Plasma Pool

Last week, a team of medical and public policy researchers working out of the Stanford University School of Medicine and the Veterans Affairs Palo Alto Health Care System published an essay in the New England Journal of Medicine suggesting that new drugs be labeled not only with what we know about them (which they currently are), but also with an accounting of “what isn’t known” about them.

The researchers, say Inside Stanford Medicine,

want the U.S. Food and Drug Administration to require drug manufacturers to state how new medications compare with similar, existing treatments. In many instance, these statements would indicate that there is no evidence that a new drug is more effective than older ones. They believe this information would make patients and health-care insurers less likely to pay for newer treatments without evidence that they lead to improved patient outcomes. It would also spur drug and medical-device companies to design more informative clinical trials to test a new product’s superiority over existing therapies.

“Drug and device manufacturers benefit from an unacknowledged information gap that develops as more and more products are tested against placebo, but not each other,” said [lead author] Randall Stafford, MD, PhD, associate professor of medicine at the Stanford Prevention Research Center.

[...]

The researchers note that the FDA doesn’t require the inclusion of statements regarding how a new drug or device compares with existing treatments. Instead, treatments are simply required to perform better than a placebo without harmful side effects. “The problem is that the public, including physicians, often view FDA approval as constituting more than it does,” Stafford said. “There’s an inherent tendency for physicians and patients to want the newest thing and to assume that newer and more expensive means better, although this is often not the case.”

Stafford and his colleagues are correct in what they have to say about the ambiguity surrounding the comparative effectiveness of recently approved drugs. But their proposal that the FDA begin labeling drugs with measures of this comparative effectiveness, while perhaps a possible step forward, ignores the realities of how pharmaceutical innovation happens today.

The private pharmaceutical industry is where most groundbreaking clinical pharmaceutical research comes from. The current method of comparing prospective drugs to placebo is the foundation of that clinical system, informing its design and funding from start to finish, from research to release. Developing a new drug to the point of public release can take years or even decades—and throughout this development period, money is constantly invested in working toward proving the drug in placebo trials. The federal government does not and cannot fund research on this massive scale. The fact that our pharmaceutical research is dictated by the drive to profit is the reality in the United States. No pharmaceutical company with any thought for its financial future will agree of its own volition to put the products of this development lengthy process in direct competition with competing firms’ released drugs, as such tests would threaten, in one motion, to invalidate in the eyes of the public the efficacy of—and the effort put into—the development of a novel drug.

The labels that Stafford and his colleagues propose would read along the lines of, “Although this drug has been shown to [...] more effectively than placebo, it has not been shown to be more effective than other members of the same drug class.” But no pharmaceutical firm is likely to agree to any label that could potentially tell consumers to look elsewhere for treatment or relief. Releasing a drug with such a label would mean an enormous risk of loss in initial sales. It would also jeopardize making back the money spent on researching that single drug that made it to market—plus the 100 experimental drugs for every one approved drug that fails in phase II and III trials, and for the 1000 experimentals that fail in phase I trials. Each drug that makes it to market represents an investment of billions—billions that, if not recouped, can’t go toward researching new and more effective treatments.

In addition to this proposal being a nonstarter with drug companies looking to safeguard investment and a potential threat to continued innovative pharmaceutical research, its potential to foster ultimately better treatment is not entirely clear. Physicians themselves routinely compare the respective outcomes of two approved drugs of the same drug class against placebo in the process of refining their treatments. But because by and large there is very little difference in efficacy among approved drugs of the same class that can be generalized to a broad population of potential patients, most comparison among them is for the purpose of ascertaining the severity and occurrence rate of each drug’s adverse effects on particular patients. People will often the pay extra money not to have the headache, nausea, diarrhea, or negative sexual side effects from their medications, especially those taken for chronic conditions. Newer isn’t always better at counteracting symptoms, but newer can be far better at allowing a patient to more effectively lead her daily life. Lessening these adverse effects in patients itself increases efficacy, and therefore outcome, patient by patient.

The system of clinical research, however, is due for a much needed overhaul. The current standard, a three-phase orientation of clinical trials, should be evaluated and revised, ideally resulting in the introduction of a hybrid phase II/III trial. These shorter, hybrid trials would use a subset of phase II patients in phase III to cut down on the time it takes to reveal long-term effects from experimental medications. The patients within phase III could be considered for post-hoc data analysis. This setup could be phased in to shorten the average interval between when a drug goes into study and when it reaches the market. A faster time to market means that the considerations for a decrease in drug patent life would be a possible compromise within the pharmaceutical industry. Shorter patent lives mean that newer medications get to the generic market quicker, which would appease both the pharmaceutical industry and healthcare subscribers as a whole.

The system proposed by the Stanford researchers seeks to open up a new space of decisionmaking for patients, a new way for patients to discriminate among various sorts of the same drugs. Its aims of promoting consumer choice and improving patient care are laudable, but it threatens to provide patients with an only vaguely useful metric for discriminating among drugs, increasing patients’ sense of security, perhaps, but not in any way that would clearly correlate with better patient care. The space of decisionmaking that Stafford and his colleagues propose to open to patients is already solidly filled by doctors—who, with their medical schooling, practical knowledge and experiential expertise, and training in analyzing the results of clinical studies, are far better equipped than a single patient to recommend a particular treatment.

One issue that is becoming a growing problem is a patient’s overuse of drug information, typically via the internet, to “self-diagnose” problems and subsequently develop a preconceived plan for a desired therapy which in most cases is not the best therapy. It is always in a patient’s best interest to research the medication he’s taking, but if a patient does not have the proper education to analyze all components of pathophysiology, pharmacology, biochemistry and pharmacokinetics, a proper drug-therapy decision is unlikely to be made without the consultation of a professional. Adding a short blurb about clinical trials in the labeling will only cause more of this, leading to frustrations for healthcare professionals and to the temptation to give patients what they ask for to make them happy. Clinical trials are usually complex, and require both a knowledge of biostatistics and an interpretation of all available clinical data. Patients (at least those who aren’t trained clinicians) will not have the medical literacy to come to educated, evidence-based treatment decisions.

Final decisions must lie with patients. But proposals that seek to reassure patients by encouraging them to make calls based on data that is systematically largely inconclusive—and thus best interpreted and utilized by medical professionals in the course of advising particular patients with individualized symptoms and side effects—are partial at best and reckless at worst. Doctors, with all their training, can and do disagree about what constitutes a statistically significant difference between two drugs. Giving patients a nudge in the direction of involving themselves in that process (and the confidence to do so) without properly equipping them to make genuinely informed decisions over-antagonizes pharmaceutical companies, threatens to undermine our confidence in our physicians, and could ultimately to diminish rather than improve the quality of patient care.

***

Dr. Daniel Roth, Pharm.D., has no current or previous relationships, affiliations, or monetary interests with pharmaceutical companies.