News & Analysis Medical News & Perspectives.....p1089
Global Health................................p1093
News From the CDC .....................p1094
Precision Medicine: The Future or Simply Politics?
HIV Prevention Trial in African Women Fails, Adherence a Problem
Higher Folic Acid Intake Needed
The JAMA Forum ..........................p1091 An Observational Study Goes Where Randomized Clinical Trials Have Not
Windblown Pesticide Hazard
Risk of HIV Infection Increases With an Injectable Hormonal Contraceptive Report Outlines Steps to Address Antibiotic Resistance
Medical News & Perspectives
Precision Medicine: The Future or Simply Politics? Rita Rubin, MA
B
arrett Rollins, MD, PhD, chief scientific officer at the Dana-Farber Cancer Institute, tells an anecdote to illustrate the promise of “precision medicine.” A 35-year-old patient at Dana-Farber was dying of myeloid sarcoma, a rare tumor consisting of a solid collection of leukemic cells outside of the bone marrow. Although the man was about to enter hospice care, he consented to having his tumor’s genome sequenced. Unexpectedly, sequencing revealed a mutation in a platelet-derived growth factor receptor gene, giving rise to a constitutively active kinase targeted by the kinase inhibitor imatinib mesylate, marketed as Gleevec. Myeloid sarcoma is not among Gleevec’s indications, but the man’s tumor shrank after he began taking the pill. Months later, he is still alive, no longer a candidate for hospice care, Rollins said. Some physicians might say that “personalized medicine” saved the patient from imminent death, Rollins said in an interview. “Most folks are using ‘precision medicine’ and ‘personalized medicine’ interchangeably,” he said. “I’ve assumed this is sort of a marketing issue: ‘personalized medicine’ has been around for a while, and ‘precision medicine’ sounds new. “But to be fair, one could argue that all good doctors have always practiced ‘personalized medicine,’ in that our treatments are always tailored to the individual patient in front of us,” he said. “‘Precision medicine’ implies something different, namely that our treatments are now more precisely tailored to specific molecular targets.”
Precision Medicine Initiative Now precision medicine has caught President Obama’s attention. In a January 30 speech at the White House, Obama explained his new Precision Medicine Initiative. The goal, he said, is “delivering the right treatment at the right time, every time, to the right person” (http://1.usa.gov /16PAwNp). He has asked Congress for $215 million to fund the initiative in fiscal year 2016. More than half of that investment, or $130 million, is earmarked for the National Institutes of Health (NIH) to develop “one of the largest research populations ever assembled,” a cohort of at least 1 million volunteers, Obama said. Another $70 million would go to the National Cancer Institute (NCI) to ramp up efforts to identify genes that drive malignant tumor development. “There’s bipartisan support for the idea,” Obama said of the initiative, “which makes me very happy.” NIH Director Francis Collins, MD, PhD, first made the case for “a US prospective cohort study of genes and environment” more than a decade ago (Collins FS. Nature. 2004; 429[6990]:475-477). At a 2-day NIH meeting in February to discuss building the precision medicine cohort, Collins said participants will share genomic data, lifestyle information, and biological samples, all of which will be linked to their electronic health records. Advances in data science, better computing power, and electronic medical records, not to mention the dramatic drop in the cost to sequence an individual’s entire ge-
jama.com
nome, make 2015 “a perfect time to launch the Precision Medicine Initiative,” Collins said at a press conference before the president’s speech. “For most of medicine’s history… physicians have been forced to approach prevention and treatment of disease based on the expected response of an average patient because that was the best that could be done,” Collins wrote in a recent JAMA viewpoint article (Collins FS. JAMA. 2015;313[2]:131-132). The Precision Medicine Initiative’s cohort will include healthy individuals as well as patients and likely will piggyback existing cohorts, such as the Framingham Heart Study and the Million Veteran Program (MVP), which is sponsored by the Department of Veterans Affairs, Collins said. The MVP’s goal is to collect health information and blood samples for future genomic analyses from 1 million US military veterans. Last summer, the MVP reported that it had enrolled 250 000 veterans (http://1.usa.gov /1EWnUCs). Enlisting 1 million volunteers in the Precision Medicine Initiative’s cohort “is not an extravagance; it’s a necessity,” said Stephen Friend, MD, PhD, president and cofounder of Sage Bionetworks, a nonprofit in Seattle. Friend is one of 2 principal investigators for the Resilience Project, aimed at identifying genetic and environmental factors that might protect individuals from catastrophic diseases for which they carry rare genetic mutations, such as early-onset Alzheimer disease. The project could lead to potential new treatments or preventive measures, he said.
(Reprinted) JAMA March 17, 2015 Volume 313, Number 11
Copyright 2015 American Medical Association. All rights reserved.
Downloaded From: http://jama.jamanetwork.com/ by a University of Leeds User on 05/17/2015
1089
News & Analysis
Thousands of volunteers have signed up to participate in the Resilience Project’s prospective study, making them likely candidates to join the Precision Medicine Initiative’s cohort, Friend said. “They are excited to give information on themselves.”
Considerations and Challenges Not all physicians are as enthusiastic about the initiative as Friend. Skeptics question why the president decided to focus on precision medicine instead of, say, health disparities or other pressing public health problems. Nigel Paneth, MD, MPH, a professor of epidemiology and biostatistics and pediatrics at the Michigan State University College of Human Medicine, said he often shows a slide about a treatment that can cut the risk of converting from prediabetes to diabetes by nearly two-thirds. That treatment is diet and exercise. “Do we hear about this?” he said. “Of course not. It’s not sexy.” Jeffrey Matthews, MD, chair of surgery at the University of Chicago, tweeted on February 4 that precision medicine “will fall short of its catchy name” (http://bit.ly/1CdkDZy). “The idea of packaging it as a new paradigm, precision medicine, (suggests) that somehow everything else is not precise medicine,” Matthews said in a recent interview. “It sounds great. But it is being oversold and overhyped, and it’s creating unrealistic expectations on the part of patients and clinicians.” Precision medicine implies that “if you know somebody’s genes, you’ll be able to fit the treatment to them, which is reductionist,” said Zackary Berger, MD, PhD, an internist and epidemiologist at the Johns Hopkins School of Medicine who also holds joint appointments in the department of health, behavior, and society at the Bloomberg School of Public Health and in the Berman Institute of Bioethics. Still, Berger noted in an interview, “it’s hard to be against more money for research. You don’t want to poison your own well.” Others said Obama’s requested allocation won’t buy much precision. “There’s no way you can do this justice with $215 million,” said cardiologist Eric Topol, MD, director of the Scripps Translational Science Institute. “This, to me, is to get it off the ground… but at least it’s a start.” Writing in the New York Times on January 29, Michael Joyner, MD, an anesthesiologist and physiologist at the Mayo Clinic in Rochester, Minnesota, referred to Obama’s 1090
precision medicine plan as a “‘moonshot’ medical research initiative” (http://nyti.ms /16JHPG2). “We would be better off directing more resources to understanding what it takes to solve messy problems about how humans behave…,” Joyner wrote. “Ultimately, we almost certainly have more control over how much we exercise, eat, drink, and smoke than we do over our genomes.” Topol said Joyner’s piece is off-base. “He is totally out of touch with how the field is moving,” Topol said in an interview. “The science is catapulting forward. You can now come up with so much big data on each individual, and it is changing medicine.” In fact, he noted, the United States lags behind several European countries. Great Britain, for example, has already launched the 100,000 Genomes Project with the goal of sequencing the entire genomes of 100 000 National Health Service patients by 2017 (http://bit.ly/1AU0cp6). “However, it’s not just about the sequence,” Topol added. “That’s just one layer of the information. If you really want to change medicine, you have to have all the information on the individual.” That includes their environment, the bacteria in their gut, and other distinguishing characteristics, he said.
Weighing Costs and Benefits During his White House remarks, Obama introduced William Elder Jr, who was diagnosed with cystic fibrosis 20 years ago. In 2012, he tried a new drug designed to target the specific, rare genetic defect that caused his disease. His breathing improved
within hours of his first dose. The 27-yearold Elder is now in medical school and, according to the president, expects to live to see his grandchildren. Paneth questioned whether focusing on the genetic underpinnings of disease will get the most bang for the buck when it comes to improving health. The problem, Paneth said, is that such “targeted drugs always turn out to be hugely expensive. When there’s a clinical benefit, it comes at a great price.” Kalydeco, which Elder takes, costs $300 000 a year. Although not a cure, it is the first drug to target genetic mutations that cause cystic fibrosis. It is approved for treating patients with any of 10 mutations in the cystic fibrosis gene (http://bit.ly /1Fs96ce), who represent fewer than 10% of approximately 30 000 individuals with the disease in the United States, according to the Cystic Fibrosis Foundation. Vertex, maker of Kalydeco, or ivacaftor, has applied to the US Food and Drug Administration to market the medication in combination with a second, experimental drug to treat the cystic fibrosis genetic defect responsible for about half of US cases (http://bit.ly/1Cc5PdJ). Vertex is also testing the drug combination in people with a mutation that causes another 40% of US cases. Collins said he expects the initiative’s earliest successes will be in pharmacogenomics and cancer. “This is a bold effort, but… it is closer than many people realize,” he said. Already, labels on more than 150 medications contain pharmacogenomic information, although they don’t necessarily recommend genetic testing before use (http: //1.usa.gov/1DB0lxv). Pharmacogenomics can provide vital information about dosing drugs, as highlighted in research published last month (Diouf et al. JAMA. 2015;313[8]:815-823). The study found that children with acute lymphoblastic leukemia who had inherited a particular genetic variation were more likely to experience severe peripheral neuropathy when treated with vincristine. “If replicated in additional populations, this finding may provide a basis for safer dosing of this widely prescribed anticancer agent,” the authors wrote.
Present and Future Promise In the short-term, precision medicine likely holds the greatest potential in the development of cancer therapeutics, Collins said.
JAMA March 17, 2015 Volume 313, Number 11 (Reprinted)
Copyright 2015 American Medical Association. All rights reserved.
Downloaded From: http://jama.jamanetwork.com/ by a University of Leeds User on 05/17/2015
jama.com
News & Analysis
“The cancer focus, I think, is a natural,” he said. “To be able to ramp that up is timely and very appealing.” Even prior to the announcement of the Precision Medicine Initiative, the NIH launched 3 trials that are screening patients’ tumors for genetic abnormalities. Based on the screening results, patients are enrolled into a clinical trial of an investigational drug that might target the specific molecular pathology driving their cancer (http: //1.usa.gov/1EdWhDQ). The NCI MATCH Trial is enrolling adults with advanced solid tumors and lymphomas that have stopped responding to standard therapy. Pediatric MATCH is the counterpart trial for children. The third trial, the Lung Master Protocol, or Lung-MAP, is a public-private collaborative
effort implementing a similar approach for patients with squamous cell lung cancer, which currently has few treatment options beyond surgery (http://bit.ly/1zIq85a). The participants in these trials could potentially become a part of the Precision Medicine Initiative cohort. “Efforts such as Lung-MAP and the NCI MATCH program are within the scope of this initiative,” said Vassiliki Papadimitrakopoulou, MD, professor of medicine at MD Anderson Cancer Center and a co–principal investigator for Lung-MAP. In September 2011, Dana-Farber also launched its Profile program, becoming the first hospital to offer tumor genotyping to all patients with cancer, Rollins said. “We see 16 000 new patients a year. We want to turn them into a giant cohort
study, like the Framingham Study,” he said. “Breast cancer patients with a mutation in gene X: do they live longer? do they live shorter? That’s a very powerful scientific thing to do.” Rollins said Dana-Farber “would definitely consider contributing the Profile patient cohort to the Precision Medicine Initiative if the protections for patient confidentiality are sufficiently stringent.” While improving the treatment of cancer is one of the initiative’s shorter-term aims, it has a more ambitious longer-term goal, Collins said at last month’s NIH meeting. Eventually, he said, the plan is to “generate the knowledge base necessary to move precision medicine into virtually all areas of health and disease.”
The JAMA Forum
An Observational Study Goes Where Randomized Clinical Trials Have Not Austin B. Frakt, PhD
Doug Levy
R
andomized clinical trials (RCTs) are considered the “gold standard” for providing actionable evidence to guide clinical decision making. However, they cannot always address important questions. For instance, statistically significant results for low-frequency outcomes like mortality sometimes require longer follow-up times or larger studies than can be practically undertaken. In such cases, we have a choice: we can either go without evidence or we can turn to observational studies. Such studies often can be much larger and accommodate longer follow-ups. But because participants are not explicitly randomly assigned to treatment and control groups, observational studies can produce biased results. There are, however, advances in methods that can minimize that bias and increase our confidence in findings. Consider a recent observational study comparing 2 classes of drugs that are used to treat type 2 diabetes when initial treatment fails to control blood-sugar level (http: //bit.ly/1E2RSV3). The investigators found that use of sulfonylureas (SUs) is associated with greater mortality and more avoidable hospitalizations than the use of thiazo-
lidinediones (TZDs). Both types of medications are frequently prescribed as second-line treatments, but concerns about the cardiovascular safety of TZDs have been a focus of controversy. Given the new findings, should clinicians now favor TZDs? That depends on an assessment of the study’s sample and methods. An advantage of the study, published in Value in Health, is that it was 20 times larger and had a much longer follow-up than any prior comparative-effectiveness RCT of second-line diabetes medications (http://bit.ly/1E2RSV3). This permitted the investigators to obtain outcomes on lowfrequency events like mortality; prior RCTs principally only had power to examine blood glucose control. The study, based on merged Veterans Health Administration (VA) and Medicare data, examined more than 80 000 patients for up to 10 years. It found that, relative to TZDs, SUs cause a 68% increase in risk of avoidable hospitalization and a 50% increase in risk of death. (Full disclosure: the study was led by my colleague Julia Prentice, PhD, and I work closely with another coauthor, Steven Pizer, PhD.)
jama.com
Austin B. Frakt, PhD
That the study by Prentice and colleagues is not an RCT should be viewed as only a mild weakness, in my view, because the instrumental variable methods it employed were rigorously tested and found to be very strong. Admittedly, some would disagree with the interpretation of this design as a mild weakness. The key threat to any observational study is bias from factors that cannot be observed and controlled. Randomized clinical
(Reprinted) JAMA March 17, 2015 Volume 313, Number 11
Copyright 2015 American Medical Association. All rights reserved.
Downloaded From: http://jama.jamanetwork.com/ by a University of Leeds User on 05/17/2015
1091
Global Health................................p1093
News From the CDC .....................p1094
Precision Medicine: The Future or Simply Politics?
HIV Prevention Trial in African Women Fails, Adherence a Problem
Higher Folic Acid Intake Needed
The JAMA Forum ..........................p1091 An Observational Study Goes Where Randomized Clinical Trials Have Not
Windblown Pesticide Hazard
Risk of HIV Infection Increases With an Injectable Hormonal Contraceptive Report Outlines Steps to Address Antibiotic Resistance
Medical News & Perspectives
Precision Medicine: The Future or Simply Politics? Rita Rubin, MA
B
arrett Rollins, MD, PhD, chief scientific officer at the Dana-Farber Cancer Institute, tells an anecdote to illustrate the promise of “precision medicine.” A 35-year-old patient at Dana-Farber was dying of myeloid sarcoma, a rare tumor consisting of a solid collection of leukemic cells outside of the bone marrow. Although the man was about to enter hospice care, he consented to having his tumor’s genome sequenced. Unexpectedly, sequencing revealed a mutation in a platelet-derived growth factor receptor gene, giving rise to a constitutively active kinase targeted by the kinase inhibitor imatinib mesylate, marketed as Gleevec. Myeloid sarcoma is not among Gleevec’s indications, but the man’s tumor shrank after he began taking the pill. Months later, he is still alive, no longer a candidate for hospice care, Rollins said. Some physicians might say that “personalized medicine” saved the patient from imminent death, Rollins said in an interview. “Most folks are using ‘precision medicine’ and ‘personalized medicine’ interchangeably,” he said. “I’ve assumed this is sort of a marketing issue: ‘personalized medicine’ has been around for a while, and ‘precision medicine’ sounds new. “But to be fair, one could argue that all good doctors have always practiced ‘personalized medicine,’ in that our treatments are always tailored to the individual patient in front of us,” he said. “‘Precision medicine’ implies something different, namely that our treatments are now more precisely tailored to specific molecular targets.”
Precision Medicine Initiative Now precision medicine has caught President Obama’s attention. In a January 30 speech at the White House, Obama explained his new Precision Medicine Initiative. The goal, he said, is “delivering the right treatment at the right time, every time, to the right person” (http://1.usa.gov /16PAwNp). He has asked Congress for $215 million to fund the initiative in fiscal year 2016. More than half of that investment, or $130 million, is earmarked for the National Institutes of Health (NIH) to develop “one of the largest research populations ever assembled,” a cohort of at least 1 million volunteers, Obama said. Another $70 million would go to the National Cancer Institute (NCI) to ramp up efforts to identify genes that drive malignant tumor development. “There’s bipartisan support for the idea,” Obama said of the initiative, “which makes me very happy.” NIH Director Francis Collins, MD, PhD, first made the case for “a US prospective cohort study of genes and environment” more than a decade ago (Collins FS. Nature. 2004; 429[6990]:475-477). At a 2-day NIH meeting in February to discuss building the precision medicine cohort, Collins said participants will share genomic data, lifestyle information, and biological samples, all of which will be linked to their electronic health records. Advances in data science, better computing power, and electronic medical records, not to mention the dramatic drop in the cost to sequence an individual’s entire ge-
jama.com
nome, make 2015 “a perfect time to launch the Precision Medicine Initiative,” Collins said at a press conference before the president’s speech. “For most of medicine’s history… physicians have been forced to approach prevention and treatment of disease based on the expected response of an average patient because that was the best that could be done,” Collins wrote in a recent JAMA viewpoint article (Collins FS. JAMA. 2015;313[2]:131-132). The Precision Medicine Initiative’s cohort will include healthy individuals as well as patients and likely will piggyback existing cohorts, such as the Framingham Heart Study and the Million Veteran Program (MVP), which is sponsored by the Department of Veterans Affairs, Collins said. The MVP’s goal is to collect health information and blood samples for future genomic analyses from 1 million US military veterans. Last summer, the MVP reported that it had enrolled 250 000 veterans (http://1.usa.gov /1EWnUCs). Enlisting 1 million volunteers in the Precision Medicine Initiative’s cohort “is not an extravagance; it’s a necessity,” said Stephen Friend, MD, PhD, president and cofounder of Sage Bionetworks, a nonprofit in Seattle. Friend is one of 2 principal investigators for the Resilience Project, aimed at identifying genetic and environmental factors that might protect individuals from catastrophic diseases for which they carry rare genetic mutations, such as early-onset Alzheimer disease. The project could lead to potential new treatments or preventive measures, he said.
(Reprinted) JAMA March 17, 2015 Volume 313, Number 11
Copyright 2015 American Medical Association. All rights reserved.
Downloaded From: http://jama.jamanetwork.com/ by a University of Leeds User on 05/17/2015
1089
News & Analysis
Thousands of volunteers have signed up to participate in the Resilience Project’s prospective study, making them likely candidates to join the Precision Medicine Initiative’s cohort, Friend said. “They are excited to give information on themselves.”
Considerations and Challenges Not all physicians are as enthusiastic about the initiative as Friend. Skeptics question why the president decided to focus on precision medicine instead of, say, health disparities or other pressing public health problems. Nigel Paneth, MD, MPH, a professor of epidemiology and biostatistics and pediatrics at the Michigan State University College of Human Medicine, said he often shows a slide about a treatment that can cut the risk of converting from prediabetes to diabetes by nearly two-thirds. That treatment is diet and exercise. “Do we hear about this?” he said. “Of course not. It’s not sexy.” Jeffrey Matthews, MD, chair of surgery at the University of Chicago, tweeted on February 4 that precision medicine “will fall short of its catchy name” (http://bit.ly/1CdkDZy). “The idea of packaging it as a new paradigm, precision medicine, (suggests) that somehow everything else is not precise medicine,” Matthews said in a recent interview. “It sounds great. But it is being oversold and overhyped, and it’s creating unrealistic expectations on the part of patients and clinicians.” Precision medicine implies that “if you know somebody’s genes, you’ll be able to fit the treatment to them, which is reductionist,” said Zackary Berger, MD, PhD, an internist and epidemiologist at the Johns Hopkins School of Medicine who also holds joint appointments in the department of health, behavior, and society at the Bloomberg School of Public Health and in the Berman Institute of Bioethics. Still, Berger noted in an interview, “it’s hard to be against more money for research. You don’t want to poison your own well.” Others said Obama’s requested allocation won’t buy much precision. “There’s no way you can do this justice with $215 million,” said cardiologist Eric Topol, MD, director of the Scripps Translational Science Institute. “This, to me, is to get it off the ground… but at least it’s a start.” Writing in the New York Times on January 29, Michael Joyner, MD, an anesthesiologist and physiologist at the Mayo Clinic in Rochester, Minnesota, referred to Obama’s 1090
precision medicine plan as a “‘moonshot’ medical research initiative” (http://nyti.ms /16JHPG2). “We would be better off directing more resources to understanding what it takes to solve messy problems about how humans behave…,” Joyner wrote. “Ultimately, we almost certainly have more control over how much we exercise, eat, drink, and smoke than we do over our genomes.” Topol said Joyner’s piece is off-base. “He is totally out of touch with how the field is moving,” Topol said in an interview. “The science is catapulting forward. You can now come up with so much big data on each individual, and it is changing medicine.” In fact, he noted, the United States lags behind several European countries. Great Britain, for example, has already launched the 100,000 Genomes Project with the goal of sequencing the entire genomes of 100 000 National Health Service patients by 2017 (http://bit.ly/1AU0cp6). “However, it’s not just about the sequence,” Topol added. “That’s just one layer of the information. If you really want to change medicine, you have to have all the information on the individual.” That includes their environment, the bacteria in their gut, and other distinguishing characteristics, he said.
Weighing Costs and Benefits During his White House remarks, Obama introduced William Elder Jr, who was diagnosed with cystic fibrosis 20 years ago. In 2012, he tried a new drug designed to target the specific, rare genetic defect that caused his disease. His breathing improved
within hours of his first dose. The 27-yearold Elder is now in medical school and, according to the president, expects to live to see his grandchildren. Paneth questioned whether focusing on the genetic underpinnings of disease will get the most bang for the buck when it comes to improving health. The problem, Paneth said, is that such “targeted drugs always turn out to be hugely expensive. When there’s a clinical benefit, it comes at a great price.” Kalydeco, which Elder takes, costs $300 000 a year. Although not a cure, it is the first drug to target genetic mutations that cause cystic fibrosis. It is approved for treating patients with any of 10 mutations in the cystic fibrosis gene (http://bit.ly /1Fs96ce), who represent fewer than 10% of approximately 30 000 individuals with the disease in the United States, according to the Cystic Fibrosis Foundation. Vertex, maker of Kalydeco, or ivacaftor, has applied to the US Food and Drug Administration to market the medication in combination with a second, experimental drug to treat the cystic fibrosis genetic defect responsible for about half of US cases (http://bit.ly/1Cc5PdJ). Vertex is also testing the drug combination in people with a mutation that causes another 40% of US cases. Collins said he expects the initiative’s earliest successes will be in pharmacogenomics and cancer. “This is a bold effort, but… it is closer than many people realize,” he said. Already, labels on more than 150 medications contain pharmacogenomic information, although they don’t necessarily recommend genetic testing before use (http: //1.usa.gov/1DB0lxv). Pharmacogenomics can provide vital information about dosing drugs, as highlighted in research published last month (Diouf et al. JAMA. 2015;313[8]:815-823). The study found that children with acute lymphoblastic leukemia who had inherited a particular genetic variation were more likely to experience severe peripheral neuropathy when treated with vincristine. “If replicated in additional populations, this finding may provide a basis for safer dosing of this widely prescribed anticancer agent,” the authors wrote.
Present and Future Promise In the short-term, precision medicine likely holds the greatest potential in the development of cancer therapeutics, Collins said.
JAMA March 17, 2015 Volume 313, Number 11 (Reprinted)
Copyright 2015 American Medical Association. All rights reserved.
Downloaded From: http://jama.jamanetwork.com/ by a University of Leeds User on 05/17/2015
jama.com
News & Analysis
“The cancer focus, I think, is a natural,” he said. “To be able to ramp that up is timely and very appealing.” Even prior to the announcement of the Precision Medicine Initiative, the NIH launched 3 trials that are screening patients’ tumors for genetic abnormalities. Based on the screening results, patients are enrolled into a clinical trial of an investigational drug that might target the specific molecular pathology driving their cancer (http: //1.usa.gov/1EdWhDQ). The NCI MATCH Trial is enrolling adults with advanced solid tumors and lymphomas that have stopped responding to standard therapy. Pediatric MATCH is the counterpart trial for children. The third trial, the Lung Master Protocol, or Lung-MAP, is a public-private collaborative
effort implementing a similar approach for patients with squamous cell lung cancer, which currently has few treatment options beyond surgery (http://bit.ly/1zIq85a). The participants in these trials could potentially become a part of the Precision Medicine Initiative cohort. “Efforts such as Lung-MAP and the NCI MATCH program are within the scope of this initiative,” said Vassiliki Papadimitrakopoulou, MD, professor of medicine at MD Anderson Cancer Center and a co–principal investigator for Lung-MAP. In September 2011, Dana-Farber also launched its Profile program, becoming the first hospital to offer tumor genotyping to all patients with cancer, Rollins said. “We see 16 000 new patients a year. We want to turn them into a giant cohort
study, like the Framingham Study,” he said. “Breast cancer patients with a mutation in gene X: do they live longer? do they live shorter? That’s a very powerful scientific thing to do.” Rollins said Dana-Farber “would definitely consider contributing the Profile patient cohort to the Precision Medicine Initiative if the protections for patient confidentiality are sufficiently stringent.” While improving the treatment of cancer is one of the initiative’s shorter-term aims, it has a more ambitious longer-term goal, Collins said at last month’s NIH meeting. Eventually, he said, the plan is to “generate the knowledge base necessary to move precision medicine into virtually all areas of health and disease.”
The JAMA Forum
An Observational Study Goes Where Randomized Clinical Trials Have Not Austin B. Frakt, PhD
Doug Levy
R
andomized clinical trials (RCTs) are considered the “gold standard” for providing actionable evidence to guide clinical decision making. However, they cannot always address important questions. For instance, statistically significant results for low-frequency outcomes like mortality sometimes require longer follow-up times or larger studies than can be practically undertaken. In such cases, we have a choice: we can either go without evidence or we can turn to observational studies. Such studies often can be much larger and accommodate longer follow-ups. But because participants are not explicitly randomly assigned to treatment and control groups, observational studies can produce biased results. There are, however, advances in methods that can minimize that bias and increase our confidence in findings. Consider a recent observational study comparing 2 classes of drugs that are used to treat type 2 diabetes when initial treatment fails to control blood-sugar level (http: //bit.ly/1E2RSV3). The investigators found that use of sulfonylureas (SUs) is associated with greater mortality and more avoidable hospitalizations than the use of thiazo-
lidinediones (TZDs). Both types of medications are frequently prescribed as second-line treatments, but concerns about the cardiovascular safety of TZDs have been a focus of controversy. Given the new findings, should clinicians now favor TZDs? That depends on an assessment of the study’s sample and methods. An advantage of the study, published in Value in Health, is that it was 20 times larger and had a much longer follow-up than any prior comparative-effectiveness RCT of second-line diabetes medications (http://bit.ly/1E2RSV3). This permitted the investigators to obtain outcomes on lowfrequency events like mortality; prior RCTs principally only had power to examine blood glucose control. The study, based on merged Veterans Health Administration (VA) and Medicare data, examined more than 80 000 patients for up to 10 years. It found that, relative to TZDs, SUs cause a 68% increase in risk of avoidable hospitalization and a 50% increase in risk of death. (Full disclosure: the study was led by my colleague Julia Prentice, PhD, and I work closely with another coauthor, Steven Pizer, PhD.)
jama.com
Austin B. Frakt, PhD
That the study by Prentice and colleagues is not an RCT should be viewed as only a mild weakness, in my view, because the instrumental variable methods it employed were rigorously tested and found to be very strong. Admittedly, some would disagree with the interpretation of this design as a mild weakness. The key threat to any observational study is bias from factors that cannot be observed and controlled. Randomized clinical
(Reprinted) JAMA March 17, 2015 Volume 313, Number 11
Copyright 2015 American Medical Association. All rights reserved.
Downloaded From: http://jama.jamanetwork.com/ by a University of Leeds User on 05/17/2015
1091
