Last week, I blogged on the issue of generic biologics: should companies that make vaccines, monoclonal antibodies, cell therapies, etc. get 12 years of data exclusivity before competing companies begin offering generics? Or should they be held to the same standard as makers of drugs, who get five years of exclusivity?
Looks like the U.S. Senate is caving in to pressure from Pharma and the Biotech industry by opposing the Obama’s “compromise” position: the Senate bill urges 12 years. But in today’s New York Times, journalist Andrew Pollack suggests the exclusivity debate might not matter in the end: most biologics are protected by patents beyond 12 years after FDA approval. Meaning: short exclusivity periods advocated by various public interest groups would have no material impact on development of generic biologics, because generics would be prevented by patents. The article contains a graphic showing that patents on several leading biologics products extend well beyond 12 years.
So is this just a symbolic debate? I think not (disclaimer: I am not a health care economist!). Towards the end of the article, Pollack acknowledges that the exclusivity debate might matter where patents do not provide strong protection. That’s a crucial issue for biologics. Intellectual property law around biologics is notoriously unstable and uncertain. And owing to their complex composition, generic manufacturers might plausibly argue that their products are biosimilar while not infringing patents. Advocates of the 12 year policy will argue that longer exclusivity is necessary to entice investors who might otherwise worry that lead products will not withstand patent challenges. Advocates of the shorter policy (like myself) will argue that we owe it to present day patients and their families to take that risk. (photo credit: sortofbreakit 2008).
Gene transfer, cell transplantation, monoclonal antibodies, enzyme replacements, tissue engineering all have great potential to improve health care. But will we be able to afford them? Various economists have shown that a large proportion of health care cost inflation is attributable to new technology, and the significant costs of development and production for drugs involving genes, cells, and large proteins- what regulators call “biologics”- provide grounds for concern that new biotech products will break the bank.
Questions about the affordability of biotech drugs are heating up in DC as Congress takes a look at generic biologics. Under current policy, there are no regulatory pathways for approving generic versions of biologics. This effectively means that companies that develop biologic drugs have a monopoly on them long after patents expire. Representative Henry Waxman, who previously sponsored legislation creating a pathway for generic drugs, is presently spearheading efforts to establish a way of reviewing and approving generic biologics as well.
The policy and economic issues here are profoundly complex, and much of the debate about legislation revolves around the issue of “data exclusivity.” Briefly, this refers to the period after drug approval during which generic competitors are barred from using data from the innovator’s clinical trials to apply for generic approval. In the U.S., for example, generic drug companies cannot file applications with FDA until five years after the new drug is approved by FDA. The aim of exclusivity is to reduce the economic impact of free rider generic companies that depend on trial data collected by the innovator.
The biotech industry, and many economists, argue that much longer periods of data exclusivity are required for biologics. They argue that without longer exclusivity periods (like 12 to 14 years), companies will have insufficient incentive to develop new biologics. Consumer advocates often argue otherwise, citing the mouth dropping costs associated with using many new biologics.
It remains to be seen who will prevail in this debate, but Waxman and the Obama administration appear inclined toward the consumer advocates, with the former urging a 5 year period, and the latter endorsing a “compromise” of 7 year exclusivity.
At stake is not simply question of markets and economics, but also one of ethics. Namely, should how should health care economies balance the need of current patients (who can ill afford expensive biologics) against those of future patients (who might benefit from greater innovation should exclusivity periods be extended)?
Sound ethical analysis must discount benefits accruing to future patients and consider the justice implications of excluding current patients from otherwise available treatment so that others in the future might benefit from new drugs. If implemented, the Obama administration’s plan for generic biologics promises to reduce an important hurdle in ensuring an equitable future for cutting edge therapies. (photo credit: shazam791, a true generic brand, 2008)
Here is an irresistible news headline: “Public Policy That Makes Test Subjects of Us All.”(New York Times, April 6, 2009). Then you open to the story only to discover, to your disappointment, that the piece is written by John Tierney, probably the most uninformed and underqualified members of the NYTimes staff.
His argument is ridiculous: that the New York City mayor’s initiative to “pressure” the food industry to cut salt amounts to a big experiment that would normally have to undergo IRB review and informed consent (never mind that the initiative is not an experiment designed to further knowledge. Never mind that the initiative is not aimed at generalizable knowledge, or that public health initiatives grounded in a state-based interest that are enacted by elected leaders have the “consent of the governed”).
But in the most recent issue of JAMA, a news story (Bridget M. Kuehn, “Rare Neurological Condition Linked to Newer Monoclonal Antibody Biologics,” April 8, 2009) reminds us that, in some small sense, licensure of novel biologics makes guinea pigs of us all. The report describes how FDA recently issued an advisory on the psoriasis drug efalizumab after reports emerged that it may be associated with a risk of developing a rare and fatal brainwasting disease (progressive multifocal leukoencephalopathy, or PML). FDA had previously issued warnings on two similar, immunomodulating drugs, and established a restricted distribution system for a third (natalizumab– for multiple sclerosis).
In the case of natalizumab, cases of PML occurred in pre-marketing clinical trials. For the other drugs, knowledge of the risk emerged only after drug licensing. Risk of PML was totally unexpected, and is a reminder of the high degree of uncertainty surrounding interventions directed at the immune system.
Premarketing clinical trials are statistically powered only to detect common, “signature” adverse events. As we move into an era of biologics-based pharmaceuticals (and accelerated approval), expect that many adverse events will only be discovered once a drug is in widespread use. Robust systems of pharmacovigilence will be especially critical (photo credit: Peter Guthrie, 2006).
Approving new drugs is a risky business. Despite best efforts (and frankly, some less than best efforts), newly approved drugs frequently turn out to have unexpected toxicities. One example is unexpected heart toxicity associated with the use of the common pain-killers like rofecoxib (i.e. Vioxx). Another is the surprising heart toxicity associated with the wonder drug for AML (a type of leukemia), imatinib mesylate (i.e. Gleevec).
According to a 2002 paper in JAMA, 8% of new drugs approved by FDA receive “black box” labels warning of toxicities that were not originally detected in drug trials. Another 3% are withdrawn from the market because of safety concerns.
But what about biologics- vaccines, monoclonal antibodies, recombinant protein products, cell derived agents, etc.? There are a number of reasons why one might anticipate even higher rates of “unexpected” toxicities with this class of therapeutics. For one, they frequently cause immune reactions that are exceedingly difficult to anticipate in animal studies. For another, small alterations in production can dramatically change the composition and properties of a biologic product. For still another, biologics often have a very high degree of species specificity, limiting the predictive value of animal studies.
According to a recent report in JAMA led by Thijs Giezen (October 22/29, 2008), 24% of biologics approved for marketing in Europe received “black box” warnings. For first-in-class agents, five of eight compounds were subject to regulatory action following approval. A story in the January 2009 issue of Nature Biotechnology (Jim Kling) provides some perspective on these findings: most biologics are used to treat life threatening illnesses, which may make people more susceptible to toxic reactions (on the other hand, toxicity might be difficult to detect amidst the noise of disease course).
Bottom line: as translational researchers pursue biologics, uncertainty will continue to present a major challenges, necessitating new approaches to pharmacovigilence and trial design. (photo credit: teotwawki 2005)