2 of 8 | JNCI J Natl Cancer Inst, 2015, Vol. 107, No. 7
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Process Is Product Biosimilar products start with essentially the same genetic sequence. But they are produced in living cells, and the particulars of those production processes are guarded trade secrets. Because of the vagaries of biological systems, differences in cell culture systems can
influence the product. That’s why FDA pays as much attention to the manufacturing process as to the product. “It is a challenge to run a complex manufacturing process for biopharmaceuticals,” said Stephen P. Creekmore, M.D., Ph.D., chief of the Biological Resources Branch at the National Cancer Institute. “There is a risk to using these products, and the FDA is trying to minimize the risk to make sure the biosimilar is as close to the reference product as they can.” Even if a manufacturer can show that a product meets the FDA standard for biosimilarity, some oncologists may be concerned about extrapolation, Zelenetz said. FDA states that a biosimilar must show analytical comparability to the U.S. licensed reference product but might not require full clinical trials for all indications. “From an ethical standpoint—and the European Medicines Agency and the FDA share this—we don’t want companies to have to repeat clinical trials, so we have established a scientific approach that both entities have
adopted in order to support global development,” Christl said. In practice, that may mean companies conduct a trial in what FDA calls the most sensitive population. But the definition of “most sensitive” may be left up to the company. For instance, several companies are in phase III clinical trials to compare biosimilars of rituximab with its patented reference product in rheumatoid arthritis patients. But if these products become licensed in the U.S., oncologists may not be comfortable prescribing them for lymphoma, Zelenetz said. Many oncologists may want to see direct comparator trials, Creekmore said. “And I would talk to colleagues about their experience with it, just to be a little cautious.” Zelenetz is on the biosafety monitoring board for a company developing a biosimilar, but he has no financial stake or stock in any company and is conducting no clinical trials on any of these products. © Oxford University Press 2015. DOI:10.1093/jnci/djv191 First published online July 3, 2015
Policymakers Work To Develop E-Cigarette Guidelines and Restrictions By Mike Fillon Are e-cigarettes different enough that they can’t be regulated like cigarettes? Are they less harmful than their tobacco counterparts? Are e-cigarettes a public nuisance? Do restrictions or bans compromise individual freedoms? Should e-cigarettes be taxed like cigarettes? The emergence of nicotine-laced e-cigarettes has caught everyone, including government regulators and policymakers, by surprise. National guidelines or regulations legislation has lagged, and the number of e-cigarette users has soared. At the federal level, the answers are nowhere near settled. “Meaningful action by the Food and Drug Administration is years away, if ever,” said Stanton A. Glantz, Ph.D. Glantz is professor of medicine in the division of cardiology, the American Legacy Foundation distinguished professor of tobacco control, and
director of the Center for Tobacco Control Research and Education at the University of California, San Francisco, school of medicine. As federal regulators struggle to formulate an overarching national policy, state and local governments are devising their own strategies. Some locales have sought to prevent the sale of e-cigarettes to minors, whereas others have taken drastic steps to either tax or limit where e-cigarettes can be used: • New Jersey treats e-cigarettes the same as tobacco cigarettes, and the same restrictions apply to both under the New Jersey Smoke-Free Air Act. • In July 2010, New Hampshire made selling e-cigarette to minors illegal. • In April 2014, New York City banned use of e-cigarettes in any place where smoking regular cigarettes is pro-
hibited, including bars, restaurants, offices, parks, and beaches. • Maryland banned sales to minors. Taking it even further, the California Department of Public Health (CDPH) released the State Health Officer’s Report on E-cigarettes: A Community Health Threat (http://www.cdph.ca.gov/Pages/NR1512.aspx). “This report was released to inform health care providers and the public about the health risks associated with e-cigarettes,” said CDPH spokesman Scott Sandow. “The report concludes that e-cigarettes should be strictly regulated and that restrictions on marketing to youth, access by youth, and poison prevention are critical areas where regulation is needed to protect children and teens from harm caused by e-cigarettes.” E-cigarettes are being marketed as healthier alternatives to cigarettes,
Downloaded from http://jnci.oxfordjournals.org/ at Florida International University on November 17, 2015
pharmacy and therapeutics committees can make automatic substitutions, a delay may occur before people see cost savings from biosimilars, according to Zelenetz. Even the definition of how similar a copy of a biological drug need be is not set. That’s the “million-dollar question,” said Leah Christl, Ph.D., FDA’s associate director for therapeutic biologics. “A sponsor can’t use a clinical study to compensate for a lack of analytical similarity.” Conversely, if a product doesn’t share a safety and toxicity profile with the originator drug, it doesn’t meet the biosimilar bar, and can’t claim to be a biosimilar, she said.
NEWS | 3 of 8
“I believe they’re a gateway to dual use. Plus, we have to keep in mind that it’s not just cigarettes that are harmful; so is nicotine. We can’t suddenly change course and say that nicotine and addiction to it is not so bad. Our risk of inaction is definitely going to be more harmful than any risk from action.” • Exposure to nicotine during adolescence can impair brain development. • E-cigarettes do not emit a harmless water vapor, but rather an aerosol that contains at least 10 chemicals appearing on California’s Proposition 65 list of agents that cause cancer, birth defects, or other reproductive harm. • The variety of fruit- and candy-flavored e-cigarettes entices small children, for whom ingesting even a fraction of e-liquid may be lethal. • E-cigarette cartridges can leak and do not have child-resistant caps, which can lead to poisoning through swallowing, skin or eye contact. • Between 2011 and 2013, e-cigarette advertising surged more than 1,200% and used marketing tactics to appeal to youth. Those tactics include using cartoon characters, a practice the
law prohibits in traditional cigarette advertising. • School and law enforcement officials have reported that e-cigarette devices have also been used to inhale illegal substances, such as marijuana and hash oil. Because many of these devices look like a ball-point pen, it is difficult to detect if inappropriate use of nicotine and illegal substances is occurring. Primack said that although he understands that the U.S. Food and Drug Administration must move cautiously, he believes bold steps to curtail e-cigarette use “needs to be taken sooner than later, since ads for nicotine-laced e-cigarettes are already appearing where cigarettes ads have been outlawed. And they’re having an effect.” Statistics support Primack’s contention. Studies show e-cigarette use increasing dramatically each year, especially among young adults and teens. In California, e-cigarette use among young adults, aged 18–29 years, increased from 2.3% in 2012 to 7.6% in 2013. California is not alone. In 2014, e-cigarette use among U.S. teens nationally exceeded that of cigarettes, with more than twice as many 8th and 10th graders reporting using e-cigarettes more than traditional cigarettes. Among 12th graders, 17% said they currently use e-cigarettes, compared with 14% using traditional cigarettes. Defenders of e-cigarettes say the statistics prove that the Brian A. Primack, M.D., devices are prePh.D. venting youngsters from getting “hooked” on tobacco products. Primack disagrees. “I believe they’re a gateway to dual use. Plus, we have to keep in mind that it’s not just cigarettes that are harmful; so is nicotine. We can’t suddenly change course and say that nicotine and addiction to it is not so bad. Our risk of inaction is definitely going to be more harmful than any risk from action.” © Oxford University Press 2015. DOI:10.1093/jnci/djv192 First published online July 3, 2015
news
used by e-cigarette companies,” Sandow said. The 14-week awareness-raising campaign includes TV, digital, and outdoor advertising. “The report that California prepared is carefully written and evidence-based,” Glantz said. “It is an excellent model for state and local action, which is where the e-cigarette problem is being addressed.” Here are a few highlights of the CDPH report:
Downloaded from http://jnci.oxfordjournals.org/ at Florida International University on November 17, 2015
much less offensive in public places and offering a means to quit conventional smoking. E-cigarette marketers reject the notion that they target children and that e-cigarettes can serve as a gateway to nicotine addiction and tobacco use. Brian A. Primack, M.D., Ph.D., vehemently disagrees with the companies selling the products. Primack is associate professor of medicine and pediatrics and director of the Center for Research on Media, Technology, and Health, and assistant vice chancellor for research on health and society at the University of Pittsburgh. “Do addicted smokers, who are trying desperately to get off cigarettes, really need mango-flavored e-cigarettes? Also, if they are not marketing to children and trying to hook them on nicotine, why do they sell them with flavors that appeal to children? I see flavored e-cigarettes as a starter cigarette to nicotine addiction.” Marketing of e-cigarettes works. In the March 11, 2015, edition of Health Communications, researchers from the Annenberg School for Communication at the University of Pennsylvania found that visual depictions of “vaping”— inhaling e-cigarette vapors to mimic smoking—in electronic cigarette advertisements “may serve as smoking cues to smokers and former smokers, increasing urge to smoke and smoking behavior, and decreasing self-efficacy, attitudes, and intentions to quit or abstain.” The study included 301 daily smokers, 272 intermittent smokers, and 311 former smokers randomly assigned to view e-cigarette commercials depicting people vaping (the cue condition), to view commercials not showing vaping (the no-cue condition), or to answer unrelated media-use questions (the no-ad condition). Participants then answered a questionnaire. The researchers said their data suggest that visual depictions of vaping in e-cigarette commercials increase daily smokers’ urge to smoke cigarettes and may lead to more smoking behavior. “For former smokers, these cues in advertising may undermine abstinence efforts,” they wrote. On March 23, 2015, CDPH launched an campaign to educate the public about the dangers of e-cigarettes. “The new ads help to expose the health risks, misinformation, and aggressive marketing tactics
news
Process Is Product Biosimilar products start with essentially the same genetic sequence. But they are produced in living cells, and the particulars of those production processes are guarded trade secrets. Because of the vagaries of biological systems, differences in cell culture systems can
influence the product. That’s why FDA pays as much attention to the manufacturing process as to the product. “It is a challenge to run a complex manufacturing process for biopharmaceuticals,” said Stephen P. Creekmore, M.D., Ph.D., chief of the Biological Resources Branch at the National Cancer Institute. “There is a risk to using these products, and the FDA is trying to minimize the risk to make sure the biosimilar is as close to the reference product as they can.” Even if a manufacturer can show that a product meets the FDA standard for biosimilarity, some oncologists may be concerned about extrapolation, Zelenetz said. FDA states that a biosimilar must show analytical comparability to the U.S. licensed reference product but might not require full clinical trials for all indications. “From an ethical standpoint—and the European Medicines Agency and the FDA share this—we don’t want companies to have to repeat clinical trials, so we have established a scientific approach that both entities have
adopted in order to support global development,” Christl said. In practice, that may mean companies conduct a trial in what FDA calls the most sensitive population. But the definition of “most sensitive” may be left up to the company. For instance, several companies are in phase III clinical trials to compare biosimilars of rituximab with its patented reference product in rheumatoid arthritis patients. But if these products become licensed in the U.S., oncologists may not be comfortable prescribing them for lymphoma, Zelenetz said. Many oncologists may want to see direct comparator trials, Creekmore said. “And I would talk to colleagues about their experience with it, just to be a little cautious.” Zelenetz is on the biosafety monitoring board for a company developing a biosimilar, but he has no financial stake or stock in any company and is conducting no clinical trials on any of these products. © Oxford University Press 2015. DOI:10.1093/jnci/djv191 First published online July 3, 2015
Policymakers Work To Develop E-Cigarette Guidelines and Restrictions By Mike Fillon Are e-cigarettes different enough that they can’t be regulated like cigarettes? Are they less harmful than their tobacco counterparts? Are e-cigarettes a public nuisance? Do restrictions or bans compromise individual freedoms? Should e-cigarettes be taxed like cigarettes? The emergence of nicotine-laced e-cigarettes has caught everyone, including government regulators and policymakers, by surprise. National guidelines or regulations legislation has lagged, and the number of e-cigarette users has soared. At the federal level, the answers are nowhere near settled. “Meaningful action by the Food and Drug Administration is years away, if ever,” said Stanton A. Glantz, Ph.D. Glantz is professor of medicine in the division of cardiology, the American Legacy Foundation distinguished professor of tobacco control, and
director of the Center for Tobacco Control Research and Education at the University of California, San Francisco, school of medicine. As federal regulators struggle to formulate an overarching national policy, state and local governments are devising their own strategies. Some locales have sought to prevent the sale of e-cigarettes to minors, whereas others have taken drastic steps to either tax or limit where e-cigarettes can be used: • New Jersey treats e-cigarettes the same as tobacco cigarettes, and the same restrictions apply to both under the New Jersey Smoke-Free Air Act. • In July 2010, New Hampshire made selling e-cigarette to minors illegal. • In April 2014, New York City banned use of e-cigarettes in any place where smoking regular cigarettes is pro-
hibited, including bars, restaurants, offices, parks, and beaches. • Maryland banned sales to minors. Taking it even further, the California Department of Public Health (CDPH) released the State Health Officer’s Report on E-cigarettes: A Community Health Threat (http://www.cdph.ca.gov/Pages/NR1512.aspx). “This report was released to inform health care providers and the public about the health risks associated with e-cigarettes,” said CDPH spokesman Scott Sandow. “The report concludes that e-cigarettes should be strictly regulated and that restrictions on marketing to youth, access by youth, and poison prevention are critical areas where regulation is needed to protect children and teens from harm caused by e-cigarettes.” E-cigarettes are being marketed as healthier alternatives to cigarettes,
Downloaded from http://jnci.oxfordjournals.org/ at Florida International University on November 17, 2015
pharmacy and therapeutics committees can make automatic substitutions, a delay may occur before people see cost savings from biosimilars, according to Zelenetz. Even the definition of how similar a copy of a biological drug need be is not set. That’s the “million-dollar question,” said Leah Christl, Ph.D., FDA’s associate director for therapeutic biologics. “A sponsor can’t use a clinical study to compensate for a lack of analytical similarity.” Conversely, if a product doesn’t share a safety and toxicity profile with the originator drug, it doesn’t meet the biosimilar bar, and can’t claim to be a biosimilar, she said.
NEWS | 3 of 8
“I believe they’re a gateway to dual use. Plus, we have to keep in mind that it’s not just cigarettes that are harmful; so is nicotine. We can’t suddenly change course and say that nicotine and addiction to it is not so bad. Our risk of inaction is definitely going to be more harmful than any risk from action.” • Exposure to nicotine during adolescence can impair brain development. • E-cigarettes do not emit a harmless water vapor, but rather an aerosol that contains at least 10 chemicals appearing on California’s Proposition 65 list of agents that cause cancer, birth defects, or other reproductive harm. • The variety of fruit- and candy-flavored e-cigarettes entices small children, for whom ingesting even a fraction of e-liquid may be lethal. • E-cigarette cartridges can leak and do not have child-resistant caps, which can lead to poisoning through swallowing, skin or eye contact. • Between 2011 and 2013, e-cigarette advertising surged more than 1,200% and used marketing tactics to appeal to youth. Those tactics include using cartoon characters, a practice the
law prohibits in traditional cigarette advertising. • School and law enforcement officials have reported that e-cigarette devices have also been used to inhale illegal substances, such as marijuana and hash oil. Because many of these devices look like a ball-point pen, it is difficult to detect if inappropriate use of nicotine and illegal substances is occurring. Primack said that although he understands that the U.S. Food and Drug Administration must move cautiously, he believes bold steps to curtail e-cigarette use “needs to be taken sooner than later, since ads for nicotine-laced e-cigarettes are already appearing where cigarettes ads have been outlawed. And they’re having an effect.” Statistics support Primack’s contention. Studies show e-cigarette use increasing dramatically each year, especially among young adults and teens. In California, e-cigarette use among young adults, aged 18–29 years, increased from 2.3% in 2012 to 7.6% in 2013. California is not alone. In 2014, e-cigarette use among U.S. teens nationally exceeded that of cigarettes, with more than twice as many 8th and 10th graders reporting using e-cigarettes more than traditional cigarettes. Among 12th graders, 17% said they currently use e-cigarettes, compared with 14% using traditional cigarettes. Defenders of e-cigarettes say the statistics prove that the Brian A. Primack, M.D., devices are prePh.D. venting youngsters from getting “hooked” on tobacco products. Primack disagrees. “I believe they’re a gateway to dual use. Plus, we have to keep in mind that it’s not just cigarettes that are harmful; so is nicotine. We can’t suddenly change course and say that nicotine and addiction to it is not so bad. Our risk of inaction is definitely going to be more harmful than any risk from action.” © Oxford University Press 2015. DOI:10.1093/jnci/djv192 First published online July 3, 2015
news
used by e-cigarette companies,” Sandow said. The 14-week awareness-raising campaign includes TV, digital, and outdoor advertising. “The report that California prepared is carefully written and evidence-based,” Glantz said. “It is an excellent model for state and local action, which is where the e-cigarette problem is being addressed.” Here are a few highlights of the CDPH report:
Downloaded from http://jnci.oxfordjournals.org/ at Florida International University on November 17, 2015
much less offensive in public places and offering a means to quit conventional smoking. E-cigarette marketers reject the notion that they target children and that e-cigarettes can serve as a gateway to nicotine addiction and tobacco use. Brian A. Primack, M.D., Ph.D., vehemently disagrees with the companies selling the products. Primack is associate professor of medicine and pediatrics and director of the Center for Research on Media, Technology, and Health, and assistant vice chancellor for research on health and society at the University of Pittsburgh. “Do addicted smokers, who are trying desperately to get off cigarettes, really need mango-flavored e-cigarettes? Also, if they are not marketing to children and trying to hook them on nicotine, why do they sell them with flavors that appeal to children? I see flavored e-cigarettes as a starter cigarette to nicotine addiction.” Marketing of e-cigarettes works. In the March 11, 2015, edition of Health Communications, researchers from the Annenberg School for Communication at the University of Pennsylvania found that visual depictions of “vaping”— inhaling e-cigarette vapors to mimic smoking—in electronic cigarette advertisements “may serve as smoking cues to smokers and former smokers, increasing urge to smoke and smoking behavior, and decreasing self-efficacy, attitudes, and intentions to quit or abstain.” The study included 301 daily smokers, 272 intermittent smokers, and 311 former smokers randomly assigned to view e-cigarette commercials depicting people vaping (the cue condition), to view commercials not showing vaping (the no-cue condition), or to answer unrelated media-use questions (the no-ad condition). Participants then answered a questionnaire. The researchers said their data suggest that visual depictions of vaping in e-cigarette commercials increase daily smokers’ urge to smoke cigarettes and may lead to more smoking behavior. “For former smokers, these cues in advertising may undermine abstinence efforts,” they wrote. On March 23, 2015, CDPH launched an campaign to educate the public about the dangers of e-cigarettes. “The new ads help to expose the health risks, misinformation, and aggressive marketing tactics
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