Current policies affecting drug patents and drug manufacturer advertising could be adjusted to better balance the needs of consumers with the interests of pharmaceutical companies, advises Robert Wood Johnson Foundation (RWJF) Investigator in Health Policy Research (2009) Aaron Kesselheim, MD, JD, MPH. In new research, Kesselheim explores the way companies build dense webs of patents around their drugs and considers the circumstances under which drug companies may be able to make promotional claims based on comparative effectiveness research.
In the first of two studies, published in the October 2012 issue of Health Affairs, Kesselheim and Tahir Amin, director of intellectual property at the Initiative for Medicines, Access & Knowledge (a group that works to increase access to affordable medicines), conducted a case study evaluating secondary drug patents that protect Kaletra, an important drug product used in HIV treatment, from low-cost, generic competitors.
Multiple Patents May Equal High Costs
“After drugs are approved, there are a number of methods drug companies use to extend their market exclusivity time,” Kesselheim explains. One of these strategies is obtaining a number of additional patents, apart from those on a drug’s active ingredient, which “allow the company to maintain market exclusivity and high prices on the product for a much longer time than that covered by the initial patent.”
Some of the multiple patents on drugs have value because they may protect formulations that help the drug perform better. Other patents may have no purpose other than to extend market exclusivity. A company can patent many things related to a drug, such as chemical formulations (a gel cap instead of a tablet); inactive ingredients; or even uses of the drug in conjunction with other medications. “To determine which of these secondary patents were more common and what effect they might have on market exclusivity in the case of the protease inhibitors ritonavir (Norvir) and ritonavir/lopinavir (Kaletra), we systematically reviewed all patents covering these products,” Kesselheim says.
Their results were published in “Secondary Patenting Of Branded Pharmaceuticals: A Case Study Of How Patents On Two HIV Drugs Could Be Extended For Decades.” “We identified 108 patents on the drugs which, if enforced, could delay generic competition until at least 2028—12 years after the expiration of the patents on the drugs’ base compounds and 39 years after the first patents were filed. In addition, when we reviewed the patents, we found that some of them were of questionable validity,” Kesselheim notes, adding that they also found useful secondary patents on features that enhanced the drug’s performance.
Shedding Light on the Patent Process
Considering the pressing need for low-cost, generic versions of HIV/AIDS medications, the obvious question is: What can public health advocates or generic competitors do to prevent situations where a company accumulates possibly invalid patents on a drug to extend market exclusivity? To remedy this situation, Amin and Kesselheim recommend:
l. Third-party patent review. “Patient advocates, medical experts or other concerned parties should be allowed to submit objections to patent applications during the United States Patent and Trademark Office [USPTO] review process,” Kesselheim advises. Currently, objections are only heard after the patent has been granted, at a point when it is very difficult to get a decision overturned.
2. Transparency. Another problem is that there is no easy way for the public to learn when a company is seeking patents on a product. “We suggest that all patent applications be listed in a public database, similar to the way all clinical trial protocols are now listed on Clinicaltrials.gov,” Kesselheim says.
3. Reassess patenting standards. The USPTO takes in fees from patent applications, and “the Food and Drug Administration (FDA) presumptively assumes that all patents are legitimate,” Kesselheim says. Policy-makers may need to reconsider the standards that the USPTO uses to judge the validity of pharmaceutical product patents.” Recent Supreme Court decisions have raised the bar for what is required to earn a patent, but additional steps can be taken, he says.
FDA Oversight of Drug Company Advertising
In his second study, Kesselheim and co-author Jerry Avorn, MD, a professor of medicine at Harvard Medical School, reviewed legal and policy reasons the FDA can reject promotional claims for medications based on observational research, the form of the vast majority of comparative effective studies.
In a law that offers a great deal of protection to consumers, the current Food, Drug, and Cosmetic Act gives the FDA authority to prevent a manufacturer from making claims about the effectiveness of a drug, unless “there is a lack of substantial evidence that the drug will have the effect it purports or is represented to have under the conditions of use.” The term “substantial evidence” is further defined as consisting of “adequate, well-controlled investigations.” As a result, Kesselheim explains, “the FDA has traditionally required randomized, controlled clinical trials to support claims made by manufacturers in drug advertising.”
Pharmaceutical companies, on the other hand, have chafed under what they see as unnecessarily restrictive limitations on the type of research they can use to support their claims. “Some advocates argue that the First Amendment should allow pharmaceutical manufacturers to make any statement they want about their drugs, as long as it is not outright fraud,” Kesselheim says.
“But without FDA regulation, it would be easy for companies to cherry pick certain studies or outcomes that support their views and therefore present an unbalanced picture of their products’ risks and benefits. There’s a great deal of information that is not exactly fraudulent that can still present a skewed picture of the effectiveness of medication. Observational research is particularly prone to such manipulations because many design elements and unmeasured confounders can inject bias into the outcomes.”
As examples, Kesselheim and Avorn note, “observational studies have suggested the utility of widely implemented clinical practices, such as hormone replacement therapy to prevent cardiovascular disease in postmenopausal women, or the use of vitamins D and E to prevent certain illnesses, that prospective clinical trials later found to be erroneous.”
Kesselheim and Avorn analyzed these issues in the context of two fictional observational studies addressing hypothetical drugs designed by the Health Affairs editors. They published their results in,“The Food and Drug Administration Has The Legal Basis To Restrict Promotion Of Flawed Comparative Effectiveness Research.” After describing the pitfalls inherent in basing drug claims on observational studies, Kesselheim and Avorn concluded, “The FDA’s current reluctance to authorize promotional claims based on observational research is understandable, until there is further work to define the characteristics of high-quality observational research.”
The two issues highlighted in Kesselheim’s current work may have tremendous impact on the health care marketplace. The difference between a generic drug and the original can be a few cents per pill versus a few dollars a pill. The problems associated with an inaccurate assessment of a drug’s effectiveness are harder to measure, but obviously of great concern as pharmaceutical manufacturers’ promotional statements have been shown to strongly influence the prescribing practices of physicians and the therapies that patients receive.
Kesselheim’s hope is that his growing body of work—advanced during his tenure as an RWJF Investigator in Health Policy Research—will ultimately lead to greater equity and fairness across the pharmaceutical market for manufacturers and consumers.