Category Archives: Policy

Patient, Consumer, and Public Health Coalition Senate Briefing: Innovation for Healthier Americans

Policy, Testimony & Briefings
March 4, 2016

Below are the materials from the Senate briefing we hosted with the Patient, Consumer, and Public Health Coalition titled “Innovation for Healthier Americans: The Impact of Proposed Health Bills on Patients & Consumers”.

Lab-Developed Tests (LDTs): A Critical Role for the FDA

Examples that illustrate the need for FDA regulation of LDTs

FDA and Medical Software

Lab-Developed Tests (LDTs): A Critical Role for the FDA

Laboratory developed tests (LDTs) serve an increasingly important role in health care today. Compared to just a few decades ago, the tests are more complex, and inaccurate results are much more likely to endanger patients. When the FDA was given the responsibility to regulate medical devices in 1976, LDTs were basic laboratory tests, such as a blood sugar test. For that reason, the FDA chose not to regulate most LDTs. But today’s diagnostic tests are more complicated and, for example, may be used to obtain a genetic analysis of a cancer cell to guide treatment decisions. FDA regulation of LDTs will ensure patients and physicians are relying on tests that are safe and effective.

CLIA Cannot Substitute for FDA Assurance of Safety and Effectiveness

The CMS CLIA program does not determine if a test is accurate (which is called clinical validity). It instead ensures quality control mechanisms are in place. In contrast, the FDA review process evaluates the clinical validity of a test before it is approved (premarket) and after it is on the market (post-market surveillance). Clinical validity is essential to understanding the risks and benefits of any test. For example, an ovarian cancer test with a high rate of false positives will result in women receiving unnecessary hysterectomies, whereas a high rate of false negatives will result in cancer going undetected.

Transparency Will Increase Physician and Patient Confidence in LDTs and Encourage Innovation

Faulty tests erode the confidence of physicians and patients, and put patients’ lives at risk. The American Society of Clinical Oncologists (ASCO) has expressed agreement with the FDA’s proposals to improve regulation of LDTs, stating that “a patient’s treatment options are increasingly driven by detection of molecular abnormalities in the tumor that drive treatment selection. ASCO believes that the tests used to detect those abnormalities must be of the highest quality and thoroughly validated before being offered to doctors and patients.” Requiring FDA review prior to allowing a test to be sold and giving FDA the authority to gather and publicly share information about adverse events will give patients and providers the information they need to make informed treatment decisions. Non-LDT in vitro diagnostics (IVDs) are already under FDA regulation. Using the same regulatory processes will ensure higher quality tests for patients. That will stimulate, not hamper, the kind of innovation that saves lives and improves the quality of patients’ lives.

FDA’s Plan Follows a Risk-Based, Phased-In Approach to Ensure Efficiency and Responsiveness

The FDA draft guidance on LDTs lays out a risk-based, phased-in approach that will proceed over several years. This approach allows ample time for laboratories to come into compliance and will also ensure that the highest-risk devices are regulated as quickly as possible. The guidance document also proposes a series of carve-outs, permitting manufacturers of LDTs for unmet needs or rare diseases to escape the most stringent pre-market review requirements. This type of regulatory framework will protect the public health while being flexible enough to encourage the development of new tests for serious conditions.

Conclusions

In response to the FDA’s proposed regulatory framework, NIH Director Dr. Francis Collins stated that “this is good news for all who are working to turn the dream of personalized medicine into a reality.”1 We agree. The FDA’s draft guidance displays the agency’s willingness to balance its goals regarding safety and efficacy with its concerns about innovation and patient access — and all parties should work together to move our regulatory framework for LDTs into the 21st century.

Examples that illustrate the need for FDA regulation of LDTs

OvaSure Ovarian Cancer Test

The OvaSure ovarian cancer test shows the importance of FDA oversight of LDTs in protecting patients’ lives.

  • In June 2008, the test was marketed to screen for early-stage ovarian cancer in high-risk women based on peer-reviewed published data showing it could detect ovarian cancer with a positive predictive value (PPV) of 99.3%.
  • It was later discovered that poor study design led to a falsely high predictive value. The actual PPV was only 6.5%, meaning that only 1 in 15 patients who tested positive actually had ovarian cancer.
  • OvaSure was pulled from the market by October 2008 after a warning letter from the FDA but not before many women underwent unnecessary hysterectomies because of a faulty test.

Oncotype DX HER2 Breast Cancer RT-PCR Test

FDA regulation will help ensure the validity of LDTs that detect genetic tumor markers and guide drug therapy decisions. These LDTs are critical to the success of the Precision Medicine Initiative. Patients and their providers must be able to trust them.

  • The Oncotype DX HER2 breast cancer RT-PCR test was intended to diagnose early stage HER2 receptor positive breast cancers so that the appropriate HER2 targeted drug could be used.
  • In 2011, a group of prominent pathologists from three independent laboratories found discrepancies between this HER2 RT-PCR and other tests that are FDA-approved. They discovered that the test has poor sensitivity, resulting in many false negatives and women not receiving life-saving treatment. Patients died as a result.

FDA and Medical Software

Jay G. Ronquillo, MD, MPH, MMSc, MEng

In a study of FDA reported recalls, completed in 2016, we found:

  • Over the last 5 years, more than 600 different software devices totaling over 1.4 million units were recalled for moderate or high risk patient safety issues.
  • Nearly 200,000 units were recalled for having the most serious (life-threatening) risk to patients. Although recalls are officially considered voluntary, few would take place without FDA regulatory authority.

If MEDTECH becomes law, the FDA would not be gathering adverse event reports and encouraging recalls of many stand-alone IT devices with life-threatening flaws. The results of this study show that software flaws affect millions of patients and removing medical software from FDA regulatory oversight would be dangerous. The Senate can do better.

Medical software represents an increasingly important aspect of medicine. The MEDTECH Act and related bills would remove some health IT entirely from FDA’s regulatory oversight (e.g. electronic health records, clinical decision support). For other types of software, the FDA would be limited in its ability to identify safety risks. Industry says that deregulation would foster the creation of innovative new medical devices. However, the data above indicate that medical software must remain regulated by the FDA in order to protect patients from harm.

Some examples of the devices that were recalled in recent years because of their potential to seriously harm or even kill patients due to software errors include:

  • Oncology electronic medical record systems: recalled because they calculated and recorded incorrect drug dosage treatment.
  • Clinical decision support systems used during surgery: recalled because they erroneously switched patient data and failed to warn physicians about dangerous drug reactions.

Software devices are re-used repeatedly for different patients. A conservative estimate is that millions of patients being treated by hundreds of physicians would have unknowingly been at risk for poor care, serious injury, and even death if the software had not been recalled.

Conclusion: If medical software is removed from FDA regulatory oversight, millions of patients would be at risk from defective software.

What would impact of 21st Century Cures Act be on cancer and your healthcare costs?

In the News, Legislation, New Cancer Research, Policy
 NOVEMBER 23, 2015

This summary of an analysis published online in the prestigious medical journal BMJ on November 23, 2015, shows that using preliminary research to approve new medical treatments has high costs for patients’ lives and healthcare dollars.  These three very promising medications did not work, and one of them caused skin cancer and also made Alzheimer’s symptoms worse.

21ST CENTURY CURES ACT AND SIMILAR POLICY EFFORTS: AT WHAT COST?

BMJ 2015; 351 doi: http://dx.doi.org/10.1136/bmj.h6122 (Published 23 November 2015) Cite as: BMJ 2015;351:h6122

By Diana M Zuckerman, Nicholas J Jury, and Christina E Silcox

A controversial proposed law in the United States, the 21st Century Cures Act, is described by supporters as an innovative attempt to jump start the process of finding new cures for the thousands of diseases that currently lack effective treatments. But would this bill promote new cures, or increase the availability of new medical products that do not necessarily work? Alzheimer’s disease is often cited as an example of a devastating disease with enormous costs and no cure in sight. We examine the potential harms and costs that would have been incurred by three Alzheimer’s drugs that were rejected under current Food and Drug Administration approval standards but could have been approved under the standards promoted by 21st Century Cures and similar legislation.

We selected for analysis all the Alzheimer’s drugs reviewed by the FDA within the past five years for which a determination was made, to determine the likely impact of the proposed changes on their approval.

All three drugs had impressive results in preliminary clinical trials.  Two of the drugs showed great improvement based on the well-established biomarker of beta amyloid plaques on the brain, and the third based on tests of memory and cognition.  When larger, better designed clinical trials were conducted, however, two of the Alzheimer’s drugs were found to be ineffective, and the third drug caused an increase in memory problems and an increase in skin cancer.

Cost estimates

More than five million patients in the US have Alzheimer’s disease, about 1.3 million of whom are being treated with an Alzheimer’s drug. To conservatively estimate market share, we looked at the cholesterol lowering drug atorvastatin (Lipitor), which garnered 18% of market share during its first year on the US market based on biomarker data. If one of these drugs had gained a similar market share it would translate to 234,000 patients a year taking a drug that put them at risk of a greater loss of cognitive skills than if they had taken a drug already on the market, or perhaps no treatment at all. If semagacestat was the drug approved, almost 19,000 more patients would have developed skin cancer, based on the phase III results.

Most current Alzheimer’s drugs are available as generics, which has reduced their price. Donepezil has most of the US market share. The brand name version (Aricept) costs about $7500 a year at Walgreens, the largest pharmacy chain in the US. The brand name versions of memantine, galantamine, rivastigmine, and memantine-donepezil each cost over $5000 a year at Walgreens.

New drugs are priced based on the current market price of competing drugs, not on research and development costs. A conservative estimate is that a promising new Alzheimer’s drug would be priced similarly to Aricept ($7,500 a year). This is 87% more than generic donepezil, almost doubling the cost for any patient who switched to the new drug.

Assuming 18% of the market share before postmarket studies  are completed, we estimate the cost of treating 234,000 patients at $1.76 billion a year, or $7 billion over four years until postmarket studies were completed.  Given the modest benefit of current Alzheimer’s drugs, and the impact of current direct-to-consumer advertising practices in the US, a promising new drug would be expected to garner higher prices and more prescriptions, so the cost could easily double.

Since the cognitive abilities of patients with Alzheimer’s disease tend to worsen over time regardless of treatment, it would be virtually impossible for physicians to realize that semagacestat was causing cognitive decline or that the other drugs were ineffective. Physicians would also have been unlikely to notice that semagacestat increased patients’ risk of skin cancer. It would not have been until post-market phase III studies of cognitive and health outcomes were completed years later that physicians and families would have realized that the drugs were ineffective and possibly harmful.

Under pressure from Congress and industry, FDA standards have loosened in recent years, and the agency often approves products based on biomarkers that have good but inconclusive evidence of clinical benefit. For example, cancer drugs are often approved based on tumor shrinkage or progression-free survival and studies conducted after the drugs are in widespread use have shown that many do not help patients live longer. Osteoporosis drugs have been approved based on bone mineral density or microscopic bone fractures, rather than hip fractures that harm health. The proposed law and several other Congressional proposals would weaken current FDA standards further. As our examples show, this could to lead to patients taking ineffective and potentially harmful drugs and waste billions of healthcare dollars.

Read the whole article here.

Testimony of Dr. Anna Mazzucco before the FDA on “Framework for Regulatory Oversight of Laboratory Developed Tests”

Policy, Testimony & Briefings
By Dr. Anna Mazzucco
January 8, 2015

Thank you for the opportunity to speak today at this very important meeting.  My name is Dr. Anna Mazzucco, and I am speaking on behalf of the National Center for Health Research.   I received my Ph.D. in cell biology from Harvard Medical School, and I conducted post-doctoral research here at NIH. Our nonprofit organization conducts research, scrutinizes data in the research literature, and then explains the evidence of risks and benefits to patients and providers.  [Our organization does not accept funding from companies that sell medical products, and therefore I have no conflicts of interest.]

I am speaking as a scientist who appreciates the power of data and who also wants patients and physicians to have the best information possible before they make potentially life and death decisions.  The FDA released new guidance on laboratory-developed tests because of evidence that patients are harmed by faulty tests.

We applaud the FDA for their plan to improve oversight of lab tests and the NIH for their commitment to medical care. We have a few key points:

  • Many of these tests are used to diagnose a disease or determine a course of treatment.  If the test doesn’t work correctly, the patient may be exposed to risks from a treatment they didn’t need, OR not receive treatment that would help them.
  • When the FDA started regulating devices almost 40 years ago, these tests were very different.  They are now widespread and are the basis of high-risk decisions.
  • Under CLIA, test makers do not have to demonstrate “clinical validity”.  At FDA, approval standards include safety and effectiveness.  FDA review will improve transparency and data quality.
  • Current policies do not require adverse event reporting or manufacturing safeguards.  FDA approval does.  Patients using high-risk diagnostics deserve those protections.

Our Center has frequently urged the FDA to improve their oversight of medical devices. Despite past criticisms, we believe it is essential that FDA have the authority to regulate laboratory-developed tests in order to stimulate even better science, and help ensure that patients receive the full benefit of our growing scientific knowledge.

To paraphrase Dr. Josh Sharfstein’s JAMA article:

Patients travel in ambulances that are regulated, to hospitals that are regulated, for care using medicines that are regulated, administered by nurses and physicians, who are regulated. That same patient’s life or death should NOT depend on whether an unregulated diagnostic test result is accurate.

Thank you for the opportunity to speak today.

Statement of Dr Diana Zuckerman: regarding the introduction of The Prescription Drug Affordability Act of 2015

Legislation, Policy
Dr. Diana Zuckerman, PhD
September 10, 2015

We applaud Sen. Sanders and Sen. Cummings’ bill, which is tackling an issue of great importance to all Americans.  The cost of medications should reflect the value they provide, not “whatever the market will bear.”  We call on Congress to support these efforts and find a way to stop the epidemic of unaffordable medications.

To learn more about the bill, click here. For an example of unfair pricing of medical products, see this article in the New York Times.

August 24, 2015 Letter to the FDA about ads for “natural” tobacco

Legislation

As a member of the Campaign for Tobacco-Free Kids, the Cancer Prevention and Treatment Fund recently signed on to a letter (below) to the FDA regarding advertising of “natural” tobacco. See some of the misleading ads by clicking here and here.

Three days after receiving this letter, the FDA followed our suggestion and told the tobacco companies to stop these ads.
tfk signons

August 24, 2015

Mr. Mitchell Zeller
Director, Center for Tobacco Products
U.S. Food and Drug Administration
10903 New Hampshire Ave.
Silver Spring, MD 20993

 

Dear Mr. Zeller:

We write to urge the Food and Drug Administration (FDA) to commence an appropriate enforcement action against Reynolds American, Inc. (Reynolds) and its subsidiary Santa Fe Natural Tobacco Co. (Santa Fe) for the marketing of Natural American Spirit brand cigarettes in violation of the modified risk provisions of the Family Smoking Prevention and Tobacco Control Act (TCA).

Section 911 of the Food, Drug & Cosmetic Act, as amended by the TCA,[1] prohibits the introduction of modified risk tobacco products – products sold “for use to reduce harm or the risk of tobacco-related disease” – without an FDA marketing order. That section defines “modified risk tobacco product” to mean tobacco products for which the label or advertising explicitly or implicitly represents that the product presents a lower risk of disease or is less harmful than another tobacco product, contains a reduced level of a substance, or does not contain or is free of a substance. Premarket FDA review of modified risk products is critical for the agency to determine whether the product, as used by consumers, will significantly reduce the risk of disease to individual users and to assess whether its marketing, with the claim of reduced risk, will benefit the health of the population as a whole. The potential for irreparable damage to public health from the marketing of tobacco products with modified risk claims is well illustrated by the industry’s years of deceptive advertising of “light” and “low-tar” cigarettes to persuade health-conscious consumers to continue smoking, when in fact such cigarettes, as actually used by smokers, were no less hazardous than other cigarettes.

Recently, Reynolds’ Santa Fe subsidiary launched a new national magazine advertising campaign for its Natural American Spirit brand which continues and intensifies past advertising campaigns using words and phrases such as “100% additive-free,” “natural tobacco” and “organic tobacco” that imply the brand is less hazardous than other cigarettes. The new campaign includes full-page ads (some consisting of the entire back cover) in magazines such as Sports Illustrated, Glamour, InStyle, Rolling Stone, Car and Driver, Vanity Fair and US Weekly. As demonstrated by the enclosed collection of Natural American Spirit brand ads, covering the period 2000-2015, the company long has used the terms “natural tobacco,” “organic tobacco” and “100% additive-free” to describe its cigarettes. However the new campaign features these descriptors much more prominently, and they easily overwhelm the small disclaimers at the bottom of the ads. There is no question that these terms imply that this brand is healthier than other brands and are understood by the public to mean a less hazardous cigarette.[2]  Moreover, the “100% additive-free” phrase is an explicit representation that Natural American Spirit cigarettes are free of a particular substance. Therefore, because these products are being marketed with such representations, they are modified risk tobacco products, as defined in Section 911, marketed without a premarket order from FDA in contravention of the TCA.

This conclusion is not altered by the appearance of disclaimers on the products’ packaging and advertising. As you are aware, the disclaimer “No additives in our tobacco does NOT mean a safer cigarette” is required by a Federal Trade Commission (FTC) consent order entered in 2000 to resolve FTC charges that the use of “no additives” language in Natural American Spirit ads was deceptive in implying, without a reasonable basis, that the cigarettes are safer. A second disclaimer, “Organic tobacco does NOT mean a safer cigarette,” is required by an agreement entered into in 2010 with Attorneys General from 33 states and the District of Columbia to resolve charges that the use of the words “organic” or “100% organic” violated the Master Settlement Agreement by deceptively indicating that Natural American Spirit cigarettes and roll-your-own tobacco are safer than other tobacco products. As the ads enclosed with this letter make clear, Santa Fe’s use of the terms “natural tobacco,” “100% additive-free,” and “organic tobacco,” has become increasingly prominent in its advertising and now overwhelm, and render completely ineffective, the inconspicuous disclaimers on the company’s ads. The reduced risk message is further conveyed by the use of the word “natural” in the brand name “Natural American Spirit.” Thus, despite the existing disclaimers, the current ads for Natural American Spirit cigarettes convey a dominant and clear message to consumers of reduced risk and reduced exposure to harmful substances.

The misleading effect of claims that some cigarettes are “additive-free” or contain “organic tobacco” has already been recognized in a watershed federal appellate decision. When the major tobacco product manufacturers sued to have Section 911 declared unconstitutional as an infringement on freedom of speech, they argued that such claims were not misleading but simply informed consumers of factual information about their cigarettes. The U.S. Court of Appeals for the Sixth Circuit explicitly rejected plaintiffs’ claims that “marketing of tobacco products as ‘additive-free’” was designed “to appeal to naturalists and smokers who prefer organic products, even when such preferences are not linked to perceptions of health benefit.” Discount Tobacco City and Lottery, Inc. v. U.S., 674 F.3d 509, 536 (6th Cir. 2012). The Court stated:

Plaintiffs have presented no evidence to suggest that “consumers who prefer organic products for environmental or other reasons . . . [but do not] perceived [them] . . . to convey a health benefit,” (id.), actually exist. On the contrary, we may safely presume that naturalists and those who subscribe to organic products do not engage in unmotivated or arbitrary behavior – common sense dictates the conclusion that they prefer such products precisely because they believe that natural and organic products confer health advantages over conventional products. See Centers for Disease Control and Prevention (“CDC”), Low-Yield Cigarettes and Cigarette-Like Products, 1 (2009) (finding that “[m]any smokers consider smoking . . . additive-free cigarettes to be safer than smoking regular cigarettes”). Consequently, Plaintiffs’ attempt to de-link hypothetical consumers’ preferences for “organic” and “additive-free products” from general health concerns is unsustainable.

Id.

It also is worth noting that the Natural American Spirit is experiencing significant brand growth. From 2009 to 2014, sales of Natural American Spirit cigarettes increased by 86%, while sales of all cigarettes nationally declined by 17%.[3] Reynolds CEO Susan Cameron, in a recent earnings call with investors, industry analysts and the media, stated that Santa Fe’s performance “continues to exceed even our own high expectations,” describing the Natural American Spirit brand as “the driving force” behind Santa Fe’s success. According to Cameron, the brand had volume growth of over 25% in the second quarter of 2015, is gaining market share in every state, and has achieved “a loyal and growing franchise and the brand strength is based on its distinctive additive free style, including those made with organic tobacco.” There is every reason to believe that Natural American Spirit is growing in popularity because consumers are being misled to believe that the brand offers a healthier alternative to other cigarettes.

FDA should determine that because Natural American Spirit cigarettes are being marketed with reduced risk claims as modified risk tobacco products, as defined in Section 911, they are illegally on the market without a premarket order. It should take enforcement action against Reynolds and Santa Fe to prohibit the continued sale, without an FDA order, of products advertised or promoted with the use of the terms “natural,” “additive-free” or “organic,” or any other term or phrase conveying a message of reduced risk or reduced exposure to harmful substances, including the use of any of these terms in the brand name itself.

 

Respectfully submitted,

Action on Smoking & Health
Altarum Institute Center for Prevention
American Academy of Family Physicians
American Academy of Otolaryngology—Head and Neck Surgery
American Association for Respiratory Care
American Cancer Society Cancer Action Network
American College of Occupational and Environmental Medicine
American Heart Association
American Legacy Foundation
American Lung Association
American Psychological Association
American Public Health Association
American School Health Association
American Thoracic Society
Campaign for Tobacco-Free Kids
Cancer Prevention and Treatment Fund
ClearWay Minnesota
Community Anti-Drug Coalitions of America
Global Advisors on Smokefree Policy
International Association for the Study of Lung Cancer
Lung Cancer Alliance
National Association of County & City Health Officials
Oncology Nursing Society
Prevention Institute
Society for Public Health Education
Society for Research on Nicotine and Tobacco
Tobacco Control Legal Consortium
Trust for America’s Health

Enclosure: Natural American Spirit Advertisements

—

[1] 21 U.S.C. §387k.

[2] A significant body of research establishes the association of these terms with reduced risk. See e.g. Agaku, Israel T., et al., “Cigarette design and marketing features are associated with increased smoking susceptibility and perception of reduced harm among smokers in 27 EU countries,” Tobacco Control 0:1-8, 2014 (descriptors such as “natural” or “organic” in cigarettes associated with perceptions of reduced harm among specific demographic groups); Czoli, D.D. & Hammond D., “Cigarette Packaging: Youth Perceptions of ‘Natural’ Cigarettes, Filter References and Contraband Tobacco,” Journal of Adolescent Health 54:33-39, 2014 (among Canadian youth, organic and additive-free tobacco viewed as significantly more appealing and less harmful); McDaniel, P. and Malone R., “’I always thought they were all pure tobacco”: American smokers’ perceptions of ‘natural’ cigarettes and tobacco industry advertising strategies,” Tobacco Control 16:e7, 2007 (review of tobacco industry documents shows American tobacco companies have understood, for decades, that “natural” implies unwarranted health claims); Cummings, K.M., et al., “Are smokers adequately informed about the health risks of smoking and medicinal nicotine?” Nicotine & Tobacco Research 6(3): S333-340, 2004 (60% of adult smokers surveyed believed that removal of additives made cigarettes less dangerous to the smoker); Arnett, J.J., “Winston’s ‘No Additives’ Campaign: “Straight Up”?’ ‘No Bull’?, Public Health Reports 114: 522-527, 1999 (study of Winston’s use of “No Additives” in advertising shows two-thirds of adolescents, and 27 percent of adults, interpret “No Additives” as an implicit health claim); Pearson, J.L., et al, “Quick, dirty, and cheap: crowdsourcing harm perceptions surrounding American Spirit Cigarette pack descriptors.” 2013 Society for Research on Nicotine and Tobacco Annual Meeting, Boston, MA (in a large sample of U.S. adults, American Spirit packs with the descriptors “100% additive free” and “made with organic tobacco” were associated with reduced harm perceptions compared to a Marlboro Red pack and to the same American Spirit packs without the descriptors).

[3] Reynolds American, Inc., Filings with the U.S. Securities and Exchange Commission; U.S. Alcohol and Tobacco Tax and Trade Bureau, Tobacco Statistics, http://www.ttb.gov/tobacco/tobacco-stats.shtml

NCHR Comment on the USPSTF’s Draft Recommendations for Cervical Cancer Screening

Cervical Cancer & HPV, Policy
2015

The National Center for Health Research is dedicated to improving the health and safety of adults and children by scrutinizing medical and scientific research. Based on our detailed analysis of currently available data, the Center strongly supports the existing USPSTF guidelines on cervical cancer screening which recommend Pap smears every 3 years starting at age 21, with the option of replacing that regimen starting at age 30 with a combination of a Pap smear and HPV test.

In response to the key systematic question regarding “the effectiveness of HPV testing, with or without cytology, as a primary screening strategy for reducing cancer mortality and incidence,” we strongly believe that this critical question must be divided into four questions: Is HPV testing effective with or without cytology (Pap smear) for women below 30 and for women above 30? Based on current data, the answers to those four questions seem to differ dramatically and more research will help answer those questions for different racial and ethnic groups.

Based on the research to date, HPV test without cytology should not be used as a screening tool. The HPV test by itself isn’t useful for women under 30 because many young women have HPV that will disappear without any treatment. Being objectively correct about whether HPV is present does not accurately predict whether infection with HPV will lead to cervical cancer.  On the contrary, the vast majority of women with HPV will never develop cervical cancer.   The only question is the extent to which HPV screening is useful for women over 30 and whether that is related to marital status or other measures associated with the number of sexual partners.

Positive results of an HPV test performed instead of a Pap smear, especially for women under 30, will add anxiety and lead to additional testing, as physicians follow a positive result on the HPV test with a colposcopy, an expensive and invasive procedure that could result in much lower compliance. Undergoing an HPV test without Pap smear is going to scare many women who are not at high or even moderate risk of cervical cancer.

The HPV test can only detect the presence of the virus, which in many cases will not result in cervical cancer; it cannot identify abnormal cells and it also cannot detect cancers of the cervix  that are not caused by HPV.

Although the FDA approved the use of the HPV test without cytology in 2014, it did not recommend replacing the safe and effective, well-established Pap screening regimen that has successfully prevented cervical cancer in the U.S.  FDA approval does not mean the HPV test is as good as the Pap smear, it only means it is better than placebo.

There has been little comparative effectiveness data comparing HPV-alone screening with HPV and cytology tests, known as co-testing. A new study published last month, conducted by scientists from the Quest Diagnostics laboratory and Magee-Women’s Hospital, analyzed data for over 256,000 women over 30[end Blatt AJ, Kennedy R, Luff RD, Austin RM, Rabin DS. Comparison of cervical cancer screening results among 256,648 women in multiple clinical practices. Cancer Cytopathol. 2015 May;123(5):282-8. Epub 2015 Apr 10.], and found that “approximately 19% of women with cervical cancer may be misdiagnosed by an HPV-only cervical screen.”  We urge the USPSTF to carefully review those data, and compare them to co-testing for women under 30 and those over 30.

The study data support co-testing in women ages 30 to 65 years as more effective at detecting pre-cancers and cancers. In addition, the study states that, “Co-testing performed better than HPV-alone or Pap-alone for cervical adenocarcinoma, a form of cervical cancer that is known to be harder to detect”.  It is important to consider and carefully scrutinize these data as the guidelines for cervical cancer screening undergo revision. We ask that USPSTF includes this study in its Proposed Research Approach — Evidence Review.

Current data indicate that HPV testing alone is likely to be much less accurate on women under 30, making the benefits of co-testing less likely for that age group.

In conclusion, based on current data and an excellent track record in the U.S., we believe Pap smear is an important screening tool, and that women should continue to rely on it every 3 years starting at age 21. Pap smears identify abnormalities in the cervix, which is useful by itself or together with an HPV test for women over 30. Most U.S. women who get cervical cancer did not have Pap smears within the last 5 years. In fact, some never had Pap smears. For that reason, women should continue to rely on Pap smears to screen for cervical cancer.  At the age of 30 or older, women may want to also be tested for HPV at the same time.

Letter to Secretary of Department of Health regarding application of new Tobacco Control Act

Legislation
January 29, 2015

The Honorable Sylvia M. Burwell
Secretary
Department of Health and Human Services
200 Independence Avenue, SW
Washington, D.C. 20201

 

Dear Secretary Burwell:

We are writing to affirm the public health importance of applying the new product provisions of the Family Smoking Prevention and Tobacco Control Act (Tobacco Control Act) to products the Food and Drug Administration (FDA) proposes to deem subject to its authority.

The Tobacco Control Act established a premarket review process for new tobacco products, which the statute defines as products introduced into interstate commerce after February 15, 2007 and products modified after that date. Tobacco companies that want to market a new tobacco product must first file a new product application seeking to demonstrate that their product is “appropriate to the protection of public health” or a substantial equivalence application seeking to show that their product is substantially equivalent to a grandfathered product on the market prior to February 15, 2007.

Several tobacco companies, as well as some Members of Congress, have expressed concern about how FDA has proposed applying the new product provisions to products that it is deeming subject to its authority. They have urged FDA to change the “grandfather date” in Section 910 of the statute from February 15, 2007 to the date of the proposed or final deeming rule, a request that also has been made by several members of Congress. We urge you to reject calls to change the new product “grandfather date” of the Tobacco Control Act. FDA has no statutory authority to alter the grandfather date and doing so would weaken FDA regulation of tobacco products with adverse consequences for the public health.

Premarket review of new tobacco products is central to the public health protections afforded by the Tobacco Control Act. The premarket review provisions were enacted as a response to the tobacco industry’s long history of introducing new products that are more addictive and more appealing, particularly to young people, while carrying a greater risk of disease. Any change in the grandfather date would exempt a wide variety of electronic cigarettes and other deemed products from any agency review to determine whether they pose a threat to public health.

The statute does not allow the FDA to alter the February 15, 2007 date in Section 910 and leaves FDA no discretion to either expand or contract the range of products subject to its review as “new tobacco products” by adjusting this date. If FDA were to alter this grandfather date, the effect would be to exempt a wide range of e-cigarettes, cigars and other tobacco products from any oversight or review to determine whether they constitute threats to public health, even though they deliver highly addictive nicotine. In recent years, we have witnessed the results of the unregulated e-cigarette market including a tripling of youth use of e-cigarettes in the last two years. Teen use of e-cigarettes now surpasses use of regular cigarettes, with over 16% of 10th graders and over 17% of 12th graders reporting use of ecigarettes, according to recent data from the government-sponsored Monitoring the Future survey. Ecigarette manufacturers have used marketing tactics similar to cigarette manufacturers to reach children and also used flavorings such as “Cherry Crush” and Pina Colada” that appeal to children. One study found that by January 2014 there were 466 brands of e-cigarettes and over 7700 unique flavors, a flood of new products that have not been reviewed by FDA. Furthermore, there have been significant reports of nicotine poisonings – mostly in those under 5 years old – from exposure to these products, including, tragically, one death. Grandfathering these products would make their exemption from new product review permanent.

FDA’s proposed deeming rule would afford manufacturers of e-cigarettes ample opportunity to meet the statutory standards for new products, while continuing to sell their products currently on the market, as well as introducing new products. FDA has proposed to use its enforcement discretion to give manufacturers of e-cigarettes and other deemed products a two year “compliance period” beyond the date of the final deeming rule. During this time manufacturers could file a new product application under Section 910 or a substantial equivalence application. Manufacturers would also be free to introduce new products during this time, as long as they file either a new product or substantial equivalence application prior to expiration of that period. FDA has also proposed to allow the new products for which applications have been filed during the two-year period to remain on the market until FDA acts on the application.

The Tobacco Control Act effectively created a similar compliance period for cigarettes, smokeless tobacco and roll-your-own tobacco, allowing manufacturers to introduce new products into commerce for a 21-month period following the June 22 effective date of the statute, as long as they filed substantial equivalence applications prior to expiration of that period (i.e. prior to March 22, 2011). However, the statute did not permit a “new tobacco product” to remain on the market, or be introduced into the market, unless the manufacturer alleged that it met the conditions for substantial equivalence. In contrast, the proposed deeming rule would permit the marketing of a new product even though no claim of substantial equivalence is made. Under the deeming proposal, e-cigarette manufacturers may keep their products on the market, and introduce new products, by filing for a new product marketing order before the new compliance period ends. These provisions already give ecigarettes more favorable treatment under the statute than that accorded to currently regulated tobacco products.

One of the major purposes of the Tobacco Control Act was to end the ability of the tobacco companies to introduce new, addictive products without any review or oversight. An expansion of the number of products excluded from review by the agency would be contrary to this purpose. FDA’s concern should not be that its proposed deeming rule denies market opportunities to e-cigarettes, but rather that its proposed rule would allow e-cigarette manufacturers to continue to target children for years into the future without any regulatory review of their products or their conduct.[1]

FDA should reject any request to modify the grandfather date for deemed products.

Sincerely,

American Academy of Family Physicians

American Academy of Pediatrics

American Association for Respiratory Care

American Cancer Society Cancer Action Network

American College of Cardiology

American College of Occupational and Environmental Medicine

American College of Preventive Medicine American Congress of Obstetricians and Gynecologists

American Heart Association American Lung Association

American Psychological Association

American Public Health Association

American Society of Clinical Oncology

American Thoracic Society

Association of Maternal & Child Health Programs

Association of State and Territorial Health Officials Campaign for Tobacco-Free Kids

Cancer Prevention and Treatment Fund

Legacy

National African American Tobacco Prevention Network

National Association of City and County Health Officials

National Latino Alliance for Health Equity

Oncology Nursing Society

Partnership for Prevention

Prevent Cancer Foundation

Prevention Institute

RiverStone Health

Society for Cardiovascular Angiography and Interventions

Society for Research on Nicotine and Tobacco

South Carolina Tobacco-Free Collaborative

United Methodist Church – General Board of Church and Society

 

 

[1] In comments filed in the docket in which FDA proposed to extend its regulatory authority, the undersigned groups urged FDA to shorten the compliance period during which such products could remain on the market in the absence of a new product or substantial equivalence application. We also urged FDA to allow manufacturers of deemed products to benefit from the agency’s enforcement forebearance in creating a compliance period only if they abide by various conditions to prevent marketing to youth.

 

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.

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