FDA Prescription Drug Marketing Regulatory Primer
The Food and Drug Administration (FDA) Office of Prescription Drug Promotion (OPDP), held a workshop at the Drug Information Association (DIA) 2012 Annual Meeting that walked attendees through actual examples of where promotional materials for pharmaceutical products fell short of meeting FDA requirements.
During this interactive DIA workshop, “Prescription Drug Marketing Regulatory Primer,” held June 27 in Philadelphia, Michael Sauers, team leader (DTC1) at OPDP “provided some basic tenets of prescription drug promotion regulation and then led the audience through a sampling of promotional pieces that the agency found to have violated the regulations,” noted the Coalition for Healthcare Communication.
“For example, in describing omission of risk information – a violation commonly cited in OPDP Warning Letters and Untitled Letters – Sauers showed DIA session attendees a promotional flyer for ISTA Pharmaceuticals’ BROMDAY, which was cited in a July 13, 2011, Warning Letter. Although the flyer making claims regarding the use of Bromday in cataract surgery discloses the most common adverse reactions associated with that use, it does not reveal any of the warnings and precautions for the drug.”
Promotional materials that make product claims must also provide risk information, according to Sauers, who noted that this risk information should include contraindications, warnings, precautions and pertinent adverse events. Further, even though the Bromday flyer included the statement, “Please see full prescribing information on reverse,” that reference does not fulfill regulatory requirements, Sauers explained.
One way manufacturers can violate the Food, Drug and Cosmetic Act (FDCA) provisions regarding promotion, labeling or misbranding is by “omitting risk information.” Sauers noted in his presentation that:
- Promotional materials that make product claims must also provide risk information
- Risk information should include Contraindications, Warnings, Precautions, pertinent Adverse Events
- Complete or partial omission of risk
- Reference to the PI does not fulfill this regulatory requirement
In discussing problems with the presentation of risk information, he presented a stall cling for GELNIQUE – cited in a Nov. 30, 2010, Untitled Letter to Watson Pharmaceuticals Inc. – to demonstrate that formatting factors, including the shape, size and general layout of presentations in a piece, are important in achieving adequate risk presentation. The Untitled Letter cited the company for relegating the risk information “to the bottom of the piece and written in white text on a purple background in an extremely small font size and in single-spaced paragraph format, making this information very difficult to read.” As a result, Sauers noted that another way manufacturers can violate the FDCA is by “minimizing risk information” in the presentation of promotional materials. Sauers maintained that:
- Risk information must be adequately conveyed;
- Formatting factors including the shape, size, and general layout of presentations in a piece are important in achieving adequate risk presentation;
- Inclusion of non-risk information in a risk section, or vice versa;
Another risk Sauers cited was minimization of risk information for the content of the materials. Important factors discussed were:
- Omission of material information about a risk described in the approved labeling
- Risk information as a benefit
- Disassociating risk from drug product
Sauers made it clear in his presentation that oral statements not made in response to a request for such information from a physician can be problematic if they discuss unapproved uses. For example, he cited oral statements made by a physician on behalf of Merck & Co. Inc. regarding the company’s SAPHRIS at a lunch presentation. Saphris is approved for schizophrenia and bipolar disorder, but the speaker stated that he prescribes the drug as an adjunctive treatment for major depressive disorder (MDD) and that it works just as well.
Next, the presentation addressed “Indication Communication.” Sauers pointed out that:
- Promotional materials should not suggest a drug is safe and effective for conditions or patient populations that it is not approved to treat; and
- Promotional materials should not suggest that a drug treats outcomes/consequences of a disease if the drug has not demonstrated such an effect on those outcomes/consequences
With respect to “Substantial Evidence,” Sauers added that:
- Generally, claims about efficacy/safety in promotion must be consistent with the prescribing information (PI) and supported by substantial evidence – adequate and well-controlled studies
- Prospectively defined objectives and methods of analysis
- Design that permits a valid comparison with a control
- Adequate measures are taken to minimize bias
- Methods of assessment are well-defined and reliable
- Generally, adequate and well-controlled head- to-head comparative studies are necessary to support claims of superiority
To illustrate the substantial evidence requirement, Sauers showed attendees a Noven Pharmaceuticals Inc. flash card for PEXEVA. This marketing piece, cited in a May 24, 2011, Untitled Letter, misleadingly implies that Pexeva is effective in treating patients with co-morbid MDD and generalized anxiety disorder (GAD), when this has not been demonstrated by substantial evidence or substantial clinical experience, the Untitled Letter states: “While Pexeva is indicated to treat MDD and GAD individually, no clinical studies demonstrated efficacy of Pexeva in treating patients experiencing these two conditions concurrently.”
In further elaborating on the “substantial evidence” standard, Sauers discussed Post-hoc subgroup analyses:
- Because many comparisons are theoretically possible, tests of significance become difficult to interpret
- When looking for differences between treatment groups, the study must be designed to look for these differences prospectively
- Generally, cannot be used to demonstrate statistically significant differences between treatment groups
For “substantial evidence,” he also discussed “meta-analyses:”
- Can potentially be biased because the results are known before the comparison is made
- Different patient populations can differ greatly in their responses to a given drug or class
- Non-supportive studies can get omitted from the meta-analysis
- Analysis according to a hierarchical sequence may be considered
- The study protocol should define the study endpoint measures and the criteria for the statistical analysis and interpretation of results, including a clear specification of the conditions for a positive study conclusion
- Corrections should be made for multiplicity
- Composite endpoints which are measured based on a total score can provide support for improvement on that scale
- They do not specifically evaluate efficacy for the each of the components of the composite endpoint
- Demonstrating an effect on a composite total score does not represent a clear effect on any individual components of the measure
Sauers then discussed, Superiority Claims: a drug comparison that represents or suggests that a drug is safer or more effective than another drug. Such claims can be implied or direct comparison. The standard of evidence to support superiority claims are generally well-controlled and adequate head-to-head clinical trials.
Overstatement of efficacy – often conveyed through testimonials or imagery – also is a violation that is commonly cited by OPDP. Examples include:
- Suggesting or representing the drug as more efficacious than demonstrated
- Guarantee of efficacy
- Faster onset of action
- Survival/Long-term outcome claims
Sauers’ presentation made it clear that patient testimonials and individual case studies may be an accurate reflection of one patient’s experience, but that alone does not constitute substantial evidence. “Treatment response must be reflective of results of clinical trials; “Individual results may vary” does not mitigate misleading presentation.
Finally, Sauers looked at Reminder Promotion and Disease Awareness Communications. Reminder promotion “calls attention to the name of the drug product but doesn’t include indications, dosage recommendations, or other representations or suggestions relating to the drug product.” Disease awareness communications discusses a disease or health condition but don’t mention or otherwise identify a drug.