OPDP Warning Letter Posted Sep 2017 FDA Draft Guidance Medical Product Communications That Are Consistent With the FDA-Required Labeling Q&A s (Issued January 2017) Web Meeting Sep 20, 2017 Presented by: Kimberly Belsky, DIA AdPromo WG Chair
Topics Covered Introduce the new AdPromo WG Co-Chair Conzip OPDP WL Consistent With FDA Draft Guidance What topics do you want to cover?
Welcome Dolores!
AdPromo WG Co-Chair Welcome to Dolores Shank-Samiec, Executive Director of Promotion and Advertising Review at Merck Joining us in October
Hold the Dates! The DIA AdPromo WG will generally meet on the 3 rd Wednesday of each month at noon eastern The next upcoming meetings are October 18 November 15 December 13
OPDP Warning Letter
Conzip (tramadol hydrochloride) OPDP Warning Letter Warning Letter dated Aug 24, 2017 (posted Sep 1, 2017) This is the 2 nd OPDP letter posted in 2017 (1-WL, 1-NOV) CONZIP (tramadol hydrochloride) extended-release capsules for oral use, CIV (Cipher Pharmaceuticals) Indication: an opioid agonist indicated for the management of pain severe enough to require daily around-the-clock, long-term opioid treatment and for which alternative treatment options are inadequate. Includes a boxed warning with limitations of use regarding abuse Violations: Omits important risk information and omits other material facts Additional images available from Promotional material link Warning Letter Promotional Material
Conzip (tramadol hydrochloride) OPDP Warning Letter Omission of risk: The detail aid includes representations/claims of efficacy however, the materials does not include any risk information. Omission of material facts: The complete FDA approved indication is omitted, this includes for which alternative treatment options are inadequate and the Limitations of Use (which is part of the FDA approved indication and required.)
Enforcement Letter Trending Trending by K. Belsky
Overview Issued January 19, 2017 http://www.fda.gov/downloads/drugs /GuidanceComplianceRegulatoryInfo rmation/guidances/ucm537130.pdf Applies to Rx drugs, biologics and medical devices (and animal health drugs) The term device refers to a medical device intended for human use, including a device that is licensed as a biological product If you re looking for this guidance https://www.fda.gov/drugs/guidancecomplianceregulatoryinformation/guid ances/ucm065015.htm
Overview Intent of the Guidance Describes how FDA determines whether a firm s communication is consistent with the FDA-required labeling Clarifies for firms that FDA does not view consistent with FDA-required labeling (CFL) communications alone as evidence of a new intended use Provides general recommendations for conveying CFL information in a truthful and non-misleading way Through Q&A s FDA provides some clarity on examining whether a firm s communications are consistent with the approved labeling What the guidance does not do Address off label communications Relieve firms of obligations to comply with other applicable requirements The communications should be truthful and non-misleading Change a firm s existing obligations to update its FDA-required labeling to ensure that the labeling is not false or misleading, or for other reasons
How Will FDA Assess Communications? Guidance provides a 3-factor approach to evaluate whether a communication is consistent with the product s FDArequired labeling (CFL) FDA also evaluates whether communications are truthful and non-misleading; the guidance provides recommendations for firms to consider when developing their presentations of information that is CFL DIA AdPromo Conference, February 2017 session2_gray_consistent With Draft Guidance
A View From Former FDA Commissioner Califf Califf provided a distinction between within in the label and 'off-label,' Off-Label means that it is a totally different indication make it clear that when you are providing a greater depth of information for the labeled indication that is okay or good as long as you are truthful and non-misleading about what you say about it. https://pink.pharmamedtechbi.com/ps119983/us-fdas-within-label-definition-allows-companies-to-elaborate-on-indications
Background: Substantial Evidence
Regulation Review Substantial Evidence to Establish Safety and Efficacy for Approval To approve a new drug, FDA reviews the NDA to assess, among other things, whether the drug is safe and effective for its intended purpose. FFDCA Section 505(d) refers to substantial evidence, defined as: evidence consisting of adequate and well-controlled investigations, including clinical investigations, by experts qualified by scientific training and experience to evaluate the effectiveness of the drug involved, on the basis of which it could fairly and responsibly be concluded by such experts that the drug will have the effect it purports or is represented to have under the conditions of use prescribed, recommended, or suggested in the labeling or proposed labeling thereof.. 21 C.F.R. 314.126 describes characteristics of adequate and well-controlled studies, which include a statement of objectives, an analytic plan, a control group, quantification of treatment duration and timing, and method of sample size determination. The study design would lead to the identification of appropriate research subjects and include methods to minimize bias in the assignment of subjects to treatment groups as well as in data analysis. Historically, these characteristics describe a controlled (often randomized) clinical trial
Substantial Evidence and SASS FDA Regulation at the 11th Hour Parting Shots from the Obama Administration, Sidley Webinar January 25, 2017
The January 2017 Draft Guidance
Three Factor Test to Determine Consistent With DIA AdPromo Conference, February 2017 session2_gray_consistent With Draft Guidance
Considerations for the Evidentiary Support of CFL Communications Representations or suggestions need to be: Grounded in fact and science Presented with appropriate context Any data, studies, or analyses relied on should be scientifically appropriate and statistically sound to support the representations or suggestions made in the CFL communication If a communication relies on a study that is inadequate to support the representations/suggestions presented, disclosing the limitations of the study does not correct the misleading message DIA AdPromo Conference, February 2017 session2_gray_consistent With Draft Guidance
A Consideration for Device Firms Device firms should consider these examples in conjunction with existing regulations, guidances, and policies, for example: regarding when a special control may trigger certain labeling requirements for a specific device type or a modification to the indications for use of a device would trigger the need for a new premarket submission. If the information that a firm wants to communicate represents a modification to the indications for use of the device, it would not be considered consistent with the FDA-required labeling Lines 171-176 of draft guidance
A Communication Is Determined to Be CFL Now What? If all three of these factors are met, FDA will not view that communication alone as evidence that a firm intends to promote the drug or device for a new intended use Communications that lack appropriate evidentiary support are likely to be false or misleading, and can cause patient harm FDA will not consider a communication to be misleading based only on the lack of evidence sufficient to satisfy the applicable approval/clearance evidentiary standard Nevertheless, the communication could be false or misleading for other reasons. The data, studies and/or analyses must be scientifically appropriate and statistically sound DIA AdPromo Conference, February 2017 session2_gray_consistent With Draft Guidance
Is the CFL Communication False or Misleading? DIA AdPromo Conference, February 2017 session2_gray_consistent With Draft Guidance
Other False and Misleading Considerations Caution: There must be adequate powering on individual component endpoints that may have been studied Certain analyses of pivotal trial data may provide information that elaborates on the data in the product s FDA-required labeling and could improve understanding of a product For example, information from separate analyses of the individual components of a composite endpoint successfully used as the primary endpoint and derived from appropriate statistical tests and pre- specified in the statistical analysis plan
Other False and Misleading Considerations (cont) However, if the pivotal trial was not adequately powered to determine treatment effect on the individual components of the composite endpoint and/or type 1 error (false positive rate) was not controlled for these analyses, these analyses would generally not support conclusions about a treatment effect on the individual components of the composite endpoint Variety of enforcement examples regarding promotion of individual components of a composite endpoint Representing or suggesting data support efficacy conclusions, either directly (e.g., by claiming the product has demonstrated efficacy on the individual components) or indirectly (e.g., by presenting p-values, which would imply a statistically rigorous conclusion where one does not exist), would be false or misleading
Related New Draft Guidance: Multiple Endpoints in Clinical Trials Detailed discussion of FDA s thinking about the problems posed by multiple endpoints and how these problems can be managed Generally, as the number of endpoints analyzed in a single trial increases, the likelihood of making false conclusions about a drug s effects with respect to one or more of those endpoints becomes a concern Basing a conclusion on an analysis where the risk of false conclusions has not been appropriately controlled can lead to false or misleading representations regarding a drug s effects Draft guidance describes various strategies for grouping and ordering endpoints for analysis and applying some well-recognized statistical methods for managing multiplicity [P]resenting p-values from descriptive analyses (that is, from analyses that were not prespecified and for which appropriate multiplicity adjustments were not applied) is inappropriate because doing so would imply a statistically rigorous conclusion and convey a level of certainty about the effects that is not supported by that trial. FDA Draft Guidance for Industry: Multiple Endpoints in Clinical Trials (Jan. 2017) http://www.fda.gov/downloads/drugs/guidancecomplianceregulatoryinformation/guidances/ucm536750.pdf
A Note from FDA to Medical Device Firms A caution to device firms: In addition, device firms should consider these examples in conjunction with the Agency s existing regulations, guidances, and policies, for example, regarding when a special control may trigger certain labeling requirements for a specific device type or when a modification to the indications for use of a device would trigger the need for a new premarket submission. If the information that a firm wants to communicate represents such a modification to the indications for use of the device, it would not be considered consistent with the FDA-required labeling.
Consistent v. Not Consistent FDA Regulation at the 11th Hour Parting Shots from the Obama Administration, Sidley Webinar January 25, 2017
A Deeper Look at Superiority Claim Comparing Two Drugs With Same Indication A firm s communication provides information from a head-to-head study indicating that its drug that is approved to treat high blood pressure in adults has superior efficacy to another drug that is also approved to treat high blood pressure in adults - Also can compare safety To be consistent, the information must not alter the benefit-risk profile in a way that may result in increased harm to health (Factor 2) One head-to-head study can be enough if
A Deeper Look at Additional context for Adverse Reactions FDA-required labeling for a product identifies nausea as a potential adverse reaction and further indicates the product can be taken with or without food. A firm s communication about the product provides information about how taking a product with food might reduce nausea
A Deeper Look at Onset of Action The FDA-required labeling for a product approved to treat major depressive disorder does not contain information about onset of action prior to the point in time designated as the study s endpoint, and a firm s communication provides information indicating that the product shows an effect relative to the control at 2 weeks Even though not an endpoint, interim data may be shared that shows onset of action (so long as data relates to approved indication & dose/use regimen)
A Deeper Look at Long-Term Safety & Efficacy of Chronic Use Drug A firm provides postmarketing information for its product, which was approved for chronic use based on 24-week study data, regarding persistent safety and/or efficacy over 18 months Use of post-marketing data about safety and efficacy over longer timeframe than pivotal trials --- treatment for chronic use
A Deeper Look at Effects of Drug on Subgroup A firm s communication provides information on the number of female patients that were studied in its pivotal clinical trials and the treatment effects in that patient group, or, in the case of a diagnostic product, the diagnostic performance in that patient group Can provide information about how treatment affected patient subgroups if within the approved patient population. Consider: Does the subgroup calculations need to be scientifically appropriate, statistically significant or is the original trial analysis enough?
A Deeper Look at PRO And Convenience The effects of a product that comes directly from the patient (i.e., patient-reported outcomes) - [use caution!!] For example, a firm s communication provides information concerning patient compliance/adherence, or a firm s communication provides information about patients perceptions of the product s effect on their basic activities of daily living. Product convenience [use caution!!] Patient Compliance or Adherence and Perceptions of Product s Effect on Basic Activities of Daily Living
A Word of Caution - Individual Components of Composite Endpoint FALSE OR MISLEADING IF: represent/suggest that data support efficacy conclusions thru: Direct claim that product demonstrated efficacy on the individual components Indirect claim by presenting p-values, which implies a statistically rigorous conclusion where one does not exist Trial must be adequately powered & controlled to analyze treatment effect on individual components of the composite endpoint and/or type 1 error (false positive rate)
Consistent With - Devil is in the Details For Example: Convenience Information concerning product convenience (e.g., a firm s communication for its drug product, which is indicated for in dogs, provides information about the convenient dosing schedule of the product for pet owners based on its long duration of effect) Proceed with caution. Cannot imply unsubstantiated superiority Area of historical enforcement
Consistent With Devil is in the Details For Example: Patient Reported Outcomes Information concerning the effects of a product that comes directly from the patient (i.e., patient-reported outcomes) when the product is used for its FDA- approved/cleared indication in its approved/cleared patient population (e.g., a firm s communication provides information concerning patient compliance/adherence, or a firm s communication provides information about patients perceptions of the product s effect on their basic activities of daily living) Proceed with caution. Cannot imply Quality of Life Changes. Area of historical enforcement http://www.fda.gov/downloads/drugs/guidancecomplianceregulatoryinformation/enforcementactivitiesbyfda/warninglettersand NoticeofViolationLetterstoPharmaceuticalCompanies/UCM168896.pdf
Examples of NOT Consistent With Using the product to treat or diagnose a difference disease or condition than approved/cleared for the product Treating or diagnosing a different patient population than the approved/cleared patient population Use of the product to treat a different stage, severity, or manifestation of a disease than is approved/cleared to treat (e.g. severe asthma vs. mild asthma) Use of a product as monotherapy when it is only approved/cleared for use with one or more other products or therapeutic modalities A different route of administration or use in a different tissue type than is approved/cleared Use of a different strength, dosage, or use regimen than is approved/cleared Use of a different dosage form than in the approved labeling
A Look at Comments Submitted to FDA
Selected Comments Submitted to FDA Evidentiary Standards BIO requests how FDA will reconcile the evidentiary standard ultimately adopted in final versions of both guidances with current regulations governing promotional claims One way to reconcile these standards is for the agency to state that information consistent with the final guidances shall for all purposes under existing regulations be considered information that is supported by substantial clinical experience, notwithstanding any contrary guidance or rules of construction, BIO suggestion: The agency can state that information consistent with the final guidances shall for all purposes under existing regulations be considered information that is supported by substantial clinical experience, notwithstanding any contrary guidance or rules of construction Alternatively, FDA could finalize the guidance and seek to modernize the applicable regulations to keep pace with such guidance
Selected Comments Submitted to FDA Scope of the Guidance FDA should make clear that medical product communications fall within the scope of both guidances if they meet the related to standard in the payer guidance Additional Examples Needed PhRMA requests examples other than primary endpoints from randomized, controlled trials. Prominent examples could include post-hoc analyses of clinical trial results, including subpopulation analyses; observational data; pooled analysis/integrated data; and real-world evidence, Expressly Exclude Scientific Exchange PhRMA, BIO and others request clarity that non-promotional medical product communications, traditionally referred to as scientific exchange, fall outside of the guidance s scope.
Final Thoughts
Final Thoughts FDA reminds us that the considerations described in the draft are not intended to be a comprehensive summary of everything a firm should factor into its analysis of whether its presentations are truthful and non-misleading The role of the review committee FDA recommends that, before disseminating a communication regarding a medical product, firms should have qualified medical, legal, and regulatory personnel carefully review the communication to ensure it is not false or misleading. 4 2
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Back Up
Key Points Explicitly recognizes that labeling is not intended to be an exhaustive summary of all that is known about a product for its approved or cleared uses. Representations or suggestions that are consistent will not be considered false or misleading based only on the lack of evidence to satisfy the applicable approval/clearance standard (e.g., substantial evidence for drugs) FDA will not view medical product communications that are consistent with, but not included in, the FDArequired labeling as stand-alone evidence of a new intended use, and will not subject a firm to enforcement action for misbranding so long as the representations and suggestions made in that communication are not false or misleading Consistent communications could nonetheless misbrand the product... if the representations or suggestions or suggestions made... are false or misleading in any particular
Factor 1: Comparison of Information in the Communication to the Product s FDA Labeling Consider: Will this result in an increased reliance upon your medical reviewers and time to for input by clinical/statistician DIA AdPromo Conference, February 2017 session2_gray_consistent With Draft Guidance
Factor 2: Does the Communication Increase the Potential for Harm to Health Relative to the Labeling? If a communication alters the risk-benefit profile of a product in a way that may result in increased harm to health, this indicates the communication is not CFL This includes potential for harm from abuse or misuse, or the potential for harm to the health of humans from certain animal drug uses, or the potential for harm to health from secondary exposure to certain medical products DIA AdPromo Conference, February 2017 session2_gray_consistent With Draft Guidance
Factor 3: Do the Directions for Use in the Labeling Enable the Product to Be Safely and Effectively Used? Does the product s required labeling provide the necessary information to use the product safely and effectively under the conditions suggested in the communication? Adequate information about potential or expected risks? Adequate information about the indication & population? Adequate information about dosing & administration? Adequate information about clinical effects? Not an Exhaustive List DIA AdPromo Conference, February 2017 session2_gray_consistent With Draft Guidance
PhRMA / BIO Principles on Sharing of Truthful and Non-Misleading Information: Principle #3 Companies Should Provide Scientific Substantiation if Shared Information is Not Contained in FDA-Approved Labeling Health care professionals rely on a wide range of data from a variety of sources to inform patient care. There are many types of data and analyses that are scientifically- and statistically-sound, and thus can support truthful and nonmisleading communication about medicines. When communicating evidence based on clinical research other than in the form of adequate and wellcontrolled trials, companies should disclose sufficient information for the audience to understand the specific research and any limitations. It is particularly important for a company to portray accurately the applicable methodologies and data, which can include limitations in the study methodology and/or statistical results. PhRMA / BIO Principles on Responsible Sharing of Information About Medicines with HCPs and Payors (July 2016) 4 9
PhRMA / BIO Principles and Post-hoc Analyses Post hoc analyses, including sub-population data Randomized controlled clinical trials and observational studies often collect information on the safety and effectiveness of medicines in subpopulations, including specific gender and ethnic cohorts. The analysis of these data often occurs after the conclusion of the trial, as the subpopulation data may not have been pre-specified endpoints or part of the original plan of analysis. If the trial has met its primary endpoint, this specific sub-population information can help health care professionals develop treatment strategies based on more precise safety and efficacy data for a particular cohort of patients. 5 0
References
Additional Reading and References PhRMA/BIO Principles on Responsible Sharing of Information About Medicines (July 2016) http://www.phrma.org/codes-and-guidelines/principles-on-responsible-sharing-of-truthful-andnon-misleading-information-about-medicines-with-health-care-professionals-and-payers FDA draft guidance entitled Distributing Scientific and Medical Publications on Risk Information for Approved Prescription Drugs and Biological Products Recommended Practices (June 2014), http://www.fda.gov/downloads/drugs/guidancecomplianceregulatoryinformation/guidances/ucm4 00104.pdf FDA s draft guidance Responding to Unsolicited Requests for Off-Label Information About Prescription Drugs and Medical Devices Practices (December 2011), http://www.fda.gov/downloads/drugs/guidancecomplianceregulatorylnformation!guidances/uc M285145.pdf FDA s guidance Good Reprint Practices for the Distribution of Medical Journal Articles and Medical or Scientific Reference Publication on Unapproved New Uses of Approved Drugs and Approved or Cleared Medical Devices (January 2009), http://www.fda.gov/regulatoryinformation/guidances/ucm125126.htm FDA s revised draft guidance Distributing Scientific and Medical Publications on Unapproved New Uses Recommended Practices (February 2014), http://www.fda.gov/downloads/drugs/guidancecomplianceregulatoryinformation/guidances/ucm3 87652.pdf