perspec tives these early days, standards need not be imposed (and may in fact be detrimental), but transparency and accountability can provide the research community enough insight with which to establish “best practices” in applying high-dimensional analytical methods to drug and diagnostic development. The construction of modelbased representations provides one method for validation and transparency and lays the groundwork for rapid prototyping and evaluation.
4.
CONFLICT OF INTEREST The authors declared no conflict of interest.
7.
5. 6.
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1. Roses, A.D. Pharmacogenetics and drug development: the path to safer and more effective drugs. Nat. Rev. Genet. 5, 645–656 (2004). 2. van de Vijver, M.J. et al. A gene-expression signature as a predictor of survival in breast cancer. N. Engl. J. Med. 347, 1999–2009 (2002). 3. National Institute for Health and Clinical Excellence. Diagnostics consultation
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document—gene expression profiling and expanded immunohistochemistry tests to guide the use of adjuvant chemotherapy in breast cancer management: MammaPrint, Oncotype DX, IHC4 and Mammostrat (January 2012). Subramanian, J. & Simon, R. What should physicians look for in evaluating prognostic gene-expression signatures? Nat. Rev. Clin. Oncol. 7, 327–334 (2010). Swanton, C. Intratumor heterogeneity: evolution through space and time. Cancer Res. 72, 4875–4882 (2012). Ransohoff, D.F. Bias as a threat to the validity of cancer molecular-marker research. Nat. Rev. Cancer 5, 142–149 (2005). Dupuy, A. & Simon, R.M. Critical review of published microarray studies for cancer outcome and guidelines on statistical analysis and reporting. J. Natl. Cancer Inst. 99, 147–157 (2007). Begley, C.G. & Ellis, L.M. Raise standards for preclinical cancer research. Nature 483, 531–533 (2012). Shah, S.P. et al. The clonal and mutational evolution spectrum of primary triple-negative breast cancers. Nature 486, 395–399 (2012). Ellis, M.J. et al. Whole-genome analysis informs breast cancer response to aromatase inhibition. Nature 486, 353–360 (2012).
See article volume 93, page 267 (March 2013)
It Is Important Research, but Why Is It Necessary? RL Woosley1,2 The findings regarding cardiovascular actions of dietary supplements labeled as “ephedra free” reported by Foster et al. in the March issue reaffirm decades of research that began in the 1920s with K.K. Chen’s study of naturally occurring adrenergic chemicals. Although the study by Foster et al. provides scientifically sound data needed by the US Food and Drug Administration (FDA) as it evaluates the safety of these products, we should ask, “Why was it necessary that these chemicals be studied again for their cardiovascular actions in humans?”
Evaluation of the safety of dietary supplements has become the responsibility of the FDA because current statute allows sponsors to market these prod-
ucts without any prior testing for safety. If the FDA has a concern for their safety, the agency must prove that the products are unsafe before it can take action. Of
1AZCERT, Inc., Oro Valley, Arizona, USA; 2Emeritus Professor, Sarver Heart Center, University of Arizona, Tucson, Arizona, USA. Correspondence: RL Woosley (
[email protected])
doi:10.1038/clpt.2013.15
course, every pharmacologist already knows that products containing adrenergic chemicals will affect blood pressure and increase heart rate if given in sufficient amounts. Although these effects are benign in normal subjects, they have repeatedly been associated with tragic increases in the incidence of sudden death, stroke, and heart attacks in susceptible individuals. Unfortunately, because these products are used without medical supervision, most of those who have been harmed did not know—and could not have known— that they were susceptible. With such serious risk of harm, why are these products treated as foods instead of drugs? Have we forgotten the lessons learned in the last century from the deaths caused by unregulated medical products? Deaths and public health threats convinced the US Congress of the need for a strong FDA, one that can protect the public by requiring evidence of safety and effectiveness before medical products can be marketed. Yet the Dietary Supplement Health and Education Act (DSHEA) of 1994 eliminated the requirement for preapproval of products that contain naturally occurring ingredients and that are like foods in that they are intended to “maintain the structure and function” of the body. The “structure and function” clause was included to differentiate these products from medicines that are used to treat medical illnesses. However, dietary supplements are regularly promoted like medicines for prostate and breast health, sleep, sexual performance, bone strength, weight loss/gain, metabolism boosting, and so on. The commercial names of the products and their promotional materials alluringly suggest to consumers that they will prevent or cure illnesses. It provides no reassurance that their labels include disclaimers in very small print such as “These statements have not been evaluated by the Food and Drug Administration. This product is not intended to diagnose, prevent, or cure disease. Individual results may vary.” Is the consumer really adequately informed by such labels? Shouldn’t these labels fully inform consumers, in a legible typeface, that the FDA has
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perspec tives not approved or reviewed the safety of this product? Although the products studied by Foster et al.1 are labeled “ephedra free,” the authors show that they are not free of ephedra-like actions, most likely because they contain chemicals such as synephrine or phenylethylamine that have pharmacological actions very much like those of ephedra. This should be of no surprise to anyone who has a basic understanding of cardiovascular pharmacology. It is unimaginable that those who formulated these products failed to see the chemical and pharmacological similarities between the earlier ephedra products and their “ephedrafree” replacements. It is disappointing that current statutes necessitate that the FDA and other scientists have to demonstrate again the obvious potential for these chemicals to cause harm. Recent experience with dietary supplements, cold preparations, and prescription drugs with adrenergic actions clearly predicts the potential for harm, especially when such products are used for weight loss or exercise enhancement. For example, phenylpropanolamine (PPA) is an old adrenergic drug that was an ingredient in many cold preparations and weight loss products such as Dexatrim. After numerous reports of deaths and strokes associated with PPA, a clinical study was completed that gave the FDA the data it needed to call for removal of these products from the market but only after many people had died or suffered harm.2 Amazingly, Dexatrim and many similar products were reformulated, replacing PPA with ephedra, and labeled as “dietary supplements.” Manufacturers were not required by law to have FDA approval before marketing these products, placing the burden on the agency to evaluate their potential to cause harm. After years of research and legal review, the FDA was finally able to gather the data to demonstrate the harm from ephedra products and ban it from dietary supplements. Almost overnight, many ephedra-containing dietary supplements were again reformulated to contain Citrus aurantium (also known as “bitter orange”) and other naturally occurring chemicals such as phenyleth298
ylamine or synephrine (also known as oxedrine). This is an example of déjà vu all over again, and again, and again! The experience with prescription drugs that have adrenergic actions has also confirmed their cardiovascular risk. Sibutramine, a prescription weight-loss product, was removed from the market because of increasing numbers of deaths and cardiovascular complications. 3 Fenoterol and other adrenergic bronchodilators have been clearly shown to be associated with an increased risk of sudden death and cardiovascular complications. 4 These adrenergic compounds have in common the same phenylethylamine chemical backbone as that of the pharmacophore responsible for the increased heart rate, altered blood pressure, and arrhythmias—a dangerous pattern. 3,5 The results are very consistent across these compounds and, although some adrenergic drugs may have medical applications, e.g., when prescribed by physicians for asthma or attention-deficit hyperactivity disorder, they also have a well-established and very predictable risk of harm in certain individuals. Fortunately, dedicated scientists are willing to do the research necessary to protect us from those who, knowingly or unknowingly, threaten our health by marketing untested medical products. For example, Harvey W. Wiley, founder of the Division of Chemistry in the US Department of Agriculture (a predecessor of the FDA), led efforts to expose the snake-oil salesmen of the early 1900s. It is likely that our society will always have charlatans who are willing to ignore possible risks to the public in their quest to make money. Therefore, FDA scientists must continue to work to debunk the pseudoscience that is misleading and threatening the public. It is estimated that the American consumer spends more than $25 billion annually on dietary supplements.6 Because the manufacturers are not required to test their products, the National Institutes of Health spends more than $400 million each year to examine the efficacy and safety of alternative therapies, including vitamin and mineral supplements. Unfortunately,
study after study has shown that these vitamin/mineral products lack efficacy for preventing cancer or heart disease or improving overall mortality.7,8 Perhaps because many dietary supplements lack medical benefit, some of the manufacturers adulterate their products by adding pharmacologically active drugs such as benzodiazepines, nonsteroidal anti-inflammatory drugs, caffeine, and corticosteroids. The FDA can take action against these products because they are “adulterated” with prescription drugs that have potential risks and require a doctor’s prescription. The FDA has halted the marketing of numerous dietary supplements containing lovastatin, sildenafil, taladafil, or other pharmacologically active prescription drugs.9 The Centers for Disease Control and Prevention has estimated that one in two adults in the United States regularly takes a dietary supplement, and many do so because these products are considered natural—“therefore they must be safe.”10 It seems surprising that so many people could forget that “natural” substances include rattlesnake venom, scorpion venom, poisonous mushrooms, jellyfish toxin, and Ebola viruses. There is an opportunity to improve the public’s understanding of the proper role of dietary supplements in healthy living by improving the quality of science education in our schools. In addition to attracting young people to careers in science, science courses in our schools should help everyone use scientific information more effectively as they make day-to-day decisions about how to maintain their health. Clinical pharmacologists have many options for where they can apply their professional skills. Many are attracted to the discovery of the new drugs that cure or ameliorate illnesses and improve the human condition. Others are driven to understand how medications affect human biology and how humans affect the medicines (i.e., pharmacokinetics). This work is an exciting and rewarding garden in which to toil. However, the garden is not without weeds that must be cleared. The report by Foster and coworkers1 on the cardiovascular actions VOLUME 93 NUMBER 4 | APRIL 2013 | www.nature.com/cpt
perspec tives of dietary supplements labeled as ephedra free is an example of important work that protects the public by helping rid the garden of pharmaceutical weeds. If laws such as DSHEA were reversed, less weeding would be necessary. CONFLICT OF INTEREST The author declared no conflict of interest. © 2013 ASCPT
1. Foster, L. et al. Multiple dosing of ephedrafree dietary supplements: hemodynamic, electrocardiographic, and bacterial contamination effects. Clin. Pharmacol. Ther. 93, 267–274 (2013). 2. Kernan, W.N. et al. Phenylpropanolamine and the risk of hemorrhagic stroke. N. Engl. J. Med. 343, 1826–1832 (2000). 3. Colman, E. Food and Drug Administration’sw Obesity Drug Guidance Document: a short history. Circulation 125, 2156–2164 (2012). 4. Pearce, N. et al. Case–control study of prescribed fenoterol and death from asthma in New Zealand, 1977–81. Thorax 45, 170–175 (1990).
5. James, W.P. et al. Effect of sibutramine on cardiovascular outcomes in overweight and obese subjects. N. Engl. J. Med. 363, 905–917 (2010). 6. Consumer Reports. What’s behind our dietary supplements coverage (2011). 7. Sesso, H.D. et al. Multivitamins in the prevention of cardiovascular disease in men: the Physicians’ Health Study II randomized controlled trial. JAMA 308, 1751–1760 (2012). 8. Park, S.Y., Murphy, S.P., Wilkens, L.R., Henderson, B.E. & Kolonel, L.N. Multivitamin use and the risk of mortality and cancer incidence: the multiethnic cohort study. Am. J. Epidemiol. 173, 906–914 (2011). 9. US Food and Drug Administration. FDA recalls adulterated dietary supplements (17 December 2012). 10. Qato, D.M., Alexander, G.C., Conti, R.M., Johnson, M., Schumm, P. & Lindau, S.T. Use of prescription and over-the-counter medications and dietary supplements among older adults in the United States. JAMA 300, 2867–2878 (2008).
Phenotypic vs. Target-Based Drug Discovery for First-in-Class Medicines DC Swinney1 Current drug discovery strategies include both molecular and empirical approaches. The molecular approaches are predominantly hypothesis-driven and are referred to as targetbased. The empirical approaches are referred to as phenotypic because they rely on phenotypic measures of response. A recent analysis revealed the phenotypic approaches to be the more successful strategy for small-molecule, first-in-class medicines. The rationalization for this success was the unbiased identification of the molecular mechanism of action (MMOA). Drug discovery and development in the past quarter century has focused on the promise of molecular medicine to identify medicines to treat unmet medical need by targeting specific gene products. For example, mutations, or defects,
at specific molecular locations in human DNA were found to be responsible for some cancers, raising the hope of developing successful therapies tailored to individual patients. The geneto-medicine approach has had success,
1Institute for Rare and Neglected Diseases Drug Discovery, Mountain View, California, USA. Correspondence: DC Swinney (
[email protected])
doi:10.1038/clpt.2012.236
as demonstrated by imatinib (Gleevec)1 and gefitinib (Iressa),2 and it has raised expectations for the majority of drug discovery to follow the same path. Before the advent of target-based drug discovery, new medicines were discovered by evaluating different chemicals against phenotypes—an organism’s observable characteristics—in authentic biological systems, such as animals or cells. Many factors influenced the shift from a phenotypic approach to a target-based approach, including the idea that a rational, measurable progression from gene to clinic to registration would increase research and development success and productivity. Rational, informed target-based approaches use molecular tools of genetics, chemistry, and informatics to drive drug discovery and also provide criteria and boundaries for choosing patient populations, setting doses, and quantitatively measuring efficacy and toxicity. Unfortunately, this shift in approach has not yet transformed the industry. To investigate whether some strategies have been more successful than others in the discovery of new drugs, my group analyzed the discovery strategies and the MMOA for new molecular entities and new biologics approved by the US Food and Drug Administration between 1999 and 2008 (Figure 1).3 Of the 259 agents approved, 75 were first-in-class drugs with new MMOAs. Of these, 50 (67%) were small molecules and 25 (33%) were biologics. The results also show that the contribution of phenotypic screening to the discovery of firstin-class small-molecule drugs exceeded that of target-based approaches—with 28 and 17 of these drugs coming from the two approaches, respectively—in an era when the major focus was on targetbased approaches. The first-in-class medicines discovered by phenotypic screening included those discovered using animal models such as ezetimibe (Zetia) for reducing levels of blood cholesterol; those discovered with cellular assays such as vorinostat (Zolinza), the first histone deacetylase inhibitor, which was reported to come from the observation that dimethyl sulfoxide had an
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