Substantial Evidence and
Other Standards for
Support of Promotional Claims
CDR Elaine Hu Cunningham
Senior Regulatory Review Officer
Office of Prescription Drug Promotion
Food and Drug Administration
The Food & Drug Law Institute’s
Advertising and Promotion Conference
Capital Hilton Hotel
Washington, DC
October 1 and 2, 2012
Speakers
Moderator:
Michele Hardy
Vice President of North America Regulatory Affairs, GlaxoSmithKline
Panelists:
Elaine Hu Cunningham, PharmD
Senior Regulatory Review Officer, Office of Prescription Drug Promotion
(OPDP), FDA
Mark S. Hirsch, MD
Medical Team Leader, Division of Reproductive and Urologic Drug Products,
FDA
James P. Stansbury, PhD, MPH
Reviewer, Study Endpoints and Labeling Development (SEALD), FDA
Eugene J. Sullivan, MD, FCCP
Principal, EJS Consulting, LLC
Disclosure
The views expressed are those of the
speaker, and do not necessarily represent
an official FDA position.
Presentation Outline
• Review the levels of evidence used to support
claims in prescription drug promotion
• Common data quality pitfalls and challenges in
support of treatment benefit claims
• Common data quality pitfalls and challenges in
support of non-clinical claims
• Review of illustrative OPDP enforcement
examples
• Summary and conclusions
Review of the Basics
Different levels of evidence are required to
substantiate different promotional claims for
prescription drugs:
• Adequate evidence
• Substantial clinical experience
• Substantial evidence
Review of the Basics
Adequate Evidence:
• “Competent and reliable scientific evidence”
– Standard for healthcare economic information
under FFDCA sec. 502(a)
– FTC description: “evidence based on the
expertise of professionals in the relevant areas
that has been conducted and evaluated in an
objective manner by qualified persons to do so,
using procedures generally accepted in the
profession to yield accurate and reliable
results.”
Review of the Basics
Adequate Evidence (cont’d):
• In support of promotional claims that do
not suggest a treatment benefit of the drug
(e.g., convenience, ease of use, drug
utilization, etc.)
– Can vary, depending on the claim being made
Review of the Basics
Substantial Clinical Experience:
• 21 CFR 202.1(e)(4)(ii)(c)
– “...experience adequately documented in
medical literature or by other data...on the
basis of which it can fairly and responsibly be
concluded by qualified experts that the drug is
safe and effective for such uses”
– Addressed the level of support required for
claims made for prescription drugs that have
not been evaluated by the FDA through the
NDA process
Review of the Basics
Substantial Evidence:
• The FFDCA was amended in 1962 to establish
the effectiveness requirement.
• Section 505(d) of the Act describes substantial
evidence consisting of adequate and wellcontrolled investigations...on the basis of which
it could be concluded that the drug will have the
effect it is represented to have under the
conditions of the use proposed in labeling.
Review of the Basics
Substantial Evidence (cont’d):
• Generally, at least two adequate and wellcontrolled studies, each convincing on its
own to establish effectiveness
• 21 CFR 314.126 describes the essential
characteristics of adequate and wellcontrolled trials
Review of the Basics
Substantial Evidence (cont’d):
• Section 115(a) of FDAMA
– Congress amended section 505(d) of the Act
to make it clear that the Agency may consider
“data from one adequate and well-controlled
clinical investigation and confirmatory
evidence” to constitute substantial evidence if
FDA determines that such data and evidence
are sufficient to establish effectiveness.
Review of the Basics
Claims of treatment
benefit*
Level of
Evidence
Substantial evidence /
substantial clinical
experience
Non-clinical claims
(i.e., no suggestions of
treatment benefit)
Level of
Evidence
Adequate evidence
Review of the Basics
*Treatment Benefit1:
•
•
•
•
1
The effect of treatment on how a patient
“survives, feels, or functions” in daily life
Used interchangeably with “clinical benefit”
Can be demonstrated by either an
effectiveness or safety advantage
Can be measured directly or indirectly
Guidance for Industry - Patient-reported Outcome Measures: Use in Medical Product
Development to Support Labeling Claims; December 2009
Evidence to Support
Treatment Benefit Claims:
Common Data Quality
Pitfalls and Challenges
Claims of treatment
benefit
Level of
Evidence
Substantial evidence /
Substantial clinical
experience
Common Data Quality
Pitfalls/Challenges
•
•
•
•
•
Open-label studies
Post-hoc subgroup analyses
Meta-analyses
Comparative studies
Reported assessments
– Patient-reported outcomes (PROs)
– Clinician-reported outcomes (ClinROs)
– Observer-reported outcomes (ObsROs)
Open-label Studies
The Pitfalls of Open-label Studies:
• Generally, will not support efficacy claims
– Exceptions may be made for certain diseases and
endpoints
• Cannot avoid potential bias
• Endpoints based on subjective patient or
investigator responses
– Biases can result from subject or investigator
knowledge of the assigned treatment
Open-label Studies
Enforcement Example:
Notice of Violation
issued for Equetro®
(carbamazepine)
Extended-Release
Capsules
June 25, 2012
Open-label Studies
“Relieving Acute Manic & Mixed
Symptoms of Bipolar I
Disorders...Without Inducing
Weight-Gain”
Open-label Studies
This graphic
presentation
suggests that
patients treated
with Equetro will
experience no
weight gain.
Open-label Studies
However...
• In two 3-week pivotal
trials, Equetro-treated
patients showed an
increase in weight
over baseline (+2.3
lbs) compared to
placebo (+0.1 lb).
• The referenced study
is a 6-month, openlabel extension study
with a significant dropout rate (~70%)
Post-hoc Subgroup Analyses
The Pitfalls of Post-hoc Subgroup Analyses:
• Because many comparisons are theoretically
possible, false positive results can emerge by
chance alone
• It is unclear whether an analysis was motivated
by inspection of the study data
• Generally, cannot be used to demonstrate
statistically significant differences between
treatment groups because the study was not
designed prospectively to examine the
differences
Post-hoc Subgroup Analyses
Enforcement Example:
Notice of Violation
Issued for Feraheme®
(ferumoxytol) Injection for
Intravenous Use
February 17, 2011
Post-hoc Subgroup Analyses
“Feraheme increases
Hgb, even without an
ESA”
Two bar graphs depict
mean changes in
Hgb from baseline to
day 35, stratified by
concomitant ESA use,
in Feraheme and oral
iron treatment groups
Post-hoc Subgroup Analyses
This presentation
suggests that
Feraheme
increases Hgb
levels in the
subgroup of
patients without
concomitant ESA
use.
Post-hoc Subgroup Analyses
• The 3 pivotal trials
evaluated the
efficacy of
Feraheme across
the respective study
population as a
whole.
• The referenced
study did not
prospectively
evaluate the
efficacy of
Feraheme based on
ESA use.
Meta-Analyses
The Pitfalls of Meta-Analyses:
• Can potentially be biased because the results
are known before the comparison is made
• Heterogeneity of studies:
– Different patient populations
– Different interventions (e.g., drug, dose, dosage
form)
– Endpoints evaluated
– Different clinical protocols
• Non-supportive studies can be omitted from the
meta-analysis  bias
Meta-Analyses
Enforcement Example:
Notice of Violation
Issued for Mephyton®
(phytonadione) Vitamin K1
Tablets
August 2, 2011
Meta-Analyses
“Oral and IV routes were
similar in effectiveness at 24
hours”
Meta-Analyses
Graph displays
results of a meta
analysis of 21
separate clinical
studies that compared
the efficacy of different
dosage forms of
Vitamin K (i.e., PO, IV,
SQ) to treat excessive
anticoagulation due to
warfarin
Meta-Analyses
• This presentation
suggests that at 24 hours
postdose, Mephyton is
as clinically effective as
IV phytonadione and
clinically superior to SQ
phytonadione.
• The referenced study
was a meta-analysis of
21 different studies that
were conducted in
diverse patient
populations, with
different doses and
dosage forms, drug
products, and under
varying clinical protocols.
Comparative Studies
The Challenges of Comparative Studies:
• Generally, comparative claims require support
of two adequate and well-controlled head-tohead clinical trials
• Appropriate doses and dose regimens for the
compared products
• Appropriate patient population
• Selection and timing of endpoints
Comparative Studies
Enforcement Example:
Notice of Violation
Issued for Focalin
XR®
(dexmethylphenidate
HCl) Extended-Release
Capsules, CII
May 31, 2011
Comparative Studies
“ADJUSTED MEAN CHANGE IN
SKAMP-COMBINED SCORE FROM
PREDOSE TO 2 HOURS POSTDOSE”
“Focalin demonstrated
statistically significant superior
efficacy versus Concerta 2
hours postdose”
“Two well-controlled studies
confirmed the superior efficacy
of Focalin XR 20 mg versus
Concerta 36 mg at 2 hours
postdose”
•
•
The claims and presentations suggest that Focalin XR
is superior to Concerta because of the efficacy results
at 2 hours postdose.
The referenced clinical studies only focused on one
time point (i.e., 2 hours postdose).
•
•
However... treatment of ADHD consists of symptom
relief over the entire treatment course.
A single time point (2 hours postdose) does not
account for the different pharmacokinetic profiles and
subsequent efficacy profiles when comparing Focalin
XR to Concerta over the entire treatment period.
•
•
Focalin XR is formulated to provide a biphasic release
of active drug (1st peak at ~1.5 hrs and 2nd peak at ~6.5
hours after dosing).
Conversely, Concerta is formulated to deliver an initial
dose via immediate release, followed by gradually
ascending concentrations of drug over the next 5-9
hours.
Reported Assessments
The Challenges of Reported Assessments:
• The same study principles that apply to other
clinical endpoint measures apply to reported
assessments (PROs, ClinROs, and ObsROs).
– Should be designated as primary or key
secondary endpoints
• However, there are certain considerations that
are specific to reported assessments.
– Instruments used need to be well-defined and
reliable in the clinical trial context of use
– Content validity of instruments need to be
established
Reported Assessments
Common Pitfalls of Reported Assessments:
• Inappropriately designed studies
– Endpoint measures
– Frequency of measurements
• Inappropriate assessment tools
– Not developed for the studied patient population
– Lack of content validity
• NO data referenced or submitted
• Not included early on in product development
• Claims are not appropriate for what was
measured in the study (e.g., very broad/general
claims; listing out individual items of an
instrument).
Reported Assessments
Patient-reported Outcomes
(PRO) Guidance:
• Outlines how the FDA
interprets “well-defined and
reliable” for PRO measures
intended to provide
evidence of treatment benefit
• Summarizes good
measurement principles
applicable to any PRO,
ClinRO, or ObsRO
assessment
http://www.fda.gov/ohrms/dockets/98fr/06
d-0044-gdl0001.pdf
Reported Assessments
Enforcement Example #1:
Warning Letter Issued for
Durezol®
(difluprednate ophthalmic
emulsion) 0.05%
February 18, 2010
Reported Assessments
Reported Assessments
Reported Assessments
“Formulated for patient
comfort...Emulsion
formulation with no
shaking required...
Durezol is a BAK-free
product”
Reported Assessments
• The totality of the claims
imply that certain
characteristics of Durezol
will have a positive impact
on patient comfort.
• No substantial evidence in
support of these claims –
only the PI is referenced
• In contrast, the PI states
that commonly reported
ADRs (5-15% of pts) include
eye pain, photophobia,
blepharitis, etc.
Reported Assessments
• Claims that suggest a safety
benefit need to be supported
with substantial evidence.
• In this case, the PRO
assessment should be
evaluated with a welldeveloped and reliable
instrument that is able to
measure the claimed
treatment benefit and is
specific to the intended
population and to the
characteristics of the
condition being treated.
Reported Assessments
Enforcement Example #2:
Warning Letter Issued for
Luvox CR®
(fluvoxamine maleate)
Extended-Release Capsules
July 6, 2010
Reported Assessments
The patient
brochure includes
a patient profile for
Ana, a 19-year-old
college student.
Reported Assessments
“The knots would form in my stomach
weeks ahead of anything social...So I
made excuses as to why I couldn’t go
out. I’d sit alone in my dorm room
feeling nervous and sick to my
stomach. I stopped going to class.
My grades were suffering. If it kept up,
I would flunk out of school. I knew other
people who were anxious. They went
to see a psychiatrist and took
medication.”
Reported Assessments
“Recently, I got a B on my bio midterm
and I’ve been playing flute in a jazz
quartet after classes. Small steps, but
everything is starting to go well. My
psychiatrist is really pleased and thinks
I’m doing better.
Reported Assessments
• Luvox CR has been shown to
improve total scores in the
Liebowitz Social Anxiety Scale
(LSAS) at Week 12
• The LSAS includes 6
subscales and 24 items
– Subscales include: total
fear, fear of social
interaction, fear of
performance, total
avoidance, avoidance of
social interaction, and
avoidance of performance
Reported Assessments
• However, the LSAS does not
measure the impact of
treatment on the 6 individual
subscales or the 24 individual
items.
• Clinical trial results showed
improvements of 13.4 and 8.4 in
total LSAS scores
– Scoring scale is in 15-point
increments (moderate [55-65],
marked [65-80], severe [80-95],
very severe [>95])
– No evidence that these
improvements in LSAS scores
correlate with the drastic
improvements claimed in
individual subscales
Reported Assessments
Enforcement Example #3:
Notice of Violation Issued
for Zmax®
(azithromycin extendedrelease) for oral suspension
June 19, 2012
Reported Assessments
Reported Assessments
• These claims
suggest that adult
pts and parents of
pediatric pts would
take Zmax again if
they were to have
the same infection.
Reported Assessments
However...
• Results are based on
one telephone survey
question:
– “Would you take
Zmax again?” or
– “How likely are you to
give your child Zmax
again?”
• One survey question
cannot assess all of
the various factors
that may influence
patients’ or
caretakers’ decisions
to take a particular
treatment again.
Reported Assessments
Labeling Example:
Approved Product
Labeling for Jakafi™
(ruxolitinib), tablets for oral
use
November 2011
Reported Assessments
• Clinical Studies:
– The primary efficacy endpoint was the
proportion of pts achieving ≥ 35% reduction
from baseline in spleen volume at Week 24
(measured by MRI or CT).
– A key secondary endpoint was the
proportion of pts with a >50% reduction in
Total Symptom Score from baseline to
Week 24, as measured by the modified
Myelofibrosis Symptom Assessment Form
(MFSAF) v2.0 diary.
Reported Assessments
• Instrument:
– The MFSAF is a daily diary that captures the
core symptoms of myelofibrosis (abdominal
discomfort, pain under left ribs, night sweats,
itching, bone/muscle pain, and early satiety).
– Symptom scores range from 0 (no
symptoms) to 10 (“worst imaginable”
symptoms). The scores were added to
create the daily total score (maximum=60).
Reported Assessments
• Results:
– A higher proportion of pts in the Jakafi group
had a 50% or greater reduction in Total
Symptom Score than in the placebo group,
with a median time to response of <4 weeks.
Reported Assessments
Reported Assessments
•
Indicates that all 6 of the symptoms contributed to
the higher Total Symptom Score response rate in the
Jakafi group
Evidence to Support
Non-clinical Claims
(with a focus on “convenience”
and “ease of use” claims):
Common Data Quality Challenges
Non-clinical claims
(i.e., no suggestions
of treatment benefit)
Level of
Evidence
Adequate Evidence
“Convenience” and “Ease of Use”
• “Convenience” and “ease of use” claims take
on many different forms that require different
types of supporting evidence.
• The supporting evidence depends on the claim
being made.
– Evaluated on a case-by-case basis
– There are exceptions
• The adequate evidence standard applies to
claims that do not suggest a treatment benefit.
“Convenience” and “Ease of Use”
Common Pitfalls and Challenges:
• Inappropriately designed studies
– Inappropriate endpoints
– Inappropriate assessments
– Inappropriate comparators
• NO data or references
– Misconception that these claims do not require
any supporting evidence
• Omission of material fact
• Claims that go beyond convenience or ease of
use
“Convenience” and “Ease of Use”
Enforcement Example #1:
Warning Letter Issued for
Maxair™ Autohaler™
(pirbuterol acetate inhalation
aerosol)
October 19, 2006
“Convenience” and “Ease of Use”
Background:
• Maxair Autohaler is indicated for the prevention
and reversal of bronchospasm in patients 12
years and older with reversible bronchospasm
including asthma.
• The design of the inhaler releases medicine
upon inhalation and does not require pressing
and breathing in the medication at the same
time.
“Convenience” and “Ease of Use”
“The inhaler that’s easier
to use and use correctly”
“Easier to teach”
“Easier to use”
“Convenience” and “Ease of Use”
• The claims suggest
that Maxair
Autohaler is easier
to use and teach
compared to all
other inhalers,
including other
breath-actuated
inhalers.
“Convenience” and “Ease of Use”
However...
• The referenced studies
were not designed to
measure ease of use.
• The references cited in
the piece were studies
from the 1990’s and did
not include newer press
and breathe and
breath-actuated
inhalers that were
currently on the market.
“Convenience” and “Ease of Use”
Enforcement Example #2:
Warning Letter Issued for
Testopel® Pellets
(testosterone), CIII
March 24, 2010
“Convenience” and “Ease of Use”
Background Information:
• Testopel is an implantable pellet (requiring a surgical
procedure) that is indicated in males for testosterone
replacement therapy in conditions associated with a
deficiency or absence of endogenous testosterone.
• Precautions state that Testopel is much less flexible
for dosage adjustment than other forms of
testosterone; if testosterone is to be d/c, pellets would
have to be surgically removed; pellets may slough out
of skin.
• Adverse reactions include pain and inflammation at
the site of implantation.
“Convenience” and “Ease of Use”
The sales aid includes
a chart comparing
Testopel to gel therapy
in four different
categories
“Convenience” and “Ease of Use”
• Suggests that Testopel is more convenient than
gel therapy because Testopel eliminates many
of the hassles or inconveniences associated
with gel therapy
“Convenience” and “Ease of Use”
However...
• The comparison chart selectively present
attributes that are the most favorable for Testopel
compared to gel therapy.
• The comparison chart omits material information
about other non-favorable attributes of Testopel
therapy, including serious risks, that could impede
its convenience and are highly relevant to any
decision about whether to prescribe or use
Testopel or other treatments.
• NO evidence was submitted to support the
implication that Testopel is more convenient than
other treatment options.
“Convenience” and “Ease of Use”
Enforcement Example #3:
Notice of Violation Issued
for Eligard® 45 mg
(leuprolide acetate for
injectable suspension)
April 20, 2010
“Convenience” and “Ease of Use”
Background:
• Eligard is indicated for the palliative treatment of
advanced prostate cancer.
• Eligard 45 mg is administered SQ once every 6 months
and provides continuous release of drug over a 6month tx period (vs every 3- or 4-month injections).
• Warnings: transient increase in serum testosterone
during the first 2 weeks of tx. Patients may experience
worsening of symptoms or onset of new signs and
symptoms (incl. bone pain, neuropathy, hematuria, or
bladder outlet obstruction.
“Convenience” and “Ease of Use”
Background (con’t):
• Precautions: response to Eligard should be monitored
by measuring serum concentrations of testosterone
and prostate specific antigen periodically.
• The most common systemic adverse reactions include
hot flashes/sweats, malaise/fatigue, testicular atrophy,
myalgia, weakness, gynecomastia, night sweats, and
pain in limb.
“Wants his retirement to be
interrupted less frequently”
“Convenience for patients...
There is no longer a need for
a doctor in each city”
“Wants his retirement to be
interrupted less frequently”
• This claim implies a
treatment benefit.
• Eligard can decrease the
number of injections per
year, but this decrease in the
number of injections alone
does not necessarily lead to
the outcome claimed.
• There are other aspects of
disease management (e.g.,
routine lab monitoring,
monitoring/treatment of adverse
events, etc.)
“Convenience for patients...
There is no longer a need for
a doctor in each city”
• A decrease in the
number of injections for
Eligard does not
eliminate the need for a
doctor in each city of a
patient’s residence.
• This is a patient
population with
advanced disease and
who are likely to have
multiple health issues.
Summary
• Different levels of evidence are required to substantiate different
promotional claims for prescription drugs
Claims of treatment
benefit
Non-clinical claims
(i.e., no suggestions of
treatment benefit)
Level of
Evidence
Level of
Evidence
Substantial evidence /
substantial clinical
experience
Adequate evidence
• There are many challenges and pitfalls surrounding the quality of
data necessary to support different types of promotional claims
Conclusions
Evidence to Support Treatment Benefit Claims:
• You can help overcome these challenges by
proactively discussing with the appropriate review
division how best to plan for the interpretation of
study findings to avoid conducting studies that are
not able to support your desired promotional
claims.
• The review divisions will consult SEALD and/or
OPDP as necessary.
Conclusions
Evidence to Support Non-clinical Claims:
• You may submit advisory requests directly to
OPDP with any proposed studies, assessment
tools, proposed promotional claims in its context
of use, etc.
• OPDP will consult SEALD and/or the review
divisions as necessary.
Conclusions
Early communications with FDA are the key
to optimizing your goals!
Contact Information
CDR Elaine Hu Cunningham
Senior Regulatory Review Officer, Office of Prescription Drug Promotion (OPDP), FDA
E-mail: Elaine.Cunningham@FDA.HHS.GOV
Mark S. Hirsch, MD
Medical Team Leader, Division of Reproductive and Urologic Drug Products, FDA
E-mail: Mark.Hirsch@FDA.HHS.GOV
James P. Stansbury, PhD, MPH
Reviewer, Study Endpoints and Labeling Development (SEALD), FDA
E-mail: James.P.Stansbury@FDA.HHS.GOV
Eugene J. Sullivan, MD, FCC
Principal, EJS Consulting, LLC
E-mail: Gene@EJSCONSULTING.NET
OPDP Website:
http://www.fda.gov/AboutFDA/CentersOffices/OfficeofMedicalProductsandTobacco/CDER/uc
m090142.htm