Everybody loves a bargain—except when the low price applies to a nonbranded pharmaceutical. Generics now make up about 65 percent of all prescriptions filled but a mere 10 to 15 percent of national pharmaceutical expenditures. They work as well as their name-brand counterparts and even better in some situations. Yet, despite evidence of their effectiveness, safety, and value, most doctors and patients still prefer the brand-name products.
This disconnect between science and perception may be preventing the health care system from realizing the full public health potential of generic drugs, according to experts in law, business, health policy, history, and therapeutics who gathered Dec. 11 and 12 to contemplate generics and health beyond the limited perspective of medical science.
A generic drug needs to be understood as a therapeutic ideal built on market and regulatory practices that evolved over the 20th century, said Jeremy Greene, HMS instructor in medicine at Brigham and Women’s Hospital and assistant professor of the history of science at Harvard.
“We can’t assume this is some sort of natural system,” said Greene, a co-organizer of the conference. “The relationship between generic and brand-name drugs has evolved over time and needs to be understood in its historical context.” As a field worthy of study, the topic has hidden in a term that is intrinsically uninteresting, according to Greene: “Generic suggests boring. The word itself seems to evade interest in the subject.”
Not anymore. The conference, “Unbranding Medicines: The Politics, Promise, and Challenge of Generic Drugs,” was the first major event sponsored by the Harvard Interfaculty Initiative on Medications and Society. Formed last year with the support of the University Provost’s Office, the growing initiative includes more than 60 faculty members who span departments, schools, and the Cambridge and Boston campuses.
“Science is the best guide to true and actionable knowledge and is useful to cut through anecdotes and ideology,” said initiative leader Jerry Avorn, HMS professor of medicine at BWH and chief of Pharmacoepidemiology and Pharmacoeconomics at the hospital. “But so much of how medicine operates is a product of society, politics, and economics. We need doctors and sociologists and political scientists talking to each other to understand how it all fits together and where we go from here.”
What’s in a Name?
Generics once were called “nonproprietary,” and their quality, purity, and potency were touted under the company names in an era of ethical marketing, Greene said.
The image of generics plummeted between the 1940s and the 1960s, with the rise of innovative patent-protected branded drugs available only from the firm of origin. “The reputation of the brand shifted from the pharmaceutical house to the product itself,” Greene said. “In an era of brand ascendancy, manufacturers cast generic prescribing as an act of counterfeiting and undermining of patient safety and physician autonomy.”
The modern system of generics came of age during a brand backlash, Greene said. The innovative drugs from the ’40s and ’50s came off patent in the ’60s and ’70s, but drug makers hobbled generic development with patent infringement lawsuits, regulatory challenges, and public marketing campaigns. A rolling series of Senate subcommittee hearings railed against the effective pseudomonopoly created by brand-based prescribing.
The definition of bioequivalence emerged from prolonged legislative wrangling to ensure safe and effective therapeutics. In 1984, the passage of the Hatch–Waxman Act formalized a new review of generics by the Food and Drug Administration and streamlined manufacturers’ application process. In exchange, brand-name companies received longer guaranteed periods of market exclusivity.
“The full story of generics is not always pretty,” said J. Richard Crout, former director of the FDA Bureau of Drugs (1973–1982). “It’s full of legal battles and Congressional hearings. The agency was split between doctors and lawyers on the right way to go. In the end, the good guys won.”
A New IndustrySince that time, Greene said, almost no generic drugs have been shown in studies to lack clinical equivalence, but a lingering perception of the superior therapeutic value of brands persists in the minds of physicians and consumers.
Hatch–Waxman created a new industry, observed Richard Frank, the Margaret T. Morris professor of health care policy at HMS, but its success was also driven by other institutions, such as the rise of managed care, tiered formularies, and substitution programs.
Lawyer Alfred Engelberg, a principal negotiator during the legislative process that led to the Hatch–Waxman Act, credited its success to subsequent “substitution laws in 50 states that facilitate immediate and complete market penetration, about 90 percent of the market within 60 days of a generic in most cases,” he said.
On the darker side, the regulatory mechanisms created by Hatch–Waxman also have been exploited by brand-name companies to postpone the availability of low-cost generics, said Aaron Kesselheim, HMS instructor in medicine at BWH, who has studied the interplay between patents and drug costs.
A brand-name manufacturer can use regulatory bottlenecks in the act to pay a generic maker not to market its drug. This happened with the clot-prevention drug clopidogrel (Plavix). Another trick is to patent peripheral features of the active drug ingredient and register them with the FDA, such as the protective coating of omeprazole (Prilosec), which is used to treat heartburn.
“The patent system is not optimally designed to harmonize drug development with public health goals,” Kesselheim said. “It contributes to the current emphasis on market extensions and incremental innovations, as opposed to encouraging development of new drugs for areas of therapeutic need or neglected diseases.”
Other hurdles remain after patents expire and generics hit the marketplace, said William Shrank, HMS assistant professor at BWH. Slightly more than half of journal editorials discouraged brand-name substitution, clashing with evidence (mostly from randomized controlled trials) that demonstrated the clinical equivalence of cardiovascular generics, reported Shrank, Kesselheim, and their co-authors in a systematic review and meta-analysis in the Dec. 3, 2008, Journal of the American Medical Association.
In specific cases, “care can be improved by prescribing more generics, such as with hypertensives,” Shrank said. In general, generic prescriptions promote better long-term adherence to medication and are more likely to be embraced as safe and effective by people with higher incomes and education, he said.
As the recent scandal with tainted heparin illustrates, significant new drug quality challenges are arising from globalized drug manufacturing, for both branded and generic drugs. Other big quality issues relate to the new generation of therapeutic proteins, or biologics, produced by biotechnology, which can be more variable than small molecules, said Janet Woodcock, director of the FDA Center for Drug Evaluation and Research. The interchangeability of biogenerics remains an unsolved scientific issue, she said.
Hatch–Waxman legislation worked well with small molecules in a domestic context, but the number of sites making drug products outside the United States have more than doubled from 1,200 in 2001 to 2,700 in 2007, while FDA inspections increased to only 325. More resources and legislative authority are needed to address the threats of globalization to drug safety, Woodcock said.
Students and faculty interested in the Harvard Interfaculty Initiative on Medications and Society may contact Lilia Halpern-Smith at 617-495-2724 or info@medsoc.harvard.edu for more information.
