TCS Daily

We Have It Coming

By Henry I. Miller - February 1, 2006 12:00 AM

Americans are about to learn the hard way about the unintended consequences of over-regulation and flawed policy initiatives.

Vaccination to prevent viral and bacterial diseases is modern medicine's most cost-effective intervention. Were a vaccine to be available quickly after the onset of the widely predicted pandemic from an H5N1 strain of avian influenza, it might save scores of millions of lives worldwide -- but that's not now feasible. Why can't a country that developed the atomic bomb (60 years ago) and the polio vaccine (50 years ago) and put a man on the moon (almost 40 years ago) now produce an appropriate vaccine?

The reason is that flawed public policy from the Congress and the government's Executive Branch has ensured low return on investment and high exposure to legal liability for vaccines. The predictable result: U.S. vaccine R&D and production have been decimated.

What kinds of policies? The Vaccines for Children Program, for example, was a do-gooder innovation of the Clinton administration (Hillary's toe in the water for national health care, apparently) that disrupted market forces and dealt a blow to vaccine producers. Established in 1994, it created a single-buyer system for children's vaccines, making the government by far the largest purchaser of childhood vaccines -- at a mandated discount of 50 percent. Try extorting that kind of discount from manufacturers of trucks for the U.S. Postal Service or of Meals-Ready-to-Eat (MREs) for the Department of Defense, and see how long the companies bid on government contracts.

Memo to Senator Clinton: It doesn't take a village, just good old American ingenuity combined with the expectation of a decent return on investment.

Arbitrary and excessive regulation is another obstacle. The highly risk-averse FDA has been especially tough on vaccines. The agency has rejected evidence of safety and efficacy from European and Canadian vaccine approvals; prematurely withdrawn life-saving products from the market because of mere perceptions of risk; and set the bar for the testing of new vaccines almost impossibly high.

As a result of our disastrous public policy, innovation has suffered and vaccine producers have abandoned the field in droves, leaving only four major American manufacturers and a few dozen products. As of the last flu season, there were only two producers of injectable flu vaccine for the U.S. market, for example, both using antiquated technology.

That brings us to the issue of the hour: a pandemic of H5N1 avian flu. We are woefully short of capacity to manufacture a vaccine against the pandemic strain, which cannot actually begin until we have it in hand (and have "reverse engineered" the virus to prevent it from killing the chicken embryos in which it is grown). An optimistic estimate is that there is sufficient flu vaccine capacity worldwide for approximately 450 million people -- but that calculation assumes that two inoculations of 15 micrograms each would confer protection, whereas in a recent trial (of a vaccine against the current H5N1 strain) two doses of 90 micrograms were required. Other things being equal, that suggests that the true capacity might be closer to enough for only 75 million people. (The world's population is over six billion.)

Another worry is that when a pandemic strain of H5N1 avian flu appears, virtually all of the world's flu-vaccine-development and production capacity will shift to producing a vaccine against it, which will leave us vulnerable to the non-pandemic strain(s) that causes the usual annual, or seasonal, flu. The annual flu bug kills, on average, 30,000-40,000 Americans each year -- even when we have an effective, widely used vaccine. As Anthony Fauci, director of the U.S. National Institute of Allergy and Infectious Diseases, has observed, "The biggest challenge unequivocally is vaccine production capacity."

Remedying that shortfall of production capacity won't be easy: Currently, it requires five to six years (and a massive investment) to build and validate a new manufacturing plant to the satisfaction of regulators. In the meantime, there are other possible approaches to making the vaccine we can produce go further. A proven technique is the addition to vaccines of chemical ingredients known as adjuvants, which increase their effectiveness and make it possible to use lower doses of the vaccine antigens themselves. France's Sanofi-Pasteur and Australia's CSI have begun trials of candidate pandemic vaccines that use adjuvants made of alum, an aluminum salt, the only adjuvant approved for use in humans in the United States.

California-based Chiron Corporation may have a more promising candidate. In clinical trials of an adjuvant called MF59, which has been incorporated into a vaccine being tested for protection against avian flu strain H5N1, vaccine containing adjuvant was significantly better than vaccine alone at eliciting antibodies to H5N1. An important potential advantage of this adjuvant-containing vaccine is the discovery that it may offer protection against H5N1 even if the virus's cell-surface proteins change, or "drift," in a way that makes them slightly different immunologically.

That suggests a viable, if not optimal, strategy to prepare for the pandemic: Stockpile vaccine against the current avian flu H5N1 strain, with adjuvant added to boost the immune response. Although it wouldn't be perfect, it might be useful as a first "priming" dose that could afford some protection until vaccine against the actual pandemic flu strain is available.

Another complementary approach to conserving vaccine antigen was suggested by the work of researchers at the University of British Columbia who used genetic engineering techniques to incorporate into vaccines two proteins that help cells of the immune system to process foreign antigens. They found that these proteins act as a potent booster, inducing the immunized recipient to produce more immunologically active cells against foreign antigens contained in the vaccines. In their animal model, in which a challenge of a potentially lethal dose of virus was administered after vaccination, one of their engineered vaccines "provided protection against a lethal challenge . . . at doses 100-fold lower" than controls that did not have the modification. (Their experiments involved several viruses, but not influenza.)

However, that gets us back to obstacles in the regulatory arena. MF59 has never been approved for use in a vaccine sold in the United States, at least partly because R&D on vaccines has become so unprofitable and unattractive that there has been little incentive to perfect a technology to boost their efficiency or to perform the expensive clinical testing necessary to license what regulators would regard as a new vaccine technology. Also, the addition to existing vaccines of an adjuvant -- even one with a long history -- would make a previously-approved vaccine a "new drug," requiring exhaustive testing (especially given that the products would be administered to very large numbers of healthy people).

Another strategy is the one adopted by British health authorities, who have ordered sufficient vaccine against the actual pandemic strain to treat every person with the needed two doses. The limitation of this approach is that because production cannot begin until the pandemic begins and the virus is in hand, there will be a substantial lag -- probably nine months at a minimum -- until the vaccine is available. Why so long? Certain initial genetic manipulations will be necessary; the vaccine itself must be shown to possess high levels of purity and potency reproducibly in batch after batch; the production facilities must be inspected and certified; and clinical trials performed and their results analyzed. Thus, although the development of an effective vaccine would be the most definitive intervention in the long run, it would leave the population vulnerable to at least the first wave of the pandemic.

The National Institute of Allergy and Infectious Diseases is funding yet another approach to optimize a limited vaccine supply: intradermal (under the skin) administration of the H5N1 vaccine, in order to ascertain whether a smaller intradermal dose is as effective as a larger dose administered intramuscularly (into the muscle, the usual route of immunization).

Which strategy should we adopt? My answer is all of the above - and more.

World War II's Manhattan Project to develop atomic bombs pursued various R&D strategies in parallel; at least three methods to enrich uranium for the needed (and rare) isotope U-235 were developed independently, for example. In the end, the program developed both a uranium-based bomb (dropped on Hiroshima) and one that used plutonium (Nagasaki). The Manhattan Project was arguably the most ambitious and successful R&D undertaking in history, and the threat of an avian flu pandemic argues for a similar approach: many parallel strategies pursued on many fronts.

Vaccines are widely acknowledged to have high "social value," but compared to therapeutic drugs their "economic value" to pharmaceutical companies is low. Because governmental miscues have caused rampant market failures in vaccine R&D, government actions must be an integral part of the solution to rewarding the creation, testing and production of vaccines.

We need a variety of incentives to revitalize the portion of the private sector that has been battered by policymakers and regulators -- both to push forward good scientific ideas and to pull big drug makers into the field. Public policy must reward inputs on vaccine R&D (via grants, tax credits and the waiver of regulatory registration fees) and outputs of products (with guaranteed purchases, milestone payments when regulatory approval of new vaccines are granted, indemnification from liability claims, waiver of FDA user fees for vaccine reviews, and reciprocity between U.S. regulatory approvals and those in certain foreign countries). Part of this effort should be aggressive funding of "proof of concept" R&D on various new technologies and approaches to making flu vaccine, to boosting the immune response, and to creating greater reserve capacity for the commercial production of vaccines. Finally, instead of being a major cause of the problem, regulators must become part of the solution.

Federal officials and lawmakers are largely responsible for the current lack of societal resilience needed to combat a flu pandemic. Now they must do more than fiddle while flu fulminates.

Henry I. Miller, a physician and fellow at the Hoover Institution and Competitive Enterprise Institute, headed the FDA's Office of Biotechnology from 1989 to 1994. Barron's selected his most recent book, "The Frankenfood Myth..." one of the 25 Best Books of 2004.



Curing FDA Regulation
"Finally, instead of being a major cause of the problem, regulators must become part of the solution."

The best SOLUTION to "FDA Regulation" is to eliminate it. All authority to ban and control drugs/treatments should be stripped from the FDA. Instead, the FDA should provide ongoing education, analysis and rating for all drugs and treatments. The choice to use a drug/treatment should reside with the patient/consumer.

Put labs out of business
That will put too many people out of a job.

But I do agree the FDA is not necessary.

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