POLICY & PROJECTIONSDrug Discovery & Development

16 I February 2005 www.dddmag.com

Ted AgresDeputy Managing Editor,Washington Times

FDA’s Ability to Protect Questioned

An onslaught from Congress andcritics of the pharmaceuticalindustry is expected to hit the USFood and Drug Administration(FDA) in response to a conflu-

ence of concerns raised over prescription drugsafety and allegations of interference by gov-ernment officials.

“The FDA, as it is currently configured, isincapable of protecting America from anotherVioxx. We are virtually defenseless,” said DavidJ. Graham, associate director of the FDA’sOffice of Drug Safety in congressional testimo-

ny last November. “Simply put, the FDA and itsCenter for Drug Evaluation and Research[CDER] are broken.”

The FDA’s existing postmarketing surveil-lance system is rife with “shortcomings and fail-ures,” wrote the editors of the Journal of theAmerican Medical Association (JAMA). TheBritish medical journal Lancet called theagency’s drug safety office “weak and ineffec-tive” and said the FDA is in need of “funda-mental organizational reform.”

Some sort of FDA restructuring, either enact-ed by the Administration or imposed by Con-gress, appears likely. Senator Charles Grassley(R-Iowa), chairman of the powerful SenateFinance Committee, planned to introduce legis-lation early this year to restructure the FDA bycreating a drug safety office independent ofCDER. Other ideas being discussed are ways tostrengthen FDA’s postmarketing surveillancesystem, which currently depends on voluntaryreporting of adverse events by doctors andwhich, by some estimates, captures only 10% ofthe problems. “There is clearly concern thatsomehow the system is not working as well asit could,” said CDER deputy director SandraKweder in congressional testimony.

Why all the fuss of recent months? “FDA hasa well-documented and longstanding commit-ment to openness and transparency in its reviewof marketed drugs,” said acting FDA commis-sioner Lester Crawford in a statement. “Indeed,the post-market review of Vioxx and antide-pressants were initiated and funded by FDA andmanaged by its Office of Drug Safety. That isevidence that the system is working.”

So why is the agency’s feet being held to thefire? Critics contend a structural conflict ofinterest keeps FDA safety officials from exer-cising authority because the Office of DrugSafety is part of CDER, which is responsiblefor evaluating and approving new drugs.“When a serious safety issue arises after mar-keting, [CDER’s] immediate reaction is almostalways one of denial, rejection, and heat,” saidthe FDA’s Graham. “This is an inherent con-flict of interest.”

In addition, critics allege a culture at the FDAthat views the drug industry as a client to beappeased rather than regulated. That culture,Graham told the Senate Finance Committee inNovember, “overvalues the benefits of drugs itapproves and seriously undervalues, disregards,and disrespects drug safety.” Graham, who orig-inally made the cardiovascular safety issues sur-rounding Vioxx public, told senators that hissuperiors at the FDA pressured him to soften hisconclusions and recommendations and soughtto stifle publication of his findings. FDA offi-cials denied doing so.

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POLICY & PROJECTIONSDrug Discovery & Development

Late last year, in response to a Free-dom of Information Act petition, theFDA released an internal survey con-ducted in 2002 of about 400 agency sci-entists. About two-thirds of those sur-veyed said they lacked confidence thatthe FDA “adequately monitors the safe-ty of prescription drugs once they are onthe market.” In addition, 18% reportedthat they “have been pressured toapprove or recommend approval” for adrug “despite reservations about thesafety, efficacy, or quality of the drug.”

In response to the controversies, theFDA in November announced a seriesof initiatives, including establishing aformal program to review disagree-ments among scientific reviewers, fill-ing the currently vacant position ofdirector of the Office of Drug Safety,and publishing new risk managementguidelines. “FDA encourages open andvigorous internal debate about the oftendifficult scientific questions it routinelyfaces,” Crawford said. “There are timeswhen honest scientific disagreementcannot be resolved, [and] that is whyour new program provides for a reviewby an ad hoc panel not directly involvedin the decisions.”

FDA has also commissioned theInstitute of Medicine (IOM) of theNational Academy of Sciences to con-duct a detailed study its drug safetysystem, focusing especially on thepostmarket phase. While calling allthese steps important, a lengthy edito-rial in the December 1, 2004, JAMAnoted they are “inadequate” to restorepublic trust “and certainly are insuffi-cient to dispel the perceptions that theagency appears to be unduly influ-enced by industry and seems overlyconcerned about its own public imageand relations.”

Rather, JAMA’s editors argue thedrug approval process needs to be“decoupled” from the postmarketingsafety and surveillance system. “It isunreasonable to expect that the sameagency that was responsible forapproval of drug licensing and labeling

would also be committed to activelyseek evidence to prove itself wrong,”the editors wrote, supporting the posi-tion of Grassley and others.

FDA officials and drug industry rep-resentatives want to wait for the IOMreport before considering any restruc-

turing plans. JAMA editors say FDA’sproblems are too urgent to wait. Untilrestructuring occurs, the United Stateswill “still be far short of having an effec-tive, vigilant, and trustworthy system ofpostmarketing surveillance to protectthe public,” they say.

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POLICY & PROJECTIONSDrug Discovery & Development

16 I May 2005 www.dddmag.com

Ted AgresDeputy managing editor,Washington Times

Vaccine Supplies Remain Sickly

Mounting concerns that the South-east Asian H5N1 avian influen-za virus could evolve into ahuman transmissible form andtrigger a global pandemic is

highlighting longstanding weaknesses in theworld’s vaccine discovery and development sys-tem. While such a pandemic could kill millions ofpeople, vaccine manufacturers are not able to pro-duce vaccine sufficient to counter the threat.

Manufacturers want purchasing guaranteesfrom their governments and protection fromlegal liability should safety issues arise. Buteven if these wishes were granted, manufactur-ers lack capacity to produce enough vaccine toinoculate even those most at risk. It would takesix months to produce enough vaccine for 10%

to 20% of the US and Europe, according to theWorld Health Organization (WHO). And that’snot counting vaccine for Vietnam, Cambodia,and Thailand—where H5N1 has hit—let aloneChina and Hong Kong, where the virus wasfirst detected in 1997.

“While there have been relatively few casesworldwide of H5N1 avian influenza infection in

humans, the public health community is con-cerned that the virus will develop the capabilityof efficiently spreading from human to humanand, thus, create a risk for a worldwide pan-demic,” said Anthony Fauci, director of theNational Institute of Allergy and Infectious Dis-eases of the National Institutes of Health.

Through March 2005, the WHO confirmed 69cases and 46 deaths from H5N1 avian influenzainfection in humans. The number of actual infec-tions is likely to be much higher, however,because doctors haven’t fully identified therange of observable symptoms. Should the virusmutate and trigger a pandemic, 2 million to 7.4million people around the world would beexpected to die, according to the Centers for Dis-ease Control and Prevention (CDC), Atlanta.

Against this and other threats, companies thatdevelop and manufacture vaccines have increas-ingly been struggling to survive, choking on atangle of bureaucratic and financial problems.The pressures on vaccine manufacturers are myr-iad and complex. In 1967, there were more thantwo dozen licensed vaccine makers in the US. Tosubsidize childhood immunizations, the Federalgovernment pressured manufacturers to sell atthe lowest costs. Over the years, lawsuits alleg-ing neurological and other illnesses have addedto the industry’s woes, causing the number ofmanufacturers to shrink.

The two remaining major flu vaccine manu-facturers in the US are Sanofi Pasteur MSD, for-merly Aventis Pasteur, Swiftwater, Pa., and Chi-ron Corp., Emeryville, Calif. Sanofi and Chironhave produced an experimental inactivated H5N1vaccine made from an H5N1 virus isolated inSoutheast Asia in 2004. The vaccine is currentlyundergoing phase I clinical trials in the US. Con-tamination problems at Chiron’s vaccine produc-tion facility in Liverpool, England, last yearblocked shipment of 48 million doses of its Flu-virin flu vaccine, leading to supply shortages inthe US.

Chiron wrote off $91 million due to theinventory buildup, and the company’s stockfell 30%. In March, British regulators reinstat-ed Chiron’s license to manufacture flu vaccine.The Food and Drug Administration describedit as “an extremely important milestone” in the

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process of allowing vaccine into the US in time for the 2005-2006 flu season.

But for the experimental H5N1 vaccine, production capacityproblems will persist even if it proves safe and efficacious: SanofiPasteur has only a few weeks during the summer when it isn’tmaking flu vaccine. Adding capacity is neither cheap nor easy:a current good manufacturing practices vaccine production facil-ity can cost $300 million to $500 million and take three to fiveyears to build. In early April, the US government awarded Sanofi$97 million to help fund a cell-based production facility to pro-duce human flu vaccine.

Stockpiling vaccine is clearly an option, and the federalgovernment already is storing some 2 million doses of Sanofi-produced bulk avian flu vaccine. Officials are testing to see ifthe vaccine will lose potency over time. But even if it remainsstable, an emerging pandemic strain may not respond to stock-piled vaccine since influenza viruses mutate over time.

In an effort to stay a step ahead of nature, scientists at CDC’sinfluenza labs are experimenting with swapping the genes fromthe H5N1 avian virus with those of H3N2, a common human fluvirus. It would be through such a mutation that the avian flu viruscould become transmissible to humans. Ascertaining which, ifany, of the various genetic permutations is lethal will help scien-tists design an effective vaccine. Producing it is another matter.

Problems of profitability, manufacturing capacity, and regu-latory compliance in the vaccine industry have been recognizedfor years. In 2002, the National Academy of Sciences recom-mended loosening the rules surrounding vaccine research anddevelopment. “Financial incentives, indemnification, and regu-latory changes may be needed to allow the pharmaceuticalindustry to pursue new mechanisms of therapeutics and vac-cines,” stated the report, “Making the Nation Safer: The Role ofScience and Technology in Countering Terrorism.”

“Because markets are very limited for vaccines and drugscountering potential bioterrorist agents, special institutes mayhave to be established for carrying out biohazardous research andproducing drugs and vaccines,” the report stated. The federalgovernment should explore strategies, including modifying reg-ulatory procedures, to encourage vaccine development, it added.

Citing uncertainties in vaccine manufacturing, The Collegeof Pharmacy and Pharmaceutical Sciences at Florida A&M,Tallahassee, may enter vaccine production on its own. Accord-ing to the Washington Fax news service, the $40 million Flori-da Vaccine Research Institute would focus on producinginfluenza vaccine to serve the state’s large number of vulnera-ble residents.

The University of Pittsburgh Medical Center also is con-sidering building a vaccine plant. If constructed, the Pitts-burgh plant would focus on manufacturing vaccines for dis-eases that afflict the developing world, such as tuberculosisand malaria. The manufacturing center also may focus ontherapeutic cancer vaccines.

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