Medicine's Miracle Man

Medicine's Miracle Man. By John E. Calfee
Maurice Hilleman's remarkable period of industrial scientific research yielded the most cost-effective medicines ever made.
The American, Friday, January 23, 2009

The pharmaceutical industry has been under attack for longer than most people realize. In the 1950s and 1960s, when for the first time in history we had quite a few drugs that worked very well—including many antibiotics, the first miracle drugs—there was the full panoply of congressional hearings, outraged newspaper editorials, and dour experts who described an industry in which prices were too high, marketing too important, and innovation in decline amid a flood of “me-too” drugs barely distinguishable from the original innovative brands. But I doubt that the atmosphere then was as hostile as it has been in the past five years or so. A flood of books, including some by authors with academic credentials, have re-circulated many of the same arguments (albeit with more emphasis on safety). The more scholarly works include Merrill Goozner’s The $800 Million Pill: The Truth Behind the Cost of New Drugs; Jerome Kassirer’s On The Take: How Medicine’s Complicity with Big Business Can Endanger Your Health; and Jerry Avorn’s Powerful Medicines: The Benefits, Risks, and Costs of Prescription Drugs. Others have a more muckrakian tone, beginning with the muchquoted The Truth About the Drug Companies by former New England Journal of Medicine editor Marcia Angell, and continuing on to many others including Ray Moynihan and Alan Cassels’s Selling Sickness: How the World’s Biggest Pharmaceutical Companies Are Turning Us All Into Patients; Howard Brody’s Hooked: Ethics, the Medical Professions, and the Pharmaceutical Industry; Alison Bass’s Side-effects: A Prosecutor, a Whistleblower, and a Bestselling Antidepressant on Trial (about the drug Paxil); and Philip R. Lee’s Pills, Profits, and Politics.


What’s with R&D?

To my mind, the most serious of these indictments focus on industry research. No doubt, the stakes are high for the industry. If drugs are truly innovative life-modifiers or life-savers, the argument over prices and spending tends to be marginalized. But if there hasn’t been a lot of innovation and if the innovation we do get comes mainly from the taxpayer-supported National Institutes of Health and other nonprofit organizations, the politics of drugs becomes difficult for the industry to handle.

We need to look ahead, and when we do it’s hard not to get excited. The entire field of immunology has taken off along with so much else in this age of biotechnology.

I have had occasion to write about innovation and its sources in the pages of The American. As I explained in “The Golden Age of Medical Innovation” (March/April 2007), the critics have paid too much attention to the annual count of new drug approvals by the FDA and too little attention to two crucial developments. One is the increasing importance of research that occurs after a drug is approved. Newer drugs, especially so-called biotech drugs including monoclonal antibodies, involve complex biological processes that are themselves subject to ever more sophisticated research on everything from DNA to drug interactions. Basic research and clinical trials have been running side by side, often with drugs themselves serving as research tools to find out what happens when a particular receptor is suppressed (such as the epidermal growth factor receptor, or EGFR, to cite a target that is important for cancer and much more). Sometimes, scientists harvest a series of improved treatments using existing drugs without actually getting a new one approved. Rituxan, originally approved for certain types of non-Hodgkin’s lymphoma cancer, is now approved for other types of cancer along with multiple sclerosis, rheumatoid arthritis, and Crohn’s Disease, and is being researched to treat lupus, idiopathic thrombocytopenia purpura, and chronic lymphocytic leukemia.

The other phenomenon that has been largely lost in popular discussion of drug R&D and its discontents is the extraordinary role played by “follow-on” drugs (a much more accurate term than “me-too”). The story with statin cholesterol-reducing drugs, where a decade or more of research on follow-ons revolutionized the prevention and treatment of coronary heart disease, is a familiar one. Similar stories are playing out now, but much faster. Competition among rapidly developed drugs to attack a promising target (such as tumor necrosis factor inhibitors for rheumatoid arthritis) can bring about revolutions in treatments as doctors and patients dance through one drug after another while dealing with the unique mix of side effects and drug resistance that plague each individual patient.

The interested reader can get a flavor of this blend of basic science and practical drug development by reading the fascinating discussion by Jan Vermorken, et al., of evolving treatments for head-and-neck cancer in the September 11, 2008 issue of The New England Journal of Medicine. Much of this story involves Erbitux, the monoclonal antibody that put Martha Stewart in jail after a disappointing FDA decision put the owners of ImClone, the developer, into a panic. The many years of up-and-down research and results on that drug, costing hundreds of millions or even billions of dollars back when no revenues were in sight, is probably as good an example as any of the vagaries and payoffs from high-risk drug research informed by ongoing work in pure science.

Hilleman set out to develop vaccines for the chief life-threatening viral and bacterial infectious diseases of childhood. Amazingly, he came close to clearing the table.

In another recent article in The American, I addressed the thorny question of the role of publicly supported basic research in drug development (“The Indispensable Industry,” May/June 2008). To put it in the simplest terms, a close look reveals a striking pattern that seems to be little noticed by the critics of private drug development: no matter how far-flung the curiosity-driven NIH-supported research is, the only results that seem to get translated into useable drugs are the ones that are grabbed by drug firms and put through the difficult research necessary to produce appropriate quantities of promising substances to run through years of arduous clinical trials. Take away the private sector, and basic research nearly always languishes with little practical effect, as is unceasingly and tragically illustrated by the dearth of new drugs and vaccines for malaria and tuberculosis. Sometimes, the drug firms themselves do perform crucial basic research, as in the case of Genentech’s Avastin for cancer and Lucentis to prevent blindness. These were the fruits of the firm’s own top-tier basic research forces.


Just Two Words

But there is something else in drug development that hardly gets talked about: the sheer energy and determination that you find in the private sector. Combine that with substantial financial resources and you get what John Maynard Keynes called “animal spirits,” a singular motivating force in creative capitalism. When this force attacks big problems, the results can be both spectacular and unexpected, sometimes with fabulous benefits for mankind. It so happens that animal spirits are very much involved in one of the great blessings of modern medicine: an armamentarium of vaccines, mainly given to children, which have been saving lives by the millions at astonishingly low costs. “The most cost-effective treatments ever created by mankind” is a typical summary of the value of vaccines for mumps, measles, rubella (German measles), and half a dozen or so others, including those for diphtheria, whooping cough, hepatitis A, and hepatitis B.

Where, you might ask, did all those life-saving vaccines come from? Amazingly, for half or more of them, the answer can be summarized in two words: Hilleman and Merck. You’ve likely never heard of Maurice Hilleman even though he probably saved more lives than any other scientist in the 20th century. For most of his career, Hilleman was a biologist at Merck, where he developed one vaccine after another, stretching through four extraordinary decades of productive work. Along the way, he pioneered new ways to create, test, and manufacture vaccines, and played a crucial role in the creation of an entirely different class of drugs known as interferons.

We know a lot about Hilleman’s career thanks to a wonderful book published last year by Paul Offit: Vaccinated: One Man’s Quest to Defeat the World’s Deadliest Diseases. Offit was the perfect vehicle for getting this story the attention it deserves. A prominent academic immunologist at Children’s Hospital of Philadelphia and the University of Pennsylvania Medical School, Offit is also a vaccine developer. He is a co-inventor and co-developer of Rotateq, the first fully successful vaccine for rotavirus, a cause of deadly dehydration that kills thousands of children annually in poor nations.

Offit is attuned to public policy. He has been a member of the Advisory Committee on Immunization Practices, whose child vaccination recommendations are gospel for physicians and payers. His previous book, The Cutter Incident, was an insightful historical account of how litigation over an early miracle vaccine—for polio—helped shape (very much for the worse) the entire litigation environment of vaccines and pharmaceuticals. Offit’s academic journal articles and newspaper op-eds on the consequences of unscientific attacks on vaccine safety are required reading for anyone interested in this contentious topic.

Offit’s Vaccinated is informed by 11 interviews with the 85-year-old Hilleman in 2005, during the last months of his life before he succumbed to cancer. Judging by dozens of meaty quotes, Offit is a probing interviewer, capturing a great scientist’s personality and working style to a degree that cannot be matched without personal experience with the subject, and is seldom matched even then.

His basic strategy was simple: solve whatever problems had to be solved in order to reach the goal, which was usually a new vaccine.

Who was Maurice Hilleman and what did he do? Born to a German-American family in 1919 and raised on a Montana farm near his birthplace, Hilleman was a brilliant student on scholarship at Montana State University. After graduation he moved to the Midwest intellectual mecca at the University of Chicago, where in 1944 he finished a Ph.D. in microbiology based on groundbreaking research on the chlamydia bacterium (previously thought to be a virus). To the dismay of his new intellectual peers, Hilleman left academia to work for a pharmaceutical firm, E.R. Squibb, where he achieved advances in flu vaccine development and manufacturing. In 1948, he moved to the Walter Reed military hospital in Washington. His work there culminated in an extraordinary episode in 1957 when he correctly forecast the arrival of a new Asian Flu to which almost no one was immune. He led the development and manufacturing (by private firms) of a vaccine in time to save hundreds of thousands of lives and perhaps many more.

In 1957 Hilleman returned to the private sector, this time at Merck, where he was head of virus and cell biology in Merck’s relatively new vaccine enterprise. Hilleman apparently set out to develop vaccines for the chief life-threatening viral and bacterial infectious diseases of childhood. Amazingly, he came close to clearing the table. First was the mumps, with the approval in 1967 of the “Jeryl Lynn” vaccine based on a mumps virus taken from his daughter of that same name. A measles vaccine arrived the next year. In 1969, we got a vaccine for rubella. Hilleman soon concocted the immensely useful idea of combining these three vaccines into a single shot. Approved in 1971, this proved a blessing to untold millions of small children and their mothers. The 1981 vaccine for hepatitis B (not really a childhood disease, of course) was a scientific and technological tour de force essentially from start to finish. In 1995 came the hepatitis A vaccine. For chicken pox, pneumococcus, and Hib (haemophilus influenzae type b), Hilleman transformed relatively untested vaccines into the mass-produced tools with which we are now familiar. It is hard to imagine the cumulative benefits of this research. (Hilleman also developed a vaccine for a destructive form of chicken cancer, rescuing a substantial part of the poultry industry.) Hilleman’s work sometimes ranged beyond vaccines. Starting in the late 1950s, he figured out how to mass-produce a newly discovered virus-killing substance in chickens called interferon. He soon detailed interferon’s basic physical, chemical, and biological properties, discovering that it was produced in many animals, including humans, and that it could impede or kill many viruses, such as those involved in cancer. He correctly predicted that interferon could be used to treat chronic infections and cancer. Today, it is used against hepatitis B, hepatitis C, and several types of cancer.


Problem Solving for Fun and Profit

This is more than the history of medicine, science, and technology. It is also business history, a classic story of problem solving for fun and profit and humanity. How was Hilleman able to accomplish so much in basic research, drug development, and manufacturing technology, often working essentially from scratch because vaccine development was still in its infancy when he set to work? The answer lies in Hilleman’s decision to work at Merck instead of pursuing a top-tier academic career. He realized that to attack the most pressing illnesses susceptible to immune-based prevention, he would have to marshal massive forces even after solving the purely intellectual puzzles. Merck had supported that kind of work before in Max Tishler’s research on the vitamin B complex. Offit tells us relatively little about internal Merck affairs, but it is clear that Hilleman enjoyed an extraordinary degree of autonomy combined with generous funding increases for low-profit products (now there’s a combination we’d all like to have!).

The Nobel Prize committee was not willing to award a prize to an industry scientist. It is hard not to see this as a miscarriage of scientific justice.

Hilleman sometimes exercised an iron fist over such normally mundane matters as manufacturing, where any deviation from his recipe could result in undetectable dangers. Indeed, Hilleman was apparently a bit of a tyrant, demanding almost as much of his staff as of himself, facilitated by his mastery of the art of profanity. Nonetheless, he retained the respect and often the devotion of his hard-driven staff along with near-legendary status among his academic peers.

In 1984, when Hilleman reached Merck’s mandatory retirement age of 65, he refused to retire and Merck kept him on. One result was the hepatitis A virus vaccine that arrived in 1995, along with a steady stream of academic work of all sorts until shortly before his death in 2005. Hilleman never jettisoned the problem solving method of a successful Montana farmer. Like Orville and Wilbur Wright when they built the first successful heavier-than-air flying machine, Hilleman’s basic strategy was simple: solve whatever problems had to be solved in order to reach the goal, which was usually a new vaccine. The list of problems included daunting scientific puzzles, excruciating judgments about whether dangerous side effects had been defeated, and the vagaries of regulation (much easier before the FDA got into the action).

As the 80-plus-year-old Hilleman approached death, Offit and other academic scientists lobbied the Nobel committee to award Hilleman the Nobel Prize for Medicine, based partly on his vaccine work and partly on his contributions to the basic science of interferons. The committee made clear that it was not going to award the prize to an industry scientist. (Offit has assured me that the situation was even more hopeless than he describes in his book.) It is hard not to see this as a miscarriage of scientific justice. Perhaps Hilleman would have done better if his volcanic personality had not included a surprising element of self-effacement. None of the vaccines or the crucial agents or processes he created were named after himself. At one point, he even called the developer of a new rubella vaccine to say that he thought it should replace his own because it was better. Hilleman’s absence from the academic and public spotlight was quite extraordinary. In one of the most striking of the dozens of anecdotes told by Offit, Hilleman’s death was announced to a meeting of prominent public health officials, epidemiologists, and clinicians gathered to celebrate the 50th anniversary of the Salk polio vaccine. Not one of them recognized Hilleman’s name!


Next…

Thanks to Offit and his book, Hilleman’s light and the extraordinary research achieved by the Merck company will shine for many, many years. What about vaccine research itself? There have been formidable obstacles. One was the liability system, which in the 1980s nearly killed off the child vaccine market before Congress removed child vaccines from the liability system altogether. Another, more persistent problem has been low reimbursement rates, especially by government, for traditional child vaccines (including most of Hilleman’s crop). This can discourage new research and production, and cause shortages. The situation was sufficiently worrisome to trigger a 2003 report by the federally sponsored Institute of Medicine entitled “Financing Vaccines in the 21st Century: Assuring Access and Availability.” Reimbursement seems to have improved recently. Better yet, newer vaccines are sufficiently protected by patents so that prices are set through ordinary market forces rather than government fiat. Merck and its competitors, such as GlaxoSmithKline and Sanofi-Aventis plus smaller firms, have developed a series of important new vaccines—notable among them are the pneumococcal vaccine, a vaccine for the human papilloma virus (which causes cervical cancer), and two rotavirus vaccines (including the one co-invented by Offit). Traditional vaccine research is now flourishing but will probably never again be dominated by a single person’s laboratory like the one run by Hilleman in his prime.

Hilleman was apparently a bit of a tyrant, demanding almost as much of his staff as of himself, facilitated by his mastery of the art of profanity.

But we need to look ahead, and when we do it’s hard not to get excited. The entire field of immunology—roughly speaking, the harnessing of the human immune system to fight disease—has taken off along with so much else in this age of biotechnology. We are discovering faster and more efficient ways to manufacture traditional vaccines (especially for the flu), better methods for identifying newly arrived infectious agents such as avian flu (the dreaded “bird flu” that could cause an epidemic on the scale of the one in 1918 that killed millions worldwide), and new techniques for developing vaccines once their targets have been identified.

And there is the extraordinary prospect of therapeutic vaccines, i.e., vaccines that harness the immune system to attack illnesses already present in the body rather than just preparing the body to reject infections that have not yet been encountered. None has been approved, but a brain cancer vaccine from the biotech firm Dendreon received a favorable rating from an FDA advisory committee and may yet gain approval from the FDA (despite its reluctance to approve highly innovative drugs in this era of attacks on it for paying too much attention to new benefits and too little attention to safety). Alzheimer’s Disease vaccines have achieved striking results against the beta-amyloid plaques typically found in the brains of Alzheimer’s patients. Other therapeutic vaccines are in various stages of testing.

It’s about time for the biotech revolution to hit the vaccine industry in a big way. It has already upended the treatment of rheumatoid arthritis and a few cancers, and is starting to do the same for multiple sclerosis and other conditions including rare diseases like psoriasis. Now let us see what happens in this once-quiet corner of the biopharmaceutical market. As Hilleman’s career demonstrates, when industrial science is harnessed to the profit motive, enormous advances in human welfare are possible.

John E. Calfee is a resident fellow at the American Enterprise Institute, which is about to publish a new book on recent developments in the vaccine market, U.S. Vaccine Markets: Overview, Case Studies, and Comparisons with Pharmaceuticals and Other Biologics, by economists Ernest Berndt, Rena N. Denoncourt, and Anjli C. Warner of MIT. It provides the best summary yet published of vaccine development in the past two decades, along with a preview of what is on the way.