieved net sales of USD 38.1 billion and net income of USD 6.5 billion. Approximately USD 6.4 billion was invested in R&D activities throughout the Group. Headquartered in Basel, Switzerland, Novartis Group companies employ approximately 97,000 full-time associates and operate in over 140 countries around the world. For more information, please visit http://www.novartis.com.

Many People with Incontinence Conditions Suffer without Seeking Medical Help, Recent NIH Report Shows

NEW YORK--Pfizer Inc said that the U.S. Food and Drug Administration (FDA) approved TOVIAZ™ (fesoterodine fumarate) extended release tablets for the treatment of overactive bladder (OAB) symptoms. New once-daily TOVIAZ can significantly reduce the number of urge urinary incontinence episodes and the frequency of urination over 24 hours, symptoms of OAB that can significantly impact patients’ lives. Overactive bladder is a bothersome medical condition that affects an estimated one in six Americans, yet still remains highly undertreated. TOVIAZ is currently available in Europe.

Structurally related to the most prescribed OAB medication, Pfizer’s Detrol® LA (tolterodine tartrate extended release capsules), TOVIAZ can help regulate the involuntary contractions of the bladder associated with OAB. These contractions cause frequent, sudden urges to urinate. The two efficacious and well-tolerated doses of TOVIAZ, 4 mg and 8 mg, allow dosing flexibility to optimize treatment based on the individual patient response and tolerability.

“The emotional and social implications for people who suffer from OAB are challenging, yet the condition remains underdiagnosed and highly undertreated,” said Nancy Muller, executive director, National Association For Continence. “We need to encourage people with OAB symptoms to stop simply coping and start talking to their doctors about finding treatment approaches that work for them. New treatments, like TOVIAZ, offer healthcare professionals another option to help their patients.”

Symptoms of OAB can have a profound effect on workplace productivity, social and sexual activity and sleep. Overactive bladder may also lead to other health problems, such as falls and fractures, urinary tract infections and skin disorders, sleep problems and depression. Despite the impact of OAB on patients’ lives, research, including a March 2008 National Institutes of Health (NIH) report, concludes that the embarrassment and stigma associated with incontinence can cause sufferers to try to hide the condition from families, friends and even their doctors. As a result, many with incontinence conditions suffer without seeking help.

“Pfizer is proud to offer TOVIAZ, a new treatment for OAB symptoms that builds on our strong heritage in urology,” said Jim Maffezzoli, senior director, group leader, Pfizer. “We will continue to partner with physicians and patients to provide extensive support and education to help enhance treatment success.”

Dr. Victor Nitti, professor and vice chairman of urology at the New York University Langone Medical Center and a principal investigator for TOVIAZ, added, “The FDA approval of TOVIAZ is good news for patients and treating physicians. Clinical trials with TOVIAZ showed strong efficacy and favorable tolerability, and the ability to titrate the dose of TOVIAZ allows physicians flexibility in treating each patient based on individual history and need.”

TOVIAZ Data Demonstrate Efficacy, Safety

 The approval of TOVIAZ is based on two large 12-week Phase III clinical studies of 1,964 OAB patients. In these studies, patients showed up to an 88 percent median reduction in urge urinary incontinence with TOVIAZ 8 mg versus 50 percent with placebo. Treatment with TOVIAZ 8 mg reduced the number of urinations per day by up to 19 percent compared to an 11 percent reduction with placebo treatment. Reductions in wetting accidents with TOVIAZ were seen as early as week two of treatment and maintained over 12 weeks.

In clinical studies, the most commonly reported adverse event was dry mouth (incidence of 7 percent for placebo; 19 percent for TOVIAZ 4 mg; 35 percent for TOVIAZ 8 mg). Most cases of dry mouth were mild to moderate with less than one percent of patients discontinuing TOVIAZ due to dry mouth. There was a low incidence of constipation (2 percent with placebo; 4 percent with 4 mg; 6 percent with 8 mg). TOVIAZ was evaluated for up to three years in open-label studies, with an adverse event profile similar to that seen in previous trials.

TOVIAZ will be available in the United States in the first half of 2009.

Important Safety Information for TOVIAZ and Detrol LA

 TOVIAZ and DETROL LA treat the symptoms of overactive bladder (leaks, strong sudden urges to go, going too often).

If you have certain stomach problems, glaucoma, or trouble getting urine to pass, you shouldn’t take TOVIAZ or DETROL LA.

The most common side effects (≥4%) of TOVIAZ are dry mouth and constipation.

The most common side effects (≥4%) of DETROL LA are dry mouth, headache, constipation, and abdominal pain.

TOVIAZ and DETROL LA, like all medicines, have benefits and risks. There may be other options. Ask your doctor if TOVIAZ or DETROL LA is right for you. For more information, visit TOVIAZ.com. or DETROLLA.com.

About Overactive Bladder

 Overactive bladder is a treatable medical condition defined by urinary urgency (a sudden compelling desire to pass urine that is difficult to defer) with or without urgency urinary incontinence (the involuntary leakage of any amount of urine, associated with or immediately preceded by urgency), increased daytime urinary frequency and nocturia.

Overactive bladder affects an estimated one in six Americans; yet it is not necessarily a natural part of aging as many people assume. Overactive bladder can impact a wide range of health-related quality of life issues. However, many people with OAB do not seek medical help due to embarrassment or the belief that nothing can be done to alleviate their symptoms.

Permalink: http://mediaroom.pfizer.com/news/pfizer/20081031005701/en

--Expanded EU label includes data showing 35% reduction in new fractures in Aclasta-treated patients who recently suffered a low-trauma hip fracture[2]--

--Aclasta also the only osteoporosis treatment to show 28% reduction in all-cause mortality following a low-trauma hip fracture[2]--

Basel, September 30, 2008 - The European Commission has approved once-yearly Aclasta®* (zoledronic acid 5 mg) for the treatment of osteoporosis in men who are at increased risk of fractures, and broadened the Aclasta label to include reduction of new clinical fractures in both men and postmenopausal women with osteoporosis who have recently suffered a hip fracture.

Osteoporosis is an important health concern for men, with an estimated one out of five over the age of 50 experiencing an osteoporotic fracture[1]. In cases of hip fracture - one of the most serious consequences of osteoporosis - the mortality rate is higher in men than women in the year following the fracture[3]. Over the first six months, men are approximately twice as likely to die as women of a similar age[3].

"Despite the severity and the large numbers affected, osteoporosis in men has received very little attention," said Steven Boonen, Professor of Medicine at the Leuven University Centre for Metabolic Bone Diseases and Division of Geriatric Medicine in Belgium. "Most people view osteoporosis solely as a 'woman's disease', but this is not the case. It is vital that men with osteoporosis have the same efficacious treatment options available to them as women, and today's announcement is therefore especially welcome."

In addition, the EU label has been extended to include data from the landmark Recurrent Fracture Trial, involving more than 2,100 patients, showing that once-yearly Aclasta reduced the risk of new clinical fractures by 35% in men and postmenopausal women who have recently had a low-trauma hip fracture (e.g. due to a fall from standing height or less).

The new label also includes data from the same study showing that all-cause mortality was significantly reduced by 28% in the Aclasta-treated group compared to those receiving placebo (101 vs. 141 deaths respectively)[2]. Aclasta is the only osteoporosis treatment to demonstrate these benefits in patients after a recent low-trauma hip fracture.

"For both men and women, hip fracture can be a potentially life-threatening consequence of osteoporosis," said Prof. Boonen. "Hip fracture is associated with a high risk of morbidity and mortality, and it is encouraging that we now have a treatment proven to reduce the risk of a new fracture after this has occurred."

In 2000, approximately 1.6 million hip fractures occurred worldwide[3], and in Europe the number of hip fractures was estimated at around 179,000 for men and 711,000 for women[1]. The cost of all osteoporotic fractures was estimated to be €31.5 billion[1].

"At Novartis we are committed to putting the needs of the patient first," said Trevor Mundel, MD, Global Head of Development Functions at Novartis Pharma AG. "More than a quarter of a million patients have already been treated with Aclasta, and these new approvals mean that two new populations can be treated with this once-yearly dosing regimen. This once yearly dosing represents a convenient way to help protect both men and women against the life-threatening consequences of osteoporosis."

The EU Commission approval, following a positive opinion issued in July by the Committee for Medicinal Products for Human Use (CHMP), will apply in all 27 EU member states plus Iceland and Norway.

Approval was based on pivotal data from the Recurrent Fracture Trial, involving more than 2,100 men and women aged 50 and above who had recently suffered a low-trauma hip fracture[2]. Aclasta was shown to reduce the risk of new clinical fractures by 35% compared to patients receiving placebo[2], and to increase bone mineral density (BMD). The risk of new spine fractures was reduced by 46%[2].

A two-year head-to-head trial comparing Aclasta with weekly oral alendronate provided additional data on the treatment of male osteoporosis[4]. This study involving more than 300 osteoporotic men showed that Aclasta preserved and improved lumbar spine BMD at 24 months[4].

Aclasta, which is administered by once-yearly infusion, was approved in the EU in October 2007 for the treatment of osteoporosis in postmenopausal women. It is now approved in more than 80 countries in this indication and is currently available in more than 70 countries including the US, Canada, Brazil and most EU member states. Aclasta is available in the US under the trade-name Reclast®.

Aclasta/Reclast is the only treatment for postmenopausal osteoporosis approved in the EU and US to reduce the risk of fractures at all key sites, including the hip, spine and non-spine (e.g. wrist and rib)[5].

In June 2008, the Food and Drug Administration (FDA) broadened the US label to include data showing the reduced risk of new clinical fractures in patients who have recently had a low-trauma hip fracture[6]. Novartis has applied for an indication in the US for the treatment of osteoporosis in men.

Reclast is covered by Medicare and most commercial health plans in the US. Reimbursement discussions are continuing in many other countries to maximize patient access to this innovative medication. Novartis is seeking to meet the needs of patients and physicians in different countries by establishing a network of infusion centers to promote safe and correct administration of Aclasta.

Aclasta is also approved in more than 80 countries for the treatment of Paget's disease of the bone, the second most common metabolic bone disorder.

Aclasta has a demonstrated tolerability profile. The most common adverse events associated with Aclasta were transient post-dose symptoms such as fever and muscle pain. Most of these symptoms occurred within the first three days following Aclasta administration and resolved within three days. The incidence of such post-dose symptoms can be reduced with the administration of paracetamol or ibuprofen shortly after Aclasta infusion.

Zoledronic acid, the active ingredient of Aclasta, is also available under the trade-name Zometa® for use in oncology indications.

About Novartis

Novartis AG provides healthcare solutions that address the evolving needs of patients and societies. Focused solely on healthcare, Novartis offers a diversified portfolio to best meet these needs: innovative medicines, cost-saving generic pharmaceuticals, preventive vaccines, diagnostic tools and consumer health products. Novartis is the only company with leading positions in these areas. In 2007, the Group's continuing operations (excluding divestments in 2007) achieved net sales of USD 38.1 billion and net income of USD 6.5 billion. Approximately USD 6.4 billion was invested in R&D activities throughout the Group. Headquartered in Basel, Switzerland, Novartis Group companies employ approximately 98,000 full-time associates and operate in over 140 countries around the world. For more information, please visit http://www.novartis.com.

References

[1] International Osteoporosis Foundation. Report "Osteoporosis in Men". Available at: www.iofbonehealth.org/download/osteofound/filemanager/publications/pdf/osteoporosis_in_men.pdf. Last access September 2008.

[2] Lyles KW, Colon-Emeric CS, Magaziner JS, et al. for the HORIZON Recurrent Fracture Trial. Zoledronic acid and clinical fractures and mortality after hip fracture. N Engl J Med. 2007:537:1799-1809.

[3] International Osteoporosis Foundation, Facts and statistics about osteoporosis and its impact. Available at: www.iofbonehealth.org/facts-and-statistics.html#factsheet-category-16. Last access September 2008.

[4] Novartis, Pharma AG, Data on file.

[5] Black DM, Delmas PD, Eastell R, et al. for the HORIZON Pivotal Fracture Trial. Once-yearly zoledronic acid for treatment of postmenopausal osteoporosis. N Engl J Med. 2007; 356: 1809-1822.

[6] Reclast® (zoledronic acid) Injection [Prescribing Information]. East Hanover, NJ: Novartis Pharmaceuticals Corporation; June 2008.

Source: Novartis Press Release

Q & A with Robert Temple, M.D., FDA’s Director of the Office of Medical Policy at FDA’s Center for Drug Evaluation and Research.

Dr. Temple graduated from New York University School of Medicine and completed his residency in internal medicine at Columbia's College of Physicians and Surgeons in New York City. He has been with FDA for 36 years.

Credit: FDA Consumer Health Information

e-published on MedicineandBiotech.com August 1^st, 2008

Q. What is Vytorin?

A. Vytorin is one tablet that combines two cholesterol-lowering drugs—simvastatin (Zocor), a statin made by Merck & Co., and ezetimibe (Zetia), made by Schering-Plough Pharmaceuticals—to help lower bad cholesterol (low-density lipoprotein, or LDL) further. Simvastatin works in the liver to prevent the formation of cholesterol (as do all statin medications), while ezetimibe works by preventing the absorption of cholesterol from the intestine.

Q. What is the ENHANCE study?

A. About four years ago, Merck and Schering-Plough began a study—Ezetimibe and Simvastatin in Hypercholesterolemia Enhances Atherosclerosis Regression, or ENHANCE—that compared the effect of ezetimibe combined with simvastatin (Vytorin) to simvastatin alone. The patients in the study were people with a genetic condition of very high cholesterol called familial hypercholesterolemia. Through images taken with ultrasound, the study evaluated the thickness of the walls of the blood vessels of the neck (carotid arteries). Some studies indicate that increased thickness of the carotid artery walls is associated with an increased risk for cardiovascular disease.

ENHANCE did not try to show an effect of Vytorin on important outcomes, such as the chance of a heart attack or stroke. Rather, it was an imaging study of what is often called a biomarker—in this case, the thickness of the blood vessel walls.

Q. What were the results of the ENHANCE study?

A. While the combination drug Vytorin did better at lowering LDL cholesterol levels than treatment with simvastatin alone, the effect of Vytorin on carotid artery wall thickness was no greater than that observed with simvastatin by itself.

The results were disappointing, of course, but they do not give the answer about the value of ezetimibe. At this point we know that ezetimibe lowers cholesterol modestly (not nearly as much as a statin), but we do not have definitive evidence that it lowers the risk for cardiovascular disease. The answer to whether it does should come from a large (18,000-patient) outcome study that will examine the effect of ezetimibe added to simvastatin on cardiovascular outcomes. That study is underway but will not be completed for several years.

It is not clear why the lower levels of LDL cholesterol in patients who took Vytorin did not lead to favorable changes in carotid artery wall thickness, compared to patients treated with simvastatin alone. FDA is now reviewing the final results from the ENHANCE study.

Q. Does the Vytorin situation call into question the value of lowering cholesterol levels or the benefits of statins?

A. No. There is overwhelming evidence from many studies that people with elevated LDL cholesterol—a very well-established risk factor for heart disease—reduce their risk of a heart attack or stroke and death by lowering cholesterol with a statin. FDA's initial approval of cholesterol medications is based on a drug's ability to demonstrate successful lowering of LDL cholesterol. But every statin to date has been shown in a large outcome study to improve cardiovascular outcome, and labeling for all drugs, except for the most recently approved statin, Crestor, states this clearly. A similar finding has been reported for Crestor, but the study has not yet been reviewed by FDA.

Q. Why, then, the recent public uncertainty about the value of lowering LDL cholesterol, based on the small Vytorin study?

A. We think many people may have misunderstood both the intent and the results of ENHANCE. The study was designed to show an added benefit of ezetimibe on a biomarker and clearly failed to do so. But this does not tell you whether lower cholesterol with ezetimibe will prove useful. The results of the study were released online in the New England Journal of Medicine (NEJM) in January 2008, accompanied by news reports asking whether the results have shaken confidence in the value of lowering cholesterol, even using statins.

Although the study could perhaps lead to doubts about ezetimibe—noting again that its lack of effect was on a biomarker—it casts no doubt at all on the value of lowering cholesterol with a statin. Unfortunately, the statins, which have repeatedly been shown to give large reductions in cholesterol levels and a lower risk of dying from heart disease, were also being characterized as having uncertain benefits.

In fact, there is no basis at all for questioning the cardiovascular benefits of statins in reducing the rate of death, heart attack, and stroke in people at risk from elevated LDL cholesterol. And we are worried that some people might suddenly stop taking their statins or other preventive medicines, such as antihypertensives, either because they misunderstood news reports or are affected by a more general sense of doubt.

We already know that people tend to stop taking all long-term drugs, including statins, when they're on them. And I'm very concerned that aspects of the Vytorin discussion will lead to people becoming indifferent to an extremely important measurement—LDL cholesterol.

Q. What are the benefits of lowering your cholesterol?

A. Cholesterol is essential to the formation of certain hormones. But where LDL cholesterol levels are too high, they cause or accelerate the development of arteriosclerotic plaques (fatty deposits) in blood vessels in the heart or brain, increasing the chance of a heart attack or stroke. According to the Centers for Disease Control and Prevention, heart disease is the leading cause of death for both women and men in the United States. As mentioned, statins have been shown in numerous studies to lower the risk of heart disease and stroke. A simple blood test by your doctor will measure the different kinds of cholesterol in the body, and will allow the doctor to advise on effective treatment.

Q. What is your advice for consumers?

A. People should not misunderstand ENHANCE and think it means that elevated LDL cholesterol need not be lowered. To do so could mean significant personal and public health consequences if it drives them away from continuing to reduce their risk of heart disease through lowering their cholesterol. People should not stop taking Vytorin or any other drug containing a statin without their doctor's recommendation, even if they have concerns about the study. Patients can discuss with their doctors whether they should take a larger statin dose or add ezetimibe to control LDL cholesterol adequately. The results with statins make it overwhelmingly clear that controlling LDL cholesterol is essential.

This article appears on FDA's Consumer Health Information Web page (www.fda.gov/consumer ), which features the latest updates on FDA-regulated products. Sign up for free e-mail subscriptions at www.fda.gov/consumer/consumerenews.html.

For More Information

Controlling Cholesterol with Statins

www.fda.gov/consumer/updates/statins051608.html

FDA Early Communication About an Ongoing Data Review for Ezetimibe/Simvastatin (marketed as Vytorin), Ezetimibe (marketed as Zetia), and Simvastatin (marketed as Zocor)

www.fda.gov/cder/drug/early_comm/ezetimibe_simvastatin.htm

FDA's Center for Drug Evaluation and Research

www.fda.gov/cder/

National Heart, Lung, and Blood Institute Health Information Center

www.nhlbi.nih.gov/health/infoctr/

--Historically, one in two patients experienced recurrence of GIST after surgery—

--Regulatory submissions reflect continued commitment to bringing new therapeutic approaches to patients with rare diseases—

Basel, August 27 2008 - Novartis announced that Glivec® (imatinib)* has been granted priority review status by the US Food and Drug Administration (FDA) as the first therapy to be reviewed for use after surgery in kit-positive gastrointestinal stromal tumors (GIST). FDA priority review status is granted to therapies that could potentially fill a currently unmet medical need and accelerates the standard review timing from ten to six months[1]. Similar regulatory submissions have been filed in the European Union and Switzerland and will be filed in other countries shortly.

The Glivec submissions are based on data from a Phase III, double-blind, randomized, multicenter, international study of more than 700 GIST patients who had surgery to remove their tumors. The results showed a dramatic 89% reduction in risk of GIST returning after surgery (adjuvant setting) in patients treated with Glivec versus placebo[2].

In early 2007, the study met its primary efficacy endpoint, showing an advantage for Glivec in recurrence-free survival. At that time, following the recommendation of the independent study data monitoring committee to stop the trial accrual early, the study investigators made public the interim results and offered Glivec to patients receiving placebo[3].

Approximately half of all patients with newly diagnosed GIST are considered candidates for surgical resection, or removal of their tumors. Of those who have the surgery, about half will suffer a recurrence[4]. If approved for this indication, Glivec will be the first treatment option available to GIST patients after surgery to reduce the risk of disease recurrence or to possibly prevent the disease from returning.

"FDA priority review status acknowledges the potential for Glivec to become the first post-surgery treatment available to GIST patients and may soon create a fundamental shift in the treatment of this disease," said Herve Hoppenot, Executive Vice President, Chief Commercial Officer, Novartis Oncology.

Glivec is currently indicated in both the US and EU for the first-line treatment of metastatic or unresectable (inoperable) kit-positive GIST. If approved, the use of Glivec for the treatment of GIST in the adjuvant setting would add to its eight current indications, which include Philadelphia chromosome-positive chronic myelogenous leukemia (Ph+ CML) and five other rare diseases. Novartis also has a therapy for the treatment for carcinoid tumors and acromegaly and multiple treatments in the pipeline targeting rare diseases.

Filing data

The study on which the regulatory filing is based compared the recurrence-free survival of GIST patients taking Glivec 400 mg/day versus placebo for one year immediately following surgery. The results showed that 98% of patients receiving Glivec remained recurrence free at one year following surgery compared to approximately 82% of those receiving placebo[3]. This shows that as a result of adjuvant therapy with Glivec, there was an 89% reduction in risk of GIST returning[2].

The study, known as ACOSOG Z90001, was conducted at multiple cancer centers throughout the US and Canada, under a Cooperative Research and Development Agreement between Novartis and the National Cancer Institute (NCI). The study was led by the American College of Surgeons Oncology Group (ACOSOG).

The investigators reported that Glivec therapy was well tolerated by most patients, with side effects similar to those observed in previous clinical trials with Glivec. These include nausea, diarrhea and swelling (edema)[3].

About Gastrointestinal Stromal Tumors (GIST)

Gastrointestinal stromal tumors (GIST) belong to a group of cancers known as soft tissue sarcomas. They are the most common sarcomas and can be found most often in the stomach and small intestine. The incidence of GIST is estimated to be 4,500 - 6,000 new cases per year in the US (15-20 cases per million population)[5], of which more than 90% are Kit-positive[6]. Kit - also known as CD117 - is a protein that, when mutated, has been identified as one of the major causes of GIST.

About Glivec

Glivec is approved in more than 90 countries, including the US, EU and Japan, for the treatment of all phases of Ph+ CML. Glivec is also approved in the EU, US and other countries for the treatment of patients with Kit (CD117)-positive gastrointestinal tumors (GIST), which cannot be surgically removed and/or have already spread to other parts of the body (metastasized). In Japan, Glivec is approved for the treatment of patients with Kit (CD117)-positive GIST. In the EU, Glivec is also approved for the treatment of adult patients with newly diagnosed Ph+ acute lymphoblastic leukemia (Ph+ ALL) in combination with chemotherapy and as a single agent for patients with relapsed or refractory Ph+ ALL. Glivec is also approved for the treatment of adult patients with unresectable, recurrent and/or metastatic dermatofibrosarcoma protuberans (DFSP) who are not eligible for surgery. Glivec is also approved for the treatment of patients with myelodysplastic/myeloproliferative diseases (MDS/MPD). Glivec is also approved for hypereosinophilic syndrome and/or chronic eosinophilic leukemia (HES/CEL).

The effectiveness of Glivec is based on overall hematologic and cytogenetic response rates and progression-free survival in CML, on hematological and cytogenetic response rates in Ph+ ALL, and on objective response rates in GIST and DFSP. There are no controlled trials demonstrating increased survival.

Not all indications are available in every country.

Glivec contraindications, warnings and adverse events

The majority of patients treated with Glivec in clinical trials experienced adverse events at some time. Most events were of mild to moderate grade and treatment discontinuation was not necessary in the majority of cases.

The safety profile of Glivec was similar in all indications. The most common side effects included nausea, superficial edema, muscle cramps, skin rash, vomiting, diarrhea, abdominal pain, myalgia, arthralgia, hemorrhage, fatigue, headache, joint pain, cough, dizziness, dyspepsia and dyspnea, dermatitis, eczema, fluid retention, as well as neutropenia, thrombocytopenia and anemia. Glivec was generally well-tolerated in all of the studies that were performed, either as monotherapy or in combination with chemotherapy, with the exception of a transient liver toxicity in the form of transaminase elevation and hyperbilirubinemia observed when Glivec was combined with high dose chemotherapy.

Rare/serious adverse reactions include: sepsis, pneumonia, depression, convulsions, cardiac failure, thrombosis/embolism, ileus, pancreatitis, hepatic failure, exfoliative dermatitis, angioedema, Stevens-Johnson syndrome, renal failure, fluid retention, edema (including brain, eye, pericardium, abdomen and lung), hemorrhage (including brain, eye, kidney and gastrointestinal tract), diverticulitis, gastrointestinal perforation, tumor hemorrhage/ necrosis, hip osteonecrosis/avascular necrosis.

Patients with cardiac disease or risk factors for cardiac failure should be monitored carefully and any patient with signs or symptoms consistent with cardiac failure should be evaluated and treated. Cardiac screening should be considered in patients with HES/CEL, and patients with MDS/MPD with high level of eosinophils (echocardiogram, serum troponin level).

Glivec is contraindicated in patients with known hypersensitivity to imatinib or any of its excipients. Women of childbearing potential should be advised to avoid becoming pregnant while taking Glivec.

About Novartis

Novartis AG provides healthcare solutions that address the evolving needs of patients and societies. Focused solely on growth areas in healthcare, Novartis offers a diversified portfolio to best meet these needs: innovative medicines, cost-saving generic pharmaceuticals, preventive vaccines and diagnostic tools, and consumer health products. Novartis is the only company with leading positions in these areas. In 2007, the Group's continuing operations (excluding divestments in 2007) achieved net sales of USD 38.1 billion and net income of USD 6.5 billion. Approximately USD 6.4 billion was invested in R&D activities throughout the Group. Headquartered in Basel, Switzerland, Novartis Group companies employ approximately 98,000 full-time associates and operate in over 140 countries around the world. For more information, please visit http://www.novartis.com.

References

[1.] Fast Track, Priority Review and Accelerated Approval. U.S. Food and Drug Administration - Center for Drug Evaluation and Research. http://www.accessdata.fda.gov/scripts/cder/onctools/Accel.cfm Accessed 31 July 2008.

[2.] Internal data.

[3.] Z9001: A Phase III Randomized Double-blind Study of Adjuvant STI571 (Gleevec®) Versus Placebo in Patients Following the Resection of Primary Gastrointestinal Stromal Tumor (GIST). http://www.cancer.gov/clinicaltrials/ACOSOG-Z9001. Accessed June 2008.

[4.] Van den Abbeele A., Benjamin R., Blanke C, et al. Clinical Management of GIST. Recurrence patterns and prognostic factors for survival. 2003;1-24.

[5.] American Cancer Society. Cancer Reference Information. Detailed Guide for Gastrointestinal Stromal Tumors. Key Statistics. http://www.cancer.org/docroot/CRI/content/

CRI_2_4_1x_What_Are_the_Key_Statistics_About_Gastrointestinal_Stromal_Tumors.asp?rnav=cri. Accessed 22 February 2008.

[6.] US Department of Health and Human Services. Agency for Healthcare Research and Quality (AHRQ). Technology Assessment: Report on the Relative Efficacy of Oral Cancer Therapy for Medicare Beneficiaries Versus Currently Covered Therapy, Part 2. Imatinib for Gastrointestinal Stromal Tumors (GISTs). Available at: http://www.ahrq.gov/clinic/ta/gist/gist1.htm

* Known as Gleevec® (imatinib mesylate) tablets in the US, Canada and Israel.

Source: Novartis Press Release

 Swiftwater, PA - Lyon, France - June 23, 2008 - Sanofi Pasteur, the vaccines division of the sanofiaventis Group, announced that the U.S. Food and Drug Administration (FDA) has licensed Pentacel®, Diphtheria and Tetanus Toxoids and Acellular Pertussis Adsorbed, Inactivated Poliovirus and Haemophilus b Conjugate (Tetanus Toxoid Conjugate) Vaccine. Pentacel® vaccine is indicated for active immunization against diphtheria, tetanus, pertussis, poliomyelitis, and invasive disease due to Haemophilus influenzae type b (Hib). Pentacel® vaccine is approved for use in infants and children

6 weeks through 4 years of age (prior to fifth birthday). Pentacel® vaccine is the first and only four-dose diphtheria, tetanus, and acellular pertussis (DTaP)- based combination vaccine for use in infants and young children in the U.S. that includes both poliovirus and Hib antigens.

Pentacel® vaccine is approved for administration as a four-dose series at 2, 4, 6 and 15-18 months of age. The first dose may be given as early as 6 weeks of age. According to the current Recommended Childhood Immunization Schedule of the U.S. Centers for Disease Control and Prevention (CDC), up to 23 injections are needed by the time a child reaches 18 months of age with single-entity vaccines. The use of Pentacel® vaccine could reduce that number of shots by seven.

“Pentacel® vaccine will help simplify the immunization schedule by reducing the number of injections infants and young children will receive in their first two years of life,” said Wayne Pisano, President and Chief Executive Officer, sanofi pasteur. Pentacel® vaccine has been used in Canada for a decade and is licensed in seven other countries. “We are pleased that the U.S. FDA has now taken this important step, to make the convenience of Pentacel® vaccine available to health-care providers

and parents in the U.S.,” Pisano added.

“The FDA approval of Pentacel® vaccine is great news for parents and pediatricians who want to reduce the stress of well-baby visits,” said Tina Q. Tan, M.D., infectious disease specialist, Children’s Memorial Hospital, Chicago. “Pertussis disease continues to remain a threat to young infants, who are at the highest risk for severe complications and death. With a four-dose primary series of Pentacel® vaccine, pediatricians can reduce the number of vaccination shots while providing protection against five diseases, including pertussis.”

Pentacel® vaccine is also the first five-component (pentavalent) pediatric combination vaccine in the U.S. to contain sanofi pasteur’s five acellular pertussis antigens, which are also used in its DTaP vaccine for children (DAPTACEL®a vaccine, licensed in 2002) and its tetanus, diphtheria, and acellular pertussis (Tdap) vaccine for adults and adolescents (Adacel®b vaccine, licensed in 2005). Pertussis is commonly known as whooping cough because of the sound some patients—especially children—make while gasping for air during coughing spells.

The FDA licensure of Pentacel® vaccine is based on the results of multi-center clinical studies conducted in the U.S. and Canada involving more than 5,000 children who received at least one dose of Pentacel® vaccine. The immunogenicity of Pentacel® vaccine was compared to separately administered DAPTACEL, IPOL®c and ActHIB®d vaccines (studies P3T06 and M5A10), as well as to other single-entity vaccine formulations (study 494-01). The safety of Pentacel® vaccine was compared both to separately administered DAPTACEL, IPOL and ActHIB vaccines (study P3T06)

and to other single-entity vaccine formulations (study 494-01).

In clinical studies, local and systemic reactions following administration of Pentacel® vaccine were reported at rates consistent with those of the separately administered vaccines used in each trial. The most common local and systemic adverse reactions to Pentacel® vaccine include injection site redness, swelling and tenderness; fever, fussiness and crying. Other adverse reactions may occur.

Known systemic hypersensitivity reaction to any component of Pentacel® vaccine or a life-threatening reaction after previous administration of the vaccine or a vaccine containing the same substances are contraindications to vaccination.

The decision to give Pentacel® vaccine should be based on the potential benefits and risks; if Guillain-Barré syndrome has occurred within 6 weeks of receipt of a prior vaccine containing tetanus toxoid; or if adverse events have occurred in temporal relation to receipt of pertussis-containing vaccine. Encephalopathy within 7 days of administration of a previous dose of a pertussis-containing vaccine or a progressive neurologic disorder is a contraindication. Vaccination with Pentacel® vaccine may not protect all individuals.

Before administering Pentacel® vaccine, please see accompanying full Prescribing Information. The full Prescribing Information for Pentacel® vaccine is available on www.pentacel.com  and www.vaccineshoppe.com .

More than 14 million doses of Pentacel® vaccine have been distributed in Canada since 1997. Pentacel® vaccine is expected to be available for distribution in the U.S. this

summer. Sanofi Pasteur’s U.S. operations in Swiftwater, PA have long been committed to providing vaccines to prevent childhood diseases. In 1987, it licensed the first Hib conjugate vaccine. And in 1996, it was the first company to license a DTaP vaccine for use in infants (TripediaÒe vaccine).

In 2005, sanofi pasteur continued its tradition of innovation by introducing MenactraÒf vaccine to protect against meningococcal disease, and Adacel vaccine as a booster dose for protection against tetanus, diphtheria and pertussis in both adults and adolescents 11-64 years of age.

About Sanofi-aventis

Sanofi-aventis, a leading global pharmaceutical company, discovers, develops and distributes therapeutic solutions to improve the lives of everyone.  Sanofi Pasteur, the vaccines division of sanofi-aventis Group, provided more than 1.6 billion doses of

vaccine in 2007, making it possible to immunize more than 500 million people across the globe. A world leader in the vaccine industry, sanofi pasteur offers the broadest range of vaccines protecting against 20 infectious diseases. The company's heritage, to create vaccines that protect life, dates back more than a century. Sanofi Pasteur is the largest company entirely dedicated to vaccines. Every day, the company invests more than EUR1 million in research and development. For more information, please visit:

www.sanofipasteur.com  or www.sanofipasteur.us .

Source: Sanofi-aventis Press Release

--Launch of Extavia for early and relapsing forms of multiple sclerosis (MS) planned for US and Europe in first half of 2009--

--Novartis committed to MS through extensive research and development programs, including novel oral therapy FTY720 currently in Phase III--

--MS, a devastating disease causing progressive disability, affects an estimated 2.5 million people worldwide, including many young adults[2]--

Basel, May 26, 2008 - The European Commission has approved Extavia® (interferon beta-1b) for the treatment of early and relapsing forms of multiple sclerosis (MS) - the first in a new portfolio of medicines from Novartis that is planned to include both established treatments and innovative therapies for patients with MS.

Extavia is the Novartis branded version of interferon beta-1b, a first-line disease-modifying therapy injected every other day for the treatment of MS. Interferon beta-1b has been available globally for more than 13 years and is supported by more than 700,000 patient-years of experience[1].

Formerly known as NVF233, Extavia is the same medicine as Betaferon®/Betaseron®, which is marketed by Bayer-Schering and was the first beta interferon treatment for MS. Novartis gained rights to its own branded version of this medicine in agreements with Bayer-Schering related to the acquisition of Chiron.

"Novartis is committed to MS and to providing effective treatments for patients with this disease," said Trevor Mundel, MD, Head of Global Development Functions at Novartis Pharma AG. "The approval of Extavia means we are able to offer the MS community a current standard of care while preparing for the introduction of innovative therapies such as FTY720."

Novartis also recently filed for approval of interferon beta-1b with the US Food and Drug Administration. Launches in the US and EU are planned for the first half of 2009, in line with an agreement with Bayer-Schering that established the opportunity for Novartis to introduce its own branded version of interferon beta-1b.

By the end of 2009, Novartis also plans to file for approval of the innovative oral therapy FTY720 (fingolimod). Results of an ongoing Phase II study extension presented in April show sustained benefits in patients with relapsing MS after three years of treatment with FTY720. Data showed that 68-73% of patients in the study remained free from relapses after three years' continuous treatment[3].

A number of other compounds for treating MS are also in early stage development by Novartis.

Multiple sclerosis is the most common disorder of the central nervous system in young adults. It is a progressive and debilitating disorder caused by the destruction of myelin, which helps neurons carry electrical signals in the brain. MS causes problems with muscle control and strength, vision, balance, sensation and cognitive function2. MS typically presents in relapsing forms involving acute self-limiting attacks of neurological dysfunction (or "relapses") followed by complete or partial restoration of functions[4].

In the EU, Extavia is approved for patients with relapsing-remitting MS, the most common form of the disease involving relapses followed by complete or partial restoration of function, and for a steadily worsening form of the disease known as secondary progressive MS with relapses.

In addition, Extavia is approved to treat patients with early MS who:

        --Have experienced a single episode involving loss of myelin (or "demyelinating event")

 --Have an active inflammatory process that is severe enough to need treatment with intravenous corticosteroids, if alternative diagnoses have been excluded

r--Are at high risk of developing clinically definite MS.

About Novartis

Novartis AG provides healthcare solutions that address the evolving needs of patients and societies. Focused solely on growth areas in healthcare, Novartis offers a diversified portfolio to best meet these needs: innovative medicines, cost-saving generic pharmaceuticals, preventive vaccines and diagnostic tools, and consumer health products. Novartis is the only company with leading positions in these areas. In 2007, the Group's continuing operations (excluding divestments in 2007) achieved net sales of USD 38.1 billion and net income of USD 6.5 billion. Approximately USD 6.4 billion was invested in R&D activities throughout the Group. Headquartered in Basel, Switzerland, Novartis Group companies employ approximately 98,000 full-time associates and operate in over 140 countries around the world. For more information, please visit http://www.novartis.com.

References

[1] Data on file. Wayne, NJ: Bayer HealthCare Pharmaceuticals Inc; 2007.

[2] Multiple Sclerosis International Federation at www.msif.org Accessed 15 May 2008.

[3] Comi G et al. Oral FTY720 (fingolimod) in patients with relapsing multiple sclerosis. 3-year extension shows sustained low relapse rate and MRI activity. Abstract presented at 60th annual meeting of American Academy of Neurology, Chicago, 12-19 April 2008.

[4] National Multiple Sclerosis Society at www.nationalmssociety.org, Accessed 15 May 2008.

Source: Novartis Press Release

The VITROS Anti-HIV 1+2 assay can help meet the demand on laboratories created by new U.S. Centers for Disease Control and Prevention (CDC) testing recommendations. The CDC now recommends routine, voluntary HIV testing in all health care settings, including health clinics and emergency rooms, for all individuals ages 13 to 64 without written informed consent. In addition, testing is recommended at least once a year for those at high risk.2

By latest estimates, approximately 1,039,000 to 1,185,000 people in the United States are living with HIV/AIDS, with 24 to 27 percent undiagnosed and unaware of their HIV infection.3 Costs associated with unrecognized or late-recognized HIV infection are growing.

Two multicenter research teams supported in part by the National Institute on Drug Abuse, National Institutes of Health, have independently determined through the development of computer models that routine screening for HIV in health care settings is as cost effective as screening for other conditions such as breast cancer and high blood pressure, and can provide important health and survival benefits. The studies also suggest that screening that leads to a diagnosis of HIV infection may further lower health care costs by preventing high-risk practices and decreasing virus transmission.4

The VITROS Anti-HIV 1+2 Assay has been co-developed with Chiron, a business of Novartis Vaccines and Diagnostics Inc.

About the VITROS ECi/ECiQ Immunodiagnostic System

 The VITROS ECi/ECiQ Immunodiagnostic System is a simple to use, flexible and fully automated laboratory testing system that provides true continuous, STAT, random access capabilities for routine and specialty immunodiagnostic testing. The system uses proprietary enhanced chemiluminescence detection technology to provide excellent assay performance including wide dynamic ranges and exceptional precision and sensitivity. The VITROS ECi/ECiQ Immunodiagnostic System also uses Intellicheck® Technology, a proprietary technology designed to verify diagnostic checks throughout automated sample and assay processing. Intellicheck serves to increase the integrity and security of reported patient results while helping to ensure greater confidence and productivity for laboratories that generate these results.

The expanding VITROS ECi/ECiQ Immunodiagnostic System test menu now includes more than 45 tests worldwide for the sensitive measurement of thyroid function, reproductive health and fertility, bone metabolism, anemia, metabolic, oncology, emergency cardiology, and infectious diseases.

About Ortho-Clinical Diagnostics

Ortho-Clinical Diagnostics, a Johnson & Johnson company, is a leading provider of high-value diagnostic solutions for the global health care community. Committed to developing the most advanced tests for early detection or diagnosis of disease, the company brings products to market that provide timely information and help to facilitate medical decisions. Ortho-Clinical Diagnostics also provides blood screening and typing products that help to ensure the safety of the world’s blood supply. In addition, through its VITROS MicroSlide and enhanced chemiluminescence technologies, the company has transformed the way that clinical laboratories perform testing. Worldwide, health care professionals rely on Ortho-Clinical Diagnostics for innovative diagnostic solutions and services that promote effective diagnoses and enhance patient care. For more information, visit www.orthoclinical.com.

1 Refer to the VITROS Immunodiagnostic Products Anti-HIV 1+2 Reagent Pack and VITROS Products Anti-HIV 1+2 Calibrators Instructions for Use for Warnings and Limitations

2 CDC. Revised recommendations for HIV testing of adults, adolescents, and pregnant women in health-care settings. MMWR 2006; 55 (No. RR-14):1-17.

3 Glynn M, Rhodes P. Estimated HIV prevalence in the United States at the end of 2003. National HIV Prevention Conference; June 2005; Atlanta. Abstract 595.

4 http://www.drugabuse.gov/newsroom/05/NR2-09.html

Source: J&J Press Release

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February 2008. The Chicago Athenaeum Museum of Architecture and Design has awarded a 2007 GOOD DESIGN™ Award for the new SoloSTAR® disposable insulin injection pen for people with type 1 and type 2 diabetes.

“LANTUS®  SoloSTAR® and APIDRA® SoloSTAR®, the results of over four years of intensive development, have been designed in dialogue with patients, nurses and doctors and meet the high standards of the industry,” said Paul Jansen, Global Head Medical Devices, Sanofi-aventis.

 For some people with diabetes, self-injection can be a barrier to acceptance of insulin therapy. “SoloSTAR® is a marriage of sleek, handsome design styling with easy, but advanced sophisticated technology for dispensing insulin to people with diabetes,” says Christian K. Narkiewicz-Laine, President Chicago Athenaeum Museum of Architecture and Design.

“SoloSTAR® represents a design for social good and for humanitarian concerns”.

When choosing a specific insulin pen for an individual patient, clinicians consider the patient's insulin regimen, lifestyle, and other factors that may affect the ability to use a particular device, such as manual dexterity and visual acuity. Therefore certain characteristics of a given insulin pen may make it preferable for patients. The outstanding design of SoloSTAR® using breakthrough technology contributes to making this patients’ and clinicians’ choice easier.

SoloSTAR® provides a delivery option that may be more acceptable and more convenient to use in comparison with other delivery systems, thus may promote patient compliance, which could help achieve and maintain glycemic control.

A recent survey of LANTUS® SoloSTAR® use in everyday clinical practice, involving more than 2000 people with diabetes (16% with manual dexterity problems and 15% with poor eyesight not corrected by glasses) showed that more than 95% of participants declared to be “satisfied” or “very satisfied” with using SoloSTAR® to inject insulin, irrespective of diabetes type or previous device experience.

Healthcare professionals involved in teaching the people in this survey how to use LANTUS® SoloSTAR® found SoloSTAR® to be easy learn and easy to use for people with diabetes. SoloSTAR® also operates with a lower injection force and a recent study found that SoloSTAR® required 31% less injection force than the Novo Nordisk FlexPen® and 54% less force than the Eli Lilly Humulin/Humalog pen.

“Insulin injection with SoloSTAR® brings flexibility, satisfaction for the patients, and an opportunity for earlier initiation of insulin therapy which may contribute to better long term glycaemic control”, Denis Raccah, Professor of Endocrinology, University Hospital Sainte Marguerite, France, added.

About SoloSTAR®

SoloSTAR® is a new, easy-to-use disposable pen for administration of LANTUS® and APIDRA®. SoloSTAR®, allows to administer doses from 1 up to 80 units, in one unit increments, in one injection. SoloSTAR offers a 25% greater maximum capacity than other insulin pens. Consequently, the administration until 80 units of insulin can be done with only one injection. SoloSTAR uses a simple, intuitive design with easy-to-read display featured and requires only a few steps to use it properly. SoloSTAR® is small, discreet and eliminates the need for the patient to change insulin cartridges. Easy-to-use and easy-to-inject, SoloSTAR® reduces the injection force by 30% or more in comparison to other most broadly available pens in its class.

Lantus® SoloSTAR® and APIDRA® SoloSTAR® were approved by the EMEA in September 2006; LANTUS® SoloSTAR® was approved by the FDA in April 2007. LANTUS® SoloSTAR® and APIDRA® SoloSTAR® are launched in France, UK, Italy, Spain, Germany, Netherlands, Slovakia, Slovenia, Sweden, Norway, Austria, Denmark, Estonia, Finland, Greece, Hungary, Ireland, Latvia, Australia, Lithuania, Lebanon, and South Africa. LANTUS® SoloSTAR® is launched in the US, Canada and Switzerland. The preparation for launches in other countries is planned during 2008.

The elegant exterior design of Lantus® and Apidra® SoloSTAR® and its ease of use due to advanced technology is the result of the collaboration with DCA Design International Ltd. in Great Britain DCA Company.

About Sanofi-aventis’ pen portfolio

Sanofi-aventis having 85 years of innovation in the diabetes is committed to offering people with diabetes an integrated system of insulin products and delivery devices. In addition to the SoloSTAR®, the pen portfolio available for LANTUS® and APIDRA® includes the OptiSet® disposable pen, the OptiClik® and OptiPen® Pro reusable pens, and the Autopen® 24 from Owen Mumford.

About LANTUS® (insulin glargine [rDNA origin])

LANTUS® is indicated for once-daily subcutaneous administration in the treatment of adult patients with type 2 diabetes mellitus who require basal (long-acting) insulin for the control of hyperglycemia and for adult and pediatric patients (6 years of age and older) with type 1 diabetes mellitus. LANTUS® demonstrates a consistent slow, prolonged absorption and a relatively constant concentration/time profile over 24 hours.

About APIDRA® (insulin glulisine [rDNA origin])

APIDRA® is a rapid-acting insulin analog with a unique zinc-free molecular structure that maintains a rapid onset and a short duration of action, indicated for adult patients with type 1 and type 2 diabetes. APIDRA® offers patients mealtime dosing flexibility—it can be taken 15 minutes before or within 20 minutes after starting a meal. APIDRA® is also flexible for use in patients with a variety of body types, from lean to obese.

About Diabetes

Diabetes is a chronic, evaluative widespread disease in which the body reduces or does not produce or properly use insulin – the hormone needed to convert glucose (sugar) into energy. More than 240 million people worldwide are living with the disease. It is estimated that near 250 million people worldwide have diabetes, the number is expected to reach some 380 million within 20 years.

It is estimated more than 20 million Americans have diabetes, including an estimated 6.2 million who remain undiagnosed. At the same time, approximately half of those diagnosed are not achieving the general blood sugar control standard of A1C <7% recommended by the American Diabetes Association and the European Association for the Study of Diabetes (ADA/EASD). The A1C test reflects average blood glucose levels over a two- to three-month period.

Without proper insulin production and action, glucose remains in the blood, leading to chronic hyperglycaemia (raised blood sugar). This can result in short and long-term complications, many of which, if not prevented and left untreated, can be fatal. All have the potential to reduce the quality of life of people with diabetes and their families.

The most common long-term complications are:

- Diabetic nephropathy (kidney disease), which may result in total kidney failure and in the need for dialysis or kidney transplant.

- Diabetic eye disease (retinopathy and macular oedema), damage to the retina of the eye

which can lead to vision loss.

- Diabetic neuropathy (nerve disease), which can ultimately lead to ulceration and amputation of the feet and lower limbs.

- Cardiovascular disease, which affects the heart and blood vessels and may cause fatal

- complications such as coronary heart disease (leading to a heart attack) and stroke.

Diabetes is the fourth leading cause of death by disease globally. Every year, 3.8 million people die from diabetes-related causes.

About GOOD DESIGN

The Museum’s historic GOOD DESIGN program was founded in Chicago in 1950 by Edgar J.Kaufmann, Jr. with the participation of some of America’s most important designers. Every year the jury meets in New York and select products and graphics worthy of the GOOD DESIGN Award for design distinction. GOOD DESIGN remains the oldest and most important Awards program worldwide.

About Sanofi-aventis

Sanofi-aventis, a leading global pharmaceutical company, discovers, develops and distributes therapeutic solutions to improve the lives of everyone.

References:

For easy to inject

Owens DR. Comparison of insulin pen devices reveals lower injection force of Solostar® compared with novo Flexpen® and lilly® disposable pen; Diabetes Technology Meeting 25–17 October 2007, San Francisco, CA, USA. Journal of Diabetes Science and Technology, March 2008; Abstract OWEN70184; In press.

Clarke A, Spollett G. Dose accuracy and injection force dynamics of a novel disposable insulin pen. Expert Opin. Drug Deliv. (2007) 4(2):165-174.

For easy to use and patient’s satisfaction

Carter J et al. Usability, participant acceptance and safety of SoloStar in an observational survey in everyday clinical practice; Diabetes Technology Meeting 25–17 October 2007, San Francisco, CA, USA. Journal of Diabetes Science and Technology, March 2008; Abstract CART70119; In press.

Source: Sanofi-Aventis Press Release

--Drug Metabolizing Enzymes and Transporters (DMET) Early Access Solution Enables Pharmaceutical Researchers to Assess all Clinically Relevant ADME Markers in a Single Assay--

SANTA CLARA, Calif-Jan. 24, 2008--Affymetrix Inc. announced the availability of its Drug Metabolizing Enzymes and Transporters (DMET) Early Access solution, currently the world's most comprehensive method for assaying the genetics of drug metabolism. The DMET offering profiles more than 1,069 drug metabolism biomarkers, including 172 "core" genetic markers. Data is automatically interpreted into a common format that can be integrated into clinical trial workflows. The information enables researchers to make more informed drug-development decisions, which in turn significantly streamlines the drug-development process and, therefore, time to market.

The DMET solution is available as a service through Affymetrix' South San Francisco Services Laboratory and Cogenics, a subsidiary of Clinical Data. Both providers have been accepting samples since the fourth quarter of 2007, following the successful completion of a six-week training and certification program to ensure that data is complete, accurate and reproducible. Cogenics is offering DMET as a Good Laboratory Practice (GLP)-compliant service from its North Carolina facility, while Affymetrix' South San Francisco facility is running the service strictly for non-GLP research studies. Additional worldwide service providers will be certified and announced in the near future. Affymetrix and Clinical Data announced a joint marketing agreement today in a separate press release.

Pharmaceutical customers are using the DMET solution to better understand pharmacokinetics, the study of the bodily absorption, distribution, metabolism and excretion (ADME) of drugs. DMET is the only product available with comprehensive coverage of all ADME drug metabolism biomarkers, including common and rare variations, insertions, deletions, copy number, triallelic SNPs and pseudogenes. For the first time, scientists are able to assess all clinically relevant ADME markers in a single assay, unlike previously used single-plex approaches.

"Being able to measure a variety of 'core' genetic markers is critical to delivering accurate clinical assays, something the Affymetrix technology is allowing us to achieve. Accurate clinical assays have the ability to deliver improved patient outcomes because the medicines we develop become more directly targeted to the patient's specific needs," said Richard Deane Hockett, senior clinical research physician, group leader for genomic medicine, Department of Diagnostic and Experimental Medicine at Eli Lilly & Co. "We are implementing this technology across the research portfolio in all phases of clinical trials at Lilly."

Regulatory authorities have indicated a renewed interest in surveying drug metabolism biomarkers to ensure safer dosing, which in turn reduces the possibility of adverse events and improves patient safety. Just three months ago, the U.S. Food and Drug Administration (FDA) made history by updating the label on the anticoagulant drug, Warfarin, to include information on CYP2C9 and VKCORC1.

According to a commentary in Clinical Pharmacology and Therapeutics co-authored by the FDA(1), "Pharmacogenomic data can facilitate our understanding of the sources of variability in drug response and can potentially lead to improved safety and efficacy of drug therapy for individual patients. Through various initiatives, the FDA is encouraging drug developers to apply the rapidly evolving pharmacogenomic tools and integrate these data into the evaluation of patient variability."

Michael Caldwell, M.D., Ph.D., director of the Wound Healing Program at Marshfield Clinic, has been using the DMET solution to research the genetics behind an individual's drug response to Warfarin, a drug that if prescribed at the wrong dose can have serious adverse events. "The DMET panel has allowed us to better delineate the stable therapeutic dose of Warfarin for our patients at the initiation of therapy, where risk of complications from the drug are at their highest," said Dr. Caldwell. "Thus our hope is that these studies will enable us to reduce the overall complications of Warfarin therapy by a better prediction of stable therapeutic dose."

The DMET solution features easy-to-use patient consent tracking and data translation software to identify functional variants across the panel and to convert genotyping results into standardized star nomenclature, a convention commonly used in the genetic analyses of clinical trials. The automated analysis takes only a few minutes to complete and provides pharmaceutical researchers performing clinical trials with familiar data that can be easily integrated into existing workflows. Previously, this analysis was a manual and time-consuming task as scientists were required to scour literature for relevant answers.

"DMET Early Access is the result of an ongoing Affymetrix commitment to develop assays that are targeted at clinical drug development," said Maneesh Jain, senior director of marketing at Affymetrix. "We've been fortunate to work with leading pharmaceutical partners and key medical centers to design and develop an assay that's comprehensive for ADME biomarkers and directly provides information with clinical utility."

About Affymetrix

Affymetrix GeneChip(R) microarray technology is the industry-standard tool for analyzing complex genetic information. After inventing microarray technology in the late 1980s, Affymetrix scientists have been dedicated to developing innovative products that provide researchers with a more complete view of the genome. These products continue to accelerate genetic research and enable scientists to develop diagnostics and tailor treatments for individual patients by identifying and measuring the genetic information associated with complex diseases.

Today, Affymetrix technology is used by the world's top pharmaceutical, diagnostic and biotechnology companies, as well as leading academic, government and not-for-profit research institutes. More than 1,600 systems have been shipped around the world and more than 10,500 peer-reviewed papers have been published using the technology.

Affymetrix is headquartered in Santa Clara, Calif., and has manufacturing facilities in Sacramento, Calif., and Singapore. The company has about 1,100 employees worldwide and maintains sales and distribution operations across Europe and Asia. For more information about Affymetrix, please visit: www.affymetrix.com.

-Merck's Pipeline Continues to Progress with Seven Products in Phase III Development-

-Company Expects to File Applications for Expanded Indications on GARDASIL and ISENTRESS in 2008-

-Merck Intends to Initiate a Sequenced Phase III Program for Anacetrapib in 2008-

-Successful Early Launches of GARDASIL, JANUVIA, JANUMET and ISENTRESS-

-Reflect Better Alignment of Product Development and Commercialization Efforts; Replicable Model to Reduce Time to Market of New Medicines and Vaccines-

-Company Remains on Track to Deliver Long-Term, Double-Digit Compound Annual EPS Growth from 2005 to 2010, Excluding Certain Items-

 Dec. 11, 2007 - Merck & Co., Inc. hosted its Annual Business Briefing and reviewed the progress the Company has achieved under a strategic plan designed to re-engineer the way Merck develops and distributes medicines and vaccines worldwide.  Since 2005, Merck's senior management team has been developing and implementing a new operating model under which customer focus drives drug discovery, development and marketing at the Company, Merck Chairman, President and Chief Executive Officer Richard T. Clark told investors and analysts today at the Merck Annual Business Briefing.

"We are realizing the benefits of the successful execution of our strategy.  We have created a model for success that encompasses every aspect of our business, including R&D, manufacturing and commercialization," Mr. Clark said.  "As a result, Merck has a sustainable business model that will allow us to realize the goals we set for 2010 and to position the Company for future success."

During his presentation, Mr. Clark highlighted some of the goals the Company has met or expects to meet by 2010, including:

* Launched seven new drugs and vaccines in the past two years, many of them first- or best-in-class

* Compound annual revenue growth of 4 percent to 6 percent from 2005 to 2010, including 50 percent of all joint-venture revenue

* Double-digit compound annual earnings per share (EPS) growth from 2005 to 2010, excluding certain items

* Plan to return product gross margin to pre-ZOCOR levels in 2008

* Reduced clinical development cycle times relative to the pharmaceutical sector

"The changes we have made and are continuing to make at Merck are designed to be sustained over the long term.  They represent a true model for success," Mr. Clark said.  "We have not focused only on short-term successes, but we are making the necessary investments to ensure the success of this Company beyond the year 2010."

Merck's Late-Stage Pipeline Continues to Grow

Building on the seven U.S. Food and Drug Administration (FDA) approvals Merck has received in the past two years, the Company anticipates regulatory action will be taken in 2008 on two New Drug Applications (NDA) for EMEND for Injection and CORDAPTIVE, the proposed brand name for MK-0524A.  Also in 2008, the Company anticipates making two additional NDA filings with the FDA for MK-0524B, simvastatin combined with laropiprant and extended-release niacin, and MK-0364, taranabant, an investigational medication for the treatment of obesity, said Peter S. Kim, Ph.D., president of Merck Research Laboratories.

Additionally, Dr. Kim said, the Company anticipates making two supplemental filings with the FDA in 2008: one for GARDASIL, Merck's vaccine for the prevention of cervical cancer, for an expanded indication for adult women through age 45, and one for ISENTRESS, a first-in-class integrase inhibitor for the treatment of HIV-1 infection, for an expanded indication for use in treatment-naïve patients.

During his presentation, Dr. Kim also detailed the following seven drug candidates currently in Phase III development:

-MK-0524B is a drug candidate that combines the novel approach to raising HDL-cholesterol (HDL-C) and lowering triglycerides from extended-release niacin combined with laropiprant with the proven benefits of simvastatin in one combination product. The candidate already is in Phase III development, and Merck continues to anticipate filing an NDA for MK-0524B in 2008.

-MK-0364, taranabant, is a highly selective cannabinoid-1 receptor inverse agonist that in early clinical studies has demonstrated weight loss versus placebo. The Company previously announced the initiation of a targeted Phase III program in 2006. Merck anticipates filing an NDA in 2008.

-MK-0974, an investigational oral calcitonin gene-related peptide receptor antagonist, utilizes a new mechanism for the treatment of migraines that has demonstrated efficacy at least comparable to triptans in early clinical studies. The drug candidate entered Phase III development during 2007. The Company anticipates filing an NDA in 2009.

-MK-7418, rolofylline, is a Phase III investigational drug being evaluated for the treatment of acute heart failure. Merck acquired the drug candidate as part of the 2007 acquisition of NovaCardia, Inc. and anticipates filing an NDA with the FDA in 2009.

-MK-8669, deforolimus, is a novel mTOR (mammalian target of rapamycin) inhibitor being evaluated for the treatment of cancer. The drug candidate is being jointly developed and commercialized with ARIAD Pharmaceuticals, Inc. under an agreement reached in mid-2007. The Company anticipates filing an NDA in 2010.

-HEPLISAV, a novel investigational hepatitis B vaccine, currently is being evaluated in a Phase III clinical trial in adults and in patients undergoing dialysis treatment. Merck is jointly developing HEPLISAV with Dynavax Technologies Corporation under an agreement reached in late 2007. Merck anticipates filing an NDA in 2010 for adults.

-MK-0822, odanacatib, is a highly selective inhibitor of cathepsin K enzyme, which is being evaluated for the treatment of osteoporosis. The Phase III program began in mid-2007. Merck anticipates filing an NDA with the FDA in 2012.

Dr. Kim also provided an update on the development of MK-0859, anacetrapib, an inhibitor of the cholesterol ester transfer protein (CETP) that in early clinical trials has shown promise in lipid management by raising HDL-C and reducing LDL-cholesterol (LDL-C) without raising blood pressure.

"In clinical studies, inhibition of CETP raises plasma HDL-C levels and decreases LDL-C levels, which represents a potential therapeutic intervention to reduce the risk of coronary artery disease," Dr. Kim said.  "The safety and tolerability profile of anacetrapib was comparable to placebo in clinical studies conducted to date.  In 2008, we plan to initiate a sequenced Phase III program to obtain additional clinical experience in patients before initiating an outcomes study."

As of Dec. 11, 2007, Merck's updated pipeline chart includes 25 distinct candidates in Phase I and 15 in Phase II.  In addition, there are seven candidates currently in Phase III, one submission currently under FDA review, and another that has received an approvable letter and is awaiting further regulatory action.  In its pipeline review, Merck does not include backup candidates; additional indications for candidates in the same therapeutic area; or additional claims, line extensions or formulations for existing products.

New Commercial Model More Effective and Efficient

Kenneth C. Frazier, executive vice president and president, Global Human Health, provided an update on the early successes of Merck's ongoing endeavor to align the Company's product research, development and marketing efforts.

In his presentation, Mr. Frazier said that the successful launches and strong global uptake of GARDASIL, JANUVIA and JANUMET are the result of a replicable model that continues to evolve.  He said that the Merck model is not only proving more cost efficient but is allowing Merck to reduce the time it takes to get new medicines and vaccines into markets around the world.

As part of this effort, Merck Global Human Health, aligned with Merck Research Laboratories and Merck Manufacturing, is utilizing the latest technologies and broadening its engagement with customers, physicians and scientific leaders to get needed medicines and vaccines through the development pipeline and to patients sooner, Mr. Frazier said.

The strong sales of Merck's new products, coupled with continued strong growth from in-line products, especially SINGULAIR, should allow Merck to offset the impact of the loss of U.S. marketing exclusivity for FOSAMAX and other products, Mr. Frazier said.  He also said that the Company has achieved a nearly fourfold increase in global vaccine sales since 2005 and remains on track to double sales in emerging markets to $2 billion by 2010.

Merck Reaffirms 2007 and 2008 Financial Guidance

During his presentation, Executive Vice President and Chief Financial Officer Peter N. Kellogg reaffirmed Merck's previously disclosed financial outlook for 2007 and 2008.

"With our 2007 and 2008 guidance, it is clear that our products are driving a healthy top line despite lapping the ZOCOR expiry and the upcoming FOSAMAX exposure," Mr. Kellogg said.  "We are very pleased with our results in 2007, and we anticipate continued strong financial performance from our key franchises in 2008.

"As I previously noted on Dec. 4, our financial guidance in 2008 represents the next step in our journey to reach our stated 2010 top- and bottom-line goals.  Despite the loss of marketing exclusivity for FOSAMAX in the United States in February 2008, the Company anticipates solid earnings growth in 2008," Mr. Kellogg added.

He continued, "As we disclosed in 2005, Merck's new and in-line pharmaceutical products and vaccines are expected to drive revenue at a compound annual growth rate of 4 percent to 6 percent from 2005 through 2010, including 50 percent of the revenues from the joint ventures from which Merck derives equity income.  We also expect that we can fully support our expanding pipeline with mid-single-digit compound annual growth in research funding over the same period.  The productivity generated by our ongoing cost management initiatives allows Merck to fully capitalize on the promise of our expanding product portfolio while maintaining marketing and administrative expense at 2006 levels."

About Merck

Merck & Co., Inc. is a global research-driven pharmaceutical company dedicated to putting patients first.  Established in 1891, Merck discovers, develops, manufactures and markets vaccines and medicines to address unmet medical needs.  The Company devotes extensive efforts to increase access to medicines through far-reaching programs that not only donate Merck medicines but help deliver them to the people who need them.  Merck also publishes unbiased health information as a not-for-profit service.  For more information, visit www.merck.com.

Forward-Looking Statement

This press release contains "forward-looking statements" as that term is defined in the Private Securities Litigation Reform Act of 1995.  These statements are based on management's current expectations and involve risks and uncertainties, which may cause results to differ materially from those set forth in the statements.  The forward-looking statements may include statements regarding product development, product potential or financial performance.  No forward-looking statement can be guaranteed, and actual results may differ materially from those projected.  Merck undertakes no obligation to publicly update any forward-looking statement, whether as a result of new information, future events or otherwise.  Forward-looking statements in this press release should be evaluated together with the many uncertainties that affect Merck's business, particularly those mentioned in the risk factors and cautionary statements set forth in Item 1A of Merck's Form 10-K for the year ended Dec. 31, 2006, and in its periodic reports on Form 10-Q and Form 8-K, which the Company incorporates by reference.

Q&A with Gary J. Buehler, RPh.,  Director of FDA’s Office of Generic Drugs (OGD)

Credit: FDA Consumer Health Information

e-published on MedicineandBiotech.com December 1^st, 2007

VIEW VIDEO

Gary J. Buehler, RPh., is Director of the Office of Generic Drugs (OGD) in FDA's Center for Drug Evaluation and Research (CDER). A graduate of Temple University's School of Pharmacy, Mr. Buehler joined FDA in 1986.

Q: What are generic drugs?

A: A generic drug is identical to a brand-name drug in dosage form, safety, strength, route of administration, quality, performance, and intended use. Although the active ingredient is chemically the same as the branded counterpart, a generic drug is typically sold at a substantial discount from the branded product price.

Q: If they are the same, why do generic drugs cost less than their brand-name counterparts?

A: Creating a drug and conducting clinical trials is expensive. Generic drug makers don't develop a drug from scratch or have to conduct studies to prove safety and effectiveness. As the result, their expenses for bringing generic drugs to market are less. But generic drug makers must show that their product performs in the same way as the brand-name drug.

Q: What is FDA's role regarding generic drugs?

A: CDER ensures that both brand-name and generic drugs are safe and effective, and that their health benefits outweigh their known risks. And, just as it does with brand-name drugs, the agency closely inspects generic makers' production sites and assures products approved are manufactured according to regulations regarding good manufacturing practices.

Health professionals and consumers can be assured that FDA-approved generic drugs have met the same rigid manufacturing standards as the brand-name drug.

Q: What is the Generic Initiative for Value and Efficiency (GIVE) program?

A: GIVE is an initiative aimed at optimizing OGD's generic drug review process to increase efficiency. The goals of GIVE are to approve higher numbers of applications for generic products and expedite review of applications for which there are few generics available.

Q: What will the benefits of this program be for the average consumer?

A: Consumers will have timely access to safer, higher-quality generic drugs.

A more efficient regulatory and approval process will maintain FDA's high standards for generic drug products for the public, while increasing the number of available products.

Q: Why is the GIVE program necessary?

A: Over the last three to four years, the number of abbreviated new drug applications submitted to our office has increased. This has led to a growing list of pending applications. We've made a number of successful process improvements during this time. In fact, the office approved a record number of applications during the past two years. We approved 510 products in 2006, and approved more than 650 in the fiscal year that just ended.

But the advancement of medical science and the related increasing cost of health care and disease prevention have caused the role of OGD and its review staff to grow. The number of firms producing generic products and the number of products each firm proposes are growing at an unforeseen pace. The improvements we have made serve to unify and enhance the review process to address the growing workload, and to increase the efficiency of our office's review efforts.

Q: How will the goals of GIVE be accomplished?

A: GIVE will work by combining our office's various efforts into one harmonized activity to implement process improvements throughout the entire program. The initiative is a review-oriented program that is focused on three main areas:

* Mobilizing staff efforts to increase review productivity.

* Optimizing the capacity and capability of all assets within OGD, and leveraging wherever possible resources from other FDA components.

* Using every avenue possible to recruit, hire and train reviewers for our critical-need areas.

FOR MORE INFORMATION VISIT

Generic Initiative for Value and Efficiency (GIVE) at http://www.fda.gov/oc/initiatives/advance/generics.html

October 2007. GlaxoSmithKline and Tolerx, Inc. today announced the execution of a worldwide alliance to develop and commercialize otelixizumab (TRX4), a novel humanized anti-CD3 monoclonal antibody that has potential across a broad range of autoimmune and immune-mediated inflammatory diseases, including type 1 diabetes. Otelixizumab has been evaluated in type 1 diabetes in two Phase II studies and in psoriasis in two Phase I studies. In clinical trials, otelixizumab has been shown to preserve the function of insulin-producing beta cells in the pancreas in patients with type 1 diabetes, reducing the amount of administered insulin needed to control blood glucose levels.

Under the terms of the agreement, Tolerx will have responsibility for the Phase III clinical programme for type 1 diabetes in the US up to and including regulatory submission of the biologics license application (BLA). Tolerx has the option to co-promote otelixizumab in type 1 diabetes in the US with GSK, while GSK will have exclusive rights to develop and commercialise otelixizumab in all other indications in the rest of the world. GSK also has the exclusive right to develop the paediatric indication for type 1 diabetes in the US.

 As part of the collaboration, Tolerx will receive an upfront payment, equity and advance R&D funding totaling $70 million. In addition, Tolerx may receive up to $155 million in future development costs of otelixizumab in type 1 diabetes. Tolerx may earn up to $350 million in milestone payments, assuming successful development and approvals of otelixizumab for type 1 diabetes and multiple additional indications. Tolerx may also receive up to $175 million in sales milestone payments based on tiered net sales thresholds of otelixizumab. Tolerx will be entitled to receive tiered, double-digit royalty payments on worldwide sales of otelixizumab in all indications. At the time of an initial public offering of Tolerx’s common stock and at the request of Tolerx and certain other conditions, GSKwill invest up to an additional $10 million in Tolerx’s common stock.

 Dr. Moncef Slaoui, Chairman of Research and Development at GSK, commented, “Otelixizumab is another welcome addition to GSK’s rapidly expanding biopharmaceuticals pipeline. This is a key area of future growth and investment for GSK and, as a novel treatment for many T cell-mediated diseases, the potential of otelixizumab is significant. Together with Tolerx, who are pioneers in this area of science, we hope to realise the potential of this compound and bring a valuable new treatment option to patients suffering from type 1 diabetes and other autoimmune disorders.”

"GSK brings a wealth of experience, expertise, and global resources to this collaboration. The agreement with GSK enables us to operationally leverage Tolerx’s expertise in therapeutic immune regulation, expand the development of otelixizumab in type 1 diabetes and other indications, and capitalize on GSK’s considerable worldwide development, regulatory, and commercialisation infrastructure and experience,” said Dr. Douglas J. Ringler, President and Chief Executive Officer of Tolerx. “Moreover, it provides the infrastructural support required to advance our goal of being first-to-market with otelixizumab in type 1 diabetes. We anticipate the collaboration will allow the potential of this novel therapy to be fully explored globally, not only for the treatment of patients with type 1 diabetes but also for those with autoimmune disorders for which the current standard of care is inadequate.”

About type 1 diabetes

Diabetes (medically known as diabetes mellitus) is the name given to disorders in which the body has difficulty regulating its blood glucose, or blood sugar levels. There are two major types of diabetes: type 1 and type 2. Type 1, also called juvenile diabetes or insulin-dependent diabetes, is a disorder of the body's immune system. In type 1 diabetes, the pancreas produces little or no insulin as a result of the immune system attacking and destroying the insulin-producing beta cells in the pancreas. Therefore, type 1 diabetes patients require frequent administration of insulin therapy each day to control their blood sugar levels.

About otelixizumab

Otelixizumab is a monoclonal antibody that binds to a receptor component found on all T cells known as CD3, which is involved in normal T cell signaling. Otelixizumab is designed to block the function of autoreactive T-effector cells that attack the body’s tissues and cause autoimmune disease while inducing a subset of T cells called T-regulatory cells that are thought to protect against T-effector cell damage well after the drug has been eliminated from the body. In a Phase II clinical study of subjects with new-onset type 1 diabetes, otelixizumab demonstrated the potential to preserve the function of insulin-producing beta cells in the pancreas and reduce the amount of administered insulin needed to control blood glucose levels for up to 18 months after only a single six day course of therapy. In the study, residual betacell function was assessed by measuring glucose clamp-induced C-peptide release before and after the administration of glucagon. Otelixizumab administration was associated with transient symptoms of flu-like syndrome and transient Epstein-Barr Virus (EBV) reactivation. Tolerx has completed dose optimisation studies in subjects with type 1 diabetes and psoriasis and has identified a dosing regimen that thus far has significantly reduced or eliminated these side effects while maintaining important biological activity.

About GlaxoSmithKline

GlaxoSmithKline is one of the world's leading research-based pharmaceutical and healthcare companies and is committed to improving the quality of human life by enabling people to do more, feel better and live longer. For more information, visit GlaxoSmithKline at www.gsk.com.

About Tolerx

Tolerx is a biopharmaceutical company engaged in the discovery and development of novel therapies to treat patients with immune-mediated diseases. Tolerx currently has two antibodies in clinical development: otelixizumab in type 1 diabetes and psoriasis, and TRX1 in cutaneous lupus erythematosus (CLE). TRX1 is a humanised anti-CD4 antibody that is being developed in collaboration with Genentech, Inc. Tolerx is also engaged in preclinical development of new product candidates that induce immunological tolerance for the treatment of autoimmune diseases and circumvent tolerance for the treatment of cancer or chronic viral diseases. For more information, please visit www.tolerx.com.

GlaxoSmithKline forward-looking statements

Under the safe harbor provisions of the U.S. Private Securities Litigation Reform Act of 1995, GSKcautions investors that any forward-looking statements or projections made by GSK, including those made in this announcement, are subject to risks and uncertainties that may cause actual results to differ materially from those projected. Factors that may affect GSK's operations are described under 'Risk Factors' in the Operating and Financial Review and Prospects in the company's Annual Report on Form 20-F for 2006.

Source: GSK Press Release

Leverkusen, Germany, and Tarrytown, NY (August 03, 2007) – Bayer HealthCare AG and Regeneron Pharmaceuticals, Inc. announced today that the companies have initiated a Phase 3 study of the VEGF Trap-Eye in the neovascular form of age-related macular degeneration (wet AMD). The study will be a non-inferiority comparison of the VEGF Trap-Eye and ranibizumab (Lucentis®, a registered trademark of Genentech, Inc.), an anti-angiogenic agent approved for use in wet AMD. The study will be conducted pursuant to a Special Protocol Assessment from the U.S. Food and Drug Administration (FDA). This trial, known as VIEW 1 (VEGF Trap: Investigation of Efficacy and safety in Wet age-related macular degeneration), is the first study in the companies’ Phase 3 global development program in wet AMD which is planned to be carried out in the U.S., Europe and other parts of the world.

“Age-related macular degeneration continues to be one of the leading causes of blindness in adults, and new therapies are essential to providing optimal patient care,” stated Jeffrey Heier, M.D., a clinical ophthalmologist at Ophthalmic Consultants of Boston and chair of the steering committee for the trial. “The results of early phase studies of VEGF Trap-Eye suggest it has the potential to be a highly efficacious treatment with less frequent administration. If these results are confirmed in Phase 3 trials, it would be important for both patients and physicians and would be a significant advance in the treatment of these patients.”

“We will continue in our effort to improve the lives of patients suffering from wet AMD and the initiation of the first Phase 3 study is an important step forward in the development of this investigational therapy”, said Kemal Malik, M.D., Member of the Bayer HealthCare Executive Committee, responsible for Global Development. “Our program is designed to investigate VEGF Trap-Eye’s potential to improve vision in patients with wet AMD with less frequent dosing than every four weeks.“

The randomized, double-masked Phase 3 study, is expected to enroll approximately 1,200 patients in more than 200 centers throughout the United States and Canada. The study will evaluate the safety and efficacy of the VEGF Trap-Eye at doses of 0.5 milligrams (mg) and 2.0 mg administered at four-week dosing intervals and 2.0 mg at an eight-week dosing interval, compared to 0.5 mg of ranibizumab administered every four weeks, consistent with its labeled dosing schedule.

The primary endpoint of the study is the proportion of patients treated with the VEGF Trap-Eye who maintain or improve vision at the end of one year, compared to ranibizumab patients. Visual acuity is defined as the total number of letters read correctly on the Early Treatment Diabetic Retinopathy Study (ETDRS) chart. Maintenance of vision is defined as losing fewer than 3 lines (equivalent to 15 letters) on the ETDRS chart. After the first year of treatment, patients will continue to be treated and followed for another year.

In an analysis of interim data from the ongoing Phase 2 trial in wet AMD, where patients were treated with the VEGF Trap-Eye either monthly or quarterly, combined data for all patients demonstrated a statistically significant reduction in retinal thickness and improvement in visual acuity after 12 weeks, compared to baseline. There were no drug-related serious adverse events, and treatment with the VEGF Trap-Eye was generally well-tolerated. The most common adverse events were those typically associated with intravitreal injections. The interim results of this Phase 2 trial were presented at the annual meeting of the Association for Research in Vision and Ophthalmology (ARVO) this past May. The Companies expect to report final primary endpoint results of the trial at a scientific meeting later this quarter.

Bayer HealthCare and Regeneron are collaborating on the global development of the VEGF Trap-Eye for the treatment of wet AMD, diabetic eye diseases, and other eye diseases and disorders. Bayer HealthCare will market the VEGF Trap-Eye outside the United States, where the parties will share equally in profits from any future sales of the VEGF Trap-Eye. Regeneron maintains exclusive rights to the VEGF Trap-Eye in the United States.

About the VEGF Trap-Eye

Vascular endothelial growth factor (VEGF) is a naturally occurring protein in the body whose normal role is to trigger formation of new blood vessels (angiogenesis) to support the growth of the body’s tissues and organs. It has also been associated with the abnormal growth and fragility of new blood vessels in the eye, which lead to the development of wet AMD. The VEGF Trap-Eye is a fully human, soluble VEGF receptor fusion protein that binds all forms of VEGF-A along with the related placental growth factor (PlGF). The VEGF Trap-Eye is a specific and highly potent blocker of these growth factors. Blockade of VEGF, which can prevent abnormal blood vessel formation and vascular leak, has proven beneficial in the treatment of wet AMD. Blocking VEGF has been shown to be effective in patients with wet AMD; and a VEGF inhibitor, ranibizumab, has been approved for treatment of patients with this condition.

About AMD

Age-related macular degeneration (AMD) is a leading cause of acquired blindness. Patients with this condition can experience a loss of vision due to the development of abnormal, fragile blood vessels in the back of the eye. A particular type of AMD, called wet AMD, accounts for approximately 90 percent of AMD-related blindness. Wet AMD is the leading cause of blindness for people over the age of 65 in the U.S. and Europe. Macular degeneration is diagnosed as either dry (nonexudative) or wet (exudative). In wet AMD, new blood vessels grow beneath the retina and leak blood and fluid. This leakage causes disruption and dysfunction of the retina creating blind spots in central vision, and it can lead to blindness in wet AMD patients.

About Regeneron Pharmaceuticals

Regeneron is a biopharmaceutical company that discovers, develops, and intends to commercialize therapeutic medicines for the treatment of serious medical conditions. Regeneron has therapeutic candidates for the potential treatment of cancer, eye diseases, and inflammatory diseases and has preclinical programs in other diseases and disorders. Additional information about Regeneron and recent news releases are available on Regeneron’s worldwide web site at www.regeneron.com

About Bayer HealthCare

The Bayer Group is a global enterprise with core competencies in the fields of health care, nutrition and high-tech materials. Bayer HealthCare, a subsidiary of Bayer AG, is one of the world’s leading, innovative companies in the healthcare and medical products industry and is based in Leverkusen, Germany.The company combines the global activities of the Animal Health, Consumer Care, Diabetes Care and Pharmaceuticals divisions. The pharmaceuticals business operates under the name Bayer Schering Pharma AG. Bayer HealthCare’s aim is to discover and manufacture products that will improve human and animal health worldwide. Find more information at www.bayerhealthcare.com.

Forward-looking statements

This news release contains forward-looking statements based on current assumptions and forecasts made by Bayer Group management. Various known and unknown risks, uncertainties and other factors could lead to material differences between the actual future results, financial situation, development or performance of the company and the estimates given here. These factors include those discussed in our annual and interim reports to the Frankfurt Stock Exchange and in our reports filed with the U.S. Securities and Exchange Commission (including our Form 20-F). The company assumes no liability whatsoever to update these forward-looking statements or to conform them to future events or developments.

Source: Bayer Press Release

 ---Novartis leading the introduction of influenza cell culture manufacturing - the first major innovation in influenza vaccine manufacturing in more than 50 years---

---Optaflu® to help meet growing need for seasonal influenza vaccines, production technology has potential for quick scale-up in case of an influenza pandemic--

---Novartis proprietary cell culture technology offers possibility to obtain a better matched vaccine with circulating viruses than currently available technology---

Basel, April 27, 2007 - Novartis has received a positive opinion supporting European Union approval of its cell culture-derived seasonal influenza vaccine Optaflu®, which is aiming to become the first influenza vaccine to utilize a mammalian cell line, rather than chicken eggs, for antigen production.

The Committee for Medicinal Products for Human Use (CHMP), which reviews applications for all 27 countries in the EU as well as Iceland and Norway, has recommended approval of this new vaccine. The European Commission generally follows the recommendations of the CHMP and delivers its final decision within two to three months.

"Novartis Vaccines is pleased with this positive recommendation for Optaflu, the first cell culture-derived influenza vaccine and the first major innovation in influenza vaccine manufacturing in more than 50 years," said Dr. Jörg Reinhardt, CEO of Novartis Vaccines and Diagnostics. "Optaflu contributes to meeting the growing demand for seasonal influenza vaccines, and this production technology offers the potential for quick scale-up of manufacturing in the event of an influenza pandemic."

A submission is anticipated in 2008 for US regulatory approval of this cell culture-derived seasonal influenza vaccine.

More than 3,400 people received Optaflu during the clinical development program evaluating the vaccine's safety and immunogenicity. Data reviewed by CHMP from the clinical program showed Optaflu fulfilled all of the Committee's immunogenicity criteria.

The data further showed the cell culture-derived influenza vaccine was comparable to conventional egg-based vaccines in efficacy and tolerability. Additives, such as antibiotics, are avoided in the Optaflu production process. Additionally, people allergic to eggs and egg products can benefit from receiving this vaccine since it is created without egg proteins.

Like established conventional egg-based vaccines, Optaflu is administered via intramuscular injection. Data from the Phase III clincial program were presented at the Influenza Vaccines for the World Congress (IVW) meeting in October 2006.

About cell culture technology and the Novartis proprietary cell line

Cell culture manufacturing is the first major innovation in influenza vaccine manufacturing in more than 50 years. It represents a new approach to vaccine production whereby influenza virus is propagated in readily available mammalian cell lines rather than in chicken eggs.

Virus cultivation utilizing the Novartis proprietary cell line as an exclusive host offers the possibility of more robust virus proliferation since most circulating viral strains are unable to replicate in chicken eggs. In a next generation of products, it also offers the possibility for vaccine seed strain development that more closely matches the original "wild" virus because cell culture technology eliminates the need for passage through eggs where the virus may be forced to adapt in order to replicate. As a result, the antigen included in the vaccine may express more authentically the surface of the wild type virus, potentially translating into a better immunogenic and effective response.

The Novartis proprietary cell culture technology enables flexible, faster start-up of vaccine manufacturing. With the advent of this technology, Novartis Vaccines is contributing  to meet the growing need for seasonal influenza vaccines and quickly respond to a potential pandemic influenza threat.

About influenza and pandemic influenza

Influenza can cause mild to severe illness and at times can lead to death. Worldwide, influenza epidemics result in approximately 250,000 to 500,000 deaths each year[1]. Influenza-related complications can include pneumonia and dehydration, and worsening of chronic conditions, such as congestive heart failure, asthma, or diabetes[2]. The World Health Organization (WHO) and its Global Influenza Surveillance Network recommend vaccination as the principal method for preventing influenza[1].  

Increased circulation of avian influenza A/H5N1 virus has been documented in Asia and Europe. On a pandemic threat scale of one to six, the World Health Organization currently ranks the H5N1 risk at phase three. This virus is highly contagious in chickens, adding the possibility that a pandemic strain could emerge at a time when egg supplies are lower than usual due to a previous epidemic in chickens. Novartis proprietary cell culture line offers an alternative to traditional egg-derived vaccines.

References

1. World Health Organization "Influenza Fact Sheet" http://www.who.int/mediacentre/factsheets/fs211/en/index.html Accessed October 10, 2006

2. Centers for Disease Control and Prevention (CDC) "Questions & Answers: The Disease" http://www.cdc.gov/flu/about/qa/disease.htm  Accessed October 10, 2006

Disclaimer

This release contains certain forward-looking statements, relating to the Novartis Group's business, which can be identified by the use of forward-looking terminology such as "to help," "potential," "possibility," "aiming to", "recommended", "generally follows the recommendations," "anticipated," "potentially, "can," "could," or similar expressions, or by express or implied discussions regarding potential marketing approvals or future sales of Optaflu. Such forward-looking statements reflect the current views of Novartis regarding future events, and involve known and unknown risks, uncertainties and other factors that may cause actual results with Optaflu to be materially different from any future results, performance or achievements expressed or implied by such statements. There can be no guarantee that Optaflu will be approved for any indications in any market or that Optaflu will reach any particular sales levels. In particular, management's expectations regarding Optaflu could be affected by, among other things, unexpected regulatory actions or delays or government regulation generally; unexpected clinical trial results, including additional analysis of existing clinical data and new clinical data; competition in general; the ability of Novartis to obtain or maintain patent or other proprietary intellectual property protection; increased government, industry, and general public pricing pressures; and other risks and factors referred to in the Novartis AG's current Form 20-F on file with the US Securities and Exchange Commission. Should one or more of these risks or uncertainties materialize, or should underlying assumptions prove incorrect, actual results may vary materially from those anticipated, believed, estimated or expected. Novartis is providing the information in this press release as of this date and does not undertake any obligation to update any forward-looking statements contained in this press release as a result of new information, future events or otherwise.

About Novartis

Novartis Vaccines and Diagnostics is a division of Novartis focused on the development of preventive treatments and tools. Novartis Vaccines is the world's fifth-largest manufacturer and second-largest supplier of influenza vaccines in the US. The division's products also include meningococcal, pediatric and travel vaccines. Chiron, the blood testing and molecular diagnostics business, is dedicated to preventing the spread of infectious diseases through the development of novel blood-screening tools that protect the world's blood supply. For more information, please visit http://www.novartisvaccines.com.

Novartis AG (NYSE: NVS) is a world leader in offering medicines to protect health, cure disease and improve well-being. Our goal is to discover, develop and successfully market innovative-products to treat patients, ease suffering and enhance the quality of life. We are strengthening our medicine-based portfolio, which is focused on strategic growth platforms in innovation driven pharmaceuticals, high-quality and low-cost generics, human vaccines and leading self-medication OTC brands. Novartis is the only company with leadership positions in these areas. In 2006, the Group's businesses achieved net sales of USD 37.0 billion and net income of USD 7.2 billion. Approximately USD 5.4 billion was invested in R&D. Headquartered in Basel, Switzerland, Novartis Group companies employ approximately 100,000 associates and operate in over 140 countries around the world.

For more information, please visit http://www.novartis.com

Four selective COX II inhibitors are marketed in Europe and two in USA. Celecoxib (Celebrex) and valdecoxib (Bextra) are approved in the USA, while Parecoxib (Dynastat), Etoricoxib (Arcoxia) and Lumiracoxib (Prexige) are marketed in European countries. Celecoxib was the top selling coxib in 2000 and 2001 with sales of $2 billion and $3 billion, respectively but lost market leadership to rofecoxib in 2002 and 2003 due to better gastrointestinal (GI) tolerance. In the first half of 2004, global sales of COX II inhibitors were: celecoxib $1.5 billion, rofecoxib $1.3 billion, valdecoxib $545 million and etoricoxib $92 million. Celecoxib is expected to reach annual sales of $3 billion in 2004. Worldwide 80-100 million patients have used celecoxib and rofecoxib and 40 million in USA.

The history of modern drug regulations is closely linked to the incidence of drug induced injury, organ failure and deaths (Table 1). Each tragedy linked to marketed drugs resulted in increased regulations and additional testing to prevent future episodes with new drugs of the same class (Table 2). The Elixir of Sulfanilamide tragedy resulted in the Food, Drug and Cosmetic Act of 1938. The Thalidomide tragedy in early 1960 resulted in requirements for safety and efficacy testing for drugs in animals and humans. Safety testing includes testing new drugs for adverse effects; for example, can a new chemical entity (NCE) cause birth defects, cancer, organ failure, organ toxicity or some other problem. Willman of The Los Angeles Times was honored with a Pulitzer Prize in 2001 for his investigative reporting of FDA fast track approval and seven deadly drugs in 2000 including Rezulin, Fen-Phen and Duract (bromfenac) [8].

All drug withdrawals are followed by regulatory review of similar drugs to rule out a class effect, additional safety data for marketed drugs and additional requirements for drugs in development. The withdrawal of benoxaprofen resulted in a ten fold increase in number of patients (from 200-400 patient year exposure to 2500-5000 patient year exposure to the study drug) required for newer NSAID (Non Steroidal Anti Inflammatory Drugs) and trials in elderly, hepatic and renal impairment and drug interactions. International guidelines require that for long-term treatment of non-life-threatening conditions, 1500 patients should be treated with the drug: for safety-300-600 treated for at least 6 months, and for efficacy at least 100 for 12 months. FDA has routinely required 200 patients treated for 1 year. Astra Zeneca total patient exposure in clinical trials submitted for approval for rosuvastatin (12,500) was considerably greater than the 2,000-3,000 patients submitted for most of the other marketed statins. Since the withdrawal of troglitazone (Rezulin), no other Peroxisome Proliferator Activator Receptor (PPAR) agonist has been approved because of the concerns about the class carcinogenicity, hepatotoxicity and cardiotoxicity.

The published and available clinical data indicates an increased cardiac risk to patients linked to the long term use of rofecoxib [9-11]. Cardiovascular (CV) events linked to Cox-II inhibitors, include heart attack, stroke, high blood pressure, fluid retention and heart failure. After rofecoxib, a winning strategy for a safe and effective anti-inflammatory and analgesic COX-II agent is to reduce GI toxicity and not have any cardiovascular, renal, hepatic, neurological or any other toxicity. Toxicology studies in monkeys, in addition to rodents and dogs may help identifying CV risks early in drug development. Clinical trials to generate data for approval and show reduced GI toxicity and CV safety will require 25,000-30,000 patients with several thousands treated for 2-3 years. This is confirmed by recent FDA stance for additional long term safety data for the approval of etoricoxib and lumiracoxib. This has been the requirement for approvals of some new vaccines and drugs for common cold. The industrial R&D should move away from the twin focused NSAID induced GI toxicity and total COX II inhibition. The optimum COX II inhibition may provide cardiac, hepatic, renal, immunological and CNS safety [12, 13]. The total R&D costs for such a drug will be $1.5 billion over 12-15 years. If successful, the rewards are a blockbuster analgesic drug with potential annual sales of $5 billion.

The available data indicates a differentiation of available COX-II inhibitors with respect to GI and CV effects [14]. Etoricoxib (Arcoxia) show reduced GI toxicity without increased CV risk but long term data is not available. Valdecoxib (Bextra), Parecoxib (Dynastat) and Lumiracoxib (Prexige) show reduced GI toxicity with increased CV risk. Rofecoxib showed reduced GI toxicity with increased CV risk. Celecoxib (Celebrex) has a similar GI toxicity as popular NSAIDS but may have a potential cardioprotective effect according to Pfizer but increased CV risk according to its critics.