Regulating Personalized Medicine


Plugging personalized, or precision, medicine, President Obama recently announced funding for a new “research consortium” that would collect a variety of information from large numbers of people for a database. He failed to acknowledge, however, that the risk-averse posture and policies of his administration’s FDA create significant obstacles to the ultimate success of personalized medicine.

In a high-profile White House event attended by medical researchers, patients’ advocates and drug and biotechnology company executives on January 30, President Obama plugged medicine’s new mantra, “the right dose of the right drug for the right patient at the right time.” It reflects that medical treatments are gradually shifting 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 in certain patients.

The president announced funding for a new “research consortium” that would collect a variety of information from as many as a million Americans for a database that could include medical records, laboratory test results, genome sequencing data, and information about diet, lifestyle and environment. Researchers could then search the cohort for disease-gene associations and other information that could identify targets for new drugs and improve medical care in other ways.

This is hardly earthshaking, given that huge databases of this type already exist in both the private and public sectors.

Notably, but not surprisingly, there was no hint that the president would use his famous “phone and pen” to press the public policy-related levers of government that could spur medical advances. In particular, the president failed to acknowledge that the risk-averse posture and policies of his administration’s FDA have created significant obstacles to the ultimate success of personalized medicine.

The concept of personalized, or precision, medicine is not new: It has been known for decades, for example, that people genetically deficient in an enzyme called 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 injected hormone (because they make antibodies to 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, in order to estimate the likelihood that the intervention will be effective or elicit dangerous side effects.

A significant breakthrough in the use of biomarkers and therapy for personalized medicine was a drug called Kalydeco (ivacaftor) to treat cystic fibrosis in patients who have any one of nine specific mutations in a gene called the Cystic Fibrosis Transmembrane Regulator (CFTR). 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, which until recently resulted in death in childhood or early adulthood. Kalydeco is the first drug that offers 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.

Prognostic biomarkers have become increasingly important in cancer therapy. Genetic anomalies in malignant tumors can sometimes be used to predict the effectiveness of therapies. The most recent such example is a drug called Ibrance, which was approved on February 3 for “postmenopausal women with estrogen receptor (ER)-positive, human epidermal growth factor receptor 2 (HER2)-negative metastatic breast cancer who have not yet received an endocrine-based therapy.”

A preliminary study from the M.D. Anderson Cancer Center illustrated the potential benefits from matching targeted therapies with specific gene mutations across many cancer types. Patients who received a targeted therapy demonstrated a 27% response rate compared to 5% 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.

Improvements in efficacy and fewer side effects of drug therapy are a boon to doctors, patients and insurance companies, to be sure, but the long-term benefits to drug companies are less certain.

Of potential benefit to industry, 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 of the study. 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 high “relative treatment difference” between the drug and whatever it is being compared to (often a placebo, but sometimes another treatment). This will enable smaller studies to demonstrate efficacy.

Thus, when drugs are ultimately approved based on the use of biomarkers, the approved uses for the medication listed on the label might be narrower, or more restrictive, thereby reducing the size of the patient population for whom the drug is intended. That would, of course, lower the 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.

Regulators’ discretion may also affect the revenue potential and rate of advance of personalized medicine–and this is where Mr. Obama’s splashy announcement was glaringly deficient. As usual, he seems neither to understand where the choke points to innovation are found nor to appreciate the spectrum of actions available to him in order to achieve a policy goal.

FDA’s assessments of safety and efficacy often do not move closely in tandem, so that even if smaller, better-targeted clinical trials offer clear evidence of a drug’s efficacy, regulators may demand far larger studies to provide evidence of the drug’s safety.

Increasingly defensive about accusations that drugs and vaccines are inadequately tested for safety, in recent years highly risk-averse regulators have required huge, expensive and time-consuming clinical trials designed to detect even very rare possible side effects. Consider, for example, that before its U.S. approval a vaccine against rotavirus (a common, sometimes fatal gastrointestinal infection in children) was tested in more than 72,000 children–and another 40,000-plus 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.

Thus, although personalized medicine offers tremendous potential for patients, regulators’ demands for vast clinical studies to demonstrate the safety of new drugs, along with the need to develop both the diagnostic (biomarker) test to accompany the drug and a clinical algorithm to guide the use of the drug/diagnostic combination, can impose huge development costs that might never be recovered by the manufacturers. Currently, only about one in five approved drugs recoup their development costs.

The FDA often touts its record of meeting performance goals for the review of marketing applications, but that evaluation is only the last stage of the long and complex process of drug development. Overall development times have not improved in recent years, and regulators’ demands have pushed the average cost to bring a new drug to market to a whopping $2.6 billion.

Because the dual burdens of large, expensive clinical trials and diminished revenue potential could become unsustainable in the long term, the attitude of regulators will be critical to the success of personalized medicine.

A real boost to personalized medicine would have been an announcement at Mr. Obama’s recent event 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 intended for a “serious or life-threatening disease” and for which there is an “unmet medical need.”

Such approvals have two defining characteristics. First, they can be based on clinical trials that do not yet show an improvement on a definitive health endpoint such as increased longevity, reduction in the incidence of heart attacks or cancer cure, 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 “good” cholesterol.

Second, the drug sponsor (company) must perform confirmatory trials to prove that the medicine is effective in meeting a definitive endpoint (such as prolonged survival), at which time the 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, in all-politics-all-the-time mode as usual, is not really into effective remedies as much as “optics,” preferring instead to make a show of throwing money at a problem it has helped to create.

Original article, by Henry I. Miller, – Personalized Medicine Is Promising But Needs Smarter Regulation – is from Forbes here.

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John Macey

I was born, and principally educated, in the fields of biochemistry, and business management in the northeastern USA. However, my world-wide professional career has greatly expanded upon that US base to involve the many different segments of the Biotech / Life Science fields globally. – I have been dressed as a surgeon to view many, many surgical proceedures - The major players in the health care fields that I have worked for include: Johnson & Johnson, DuPont, Abbott Laboratories, and F. Hoffmann-La Roche. – Positions have included selling nuclear materials for both in-vivo & in-vitro (radio-pharmaceutical & radio-immunoassay) medical diagnostic purposes, in the four countries in Scandinavia, based south of Stockholm, to managing Ph. Ds at a global Swiss headquarters location. – At one time I held a position of Strategy Manager for Europe, Middle-East & Africa (EME&A) for a Chicago based company, but living in Germany. – I do speak fluent colloquial German. – In addition to having lived in multiple European countries, my professional career took me to Asia for well over a decade. There I had management control of Oceania, the Pacific Rim, Northern Asia, Japan, out to India. – Occasionally, management assignments have taken me to all of Latin America, and most of South America. – I am extremely culturally aware, a skilled negotiator, and a seasoned manager of men and science. – My one abiding passion has always been computing, data, and analysis. As such, my main computer operating system is Linux, and open-source computer applications. – I do also run Microsoft 7, and Mac OS X (all 3 operating systems on the same H-P Ultrabook). I hope you enjoy your time on the Blog, and should you have any comments / feedback please feel free to email me @, or visit my Linux Web Site @ (always evolving) – John J. Macey – AKA Adler, which in German means Eagle – Wildwood, New Jersey - Together, we can expand your global markets - with our partnerships. The partnerships are global utlizing multiple Law, Regulatory, Seasoned Management, Employment, M&A and buidlers of Business. Contact use.