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To Warn or Not to Warn: When the Science Behind the Hazard is Controversial
Michael D. Shalhoub
Joseph J. Welter
[email protected]
[email protected]
914.798.5471
716.566.5457 © 2017 Goldberg Segalla LLP
WARNINGS AND DEVELOPING SCIENCE • • • • • •
Human Factors Perspective Legal Duty to Warn FDA Regulatory Considerations Understanding Scientific Research Talc/Ovarian Cancer Controversy Lessons and Takeaways © 2017 Goldberg Segalla LLP
DUTY TO WARN: HUMAN FACTORS PERSPECTIVE
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The Human Factors Approach to Hazard Analysis • Threshold step for any warnings analysis is to identify whether any hazard exists • Without a hazard, there is no need to warn
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The Human Factors Approach to Hazard Analysis • Techniques available to research and determine whether a potential hazard may exist in connection with a product – product testing/experimentation – search for published documents – group meetings – focus groups – field studies – Surveys
Wogalter, Handbook on Warnings © 2017 Goldberg Segalla LLP
The Human Factors Approach to Hazard Analysis • Published documents include: – – – – – – – –
journal articles technical reports governmental reports medical case studies and position papers conference proceedings accident reports trade magazine articles newsletters, handbooks, and textbooks
Wogalter, Handbook on Warnings © 2017 Goldberg Segalla LLP
The Human Factors Approach to Hazard Analysis • The fact that a potential hazard is conceived or hypothesized is not what triggers a manufacturer’s responsibility to warn • Every day there are unproven hypothesized hazards that are pondered and studied, many of which turn out to be nonexistent © 2017 Goldberg Segalla LLP
The Human Factors Approach to Hazard Analysis • With respect to advancements in scientific and medical knowledge, that is sometimes an evolutionary process occurring over many years • It is not always clear when a manufacturer should act under these circumstances © 2017 Goldberg Segalla LLP
The Human Factors Approach to Hazard Analysis • The quality, strength, and consistency of the published medical findings are all considerations in determining whether a health hazard exists and, if it does exist, when was it sufficiently established to suggest the inclusion of a warning © 2017 Goldberg Segalla LLP
Danger of Over-warning • FDA: too many warnings and precautions “dilutes the strength of all the hazard alerts” (FDA Guidance: Guidance on Medical Device Patient Labeling) • Human factors research demonstrates this issue
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LEGAL DUTY TO WARN
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Failure to Warn State Common Law • Generally, most states say that manufacturer must warn of product’s hazards where those hazards were known or knowable when manufactured. – Manufacturer may be liable for failing to warn of potentially dangerous propensities when it has reason to anticipate the danger. – In other words, a manufacturer is required to warn where a reasonably prudent manufacturer would have warned. © 2017 Goldberg Segalla LLP
Failure to Warn State Common Law • In most jurisdictions, showing a danger was “knowable” is really a question of whether it was actually known to experts in the field. – “State of the Art” • Plaintiffs must prove that the risk in question was known or should have been known to the relevant manufacturing community. © 2017 Goldberg Segalla LLP
Failure to Warn State Common Law • When is a risk “knowable”?? – Rosa v. TASER, Inc.: 9th Circuit applying California law: • Manufacturer held to knowledge and skill of expert in the field and obliged to keep abreast of scientific discoveries and presumed to know the results of advances. • “But, a manufacturer is NOT under a duty to warn of every report of a possible risk, no matter how speculative, conjectural, or tentative, because inundating the public indiscriminately with notice of any and every hint of danger would inevitably dilute the force of any specific warning given." • “Reports of isolated or speculative injuries do not constitute generally accepted medical knowledge.” © 2017 Goldberg Segalla LLP
Failure to Warn State Common Law- California • Strict Liability for Failure to Warn – California: • Plaintiff must show a danger existed associated with a foreseeable use of the product and that defendant failed to adequately warn of a known or knowable risk where that failure caused the injury. • Whether the risk was known or knowable is assessed at the time of product distribution. © 2017 Goldberg Segalla LLP
Failure to Warn State Common Law - California • Negligence for Failure to Warn - Requires a plaintiff to prove that a manufacturer or distributor did not warn of a particular risk for reasons which fell below the acceptable standard of care, i.e., what a reasonably prudent manufacturer would have known and warned about. © 2017 Goldberg Segalla LLP
Failure to Warn State Common Law • Outlier Jurisdictions Rejecting the Knowability Requirement: – Washington (actual or constructive knowledge required for negligence claim but not for strict liability). – New Jersey (in strict liability cases culpability is irrelevant and state of the art defense is therefore inappropriate because it amounts to assertion of blamelessness). – Hawaii (in strict liability actions state of the art evidence is not admissible to show manufacturer knew or should have known of danger) © 2017 Goldberg Segalla LLP
FDA REGULATORY CONSIDERATIONS
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“The Law:” Required warnings for drugs and devices • Adequate warnings needed to protect against use – In those pathologic conditions, or by children – where its use may be dangerous to health, or – Where there may be unsafe dosage or methods, or – Duration of administration of application © 2017 Goldberg Segalla LLP
“The Law”: Required warnings for drugs and devices • Unless exempted by FDA • Warnings must be in such manner or form, as necessary for the protection of users
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“The Law”: Factors for misleading labeling for drugs and devices • Whether an article is misbranded because a warning is misleading, the following factors to be taken into account (among other things): – representations made or suggested by the seller, and
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“The Law”: Factors for misleading labeling for drugs and devices • the extent to which the labeling fails to reveal facts material in the light of such representations • or material with respect to consequences which may result from the use of the article to which the labeling or advertising relates • under the conditions of use prescribed in the labeling or • under such conditions of use as are customary or usual. © 2017 Goldberg Segalla LLP
FDA Drug Guidance • (2011): https://www.fda.gov/downloads/Drugs/ GuidanceComplianceRegulatoryInform ation/Guidances/UCM075096.pdf * • “reasonable evidence” of a causal association, but causal association need not be “definitively established.” * Warnings and Precautions, Contraindications, and Boxed Warning Sections of Labeling For Human Prescription Drug and Biologic Products Content and Format (2011) © 2017 Goldberg Segalla LLP
FDA Drug Guidance Factors • Frequency of event • Does the adverse event rate in the treatment group exceed the rate in the placebo and active-control group • Evidence of dose-response • Extent to which the adverse event is consistent with the pharmacology of the drug • Temporality • Dechallenge and rechallenge • Is the adverse event is known to be caused by related drugs? © 2017 Goldberg Segalla LLP
Drugs and Unapproved Uses • FDA may require a discussion of adverse events in unapproved uses if clinically significant risk of hazard • Must state that this use is not FDA approved – and that safety and effectiveness not established in that setting © 2017 Goldberg Segalla LLP
Devices • Similar – FDA encourages consistency between drugs and devices re labeling • Warn if there is reasonable evidence of association of a serious hazard with the use of the device. – A causal relationship need not have been proved. © 2017 Goldberg Segalla LLP
Devices • Warning is appropriate when the device is commonly used for an off-label and such usage is associated with a serious risk or hazard • Provide frequency data
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Devices • Class 1 and 2 devices – FDA reviews labeling, including warnings • Class 3 devices FDA approves labeling • All classes, FDA can require language it deems appropriate, including warnings and cautions © 2017 Goldberg Segalla LLP
FDA Guidance Documents • Labeling: Regulatory Requirements For Medical Devices (1989) • Device Labeling Guidance - #G91-1 (1991) • Human Factors Principles For Medical Device Labeling (1993) • Write it Right (1993) • Guidance on Medical Device Patient Labeling: Final Guidance For Industry and FDA Reviewers (2001) © 2017 Goldberg Segalla LLP
Cosmetics § 740.1 Establishment of warning statements. (a) The label of a cosmetic product shall bear a warning statement whenever necessary or appropriate to prevent a health hazard that may be associated with the product. (b) The Commissioner of Food and Drugs . . . , either on his own initiative or on behalf of any interested person who has submitted a petition, may publish a proposal to establish . . . a regulation prescribing a warning for a cosmetic. Any such petition shall include an adequate factual basis to support the petition. . . .
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21 C.F.R. § 740.1 Regulation promulgated under authority from Federal Food, Drug and Cosmetic Act, 21 U.S.C. § 301 et seq. The term "cosmetic" means (1) articles intended to be rubbed, poured, sprinkled, or sprayed on, introduced into, or otherwise applied to the human body or any part thereof for cleansing, beautifying, promoting attractiveness, or altering the appearance, and (2) articles intended for use as a component of any such articles; except that such term shall not include soap.
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UNDERSTANDING SCIENTIFIC RESEARCH
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Consensus in Scientific Community
No Scientific Support
A Chasm of Uncertainty
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THE SCIENTIFIC LITERATURE
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Strength of Scientific Evidence MetaAnalysis Systematic Review Randomized Controlled Trial Cohort Studies
Case Control Studies
Case Series/Case Reports
Animal Research
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What is Epidemiology? • Epidemiology is the method used to find the causes of health outcomes and diseases in populations. In epidemiology, the patient is the community and individuals are viewed collectively. By definition, epidemiology is the study (scientific, systematic, and data-driven) of the distribution (frequency, pattern) and determinants (causes, risk factors) of healthrelated states and events (not just diseases) in specified populations (neighborhood, school, city, state, country, global). It is also the application of this study to the control of health problems (Source: Principles of Epidemiology, 3rd Edition).
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What is a Case Report? • A case report is observation made in a patient presentation, nothing more • By itself, it cannot be evidence of a causal connection • It is only a basis for forming a hypothesis that would then need to be tested based on other scientific means
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What is a Case Series? • A case series is simply a bunch of case reports • A case series regardless of how many people are studied, by itself, does not provide a basis for drawing any conclusions on causation • A case series for the basis for a hypothesis © 2017 Goldberg Segalla LLP
What is a Meta-Analysis? • A meta-analysis is an epidemiological study analyzing a group of epidemiology studies on a particular issue to determine what conclusions can be drawn from the body of literature.
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What is a Cohort Study? • Retrospective- Retrospective cohort studies look at data that already exists and tries to identify risk factors for particular conditions; researchers are inherently limited in their interpretations because they cannot retrospectively gather missing data. http://www.medicalnewstoday.com/articles/281703.php
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What is a Cohort Study? • Prospective- In a prospective cohort study, researchers first raise a research question, forming a hypothesis about the potential causes of a disease. The researchers then observe a group of people, the cohort, over a period of time (often several years), collecting data that may be relevant to the disease. This allows the researchers to detect any changes in health in relation to the potential risk factors they have identified. http://www.medicalnewstoday.com/articles/281703.php
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What is a Clinical Trial? • Clinical trials are research studies that explore whether a medical strategy, treatment, or device is safe and effective for humans. These studies also may show which medical approaches work best for certain illnesses or groups of people. Clinical trials produce the best data available for health care decision-making. https://www.nhlbi.nih.gov/studies/clinicaltrials
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What is An Animal Study? • A laboratory experiment using animals to study the development and progression of diseases. Animal studies also test how safe and effective new treatments are before they are tested in people.
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TALC AND OVARIAN CANCER LITIGATION: Convergence Of Human Behavior, the Law, Regulations and Science
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Plaintiff’s Hypothesis Plaintiffs contend that women use talc-based products in the genital area which creates the opportunity for talc to migrate up the vaginal tract, leading to inflammation and the development of ovarian cancer
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American Cancer Society • Many studies in women have looked at the possible link between talcum powder and cancer of the ovary. Findings have been mixed, with some studies reporting a slightly increased risk and some reporting no increase. Many casecontrol studies have found a small increase in risk. But these types of studies can be biased because they often rely on a person’s memory of talc use many years earlier. Two prospective cohort studies, which do not have the same type of potential bias, do not find an increased risk. • For any individual woman, if there is an increased risk, the overall increase is likely to very be small. Still, talc is widely used in many products, so it is important to determine if the increased risk is real. Research in this area continues. http://www.cancer.org/acs/groups/cid/documents/webcontent/002793-pdf.pdf
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There is limited evidence in humans for the carcinogenicity of perineal use of talc-based body powder. Perineal use of talc-based body powder is possibly carcinogenic to humans (Group 2B). . . . “Group 2B: ‘Possibly carcinogenic to humans’ There is some evidence that it can cause cancer in humans but at present it is far from conclusive.”
World Health Organization, International Agency for Research on Cancer, IARC Monographs on the Evaluation of Carcinogenic Risks to Humans, Volume 93, Carbon, Titanium Dioxide and Talc (2010)
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• “Published scientific literature going back to the 1960s has suggested a possible association between the use of powders containing talc and the incidence of ovarian cancer. However, these studies have not conclusively demonstrated such a link, or if such a link existed, what risk factors might be involved.”
http://www.fda.gov/Cosmetics/ProductsIngredients/Ingredients/ucm293184.htm
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• In 2014, in response to a citizen’s petition that warning labels be placed on talc products because of the possible link to cancer, the FDA stated:
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Studies Finding No Increased Risk of Cancer • • • • • • • •
Hartge (1983) – No association Whitmore (1988) – No statistically significant trends Tzonou (1993) – No association Wong (1999) – No association demonstrable even with prolonged exposure Gertig (2000) – No overall association Huncharek (2007) – Data do not support causal association Langseth (2008) – Insufficient evidence Houghton (2014) – “Perineal powder use does not appear to influence ovarian cancer risk”
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Possible Association • Booth (1989)- increased relative risk of women using talcum powder for more than a week; “further work is needed” • Purdie (1995) • Chang (1995) • Mills (2004) • Buz’Zard (2007) • Rosenblatt (2011)- no stronger adjective than “possible” appears warranted © 2017 Goldberg Segalla LLP
Studies Suggesting Increased Risk • • • • • • • • • • • •
Cramer (1982)- 1.92 RR Harlow (1989)- 2.8 RR Harlow (1992)- 1.5 RR Rosenblatt (1992) 4.79, 2.35 OR Cook (1997)- 1.6 RR Cramer (1999)- 1.6 OR Ness (2000)- increased RR Merritt (2008)- 1.17 OR Gates (2008)- 1.36 RR Wu (2009)- 2.08 RR Terry (2013)- 1.24 OR Cramer (2016)- 1.33 OR
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The St. Louis Cases
• Fox (Feb. 2016)- $72 million verdict • Ristesund (May 2016)- $55 million verdict • Gianechinni (October 2016)- $70 million verdict • Daniels (March 2017)- Defense Verdict © 2017 Goldberg Segalla LLP
The New Jersey Cases • Carl and Balderrama (September 2016) • Following Kemp hearing, court precluded plaintiffs’ medical causation experts
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Kemp Hearing • Defendants moved to preclude plaintiffs’ medical causation experts, Dr. Graham Colditz and Dr. Daniel Cramer • Judge Nelson C. Johnson • Kemp Hearing held over seven days • Over 100 treatises considered • Nine expert witnesses testified • 33 page decision with 5 appendices
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The Court’s Rejection of Dr. Colditz’s Methodolgy • “Even the most generous reading of these four cited articles reveals that none of them proffers an articulation of a hypothesis – nor a means by which to test the same – setting forth a biologic mechanism by which talc-based powder may/can/possibly does cause ovarian cancer. Dr. Colditz’s reliance upon these four treatises supports finding by this court that he has failed to make a systematic review of the scientific literature and has ignored the rudiments of the scientific method in arriving at his conclusion.’” © 2017 Goldberg Segalla LLP
The Court’s Rejection of Dr. Cramer’s Methodology • “His opinions rely on an incomplete/irregular methodology unlike anything upon which his peers would rely, and appear to be grounded only in his instincts and personal predilections. In short, the mingling of various rick factors and the purported ‘synergy’ between talc and other health conditions is highly speculative and does not conform to any methodology utilized in the scientific community.” © 2017 Goldberg Segalla LLP
What is Coming Next? • State Court Litigation • St. Louis — 1,000-plus cases pending in St. Louis • New Jersey — MCL with140 cases pending • California — up to 2,000 cases potentially consolidated • Smattering of cases in other state courts © 2017 Goldberg Segalla LLP
What is Coming Next? • Federal Court Litigation • 54 related actions in twenty different federal district courts • MDL created in the District of New Jersey • Honorable Freda Wolfson • All pending actions transferred • Majority are personal injury or wrongful death claims • Two class actions • Ovarian and uterine cancer © 2017 Goldberg Segalla LLP
WHAT SHOULD A MANUFACTURER DO?
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LESSONS AND TAKEAWAYS
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Lessons and Takeaways • Monitor relevant literature • Carefully consider adverse event reports/MDRs • Always a balancing act • Don’t wait until you (or others) decide that it is scientifically proven • Weigh concerns about over-warning • Consider hybrid informational warning © 2017 Goldberg Segalla LLP
Lessons and Takeaways • Consider retaining FDA warnings or human factors warnings expert in assessing: – Whether to warn – What to say
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Questions?
Michael D. Shalhoub
Joseph J. Welter
[email protected] [email protected]
914.798.5471
716.566.5457 © 2017 Goldberg Segalla LLP
