WASHINGTON, D.C. It took years to build an immunization system capable of delivering routine vaccination. The system was solid and effective: disease incidence dropped dramatically as coverage rates rose to record levels, averaging about 90% for most vaccines. Lately, however, the foundation of this network has started to crack and the distribution system is threatened to the point that some people are being denied vaccine simply because physicians cannot obtain sufficient supplies.
Physicians, public health officials, pharmaceutical manufacturers and others are trying to determine what went wrong in hopes of shoring up the foundation and preventing further shortages.
It is unclear exactly where to place the blame. Weve dealt with a series of ignoble rumors attributing shortages to industry to get more money for their product to shuffle money into the private rather than the public side, said Louis Cooper, MD, professor of pediatrics at Columbia University. This is not the case, he added, the causes are more complex.
|DT, Td, tetanus toxoids||One manufacturer dropped production.|
|DTaP||Tetanus toxoids shortage due to manufacturer dropping production.|
|Pneumococcal conjugate||Rapid implementation; Good Manufacturing Practice Issues; grantee funding shortages.|
|Varicella||Good Manufacturing Practice Issues.|
|MMR||Good Manufacturing Practice Issues.|
|Hib (Merck)||Good Manufacturing Practice Issues.|
|Hep B-Hib (Merck)||Good Manufacturing Practice Issues.|
|Influenza||In 2000, difficulty in production. In 2001, one manufacturer dropped production; uneven distribution.|
Something that makes the vaccine supply system complex is that basically the production lines have to be set up and approved, and the capacity predetermined, before it is known how much will be supplied, or maybe even before it is known what price will be charged, said Pauly.
This complicated economic model results in a decreased interest in producing vaccines. In 1967, there were 26 vaccine manufacturers in the U.S. market. But by 1980 there were 17, and now there are only 12 in 2002.
One solution may be to add manufacturers to the market. However, when more manufacturers enter the same market, there is less market share to offset the fixed costs of production, infrastructure and employees. That means fewer profits and less incentive to manufacturer vaccine.
An alternative, according to Martin Myers, MD, outgoing director of the National Vaccine Program Office, is to introduce tax incentives into the system to stimulate interest in lower profit, high-need vaccines. The incentives could also offset the expense of meeting CGMPs.
Good manufacturing protocols arent going away, but they are a financial burden, said Myers. We need to figure out a way to get manufacturers to meet our common objectives.
Financial incentives, though, do not directly address availability shortfalls. To counteract temporary disruptions in supply in 1983, the CDC began stockpiling many vaccines used in the routine immunization schedule. Merck recently tapped the MMR stockpile to help address a shortage. The stockpile has been drawn down at least 11 times since creation in 1983 for various reasons, according to the CDCs Orenstein.
Expanding the stockpiles would be difficult, according to Thomas Zink, MD, vice president of immunization practices and scientific affairs at GlaxoSmithKline. Production facilities are already at full capacity in many instances, so simply buying excess doses would not be feasible.
I am worried that the stockpile idea is a little out of bloom. We have some issues where obviously we have drawn tremendously, and there are going to be some real short-term pains for a long-term gain, he said.
More importantly, said Zink, without proper infrastructure, vaccine stockpiles are useless. If the product cannot be distributed quickly to the physicians who need it, then stockpiles are just wasted resources. You could stockpile all day, but if you dont have an infrastructure to distribute this stuff in a rapid fashion, especially with bioterrorism threats, then you are just kidding yourself, said Zink.
Vaccine stockpiles are not a stand-alone solution to supply problems. Instead, they are a safety net for unforeseen supply disruptions and for bridging the gap during changes in recommendations.
Unpredictability of the market seems to be a common theme in the vaccine supply problems. Whether the growing cost of production or the uncertainty of licensure, these factors, at least peripherally, affect a manufacturers decision to enter or stay in the business of making vaccines.
The Prescription Drug User Fee Act of 1992 apportioned funds for product reviews and set timetables for review of new applications. When the act was updated by the Food and Drug Modernization Act in 1997, lawmakers added fast tracking and set priorities for FDA collaboration with other regulatory agencies, including globalization of regulatory standards.
FDA activities have already improved the regulatory process, said William Egan, PhD, deputy director in the office of Vaccines Research and Review at the FDA. Stepped up laboratory programs, including improved vaccine lot testing for sterility, potency and consistency, have sped up some licensure activities. New assays for acellular pertussis, for example, accelerated licensure by almost a year, he said.
But there is more to be done to make the business of vaccines more attractive to manufacturers, added Egan.
Last year, an Institute of Medicine report called for the creation of a National Vaccine Authority to set national policy and to oversee the creation of new vaccines. However, government involvement has been widely criticized by many.
A National Vaccine Authority would be redundant, many experts claim, because the Advisory Committee on Immunization Practices (ACIP), the AAP and the American Academy of Family Physicians (AAFP) already set recommendations for vaccine use. In addition, the National Vaccine Advisory Committee (NVAC) suggests policy changes to lawmakers and the Department of Health and Human Services.
I am worried that there are just so many talented chefs that we are going to spoil the broth, and I am hopeful that we dont add another one with the National Vaccine Authority, said Zink. Pretty soon it is just alphabet soup, and I am concerned that is more distracting than productive.
The idea of government actually producing vaccine also has some problems. Any vaccine made by the government would still be subject to the same market forces and regulatory requirements experienced by private industry, and there is nothing to stop a government plant from having the same production difficulties. Government involvement in production would require substantial capitol investment in the creation of manufacturing facilities, money that would have to be reinvested annually to comply with regulatory requirements. From a government perspective, if they want to invest in new vaccines, those investments have to be long term, and the commitment needs to be long term, otherwise theyre not going to be successful, said Peter Paradiso, PhD, vice president of scientific affairs and research strategy at Wyeth Lederle Vaccines.
Nevertheless, if the National Vaccine Authority were given autonomous power and adequate funding, it could establish vaccine priorities. Government-run or government-contracted production facilities would mean more manufacturers and the possibility for more vaccines on the market.
|Increasing financial incentives||Vaccines are costly to develop.||Tax incentives for low-profit margin vaccines and/or plant upgrades. Paying to develop vaccines.|
|Streamlining the regulatory process||Difficulty in obtaining licensure detrimental to development; pricey.||Global harmonization of regulatory process; improving testing and lot release protocols.|
|Establishing government-directed programs||National security necessitates certain vaccines
with low-profit potential.
To increase the number of vaccine manufacturers.
|Either a National Vaccine Authority or government-operated production.|
|Utilizing vaccine stockpiles||To smooth over transitions in policy and to have stores ready for shortage situation (last resort supply).||Gradual build-up of supplies through surplus buying.|
|Increasing liability protection||During the 1980s, lawsuits drove manufacturers away from the market.||Reforming the Vaccine Injury Compensation Program.|
Government involvement may be warranted in older vaccine markets without a high potential for profit and for vaccines necessary for national security. But questions remain as to what role government should play in vaccines. Would the government be able to garner tax dollars and public support for the production of vaccines in the face of growing public skepticism? Would the government be subject to the same liability as private market manufacturers? Or, would government-made vaccines come under increased scrutiny if they were perceived as unsafe?
Liability is a complex issue and increased protection could make vaccine development more attractive to investors and pharmaceutical companies. Lawsuits outside the VICP threaten public confidence and the viability of manufacturers.
However, reforms to the VICP would not have a direct effect on vaccine production. Lower risk could mean more private investment, but would not solve problems associated with production, licensure and regulation.
Additionally, the need for liability reforms begs the inevitable question: why do manufacturers need additional protection? More importantly, if vaccines are beneficial to public health, why is there reluctance on the part of the public to pay for and receive vaccinations?
Manufacturers are confident that all current production problems will be resolved by the end of this year, and the CDC anticipates returning to the full childhood immunization schedule by the first quarter of 2003. However, the vaccine manufacturers and the CDC cannot say with confidence that vaccine shortages will not occur again.
So, while public health officials busy themselves fixing the current shortage problems, they cannot lose sight of the ultimate goal: a consistent and uninterrupted supply of vaccines. Immunization is one of the most effective prevention measures we have, said the CDCs Orenstein. It is dependent on an adequate supply, and we have clearly seen over the past year that our supplies are vulnerable. There is no clear single reason for supply problems, so the solutions needed are multifaceted. We need both short-term and long-term solutions.
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- Dr. Orenstein and Dr. Cooper have no direct financial interest in the products mentioned in this article, nor are they paid consultants for any companies mentioned.
- Infectious Diseases in Children could not confirm whether Dr. Pauly has a direct financial interest in the products mentioned in this article or if he is a paid consultant for any companies mentioned.