All posts by CPTFeditor

Does abortion cause breast cancer?

Breast Cancer, Medical Treatments with Cancer Risks

No. Although there has been a great deal of controversy on this topic, scientists have agreed that abortion does not cause breast cancer.

The world’s leading experts, including epidemiologists, clinical researchers, and basic scientists, have discussed the scientific data on reproductive events in a woman’s life that could affect her risk of developing breast cancer. They evaluated the research that has been done on this topic and concluded that abortion and miscarriage do not increase a woman’s risk of breast cancer.

Breast cancer is related to reproductive experiences such as age of puberty and age of motherhood, and for years anti-abortion activists have cited research showing a link between abortion and breast cancer. That research has been quoted by some politicians as evidence that should be provided to women to discourage abortions. A workshop was held in 2003 (during the Bush Administration) at the National Cancer Institute (NCI) as a result of this controversy, and despite political pressures it concluded that the research linking breast cancer and abortion is flawed and not as credible as research indicating that there is no link between breast cancer and either abortion or miscarriage.

A medical journal article published in 20151 evaluated 15 studies on this issue, which included 31,816 women with breast cancer from seven studies in the U.S., seven studies in Europe, and one in China, conducted between 1986 and 2013. The scientists only evaluated studies which used the most reliable research design (what is known as a “prospective study”) and concluded that the evidence does not show a link between cancer and abortion.

The fact that abortion does not increase the risk of breast cancer is also supported by, among others, the World Health Organization (WHO), the National Cancer Institute and the American Cancer Society, as well as many women’s health advocacy organizations, including the National Breast Cancer Coalition, the National Women’s Health Network and Our Bodies Ourselves.

For more information on the NCI workshop and early reproductive events and breast cancer, please see: http://cancer.gov/cancerinfo/ere.

 

Congress is up to something and only you can stop them

news-you-can-use
January 23 Update

After this blog was written, Sen. Orrin Hatch (R-UT) introduced S. 160, which would repeal the tax described below. No need to look at the facts – just bow to special interests while trying to kill Obamacare! To see which 5 Democrats and 23 other Republicans who support a bill that would help destroy Obamacare, scroll below this blog. And make sure they hear from you!

Congress is Up to Something | The Huffington Post

by guest blogger Diana Zuckerman, PhD, National Center for Health Research

If you think health insurance should be affordable and you didn’t get a 65 percent raise over the last two years, keep reading!

Congress is up to something, and only you can prevent it from happening. Even though the upcoming Supreme Court decision about the Affordable Care Act could drastically curtail it, that may not be the greatest threat to the millions of Americans who don’t want to lose their health insurance.

A greater threat comes from certain U.S. companies and from hundreds of members of Congress, and the culprits might surprise you.
The senators and representatives you need to worry about include some of the most conservative Republicans, but also some Democrats that are usually strong supporters of patients and consumers–including Elizabeth Warren, Chuck Schumer, and Barbara Mikulski.

And they’re bowing to pressure from companies that advertise on NPR, your favorite TV shows, and other media, touting how they save lives every day. In truth, these companies do save lives. But they also make billions of dollars and don’t feel like giving any of it to help pay for the Affordable Care Act, as the legislation requires. And that could be fatal to countless Americans.

This is what happened: The three industries that would benefit from millions more insured Americans were asked to make small financial compromises to help pay the cost of subsidies that would make health insurance affordable to millions more Americans. The compromises included lowering certain prices, limiting profits, or paying a small excise tax on products sold.

Two of the industries kept their agreements, but the third immediately tried to repeal the part of the law that affected it.

No, it’s not Big Pharma that is the problem. Those companies understand how the Affordable Care Act helps their bottom line and their patients.

It’s not the insurance companies, either. They fought the Affordable Care Act but eventually agreed to the terms that have helped keep prices under control. They haven’t reneged, and they even lined up in greater numbers to sell policies at lower costs through the state exchanges this year.

The problem includes companies that make lifesaving heart valves and stents, hip and knee replacements, PT scanners and mammography machines, and the contact lenses that millions of us rely on.

The medical device companies selling these and other products spent more than $150 million to try to repeal a 2.3 percent tax on the devices they sell in the U.S. These include implants that cost $20 to make but that sell for $500, as well as devices that sell for half a million dollars but are as obsolete as your iPhone 2 after a few years.

They’re complaining to Congress that the tax is killing jobs and cutting funds for the research and development needed to create the innovative products that patients deserve. If they get their way and the tax is repealed, there will be $29 billion less to pay for health insurance over the next decade, and we can expect Pharma and the insurance companies to try to get out of their contributions, as well.

I’m a scientist, so I decided to examine the evidence for the “job killing” and other claims made by the device companies.

First we looked at stock prices–all publicly available online. Not all device companies have publicly traded stock, but the ones complaining the loudest about the device tax do. We looked at the 12 largest U.S.-based companies that sell nothing but devices (not ones that also sell pharmaceuticals or appliances). In the two years since the tax started, their stock went up a whopping 65 percent on average–much more than the NY Stock Exchange (25 percent) or the largest U.S.-based pharmaceutical companies (54 percent).

Then we looked at sales. Sales steadily increased over the last decade, including after the device tax was implemented. So, there would seem to be no reason to cut jobs and every reason to hire more workers.

What about R & D costs to develop new products and possibly hire new workers? Again, a steady increase over the decade, and after the tax went into effect.
What about profit margins? These were stable over the decade for most companies, despite the 2008 economic meltdown and despite the device tax. Again, no reason to cut jobs or raise a ruckus about the tax.

And yet, the House of Representatives has passed several bills that include repealing the tax, and the Senate passed a bipartisan resolution declaring its opposition to the tax. Fortunately, the resolution specified support for repeal only if another source is designated to make up for the $29 billion in revenues that the tax would provide.

Finding another $29 billion seems unlikely, yet congressional leaders keep saying there is overwhelming support to repeal the tax, and journalists repeatedly report that “widespread bipartisan opposition” to the tax will inevitably result in a repeal.

If that happens, the dominoes start to fall and the Affordable Care Act would become unaffordable.

Don’t let that happen. Here’s more information and the Senate voting record on repealing the tax. Let your voice be heard.

Diana Zuckerman is the president of the National Center for Health Research. She received her PhD from Ohio State University and was a post-doctoral fellow in epidemiology and public health at Yale Medical School. After serving on the faculty of Vassar and Yale and as a researcher at Harvard, Dr. Zuckerman spent a dozen years as a health policy expert in the U.S. Congress and a senior policy adviser in the Clinton White House. She is the author of five books, several book chapters, and dozens of articles in medical and academic journals, newspapers, and websites.

Around the same time this blog went online, 29 Senators co-sponsored a new bill to repeal the medical device excise tax: 5 Democrats and 23 Republicans. Contact the senators who haven’t co-sponsored S. 149, to urge them to reject this bill.
And if any of your senators have signed on, let them know how you feel:
S.149: Medical Device Access and Innovation Protection Act
Sponsor: Sen Hatch, Orrin G. [UT] (introduced 1/13/2015) Cosponsors (28)
Related Bills: H.R.160
Latest Major Action: 1/13/2015 Referred to Senate committee. Status: Read twice and referred to the Committee on Finance.
________________________________________
COSPONSORS(28), ALPHABETICAL:
Sen Alexander, Lamar [TN] – 1/13/2015
Sen Ayotte, Kelly [NH] – 1/13/2015
Sen Barrasso, John [WY] – 1/20/2015
Sen Blunt, Roy [MO] – 1/21/2015
Sen Burr, Richard [NC] – 1/13/2015
Sen Capito, Shelley Moore [WV] – 1/21/2015
Sen Casey, Robert P., Jr. [PA] – 1/13/2015
Sen Cassidy, Bill [LA] – 1/13/2015
Sen Coats, Daniel [IN] – 1/13/2015
Sen Collins, Susan M. [ME] – 1/20/2015
Sen Crapo, Mike [ID] – 1/20/2015
Sen Donnelly, Joe [IN] – 1/13/2015
Sen Flake, Jeff [AZ] – 1/22/2015
Sen Franken, Al [MN] – 1/13/2015
Sen Gardner, Cory [CO] – 1/20/2015
Sen Inhofe, James M. [OK] – 1/20/2015
Sen Isakson, Johnny [GA] – 1/13/2015
Sen Kirk, Mark Steven [IL] – 1/20/2015
Sen Klobuchar, Amy [MN] – 1/13/2015
Sen Lankford, James [OK] – 1/21/2015
Sen Moran, Jerry [KS] – 1/20/2015
Sen Murkowski, Lisa [AK] – 1/13/2015
Sen Portman, Rob [OH] – 1/13/2015
Sen Roberts, Pat [KS] – 1/20/2015
Sen Scott, Tim [SC] – 1/13/2015
Sen Shaheen, Jeanne [NH] – 1/13/2015
Sen Toomey, Pat [PA] – 1/13/2015
Sen Wicker, Roger F. [MS] – 1/13/2015

Mastectomy v. Lumpectomy: Who Decides?

Breast Cancer
Diana Zuckerman, PhD, Cancer Prevention and Treatment Fund

Approximately 230,000 women in the U.S. will be diagnosed with breast cancer this year. Over the last two decades, research has regularly provided new evidence that breast cancer patients can live just as long – or even longer – with less radical treatment.

In the 1990s, research indicated that for most early-stage breast cancer (stage 0, 1, 2, or 3a), lumpectomy was just as safe as mastectomy, if the lumpectomy was followed by radiation treatment.1,2,3  At a 1990 Conference sponsored by the National Institutes of Health, experts agreed that since survival rates were the same, lumpectomy followed by radiation is the preferable treatment for most women with early-stage breast cancer.4   However, by 2013, a study indicated that lumpectomy patients live longer than mastectomy patients5 and in 2021, an enormous study that followed almost 49,000 breast cancer patients for a median of 6 years confirmed that women undergoing lumpectomy with radiation were less likely to die of breast cancer or any other cause than women undergoing mastectomy, whether or not they underwent radiation.6 The benefit of lumpectomy was maintained regardless of tumor characteristics, treatment, demographics, other health issues, and socioeconomic background.  And in 2023, a study was published indicating that for women over 65, women who choose lumpectomy lived just as long whether or not they had radiation.7

Half of the U.S. women that are eligible for lumpectomy, however, will undergo mastectomy instead. Why remove the entire breast in a mastectomy if it is safer to just remove the cancer and a “margin” of tissue around it?  Why are so many women undergoing medically unnecessary mastectomies? We’ve known since 2013 that lumpectomy is preferable because women live even longer than mastectomy patients with the same diagnosis. Could it be that many women eligible for breast-conserving surgery are getting mastectomies because they do not understand that lumpectomies are a safer option?

More Mastectomies Related to Poverty, Doctors’ Preferences, Women’s Fear

One reason is economic — surprisingly, it is less expensive to perform a mastectomy than a lumpectomy. In addition to a more time-consuming surgery, radiation adds to the cost of lumpectomy but is rarely required for mastectomy. Moreover, some insurance plans do not cover all the expenses of the lumpectomy or the radiation therapy, because they are usually outpatient procedures. According to a study of one large urban hospital in Texas serving mostly indigent women, 84% of the women with early-stage breast cancer had mastectomies and only 16% had lumpectomies.8 Similarly, a study of 20,000 breast cancer patients in North Carolina reported lower lumpectomy rates among patients who did not have private insurance.9 In some hospitals, all breast cancer patients have mastectomies, regardless of their diagnosis. Now that research shows that radiation is not necessary for many older lumpectomy patients, that should make lumpectomies more affordable, convenient, and desirable for many women.

For years, older doctors were more likely to recommend mastectomies, since that used to be the standard treatment for breast cancer at any stage. A study of 157 hospitals in North Carolina found that patients were more likely to undergo breast-conserving surgery if their surgeons were trained after 1981.10 One logical explanation is that doctors trained after 1981 were trained to do lumpectomies and are more knowledgeable about the research showing the safety of lumpectomy.  Researchers also believe that physician knowledge and attitudes are a likely explanation for the dramatic regional differences they have documented in breast-conserving surgery.

Another factor is fear. Some women are very afraid of recurrence and choose mastectomy because the chances of recurrence in the same breast are reduced when the breast is removed, even though that does not affect how long women will live. Some women are afraid of radiation therapy, which can cause fatigue or cosmetic side effects such as skin irritation or more permanent dimpling. Very infrequently radiation therapy can cause long-lasting problems. And, there is the issue of access to radiation. In rural areas, patients sometimes must travel hundreds of miles five days each week for 5-8 weeks to get radiation treatment after lumpectomy.  As noted earlier, now that research shows that many older lumpectomy patients do not need radiation, that could reduce the number of unnecessary mastectomies.

Breast cancer is still relatively rare among women in their 20’s and 30’s, but there is some evidence that women diagnosed with breast cancer at an early age tend to have more aggressive cancers. Survival rates are lower.11,12,13 This does not mean, however, that young women always need mastectomies, and each patient should receive the medical treatment that is best for her, based on her own diagnosis and preferences.

Surgical Treatment Disparities for Early-Stage Breast Cancer

These are a few examples of the studies of thousands of patients, published in major medical journals, which indicate that:

  • Mastectomies are especially likely to be unnecessary for most non-invasive breast cancers, such as ductal carcinoma in situ, yet many women with those cancers undergo mastectomies.14,15,
  • Breast-conserving surgery with radiation is somewhat more expensive than mastectomy in the short run, but breast-conserving therapy is less expensive than mastectomy after 5 years.16 Breast-conserving therapy is much less expensive than mastectomy with reconstruction.17
  • Low-income women and those who are less educated are less likely to have breast-conserving surgery. Patients without private insurance are also less likely to have breast-conserving surgery.18

References:

  1. Fisher B, Anderson S, Redmond CK, Wolmark N, Wickerham DL, Cronin WM. Reanalysis and Results After 12 Years of Follow-up in a Randomized Clinical Trial Composing Total Mastectomy With Lumpectomy With or Without Irradiation in the Treatment of Breast Cancer. N Engl J Med 1995 Nov 30;333(22):1456-61.
  2. Gangi, A et al.Breast-Conserving Therapy for Triple-Negative Breast Cancer. JAMA Surg. 2014;149(3):252-258.
  3. Agarwal, S et al.  Effect of Breast Conservation Therapy vs Mastectomy on Disease-Specific Survival for Early-Stage Breast Cancer. JAMA Surg. 2014;149(3):267-274.
  4. Abrams JS, Phillips PH, Friedman MA. Commentary: Meeting Highlights: a Reappraisal of Research Results for the Local Treatment of Early Stage Breast Cancer. J Nat’l Cancer Institute, 1995 Vol. 87. No. 24, Dec 20.
  5. Hwang ES, et al “Survival after lumpectomy and mastectomy for early stage invasive breast cancer: The effect of age and hormone receptor status” Cancer 2013 April 1; 119(7); DOI: 10.1002/cncr.27795.
  6. de Boniface J, Szulkin R, Johansson ALV. Survival After Breast Conservation vs Mastectomy Adjusted for Comorbidity and Socioeconomic Status: A Swedish National 6-Year Follow-up of 48 986 Women. JAMA Surg. Published online May 05, 2021. doi:10.1001/jamasurg.2021.1438.
  7. Kunkler, I. H., Williams, L. J., Jack, W. J. L., Cameron, D. A., & Dixon, J. M. (2023). Breast-conserving surgery with or without irradiation in early breast cancer. New England Journal of Medicine, 388(7), 585–594. https://doi.org/10.1056/nejmoa2207586
  8. Dolan JT, Granchi TS. Low Rate of Breast Conservation Surgery in Large Urban Hospital Serving the Medically Indigent. Am J Surgery 1998 Dec;176(6):520-4.
  9. Kotwall CA, Covington DI, Rutledge R, Churchill MP, Meyer AA. Patient, Hospital, and Surgeon Factors Associated with Breast Conservation Surgery. A Statewide Analysis in North Carolina. Ann Surg 1996 Oct;224(4):419-26.
  10. Kotwall, CA, Covington D, Churchill P, Brinker C, Weintritt D, Maxwell JG. Breast Conservation Surgery for Breast Cancer at a Regional Medical Center. Am J Surg 1998 Dec;176(6):510-4.
  11. Xiong Q, Valero V, Kau V, Kau SW, Taylor S, Smith TL, Buzdar AU, Hortobagyi GN, Theriault RL. Female Patients with Breast Carcinoma age 30 Years and Younger Have a Poor Prognosis: the M.D. Anderson Cancer Center Experience. Cancer 2001 Nov 15;92(10):2523-8.
  12. Carey K. Anders et al., “Breast Carcinomas Arising at a Young Age: Unique Biology or a Surrogate for Aggressive Intrinsic Subtypes?,” Journal of Clinical Oncology 29, no. 1 (2011): e18-e20.
  13. Carey K. Anders et al., “Young Age at Diagnosis Correlates With Worse Prognosis and Defines a Subset of Breast Cancers With Shared Patterns of Gene Expression,” Journal of Clinical Oncology 26, no. 10 (2008): 3324-3330.
  14. Katz SJ, Lantz PM, Zemencuk JK. Correlates of Surgical Treatment Type for Women with Noninvasive and Invasive Breast Cancer. J Womens Health Gend Based Med 2001 Sep;10(7):659-70.
  15. Gomez SL, et al. Increasing mastectomy rates for early-stage breast cancer? Population-based trends from California.  J Clin Oncol. 2010 Apr 1;28(10):e155-7.
  16. Barlow WE, Taplin SH, Yoshida CK, et al. Cost Comparison of Mastectomy versus Breast-conserving Therapy for Early-stage Breast Cancer. J Natl Cancer Inst 2001 Mar 21;93(6):447-55.
  17. Desch CE, Penberthy LT, Hillner BE, et al. A Sociodemographic and Economic Comparison of Breast Reconstruction, Mastectomy, and Conservative Surgery. Surgery 1999 Apr;125(4):441-7.
  18. Roetzheim RG, Gonzalez EC, Ferrante JM, et al. Effects of Health Insurance and Race on Breast Carcinoma Treatments and Outcomes. Cancer 2000 Dec 1;89(11):2202-13

Are Bisphenol A (BPA) plastic products safe for infants and children?

Environmental Exposures, Prevention
By Diana Zuckerman, PhD, Paul Brown, Laura Walls, and Anna E. Mazzucco, PhD

Bisphenol A (BPA) is a chemical used to make plastics. It is widely used in sports equipment, water bottles, medical devices, and as a coating in food and beverage cans. The Centers for Disease Control and Prevention found measurable amounts of BPA in the bodies of more than 90 percent of the U.S. population studied.2 The highest estimated daily intakes of BPA occur in infants and children.3

BPA is more likely to leach out of plastic when its temperature is increased, as when one warms up food in the microwave or warms up a baby bottle.2  In 2012, the Food and Drug Administration (FDA) banned the use of BPA in baby bottles—after several large manufacturers had already voluntarily removed it. Before the ban, most plastic baby bottles contained BPA.

How BPA affects our bodies

BPA mimics and interferes with the action of estrogen–a hormone that helps us develop when we’re young and eventually reproduce.4   BPA has been widely detected in blood, urine, amniotic fluid and breast milk, and has been found in nearly all adults and children who have been tested 5  For that reason, scientists are concerned about BPA’s  effects on fetuses, infants, and children at current exposure levels, and whether it can affect the prostate, brain, testicles, breasts, and behavior.2   Studies suggest that the more a baby is exposed to estrogen while in the womb, the greater the risk of breast, testicular and prostate cancer later in life.6,7,8

BPA’s effects on Animals and Human Cells

A study published in October 2008 also found that cancer cells exposed to low levels of BPA were more resistant to chemotherapy.9  Studies have also linked the hormonal effects of BPA from canned cat food to the epidemic of hyperthyroidism in cats, especially females.10 After studies of rats and mice linked BPA to hyperactivity and brain activity, the first study of nonhuman primates found that BPA levels were associated with cognitive problems that could affect learning and memory.11  BPA experiments on rats linked the chemical to precancerous lesions in the prostate and mammary glands, and to early puberty in females at BPA dosages similar to human exposures, according to a 2008 report on BPA by the National Institutes of Health’s National Toxicology Program.2 A 2014 study that  used mice to model prostate cancer in humans showed that a baby’s BPA exposure in the womb may increase risk of prostate cancer later in life 12  Another similar study in mice is creating concern about liver cancer risks as well.13  While early concerns were based primarily on animal studies and research on cells, there is increasing evidence from human studies that BPA causes serious harm. For instance, researchers have discovered possible links between BPA exposure and insulin resistance (a risk factor for Type II diabetes), increased formation and growth of fat cells (which can lead to obesity), and reproductive health problems for both men and women.4

The evidence so far is based on links scientists have observed between high levels in the body and health problems. Studies in which some people are intentionally exposed to BPA and others aren’t (randomized, controlled trials) have never been done because it could be dangerous and therefore is unethical.

Health Effects in Girls and Women

There is concern about the impact of BPA on early puberty in girls. Studies have also linked BPA to frequent miscarriages.4

In addition, several studies have found a connection between high levels of BPA and decreased fertility in women, including less success with in vitro fertilization treatments.14

Health Effects in Boys and Men

A 2009 research article reported that men who were exposed to very high levels of BPA at work had less sexual desire and were four times as likely to have problems getting and maintaining an erection than men who did not work with BPA.15 BPA-exposed workers were also seven times as likely to have problems with ejaculation. Although the men in this study had much higher levels of BPA exposure than the average man, this study demonstrates that BPA can harm men’s sexual health and that workers need to be protected. Research is needed to study the effects of more typical BPA exposures on men’s sexual health.  Unfortunately, several other studies have also linked high BPA levels to poorer sperm quality in men as well.16

Earlier Responses to BPA Concerns

The National Toxicology Program 2008 report recommended that more studies be conducted on BPA’s health effects on humans, and the report stated: “The possibility that bisphenol A may alter human development cannot be dismissed.”2

Also in 2008, based primarily on two chemical industry-funded studies, the Food and Drug Administration (FDA) claimed that BPA is safe.3 However, according to a publication of the American Chemical Society, the national professional association for chemists, 153 government-funded BPA experiments on lab animals and tissues found adverse effects while only 14 did not.1

After the 2008 National Toxicology report and FDA report, new studies of humans added greatly to concerns about the health risks of BPA.

In the fall of 2008, a major study was published in the Journal of the American Medical Association indicating that adults with higher levels of BPA in their bodies were more likely to be diagnosed with diabetes or heart disease.17 Adults with higher BPA were also more likely to be obese, but diabetes and heart disease were correlated with BPA levels even when obesity was statistically controlled.

Is it possible that BPA is contributing to the obesity epidemic and diabetes epidemic among children and adults? Wouldn’t it be ironic if the most popular water bottles for athletes contributed to obesity and diabetes?

Even before these more recent studies, the FDA Science Board, which consists of independent scientists who do not work for the FDA, disagreed with the FDA’s safety claims. The Science Board recommended in October 2008 that the FDA analyze the research literature again, relying less on the two industry-funded studies and taking into account the best independent studies. It also recommended that new research be conducted to examine BPA safety concerns. Government funding for that research was announced in late 2009.

What has actually been done to limit the potentially harmful effects of BPA?

In July 2013, the FDA responded to a petition from Representative Markey and comments from consumer groups by banning the use of BPA in packaging for infant formula, following on their 2012 ban of BPA from baby bottles.  But further action from FDA to eliminate BPA from cans and other food containers still has not happened.  Prior to the FDA ban, bills had been introduced in several states, cities, and in the U.S. Senate and House of Representatives (S. 593/H.R. 1523) to ban BPA in children’s products. Suffolk County in New York became the first in the U.S. to ban BPA in baby bottles and sippy cups, in March, 2009.   In March 2009, the six major manufacturers of baby bottles in the United States announced that they would no longer sell baby bottles made with BPA in the U.S.18 A few days later, SUNOCO, a BPA manufacturer, announced that it would require customers to confirm that no BPA would be used in food or water containers for children under 3 years of age.19  In 2008, manufacturers such as Playtex and Nalgene and retailers such as Wal-Mart pledged to remove BPA from their products and stores by the end of the year.20

Despite these efforts, BPA still remains in many canned food and beverages sold to people and pets in the U.S. and other countries.  But at least two producers of canned foods in the U.S. have BPA-free cans: Eden Foods began using BPA-free cans in 1999 and now uses BFA-free cans for everything except highly acidic tomato products, and Vital Choice introduced new cans and pouches for its fish products at the end of 2008.21,22  According to Eden, it costs the company $300,000 more a year to produce BPA-free cans, which are 14% more expensive than industry standard cans; this translates into about 2 cents more per can.23  In 2012, Campbell’s also announced that it would phase out BPA from its canned foods, although this has not yet happened.

What you can do to lower your family’s exposure to BPA

While we wait for more research to be conducted, you may want to avoid BPA. Is that possible? A 2011 study from the Silent Spring Institute showed that you can lower your BPA levels significantly by avoiding pre-packaged food and keeping your food from coming into contact with plastic containers, plastic utensils, and non-stick pans during preparation, eating and storage.24

BPA is found in polycarbonate (PC) plastics, which are typically clear and hard, marked with the recycle symbol “7″ or may contain the letters “PC” near the recycle symbol.

To avoid warming up food in plastic containers with these or other chemicals, use stoneware, china, or glass dishes and containers in your microwave. In 2012, the FDA banned BPA in baby bottles and children’s drinking cups, after several large manufacturers had already voluntarily removed it. However, bottles from before 2012 may still contain BPA.  Another problem is that manufacturers are replacing BPA in plastic bottles with other chemicals that experts believe have many of the same effects as BPA but that we know even less about. For that reason, parents may want to include safer alternatives such as glass baby bottles, particularly for use at home.

Testimony of Dr. Anna Mazzucco before the EPA Scientific Advisory Panel

Testimony & Briefings
December 3, 2014
Dr. Anna E. Mazzucco

Thank you for the opportunity to participate in this meeting.  My name is Dr. Anna Mazzucco, and I am speaking on behalf of the Cancer Prevention and Treatment Fund.  I received my Ph.D. in cell biology from Harvard Medical School, and I conducted post-doctoral research at the National Cancer Institute.  Those are the perspectives I speak from today.

Our organization conducts research and shares information with health professionals, patients, and consumers.

We applaud the efforts of the EPA to protect the public from harmful chemicals in their food, water, air and products they use every day.  We strongly support the agency’s efforts to test chemicals more efficiently, and with the best possible scientific methods.  Research has implicated endocrine-disrupting chemicals in cancer, infertility, and other health problems.  We must be able to quickly identify such agents in order to prevent them from entering our food and environment, and from affecting our health for generations to come.

Use of high-throughput technologies is critical to expediting chemical screening, and we support the agency in these efforts.  However, we have several concerns regarding the high-throughput screening approach as described in the EPA White Paper.  Specifically,

  • The EPA needs to spell out more clearly how prioritizing will be decided using this screening approach. The program should explicitly prioritize compounds based on risk contexts, such as those with widespread and persistent exposure profiles, and those with the most serious potential health effects.
  • We know that chemical exposures during sensitive periods such as prenatal and adolescent development can greatly impact health in adulthood. These critical windows should be prioritized in bio-monitoring and population-based studies.  This approach would protect the most vulnerable among us, and also ensure the greatest public health benefits for everyone.
  • Other stakeholders have expressed concern over lack of clarity regarding the relationship between the area-under-the-curve model and potency as indicated by traditional assays. We are also concerned that the model has not been tested on a sufficiently diverse set of chemical structures.  The agency needs to address these issues and provide additional evidence to support use of the current methodology, as opposed to other possible models.
  • These screening assays must be relevant to real world exposures in order to be meaningful. Broad bio-monitoring and exposure studies are vital to informing extrapolation modeling in order to reap the benefits offered by high-throughput screening.
  • As these high-throughput assays are further developed, the most orthogonal assays with the most downstream read-outs possible should be used, in order to capture the broadest possible range of mechanisms-of-actions.
  • We agree with the EPA that metabolites could be missed using in vitro studies alone, and therefore some in vivo studies will be needed.
  • We strongly urge the EPA to make the computational model fully accessible for independent assessment. That would increase transparency and stakeholder participation in this project.

 

Lastly, we share the concerns expressed in the Inspector General’s 2011 report that this process has not progressed as quickly as it should have.  We strongly urge that adequate resources be dedicated to these efforts, in order that the agency may meet its goals in a timely fashion.

Thank you for the opportunity to address the panel today.

Morcellation devices: a surgical tool that can spread cancer? What you need to know

In the News, Medical Treatments with Cancer Risks, Other Cancers
By Anna E. Mazzucco, Ph.D.
2014

If you have uterine fibroids and are considering treatment or if you’ve heard about uterine morcellation in the news, this article will help you understand the issue.

What are power morcellation devices?

A power morcellation device is a small surgical tool which cut tissue into smaller pieces.  This allows organs or other tissues to be removed through smaller incisions, making surgery shorter and leaving smaller scars behind.  The front end of a power morcellator has a spinning blade that cuts the tissue into tiny pieces (pulverizes it), and the back end is connected to a tube which sucks the tissue through the device (see image below).

morcellator

Power morcellation devices were originally designed for removal of the uterus (or the womb), but are currently used for many different types of surgical procedures because they make it easier for a physician to perform surgery using smaller incisions.

What is the controversy about morcellation devices?

In 2012, two Harvard doctors had their lives tragically affected by these devices.  Dr. Amy Reed, an anesthesiologist at Beth Israel Deaconess Medical Center, which is affiliated with Harvard Medical School, had surgery in the fall of 2013 to remove her uterus due to fibroids.  After the surgery she was diagnosed with advanced (stage IV) uterine cancer, spread by the use of power morcellation during her surgery.  The morcellation left behind tiny pieces of tumor throughout her pelvic cavity, which allowed the cancer to spread.  While morcellation devices are sometimes used with a bag to contain the fibroid or tissue so that it won’t spread, the bags can be difficult to use so not all surgeons use them.   Dr. Reed was never told that morcellation would be performed during her surgery, or about the potential risks.

As a result of this surgical procedure with morcellation, a small cancer that could have been easily and completely removed through surgery has been spread and is now considered fatal.

Dr. Reed, who is now undergoing aggressive treatment for her metastasized uterine cancer, and her husband, Dr. Hooman Noorchashm, who was a surgeon at nearby Brigham and Women’s Hospital (also affiliated with Harvard), began a campaign to raise awareness of this issue and prevent other patients from being harmed.  As a result, Brigham and Women’s Hospital has since changed its policies on use of morcellation.  Since their story came out, other similar stories have surfaced, confirming that cancer has been spread by these devices, that it is not a rare event, and that it can have fatal results.  Moreover, many of these patients had not been told about these potential risks before their surgeries, and in some cases weren’t even told that morcellation would be used.  In May 2015, the Wall Street Journalreported that the FBI is investigating whether information about the risks of morcellation was not reported by hospitals, doctors, and device makers, as required by law.

What are uterine fibroids?

Uterine fibroids are non-cancerous (benign) growths on the uterus.  They are very common among women, especially during and after the reproductive years.  In many women, they do not cause any noticeable symptoms or problems.  But in some women, uterine fibroids can cause pain, discomfort during sex, and heavy bleeding.  To read more about fibroids and treatment options for them, read our in-depth article here.

What are the risks and benefits of using power morcellators?

Morcellation can allow surgeons to do shorter, less invasive surgeries.  This can reduce the chances of excessive blood loss and infection, and can reduce the amount of time spent in the hospital and result in an easier recovery afterwards.  However, in the case of fibroids, there is no way to rule out the chance of hidden cancer which could be spread by morcellation.  The Food and Drug Administration (FDA) estimates that 1 in 350 women receiving surgery for uterine fibroids has a hidden cancer that could be spread by morcellation. This is why the FDA released a warning in April 2014 recommending against morcellation for uterine fibroids.

On July 10-11, 2014, the FDA held a public meeting to discuss the risks and benefits of these devices.  Our testimony before the FDA panel on uterine morcellation, is here.

On November 24, 2014 the FDA announced that they were issuing an immediate change in the label for power morcellation devices, which will now include a black box warning as follows:

“Uterine tissue may contain unsuspected cancer. The use of laparoscopic power morcellators during fibroid surgery may spread cancer and decrease the long-term survival of patients. This information should be shared with patients when considering surgery with the use of these devices.”

These tragic events involving power morcellation devices raise questions about how medical devices are approved and monitored, and how a tragedy like this can be prevented in the future.  If larger studies had been done before the FDA allowed these devices to be used, and if cases of cancer being spread by morcellation had been reported to the FDA by doctors and companies, the FDA could have warned doctors and patients much earlier and prevented women from being exposed to these risks.

What do patients need to know?

If you are considering surgical treatment for uterine fibroids, be sure to discuss morcellation with your surgeon and make your wishes clearly known.  Depending on your particular situation, there are alternative surgical procedures, such as vaginal hysterectomy, which can be done without morcellation.  For any surgical procedure, make sure you have a clear and thorough discussion with your doctor about exactly how the procedure will be done, what choices you have, and what the risks and benefits of different options are.   If you feel that you are not getting enough information from your doctor, consider getting a second opinion.  Be sure to ask your doctor how often they perform the procedure you will have, because patients usually have a better outcome from surgery if the doctor performs the exact same surgery frequently.  If the physician does not have many years of frequent experience with the surgery, seek out a doctor who does.  For more tips on how to make smart decisions about medical treatments, especially use of medical devices, read our article here.

Gene Therapy May Provide Hope for Patients with Advanced Leukemia

Other Cancers
Margaret Dayhoff-Brannigan, Cancer Prevention and Treatment Fund

Acute Lymphoblastic Leukemia (ALL) is difficult to treat in children and adults. The most effective treatment is a stem cell transplant, but for patients whose cancer comes back after stem cell treatments, or who cannot be treated with a stem cell transplant, there are very few other options.

A study published in the prestigious New England Journal of Medicine in October 2014 tested a new treatment on terminally ill patients, 78% of whom survived at least 6 months.25

What is Acute Lymphoblastic Leukemia?

ALL is a cancer of the blood and bone marrow. It is the most common form of leukemia in children. In a healthy person, blood consists of red blood cells which carry oxygen and nutrients, platelets that help wounds to heal, and white blood cells which help the body fight infection. These different types of cells are made from stems cells in the bone marrow. In a patient with ALL, there are too many abnormal white blood cells that do not work properly to fight infections. These patients do not have enough red blood cells and platelets, and that can cause anemia or excessive bleeding. 26

Treatment Options

Currently there are four treatment options for ALL patients. Chemotherapy is a common cancer treatment that uses drugs to kill cancer cells. Radiation therapy is a treatment for cancer that uses x-rays or other forms of radiation to kill cancer cells. Targeted therapy uses very specific drugs or substances to identify and attack only cancer cells without causing harm to normal cells. Chemotherapy with stem cell transplant combines chemotherapy (and sometimes radiation) to kill cancer causing stem cells in the body, and then replaces them with a donors stem cells.2 How successful the treatment is usually depends on how old the person is when they are diagnosed and the amount of white blood cells the person has. ALL has a cure rate of 80-90% in childhood cases, but only about 40% in adults. Approximately 1,170 adults and 270 children die of ALL each year.27

Two Promising New Treatment for Patients with Relapsed ALL

There are two promising new treatments, but more research is needed before doctors will know more about which patients are most likely to benefit and before these treatments will be widely available.

Researchers at two hospitals in Philadelphia used an experimental treatment for ALL on 25 children and 5 adults.1 The children were seen at Children’s Hospital of Philadelphia by Dr. Shannon Maude and Dr. Stephan Grupp and their colleagues. The adult patients were treated at the University of Pennsylvania School of Medicine under the care of Dr. Noelle Frey. These patients all had relapsed several times or had failed to respond to any treatment. All had only a few weeks or months to live. The scientists took blood from each patient and separated out the white blood cells. These cancerous white blood cells were then genetically modified so that they could recognize and attack the diseased cells that cause the leukemia. The genetically modified cells were then put back in the patient using a blood transfusion.

One month after the treatment, 27 of the 30 patients were in remission. However, as the study continued, 7 of the 27 had a relapse, anywhere from 6 weeks to 8.5 months after treatment. More relapses are expected as the study continues.

Overall, 78% of the patients in the study were still alive 6 months after treatment, which was much longer than would have been expected without the gene therapy.1 When the results were written up for publication, one patient had survived two years after therapy. However, approximately half the patients had received the treatment less than 7 months earlier (some as little as 1-2 months earlier), making it impossible to calculate the average number of months of survival for the 30 patients.

Although patients were selected for the study if they were not eligible for stem cell transplant, several became eligible after gene therapy improved their health, and successfully underwent stem cell transplants or another treatment. However, the patient who has survived for two years did so without additional treatment.

We expect that a subsequent publication will give 2-year follow-up data for all 30 patients.

A different and also successful treatment for patients with relapsed or untreatable ALL was published recently by a different group of scientists at the Memorial Sloan-Kettering Cancer Center in New York City. They used a similar method to modify the genes in the patients’ white blood cells. However, this treatment was only effective at giving patients a short period of remission while they were waiting for a stem cell transplant. None of the patients in this study could be cured without also receiving a stem cell transplant.28 In contrast, the treatment studied by doctors in Philadelphia is the first to offer the possibility of a long reprieve or even possibly a cure in patients who had very little time left to live.

 

Statement of Dr. Diana Zuckerman at FDA Joint Public Advisory Committee Meeting on Chantix

Testimony & Briefings
October 16, 2014

Thank you for the opportunity to speak today.  I’m Dr. Diana Zuckerman, president of the National Center for Health Research.  I’m trained in psychiatric epidemiology at Yale Medical School, I’m a former faculty member at Vassar and Yale and a researcher at Harvard , and I’ve taught Research Methods courses, and those are the perspectives I bring with me today.  Our Center has no financial ties to Chantix or its competitors or to Chantix lawsuits.

We all know that smoking kills thousands of Americans and it is very difficult to quit.  That’s why we believe that Chantix should be available as an option for those who can use it safely.

At the same time, patients and their physicians need a clear black box warning for Chantix so they know to stop taking it when necessary

The challenge today is: which data should the FDA believe?  Mark Twain once said there are 3 kinds of lies: Lies, damn lies, and statistics.  I am a scientist and I believe in statistics, but I also know they can be easily manipulated to support a particular point of view.

Your task today is to make sense of conflicting data and decide which to believe.  They include:

  • Meta-analysis
  • Observation Studies based on hospital records
  • Adverse Reaction Reports from physicians
  • Reports from Patients

Meta Analysis is a valuable tool but its accuracy depends on the quality of each study and whether they fit together.  Meta analysis results can be useful or inaccurate depending on which studies you include and exclude.  No justification was given of why most studies on Chantix were excluded and only 5 were included in the meta analysis, including one study of schizophrenics, one study of depressed patients, and 3 studies of mentally healthy patients.  It is important to study schizophrenics and depressed patients, but those data should not be mixed together with 3 studies that exclude such patients.  No justification was given for that decision, but you heard from the FDA that most psychiatric events were in those two groups of mentally ill patients, clearly biasing the results.

To consider the studies showing no association between Chantix and psychiatric side effects, it is important to understand what happens to people with acute psychiatric events related to medication.  As the FDA speakers pointed out, most do not end up in hospitals or the ER.  Many of these psychiatric side effects are not reported in medical records.  Because psychiatric commitment laws depend on acts of violence, not threats of violence, many people with dramatic psychiatric symptoms end up in jail, not in hospitals.  In fact, some studies show that there are more mentally ill individuals in the criminal justice system than in psychiatric facilities — certainly those who suddenly behave violently toward others are likely to be put in jail, not in a hospital or ER.

There’s another, more positive reason why these psychiatric side effects might not be measured in a large study.  Fortunately, many stop quickly because patients or their doctors realize they should stop taking the drug, thanks to the black box.

For all these reasons, most of the studies that Pfizer is relying on are fatally flawed.

How can we make sense of the studies showing no impact in light of the thousands of reports of psychiatric side effects?

  • The studies cited did not evaluate all psychiatric side effects, they focused on depression and suicidal thoughts and behaviors
  • Those studies did not interview patients – a shortcoming of many large databases
  • They relied on hospital records, which research shows missed 82% of adverse psychiatric events
  • Some also relied on ER or medical records – which is better than hospital records, but will still miss a lot of data 

What about studies showing a significant increase in psychiatric events?  We all know that adverse reaction reports are the tip of the iceberg – it’s a voluntary system of reporting.  Compared to medical records, they can have a richness of information.  And while they are far from perfect, the sheer volume of thousands of reports – many more than for other drugs – is very compelling.

I’ve spoken with some patients who took Chantix, and their reactions are distinctly different from many other drug side effects, and don’t fit neatly into the categories that most of the Pfizer studies evaluated.  For example, I spoke to a man who was so besieged with uncontrollable thoughts that he locked his door at work and wouldn’t let anyone in.  His thoughts were so terrible that he just couldn’t deal with anyone.  That psychiatric reaction would be unlikely to fit into any of the studies.  Or a man who was so frightened that he hid in the corner of his bedroom under a blanket, trying to escape the uncontrollable thoughts by being as small as possible – trying to feel safe.  What study would accurate evaluate that?

If this Advisory Committee ignores the compelling psychiatric adverse reactions that have been reported, it would discredit thousands of doctors who made thousands of reports.  It would also discredit thousands of patients who reported them.  And it would send the message to the FDA to stop their Adverse Event Reporting systems, because what is the point of having such systems in place if you ignore thousand of such reports?

We need better studies, and I hope the post-market study underway will be better.  Based on previous research, we know that such studies must include very large numbers of patients, and must follow patients for a long enough time – not all reactions are within 30 days.  And, the studies must include patients’ reports of their side effects

In conclusion:

  • The studies Pfizer is citing are fatally flawed because they omit most psychiatric adverse reactions
  • Deleting the black box would send the message that thousands of doctors’ reports don’t count, including suicides and homicides

We strongly urge you to urge the FDA to keep the black box warning to protect patients and that you strengthen rather than weaken that boxed warning.  And, since the meta analyses are fatally flawed, as I and others have pointed out, the FDA should delete the misleading meta-analyses info from the Chantix label.

 

Comments on “Evaluation of Cancer as an Adverse Outcome Associated With Use of Non-Oncological Drugs and Biological Products in the Postapproval Setting”

Testimony & Briefings
October 9, 2014

Division of Docket Management (HFA-305)
Food and Drug Administration
5630 Fishers Lane, Rm. 1061
Rockville, MD 20852

Comments of the Cancer Prevention and Treatment Fund on
“Methodological Considerations in Evaluation of Cancer as an Adverse Outcome Associated With Use of Non-Oncological Drugs and Biological Products in the Postapproval Setting”
Docket No. FDA-2014-N-0731

The Cancer Prevention and Treatment Fund appreciates the opportunity to comment on Methodological Considerations in Evaluation of Cancer as an Adverse Outcome Associated With Use of Non-Oncological Drugs and Biological Products in the Postapproval Setting.

Challenges

Due to its biological complexity and often long latency, cancer represents a challenge for monitoring in the pre-approval or postapproval setting.  Pre-market studies are usually too short-term or too small to adequately evaluate cancer as an adverse event.  Unfortunately, many postapproval studies are also too short-term, too small, or have too many patients lost to follow-up to accurately evaluate cancer as an adverse event.

Existing voluntary databases for adverse event reporting in the post-market setting are known to greatly under-report and often do not contain sufficient information.  Postapproval studies with pre-specified endpoints often have poor patient retention or are not completed.  While cancer registries can provide another source of information they often do not contain detailed drug history and are not nationwide.  Therefore, comprehensive systems for monitoring cancer as an adverse event for drugs and biologics do not exist at this time.

Long-term surveillance is critical

Cancer development is a multi-step biological process that can occur over several years, making long-term surveillance critical to identifying a cancer safety signal.  Short pre-market studies that are not specifically designed to assess cancer outcomes are unlikely to identify this potential hazard.  In addition, patient subgroups that may be particularly susceptible to cancer risks, such as children, adolescents and elderly adults taking multiple medications, are typically under-represented in pre-market studies, further decreasing the likelihood of detecting a cancer risk.

Post-market surveillance should consider all cancer types           

While concerns over specific cancer types may arise from pre-market studies, post-market surveillance should include consideration of all cancer types.  As any cancer signal can be difficult to detect pre-market, post-market surveillance needs to account for all possibilities.  As mechanisms of carcinogenesis are often shared across different tissues of origin, the possibility of cancer at multiple sites cannot be ruled out.

In 2006, the Government Accountability Office issued a report stating that the FDA needs to address weaknesses in its post-market surveillance system, including the need for larger and more diverse datasets using uniform systems such as electronic health record information.  That same year, the Institute of Medicine recommended that the FDA should take action to partner with other federal agencies and use all available resources to bolster its post-market surveillance efforts.  We strongly agree.  We recommend that the Sentinel System be used to mine specific data on the possible increased cancer risk due to the effects of non-oncological prescription medications and biological products, but Sentinel should not replace postapproval studies designed to evaluate those risks.

Concerns about cancer risks in pre-market development

If concern over a potential cancer risk arises during pre-market development, well-designed preclinical and clinical studies to directly examine this possibility need to definitively address this issue.  Specifically, sponsors need to have a clear understanding of the biological mechanism of action of their product, and perform comprehensive carcinogenicity testing.  This should include sensitized animal model systems as appropriate, and should also address non-genotoxic mechanisms of carcinogenicity, such as hormonal effects, which may display non-traditional pharmacological behavior, i.e. non-monotonic dose responses.  Any cancer concerns identified in pre-market studies should also be adequately addressed in labeling information, special warnings, and post-market studies as needed, if the product is approved.

Conclusions

To better evaluate the challenges in designing postapproval studies to determine whether a non-oncological drug causes or influences cancer, the FDA should develop long-term studies that include susceptible subgroups such as children, adolescents and the elderly.  The post-market surveillance should consider all types of cancer, and include large and diverse data sets utilizing electronic health records and the Sentinel System.  However, Sentinel should not be used as a replacement for postapproval studies.  Also, if pre-market studies flag a cancer concern, it should be addressed in the label of the drug with a special warning.

Cancer Prevention and Treatment Fund

The Cancer Prevention and Treatment Fund can be reached through Paul Brown at (202) 223-4000 or at pb@center4research.org

Chantix citizen petition

Legislation
October 8, 2014

Margaret A. Hamburg
Commissioner
Food and Drug Administration

through

Division of Dockets Management
Food and Drug Administration
Department of Health and Human Services
5630 Fishers Lane, Room 1061
Rockville, MD 20852

Citizen Petition

Five leading nonprofit consumer, research and medical organizations identified below petition the Food and Drug Administration (FDA) pursuant to the Food, Drug, and Cosmetic Act 21 USC 352, 505(o)(4), and 21 CFR 10.30 to take action to improve the safety information included in the label for CHANTIX® (varenicline) tablets , a smoking cessation aid approved under NDA 021-928.

The petitioners are the Institute for Safe Medication Practices, a nonprofit organization devoted entirely to medication error prevention and safe medication use; Consumer Reports, which serves consumers through unbiased product testing and ratings, research, public education and advocacy; National Center for Health Research, a nonprofit think tank that scrutinizes scientific and medical research with public health implications; National Physicians Alliance, a non-profit organization that promotes health and fosters physicians’ active engagement with their communities to achieve high quality affordable health care for all; and Public Citizen, a consumer advocacy organization with more than 350,000 members and supporters.

Action Requested
The petitioners request that FDA amend the Boxed Warning and Indications sections of the label for CHANTIX® (varenicline) Tablets [1] to reflect new scientific information that has become available since the agency required a Boxed Warning in July 2009. We request specifically the following:
Clarify and expand the scope of reported serious neuropsychiatric adverse effects in the Highlights and main Boxed Warning to include the full spectrum of events now known: suicidal behavior, aggression/violence, psychosis, and depression.

Add language to the Boxed Warnings describing the risk of blackouts, convulsions, and impaired vision, adverse effects that could also endanger others in some settings such as operating aircraft, driving ambulances or large trucks.

Add to the Indications section restrictions against use in persons in sensitive or hazardous occupations such as pilots, air traffic controllers, military missile crews, police, fire fighters, and emergency medical workers. Existing actions by the FAA, the Department of Transportation, and the Department of Defense should be expanded by a clear and uniform label restriction that would include non-federal workers.

Remove inappropriate promotional material about CHANTIX benefits from paragraph 3 of the Highlights section Boxed Warning. A survey of Boxed Warnings for 10 classes of drugs showed no other Boxed Warning containing extraneous promotional statements about benefit.

Delete recently-approved but misleading description of meta-analyses about the neuropsychiatric adverse effects of CHANTIX from the Warnings and Precautions section.

B. Grounds
Compelling Scientific Evidence
The scientific evidence that CHANTIX (varenicline tartrate) increases the likelihood of suicidal thoughts and behavior, aggression/violence, psychosis, accidents, and depression is compelling and thoroughly documented. The adverse effects can be catastrophic, resulting in death, disability, and disruption of marriage, family relationships, and jobs. Severe symptoms can begin with the first doses even before stopping smoking, and many resolve soon after treatment is stopped. In some cases, symptoms reappear if treatment is resumed. The adverse effects of CHANTIX have been documented in three special studies by the FDA Office of Surveillance and Epidemiology (OSE),[2–4] by six studies in the peer reviewed literature,[5–10] and six reviews in QuarterWatch, a scientific publication about adverse drug events.[11–16] Psychiatric adverse effects of CHANTIX have also been observed worldwide and publicly reported in Canada,[17] France,[9] New Zealand,[5] and Australia.[18] The psychiatric adverse effects of CHANTIX have been reported to the FDA steadily and continuously over the eight years since the drug was approved, and have been roughly proportional to patient exposure.[14,16]

Why Clear Warnings Are Essential
Prominent warnings about the psychiatric and other adverse effects of CHANTIX provide important safety benefits to patients and the public. In many cases symptoms appear early, often in the first week, before stopping smoking. Effective patient and physician warnings to stop treatment immediately can prevent tragic events such as suicide and assault. In addition, two kinds of CHANTIX adverse effects—aggression/violence and impaired consciousness/vision—can and have caused injury to others. The highest public health duty to warn involves emphasizing potential serious harm to innocent persons that can be prevented with early and appropriate action.
An Estimated 2,500 CHANTIX Victims Compensated
An exhaustive scientific evaluation of CHANTIX took place over four years in United States District Court, and involved thousands of cases of alleged injury caused by CHANTIX. Millions of pages of scientific data, analysis, and other records were available under seal to batteries of qualified scientific experts representing both the victims and the manufacturer. This mass of evidence was distilled into expert reports that were subject to rigorous legal criteria monitored by a federal judge to ensure that the judgments therein were reliable and met accepted scientific standards. The result of this exhaustive process was that Pfizer, the manufacturer, paid approximately $300 million in damages to an estimated 2,500 CHANTIX victims.[19] Thousands of other CHANTIX victims were not eligible for compensation because the judge barred payment if the injuries occurred after the July 2009 Boxed Warning.

The Need to Update 2009 Warnings
It is important for the FDA to revisit the Boxed Warnings because its 2008 assessments, through no fault of the agency, substantially underestimated the psychiatric adverse effects and accident risks of CHANTIX. It was not until July 2010 that the FDA learned that Pfizer had failed to properly submit 26,000 adverse event reports, including 589 serious cases, 150 completed suicides, 102 cases of hostility/aggression, and 56 cases of psychosis.[15] In addition, later peer reviewed studies provide important new insights into CHANTIX cases involving aggression/violence, as well as comparisons with other smoking cessation treatments.

Information Adverse to Petition
21 CFR 10.30 requires citizen petitioners to consider and report information adverse to the petition request. Safety concerns have contributed to a 73% decline in CHANTIX patient exposure since 2008, lessening its use in smoking cessation treatment.[16] Clearer warnings might further reduce smoking cessation treatment using CHANTIX. However, safer alternatives of approximately comparable long-term effectiveness are available.

The two Pfizer-sponsored meta-analyses of its clinical trials that were recently added to the product label did not identify psychiatric adverse effects described in the current or proposed expanded Boxed Warning.[1] However, the clinical trials included in the meta analyses were inadequate in methodological design, including patient selection, adverse event ascertainment, and statistical power, to identify the infrequent but serious psychiatric adverse effects now known.

The FDA also conducted an observational study in electronic health records of the Departments of Defense and Veterans Affairs. It reported no difference in the rate of psychiatric hospitalization in the first 60 days after initiating treatment with CHANTIX or the nicotine patch.[20,21] However, those studies can not be considered conclusive because neither the underlying diagnosis codes nor the hospitalization endpoint was validated for regulatory purposes or previously used in a peer reviewed publication. In addition, the psychiatric hospitalization endpoint omits the 85% of reported psychiatric adverse events that do not result in hospitalization.[22] Additional studies and analysis on this topic appear in the Detailed scientific documentation section of this document.

Environmental Impact
Granting the actions requested in this petition would have no identifiable environmental impact.
Economic impact
The economic impact of this petition cannot be determined in absence of adequate data to assess the costs of reduced injuries resulting from more effective and accurate safety warnings.
Certification
Signature pages and certification appear at the end of this petition.

F. Detailed Scientific Documentation
Part 1: Four Psychiatric Adverse Effects of CHANTIX: the Evidence
Part 2: Impairment in Sensitive/Hazardous Occupations
Part 3: Inappropriate Promotional Material in Boxed Warning
Part 4: Meta-Analysis and Observational Studies
Part 5: References

Section F: Detailed Scientific Documentation
Part 1: Four Psychiatric Adverse Effects of CHANTIX: the Evidence
The psychiatric adverse effects of CHANTIX fall into these four psychiatric diagnostic categories: suicidal behavior, aggression/violence, psychosis, and depression. The primary scientific evidence in this section is shown in Table 1.

Many CHANTIX psychiatric episodes share distinctive features and overlap these four analytical categories: An episode of paranoia may lead to or involve violence. Aggression and rage are rechanneled and result in self-harm. Depression may lead to suicidal behavior. Sleep disturbances may border on exceptionally vivid dreams that resemble psychotic hallucinations. Sleep disruptions have erupted in violence.
This analysis focuses on the most clearly researched common features that include early onset, often before stopping smoking; remission on discontinuation; a senseless act in patients with no previous psychiatric history; and rechallenge, the reappearance of symptoms if the medication is restarted. There is less published scientific information available for two additional subsets of psychiatric cases: a) Cases that begin on discontinuation; b) Cases where the adverse effects are persistent. These cases require further research.

Suicidal Behaviors
Suicidal and self-injurious thoughts and acts are a prominent and established side effect of many therapeutic drugs, with at least 58 drugs currently carrying some form of warning on the product labels.[10] For CHANTIX, suicidal ideation, attempted suicide, and completed suicide carry the most prominent label warning language and have been documented through multiple sources. The 2008 FDA OSE Suicidal Behavior Study of adverse event data [3] had only limited cases available but concluded:
“The AERS data suggest a possible association between suicidal events and use of varenicline and bupropion, given that there were postmarketing cases of positive dechallenge/rechallenge, close temporal relationship between the event and drug use, and the occurrence of suicidal events in patients without any psychiatric history.”
This report was a primary source in the FDA decision to mandate a boxed warning in 2009.

A peer-reviewed survey of British adverse event data found a disproportionate number of cases of suicidal behaviors for CHANTIX, notably fewer cases for bupropion, and few or none for nicotine replacement products. For completed suicides, for example, there were 22 reported for CHANTIX, 6 reported for bupropion, and none for nicotine products. For suicidal ideation, there were 377 cases reported for CHANTIX, 131 for bupropion for all indications, and 2 for nicotine.[8] Exposure to nicotine replacement products was 7 times larger than varenicline, but bupropion exposure for smoking cessation could not be assessed because of its multiple indications.

A larger and more formal disproportionality analysis reported similar results in a peer-reviewed study.[10] When CHANTIX was compared to nicotine replacement products for suicidal/self injury, the odds ratio (OR) was 8.4, (95% CI 6.8-10.4). For CHANTIX compared to bupropion the results were: OR = 2.9 (95% CI 2.3-3.7). The large number of CHANTIX reported cases also adds scientific weight to the findings. In the Suicidality/Depression in Smoking Cessation study, CHANTIX accounted for 1,818 reported cases of suicidal thoughts or behavior compared to just 50 for nicotine products, even though patient exposure to nicotine replacement products was much greater and measured over a longer period of time. [10]
Suicidal behaviors were also prominently featured in regulatory agency reports of adverse events in Canada [23] and Australia,[18] and in the New Zealand patient monitoring study.[5]

Aggression/Violence
Thoughts and acts of aggression/violence associated with drugs are quite familiar (such as domestic violence associated with alcohol intoxication), but the association with correctly administered therapeutic drugs (involuntary intoxication) has not been well studied in systematic scientific research.
CHANTIX, however, has proved a valuable research topic because adverse event reports were so numerous, and they occurred in a diverse smoking cessation population (most often women of middle years) where fewer alternative causes of violence were likely confounding variables.
The FDA’s OSE studied five report terms describing aggression and violence using a Bayesian statistical technique applied to a small early subset of CHANTIX adverse event data.[4] The primary measure–Empirical Bayes Geometric Mean (EBGM)–returned a relative risk equivalent compared to all other drugs that ranged from 17.1 for homicidal ideation to 5.4 for hostility. In comparison, bupropion had an EBGM of 4.4 for homicidal ideation and no reported cases of hostility.

A peer-reviewed study of violent thoughts and acts reported for all evaluable drugs used a different statistical technique to measure disproportionality—the Proportional Reporting Ratio (PRR)—and a much larger universe of all case reports from all drugs from 2004 through the third quarter of 2009.[6]

This Aggression/Violence PRR study identified 31 drugs associated with thoughts and acts of violence and ranked them by PRR (a relative risk concept). The study compared the proportion of aggression/violence events for each drug, to the proportion for all other drugs, thereby adjusting for differences in the total number of reports. CHANTIX accounted for more thoughts/acts of violence than any other therapeutic drug by all measures in the study.

Table 2 shows that CHANTIX accounted for 18 times as many reports of violent thoughts and acts as would be expected given the total number of reports for that drug (PRR = 18), and compares it to two other smoking cessation treatments. CHANTIX accounted for 408 cases in total, more than any other therapeutic drug, even though it was only marketed for 14 of the 23 calendar quarters in the study. Bupropion also indicated increased risk but to a lesser degree.

A French pharmacovigilance research team performed a related case/non-case study in the French PharmacoVigilance Database.[9] Although the French data universe was substantially smaller, the Reporting Odds Ratio (ROR) for CHANTIX was 29.2 (95% CI 10.8-78.9). Note that the CHANTIX PRR of 18 in the U.S. study overlaps the broad confidence intervals in the French study.

An additional study in QuarterWatch examined all reports of homicidal thoughts for all drugs, but focused on all the adverse event data from 2007 through the third quarter of 2013, essentially capturing the entire period CHANTIX was marketed. An unadjusted ranking is shown in Table 3.[16]

These data show that CHANTIX accounted for more reports of homicidal ideation than any other therapeutic drug over a 75-month period. The number of cases was 5-times larger than second-ranked quetiapine, and 12-times larger than pregabalin. In 2013 Q3 all the other drugs on the list of 10 most frequently reported drugs had greater patient exposure than CHANTIX, except for interferon beta, where exposure was unknown and the patient population is smaller.

Psychosis
Psychosis may involve auditory or visual hallucinations, paranoia, delusions, or disorganized speech. These may involve acts of violence related to the delusions or paranoia. These are not typical symptoms of smoking cessation.
Psychotic behaviors have been identified in CHANTIX patients in clinical studies [24], the Pfizer-Tonstad meta-analysis [25], an FDA OSE report[4], and in QuarterWatch assessments [11].
The 2008 FDA OSE report identified 98 cases of psychosis for CHANTIX with 3.5 times as many cases as bupropion, adjusted for prescription volume. The OSE disproportionality analysis compared CHANTIX to all other drugs and showed an unexpectedly large number of reports for eight different symptoms ranging from an EBGM of 7.7 for paranoia to 3.5 for hallucinations. In these OSE data, psychosis reports (n = 98) were more numerous than and disproportional to those categorized as aggression (n = 48). The report also quoted Pfizer as stating two cases were seen in preapproval clinical studies. In the Pfizer-Tonstad meta-analysis of selected clinical trial data, “Disturbances in thinking and perception” were reported more frequently with CHANTIX than placebo (13 vs 2 cases, RR = 3.29, p = not significant).

The New Zealand Prescription Event Monitoring Program [5] provided additional insights because despite a relatively small population of 3,415 patients, it had access to medical and other records, which provides an improved follow-up compared to adverse event reports. It also conducted case causality assessments. This report identified three cases of hospitalization for psychosis; all occurred within 2 weeks of starting CHANTIX and all resolved on discontinuation of CHANTIX.

A small Pfizer-supported clinical trial [26] in patients with previous mental illness compared 208 patients on CHANTIX with 204 taking nicotine replacement therapy. It reported one CHANTIX case as “a severe psychological reaction likened to a ‘bad LSD trip’, including anxiety, paranoia, confusion and impaired motor control.” It was not reported whether symptoms resolved on discontinuation and no case was reported in the comparison group.

In the initial 2008 QuarterWatch report on CHANTIX adverse events, reports of psychosis/psychotic disorders (n = 397) outnumbered those of suicide/self-injury (n = 227).[11]

In the most recent FDA adverse event data for the 12 months ending 2013 Q3, report totals for the two kinds of injury were similar: Psychosis (n = 102) and suicide/self-injury (n =123). In both comparisons, however, a case could include symptoms in both categories.[16]

Depression
Depression raises measurement and identification issues because it varies in severity and waxes and wanes, rather than being a single dramatic episode such as completed suicide or psychotic break, and has much higher prevalence. In addition, although it was prominent in the 2009 Boxed Warning, a specific FDA OSE report supporting the regulatory action was not identified. However, strong evidence that CHANTIX causes or exacerbates depression can be seen in numerous other reports.

In the Suicide/Depression Smoking Cessation Study [10], the depression odds ratio for CHANTIX compared to nicotine replacement products was similar to the suicidal behaviors: OR = 8.5 (95% CI 6.5-11.0). As with suicidal behavior, the volume of cases adds scientific weight. CHANTIX accounted for 2,000 reported cases of depression assessed as serious, compared to 58 for nicotine replacement products.

In the initial 2008 QuarterWatch report on CHANTIX, reports of depression (n = 287) were second only to nausea, the most frequent side effect in clinical studies. In the Pfizer-Tonstad meta-analysis, depression was the second most frequently reported psychiatric side effect.

Reports of depression have continued for many years. In the FDA adverse event data 12 months ending 2013 Q3, “Depression” was the single most frequent adverse event term for the drug (n = 93).

Distinctive Features of CHANTIX Reactions
While the four psychiatric event categories in this petition—suicidal ideation and behavior, aggression/violence, psychosis, and depression—capture the spectrum of CHANTIX adverse effects, they do not fully portray the unique character that distinguishes many CHANTIX events. Examining individual cases and case series provides insight into CHANTIX events and show how to identify and prevent them.

Case # 1: Assault
By the third day of taking Chantix I was completely out of control. I woke my boyfriend up in the middle of the night and started physically beating him. I contemplated suicide about 5 times a day and contemplated homicide about 3 times a day.
This case shows early onset prior to smoking cessation, sleep disturbance, homicidal ideation, suicidal ideation, and later but not shown here, attempted suicide. Female, age 24, (ISR 5742066 )

Case #2: Terrifying Nightmares
She had a nightmare on 23Dec2007 that she was lying in prison laying on a cold wet floor shackled to a corpse. On 26Dec2007 she wanted to get the key to the gun cabinet and shoot her husband.” She stopped taking Chantix and “everything setting her off resolved on 28Dec2007.”
This case shows a sleep disturbance so vivid it approaches a hallucination, and is followed by an apparently unrelated episode of homicidal ideation and dechallenge. Female, age 43 (ISR 5587336)

Case # 3: Anger/Aggression
She swung at her mother (who was in her late 90’s) due to the extreme rage as she almost struck her and missed. She went out in the back yard and broke a weed wacker, a couple of glasses, the frame work on a couple of lamps, she threw concrete in the backyard and she began stabbing chunks of wood with the garden tools to get her rage out.
In this case report reviewed by FDA OSE the index event was suicidal ideation, but the narrative excerpt portrays uncontrolled aggression/anger and senseless violence.[4]

Case #4: Screaming and Crying
On Saturday while at home she got into a verbal argument with her mom over a minor issue and reports now that she was ‘totally out of hand’ and she was unable to control her impulses and was yelling and screaming and crying. She acutely became suicidal and also became homicidal threatening her mother with a shotgun. Her mother fled the house and called police. She locked herself in the bathroom and eventually calmed down.
Suicidal behavior and senseless aggressive acts occur together. Female, age 21 (ISR 5821157)

Case #5: Suicide Attempt
After 2 weeks of taking Chantix, I flew into a fit of uncontrollable rage after consuming alcohol one evening – resulting in me beating my boyfriend, followed by an attempt to take my own life. An overnight stay in the ER followed.
Senseless aggression and suicide attempt. Symptoms resolved on discontinuation. Female, age 28 (ISR 5626093)

Case #6: Homicide
Appellant was nineteen years old and had been in the service for approximately a year. Prior to enlisting, Appellant was an active member of his community and led various volunteering and mentoring projects as an Eagle Scout. Upon turning eighteen, both Appellant and his twin brother enlisted in the United States Army. After successfully completing Infantry Training and the Airborne Course, they were both selected for an appointment to the United States Military Academy Preparatory School (USMAPS), class of 2009. [Was temporarily assigned to a supply room at Fort Benning and prescribed Chantix ].

Appellant had been experiencing “new and strange thoughts” including a “person [was] telling me . . . dangerous things that arent [sic] me.” These included violent thoughts of killing someone. On May 18, 2008, one month after the Army doctor prescribed Chantix, Appellant fatally attacked Private (PVT) Bulmer while he was sleeping, stabbing him to death. Prior to this attack, Appellant did not know nor had he ever interacted with PVT Bulmer.

This case includes nightmares, psychosis, homicidal ideation, senseless act, and homicide. Male, age 19. Extracted from appeals court judgment reversing his murder conviction because the judge did not allow a CHANTIX defense of involuntary intoxication.[28]

Published Case Series
Based on a peer reviewed case series analysis of 26 cases involving thoughts and acts of aggression/violence in association with CHANTIX [7], the distinctive characteristics of these events are described in Table 2, reproduced below from the published study. This is one of the first studies that examined the characteristics of cases of violence associated with involuntary drug intoxication.

Findings Are Robust
The scientific evidence that CHANTIX causes four types of psychiatric adverse effects is robust. The numbers of reported cases are so large it would be illogical to conclude that thousands of trained medical professionals who observed these cases were always wrong. It would be illogical to discount the reports of thousands of consumers who told of frightening or destructive experiences with CHANTIX that had never occurred before. This disproportional reporting of CHANTIX psychiatric adverse effects was established using three different statistical methods: Proportional Reporting Ratio, Reporting Odds Ratio, and a Bayesian method, the Empirical Bayes Geometric Mean (EBGM). Consistent results were seen by different research teams in the United States, France, and New Zealand. Many cases were confirmed using case-causality tools. They showed events occurring in patients with no previous history of psychiatric illness in which symptoms began soon after starting treatment, often prior to quitting smoking. In most—but not all—episodes, symptoms resolved on discontinuation. In addition, cases from multiple sources documented that symptoms resumed if treatment started again.

Limitations
Although reports are numerous, worldwide, and extend over many years, they do not provide a reliable estimate of the incidence of serious psychiatric adverse events in CHANTIX patients. The observational studies and meta-analysis studies below suggest that such cases, although catastrophic and distinctive, are comparatively rare. This is a characteristic shared by many well-documented serious adverse effects such as Stevens-Johnson syndrome, rhabdomyolysis, osteonecrosis of the jaw, and progressive multifocal leukoencephalopathy (PML). All these adverse effects are rare and are seldom identified in clinical trials. Further, while many of the adverse event cases described above included specific causality assessments, the statistical studies were based on all submitted reports. However, these limitations would apply to all of the comparison drugs; there is no evidence that the CHANTIX reports were uniquely defective.

Part 1: Conclusion
Studies from multiple sources using varying scientific approaches demonstrate that CHANTIX causes serious psychiatric adverse effects. The first paragraph of the Boxed Warning Highlights should state:
Serious neuropsychiatric events have been reported in patients taking CHANTIX, including suicidal behavior, aggression/violence, psychosis, and depression.
These same four adverse effects should also be delineated more clearly in the longer Boxed Warning in the main section of the product label.

Part 2: Impairment in Sensitive Occupations
It is self-evident that a drug capable of inducing episodes of anger, rage, psychosis, and hostility should be banned in sensitive occupations such as pilot, air traffic controller, military crews, police, and many other military personnel. The CHANTIX accident risk also extends to a series of neurological (or possibly cardiac) effects that include blackout/syncope, convulsions, and impaired vision. Less severe forms of impairment include dizziness and somnolence.

Evidence
Concerns about the use of CHANTIX in sensitive or hazardous occupations were published as early as May 2008.[11] Of particular concern were reports of accidents and injuries (n = 173) and in particular 28 road traffic accidents. Another 148 case reports indicated vision disturbances with the potential to cause accidents.
The FDA OSE followed up on those published findings with its own assessment in October 2008, “Varenicline and automobile accidents.”[29] By this later date, the FDA knew about 441 cases of accidents and injuries, including 68 road traffic accidents. The FDA analyzed 39 cases and listed contributing factors, in order of frequency, as anxiety-related, abnormal behavior, memory impairment, visual disturbance, dizziness-related, and loss of consciousness.

That 2008 FDA report was the first and possibly only assessment to examine event onset, and the results raised an additional safety concern. Unlike many psychiatric adverse effects where onset appeared to be quite early, that was not necessarily the case for these adverse effects. It showed that in 7/35 (20%) of cases the impairment/accident occurred between 60 and 140 days after initiating treatment. Given a recommended initial treatment period of 12 weeks (84 days) this means that his adverse effect could appear at any time during treatment despite no serious initial reactions.

The accident/ impairment risks are also supported by the clinical trials data.[1] In the current product label description of clinical trials experience, these are frequent neurological adverse effects: disturbance in attention, dizziness, sensory disturbance. Infrequent events included amnesia, syncope, tremor, and psychomotor hyperactivity.

Actions Taken
Currently, the Federal Aviation Administration has banned the use of CHANTIX by pilots and air traffic controllers.[30] The Department of Defense has banned it for pilots, missile crews, and possibly other military personnel.[31] The Department of Veterans Affairs has restricted CHANTIX only to patients who have failed alternative smoking cessation treatments, and requires psychiatric screening before use and weekly monitoring.[32] We do not know whether state or local entities have restricted CHANTIX in other sensitive occupations such as police, fire fighters, ambulance drivers, nuclear power plant operators, and construction crane operators.
The FDA required a specific label warning for accident risk, noting reports but stating “Advise patients to use caution driving or operating machinery or engaging in other potentially hazardous occupations until they know how CHANTIX may affect them.”

Part 2: Conclusion and Actions Requested
The Indications section of the label should contain a clear and unambiguous restriction on the use of CHANTIX in hazardous or sensitive occupations. The list should include as examples specific occupations such as airline pilot, military missile crew, nuclear power plant operator, and police officers who carry weapons in the field.
Deficiencies in the current warning increase safety risks because the vague phrase “until they know how CHANTIX may affect them” implies that in the absence of early symptoms there is no further risk. On the contrary, neurological or cardiac impairment can occur at any time during treatment. This vague statement increases risk of accidental injury and should be removed without delay.

Part 3: Inappropriate Promotional Material in Boxed Warning
The Highlights section Boxed Warning may be unique in FDA regulation because in addition to the warning, it contains promotional material about the benefits of smoking cessation. Here is the passage, which FDA documents show was inserted at the request of Pfizer.
Weigh the risks of CHANTIX against benefits of its use. CHANTIX has been demonstrated to increase the likelihood of abstinence from smoking for as long as one year compared to treatment with placebo. The health benefits of quitting smoking are immediate and substantial.
The benefits of quitting smoking are well known. The petitioners request that this promotional language be removed for two reasons: a) The force and clarity of the FDA’s most important warning format should not be diluted with extraneous benefits information; b) The specific promotional language is misleading and not an accurate summary of CHANTIX benefits.
Diluting Warnings
Because it was not feasible to screen more than 60,000 product labels on the FDA/National Library of Medicine web site, the petitioners inspected Boxed Warnings for a diverse sample of drugs in 10 different therapeutic classes. The following table shows the drugs and type of adverse effects identified for this most prominent FDA warning type.
Table 3 shows that the types of risks described are all appropriate for a Boxed Warning and of roughly the same severity or clinical importance as the psychiatric adverse effects of CHANTIX. However, not one of the 10 Boxed Warnings contained even a sentence or phrase about treatment benefits. In fact it would be quite odd for an anti-neoplastic drug to contain language about the importance of treating cancer in the warning section.

Specific Misleading Content
The sentence “The health benefits of quitting smoking are immediate and substantial” is misleading because none of the clinical trials of CHANTIX have demonstrated an “immediate” or “substantial” health benefit. In smoking cessation literature, that passage normally refers to the fact that while pulmonary toxicity of tobacco products takes years to resolve, reduced cardiovascular risk is the most important immediate benefit of quitting. In the case of CHANTIX the opposite is true. Meta-analysis has shown 30% increased cardiovascular risks [33] over 52 weeks of treatment rather than the lower risks predicted by other smoking cessation studies. Thus, for CHANTIX this statement is at best unproven, and probably false.
The sentence “CHANTIX has been demonstrated to increase the likelihood of abstinence from smoking for as long as one year compared to treatment with placebo” is vague and could be misunderstood. The placebo group was an unusual and unique comparison group. Enrolled patients were informed they might be given medication that investigators believed could reduce their tobacco craving, but instead, by getting a placebo, many subjects underwent abrupt nicotine withdrawal symptoms. Typically in clinical trials, most placebo controls are not subject to harmful effects. The Boxed Warning statement also might lead to an overestimation of the likely results of CHANTIX smoking cessation treatment. Clinical trials with 52-week follow up showed confirmed abstinence rates that ranged from approximately 21% for CHANTIX compared to 14% for bupropion and 10% for “placebo.[1]” In addition, the current label omits the most relevant efficacy study, which compared CHANTIX to the nicotine patch. In that study, at 52 weeks there was no statistically significant difference between CHANTIX and nicotine replacement in 7 day point prevalence of abstinence (34.8% vs 31.4%, p = 0.285) and a small difference in continuous abstinence rate (25.9% vs 19.8%, p = 0.04). Moreover, the analysis of efficacy belongs in Section 14, the Clinical Studies section of the label.

Part 3: Conclusion
The entire paragraph of misleading promotional information should be removed from the CHANTIX label Boxed Warning. The agency’s most important warning statements should be brief and focused to maximize their impact to promote drug safety, not diluted with other material.

Part 4: Meta-Analysis and Observational Studies
Sound drug risk analysis should be based on the full scope of scientific information available, including mechanism of action, case reports in clinical studies, spontaneous adverse event reports, meta-analysis of clinical studies, and observational studies.
On September 17, 2014, the FDA approved a new version of the CHANTIX label that described two new meta-analyses (unpublished) and four observational studies.[1] The studies are shown in Table 4. The first two observational studies shown in the Table 4 as “FDA DoD Hospitalization” and “FDA VA Hospitalization” are very similar, were led by the same FDA OSE team using the same endpoint in two different databases, and were reported together in the same Drug Safety Communication. [20]

Key Scientific Questions
The scientific question is whether studies with no statistically significant difference with a comparison group provide an assurance of safety (since no increased risk was seen) or whether the methodologies were simply incapable of detecting a difference if one existed. Did these studies have an appropriate sample, validated outcome measures, and adequate control groups to demonstrate whether or not CHANTIX increases the risk of psychiatric adverse effects? Finally a pivotal regulatory question is whether these studies are so well done and compelling that they should persuade the scientific community to disregard or discount all the other evidence gathered through other methods.

All six studies detected no statistically significant differences in selected psychiatric adverse effects between CHANTIX and various comparators. All six studies share the methodological flaw that they could only assess a small fraction of the four serious CHANTIX psychiatric side effects, suicidal behavior, aggression/violence, psychosis, and depression. This is a critical drawback in assessing serious psychiatric adverse effects known to be rare.

The Suicidal Ideation/Behavior meta-analysis included only five studies and did not assess hostility/aggression, depression or psychosis. In addition, the meta analysis excluded a majority of 14 or more trials that monitored psychiatric adverse effects.[25] Moreover, one of the five studies was of smokers with a history of schizophrenia; no explanation was given for including that study in a meta analysis with 4 studies of non-schizophrenic smokers. The meta-analysis has not been published in the peer reviewed literature and no justification for the inclusion or exclusion criteria is provided on the label. With so much data excluded without explanation, the results of this meta analysis are questionable and should be excluded from the label.

The Psychiatric Adverse Events meta-analysis excluded both the most common psychiatric side effects (nightmares/ sleep disturbances), and all of the rarest side effects (a 1% threshold). There is no justification for these exclusions, which bias the results.

Two FDA OSE observational studies were limited to psychiatric hospitalizations, even though 85% of the four serious psychiatric side effects seen in adverse event data did not result in hospitalization.[22]

The British Medical Records Study examined only suicidal behaviors and depression, and had limited capability to detect depression because nearly 47% of the study population had present or previous use of antidepressant medication, and was excluded from this calculation.[34]

The Danish Medical Records study [35] only captured hospitalization and emergency room visits for the first 30 days after CHANTIX use was initiated.

None of the six studies reported investigating whether the psychiatric adverse effects remitted on discontinuation of treatment.
None of the six studies reported a statistically significant difference between CHANTIX and comparators for any adverse endpoints. However, it is impossible to determine whether this lack of a statistically significant difference was because of a weak design that did not capture all psychiatric side effects or whether it indicates safety. The two FDA OSE studies were based on diagnostic codes in electronic health records that had not been validated. The Danish Medical Record study only compared CHANTIX to bupropion, which also has labeled psychiatric side effects, and only assessed the first 30 days of treatment. None of the studies reported assessing violence/aggression, a problematic endpoint in medical records based studies but one of the most commonly reported.

Incidence Evaluated
Clinical trials and observational studies provide limited basic information about incidence, which is problematic in adverse drug event reporting. In the CHANTIX New Drug Application (n = 3,490 on active drug), clinical studies were conducted in a selected patient population that excluded persons with a mental disorder (including current depression) and those taking nearly any psychoactive or stimulant drug, including the cold medication pseudoephedrine.[24] The sponsor reported 1 CHANTIX suicide and 2 CHANTIX psychosis cases, versus none in comparators. However, this was a very limited study population that is not generalizable to most smokers. CDC estimates that approximately 25% of the public reports having a mental illness in the past year, and that smoking rates are 76% higher among those with current mental illness (36% vs 21%).[36,37]

The Danish Medical Records study reported an incidence of the emergency room/hospitalization events of approximately 2 per 1,000 prescription starts. However, this study could not capture the many psychiatric side effects that would not result in emergency medical treatment or hospitalization.
The New Zealand patient monitoring study used case causality assessment and reported new onset depression in 26 of 3415 patients or approximately 7 per 1000 starts and psychosis in 3 cases.[5]
It is difficult to evaluate acute psychiatric adverse reactions in large studies because of limitations in the availability of those data; most patients are not hospitalized and many such episodes are not included in medical records. The data from these studies therefore provide limited assurance that serious adverse reactions are probably rare, but unfortunately the studies are not adequate to determine the incidence of these adverse reactions because of the aforementioned substantial methodological shortcomings of each of these studies.

Part 4: Conclusion
The meta-analysis and observational study results establish that the four serious psychiatric side effects of CHANTIX may be uncommon. However, none of the studies are of sufficient quality to establish a convincing estimate of incidence, provide a valid comparison to other treatments, or have the scientific weight to refute evidence from other scientific methods.

Part 5: References

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2. Pollock M. (2008) Varenicline and automobile accidents. Silver Spring, MD: FDA Center for Drug Evaluation and Research.
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C. Certification and signature pages follow in official filed document