4. 4
OPDP NOV/Untitled Letters 2015
• Omission of important risk information
• Unsubstantiated claims
• Omission of important risk information/Omission of
Material facts
• Misleading claims and presentations
• Unsubstantiated superiority claims/Lack of adequate
directions/Intended new use
• Promotion of an Investigational New Drug
• Lack of adequate directions for use/Intended new
use/Minimization of risk/Omission of material
facts/Misleading claims
5. 5
OPDP WARNING Letters 2015
• Omission of risk information/omission of
material facts
• Omission of risk information/Inadequate
communication of indication/Unsubstantiated
claims
6. 6
OPDP Letters 2016
2 NOV/Untitled Letters
•Omission of risk information
•Omission of risk information and material facts
7. 7
Cited Violations 2015 - 2016
•Omission/minimization of risk (7 letters)
•Omission of material facts (4)
•Unsubstantiated claim/superiority (2)
•Misleading claim (2)
•Lack of adequate directions/intended new use (2)
•Investigational new drug
8. 8
Letters citing Intended New Use/Lack of
Adequate Directions for Use
•Ribasphere RibaPak (ribavirin, USP) Intro Letter –
November 2013 WARNING Letter
•Aranesp (darbepoetin alfa) Direct Mailer – November
2013
•Lanoxin (digoxin) Physician Letter – December 2013
•Viread (tenofovir disoproxil fumarate) Sponsored Link –
June 2014
•Injectafer (ferric carboxymaltose injection) Balancing Act
Video Segment – January 2015
•Surfaxin (lucinactant) Intratracheal Suspension Website –
March 2015
10. 10
What did OPDP say
•These claims and presentation suggest that Aranesp is
useful to treat chemotherapy-induce anemia in any patient
with metastatic cancer whose hemoglobin is falling, or has
fallen below 10g/dL, when this has not been demonstrated
by substantial evidence
•Approved indication is for non-myeloid malignancies
where the anemia is due to the effect of myelosuppressive
chemo, and with planned additional two months of chemo
•Not indicated for pts receiving hormonal agents, biological
products, or radiotherapy, without concomitant
myelosuppressive chemo; …
11. 11
LANOXIN (digoxin) NOV December 2013
Physician Letter sent by TOPS Pharmacy
•Broadened the Patient Population or Condition
• In the letter itself - Lanoxin is indicated…for the
control of ventricular response rate in patients with
chronic atrial fibrillation
• In the Important Safety Info - LANOXIN is also
indicated for the control of ventricular response
rate in patients with chronic atrial fibrillation
12. 12
What did OPDP say
• Suggest Lanoxin is useful in a broader range of
conditions or patients than has been
demonstrated by substantial evidence
• Approved indication is for control of ventricular
response rate in adult patients with chronic
Afib
• Evidence “that Lanoxin is intended for a new
use for which it lacks approval, and for which
its labeling does not provide adequate
directions for use.”
14. 14
What did OPDP say?
Misleading due to implication that Surfaxin is superior
because it “evolved” from “more-primitive, animal-derived
surfactants” to a synthetic surfactant represented by a
“human-like robot”.
No evidence to support superiority
16. 16
What did OPDP say?
Surfaxin is not an alternative to all available animal-derived
surfactants
Surfaxin only approved for prevention of RDS,
while Curosurf is approved for treatment of RDS.
The PI for Surfaxin does not provide instructions for, or
indicate that Surfactin will be safe or effective for treatment
of RDS.
These claims provide evidence that Surfaxin is intended
for a new use for which it lacks approval.
17. 17
What do the letters have in common?
Besides “evidence of an intended new use/lack of
adequate direction for use
•2 Letters, 1 Direct Mailer, 1 Sponsored Link, 1 Video, 1
Website
•Omission/minimization of or failure to communicate risk –
5 letters
•Unsubstantiated efficacy/superiority – 3 letters
•Misleading superiority – 1 letter
•Omits material facts – 3 letters
19. 19
What did OPDP say?
•D&A of the PI provides dosing for bunionectomy and
hemorrhoidectomy only
•CLINICAL STUDIES section of PI states – “EXPAREL has
not been demonstrated to be safe and effective in other
procedures.”
•“In sum, these presentations provide evidence for new
uses for which it lacks approval, and for which its labeling
does not provide adequate directions for use.”
•OPDP also concerned with other materials not discussed
in this letter suggesting EXPAREL is safe and effective in
other surgical procedures (knee arthoplasty, gastric sleeve,
open hysterectomy, lumbar interbody fusion, …)
20. 20
Exparel: Post-Warning Letter developments
• April 2015 – Pacira announces receipt of subpoena
from U.S. Department of Justice
• September 2015 – Pacira files suit against FDA
• October 2015 – FDA rescinds the Warning Letter and
removes it from OPDP website
• December 2015 – FDA approves labeling supplement
to clarify that Exparel’s indication is not limited to
bunionectomy and hemorrhoidectomy
• December 2015 – Janet Woodcock issues FDA letter
explaining why FDA rescinded the Nov 2014 Warning
Letter
21. 21
Conclusions
• Be precise in wording of claims. Don’t give
OPDP the chance to say you implied an
intended new use.
• Don’t minimize/omit or fail to communicate
safety
• Do have substantial evidence
• Do provide training on appropriate messaging
• Do ongoing reviews of OPDP website
• Do have a rigorous review process with trained
Medical, Legal, and Regulatory personnel
