In a splashy White House event on February 25, President Obama once again touted his precision, or personalized, medicine initiative, which is intended to advance medicine’s new mantra, “The right dose of the right drug for the right patient at the right time.” This approach reflects the shift in medical treatments from a relatively imprecise “one size fits all” approach to a more personalized one, so that patients can be matched to the best therapy based on their genetic makeup and other predictive factors. This enables doctors to avoid prescribing a medication that is unlikely to be effective or that might cause serious side effects.
The National Institutes of Health (NIH) will be responsible for the largest part of the White House plan. It will involve at least a million volunteers who will help researchers to test innovative methods and technologies for user-friendly data collection, which NIH director Francis Collins characterized as the foundation for a “democratized, transformative research environment.”
Some revision of the FDA’s requirements may be necessary as well, according to President Obama: “There may be other areas where we need to break down regulations that might have applied and made sense in another era of medicine but aren’t going to apply now. And that’s the kind of evaluation that we’re doing.” However, the Obama administration has shown not only a disinclination to regulatory reform but also remarkable ignorance about how to operate the levers of government in order to achieve desirable policy goals.
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The concept of personalized medicine is far from new: It has been known for decades, for example, that persons genetically deficient in the enzyme G6PD can experience a severe and precipitous anemia if they are exposed to certain drugs, and that children lacking the gene for human-growth hormone will not respond to injections of it (because they make antibodies that neutralize it). In its most sophisticated form, personalized drug therapy uses biological indicators, or biomarkers — such as variants of DNA sequences, the levels of certain enzymes, or the presence or absence of drug receptors — as an indicator of how patients should be treated and to estimate the likelihood that the intervention will be effective or elicit dangerous side effects.
A breakthrough in the use of biomarkers and therapy for personalized medicine was the FDA’s approval of Kalydeco (ivacaftor), a drug to treat cystic fibrosis in patients who have any one of nine specific mutations in the cystic-fibrosis transmembrane regulator (CFTR) gene. Mutations in that gene, which expresses a protein that regulates ion (such as chloride) and water transport in the body, cause the accumulation of thick mucus in the lungs and digestive tract. That in turn leads to severe respiratory and digestive problems as well as other complications, such as infections and diabetes, and used to result in death in childhood or early adulthood. Kalydeco was the first drug that offered a way to work around the defects caused by the genetic mutations and to facilitate the flow of chloride ions, instead of just treating the symptoms of the disease.
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Prognostic biomarkers have become increasingly critical to cancer therapy. Genetic anomalies in malignant tumors can sometimes be used to predict the effectiveness of therapies. For example, the amplification of HER2, a gene seen in approximately 25 percent of breast cancers, leads to overexpression of HER2 protein, which results in increased cell division and accelerated cell growth and a worse prognosis. However, it also correlates with responsiveness to Herceptin, which has been dubbed the first “pharmacogenetically developed drug.”
A preliminary study from the M. D. Anderson Cancer Center illustrates the potential benefits from matching targeted therapies with specific gene mutations across many cancer types. Patients who received a targeted therapy demonstrated a 27 percent response rate, compared with 5 percent for those whose therapy was not matched. This approach will reduce sharply the number of patients who are unnecessarily subjected to the side effects (and expense) of drugs that won’t work.
Another example of how biomarkers can affect the choice of drugs was the discovery that almost a third of the roughly 3.5 million patients prescribed a common anticoagulant, or blood thinner, to prevent clots that cause strokes and heart attacks have an abnormal, low-activity genetic variant of an enzyme that converts the anticoagulant Plavix to the active form and enables the drug to work. Because these patients have less enzymatic activity than normal, their ability to activate the drug is impaired. This puts them at increased risk from clots, so they should receive a different drug.
#share#Improvements in efficacy and reductions in the side effects of drug therapy offer benefits to doctors, patients, and insurance companies, but the benefits to drug companies are less certain. Nevertheless, various aspects of personalized medicine are being pursued aggressively by the drug and medical-device industries.
Of potential benefit to the pharmaceutical industry is that the presence of biomarkers will enable drug companies to perform smaller, better-targeted clinical studies in order to demonstrate efficacy. The reason is related to the statistical power of clinical studies: In any kind of experiment, a fundamental principle is that the greater the number of subjects or iterations, the greater the confidence in the results. Conversely, small studies generally have large uncertainties about results unless the effect of the intervention is profound — and that is where biomarkers can make a difference. By better defining the experimental groups, they can help drug makers design clinical studies that will show a higher “relative treatment difference” between the drug and whatever it is being compared to (often a placebo, but sometimes another treatment).
The presence of biomarkers will enable drug companies to perform smaller, better-targeted clinical studies in order to demonstrate efficacy.
So when drugs are ultimately approved based on the use of biomarkers, the description, printed on the label, of the medication’s approved uses might be narrower or more restrictive, thereby reducing not only the size of the patient population for whom the drug is intended but also the drug’s revenue potential. For example, a drug broadly approved for “breast cancer” in the pre-biomarker era could be more widely marketed than one approved to treat only the sub-populations of patients with certain biomarkers. Likewise, in the Plavix example above, the recent advances in our understanding of how enzyme levels affect the drug’s efficacy will markedly reduce the number of patients taking the drug.
Regulatory issues, too, could affect the revenue potential of personalized medicine and its rate of advance. The FDA’s assessments of safety and efficacy often do not move closely in tandem. Long after smaller, better-targeted clinical trials have offered clear evidence of a drug’s efficacy, it still might not be on the market because regulators have demanded far larger studies to provide evidence of the drug’s safety.
Consider, for example, that before the U.S. approval of a vaccine against rotavirus (a common, sometimes fatal gastrointestinal infection in children), the FDA required that it be tested in more than 72,000 children — and more than 40,000 more in post-marketing studies. On a similar scale, a vaccine to prevent human papilloma virus infection and cervical cancer was tested in almost 30,000 young women. By any reasonable standard, these numbers are grossly excessive for vaccines that showed no hint of serious side effects in the early clinical trials.
The Obama administration is not really into effective remedies. It prefers optics.
Thus, although personalized medicine offers tremendous potential for patients, manufacturers may face huge development costs that they might never recover, as regulators impose demands for vast clinical studies to demonstrate the safety of a new drug, while the manufacturers need also to develop both the diagnostic (biomarker) tests to accompany the drug and a clinical algorithm to guide the use of the drug–diagnostic combination, which could involve two or more companies. Currently, only about one in five approved drugs recoup their development costs, which is not surprising, given that bringing a new drug to market currently takes ten to twelve years and on average costs a whopping $2.6 billion.
Because the dual burdens of large, expensive clinical trials and diminished revenue potential could make applications of personalized medicine infeasible in the long term, the attitude of regulators will be critical. A real boost to personalized medicine would have been an announcement by Mr. Obama of new FDA initiatives to improve coordination between drug and diagnostic-device regulators and to grant more “accelerated approvals,” which are, in effect, limited, or conditional, approvals of a new drug that is intended for a “serious or life-threatening disease” and for which there is an “unmet medical need.”
#related#Such approvals have two defining characteristics. First, they can be based on clinical trials that do not yet show that a drug leads to a patient’s improvement on a definitive health endpoint — such as increased longevity, cancer cure, or reduction in the incidence of heart attacks — but merely on a “surrogate endpoint” that is thought to correlate with actual clinical benefit. Examples of surrogate endpoints are the shrinking of a tumor, the lowering of blood pressure, or improvement in a laboratory value, such as an increase in “good” cholesterol.
Second, the drug sponsor — the pharmaceutical company — must perform confirmatory trials to prove that the medicine is effective in meeting a definitive endpoint. Then the accelerated approval is converted to a standard, unconditional approval. If the studies fail to provide such confirmation, the FDA can pull the drug from the market. The granting of more accelerated approvals would reduce the size and possibly the number of phase-3 clinical trials, the most costly and time-consuming stage of drug development.
But the Obama administration is not really into effective remedies. It prefers optics, making a show of throwing money at a problem it has helped to create.