Alan BergstromExecutive Director, Commercial Regulatory AffairsDaiichi Sankyo, Inc.

ExL Off-Label Regulatory Compliance CongressMay 10-11, 2016

OPDP Enforcement Letters Update

The content, views, and opinions in this presentation are my own and do not in anyway represent the views or opinions of Daiichi Sankyo, Inc.

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OPDP Letters 2000 – 2015

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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

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OPDP WARNING Letters 2015

• Omission of risk information/omission of material facts

• Omission of risk information/Inadequate communication of indication/Unsubstantiated claims

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OPDP Letters 2016

2 NOV/Untitled Letters•Omission of risk information•Omission of risk information and material facts

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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

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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

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ARANESP (darbepoetin alfa) NOV November 2013

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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; …

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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

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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.”

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Surfaxin (lucinactant) Intratracheal Suspension NOV March 2015

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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

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Surfaxin (lucinactant) Intratracheal Suspension NOV

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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.

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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

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Exparel (bupivacaine liposome injectable suspension) Warning Letter (Issued Sept 2014,rescinded Oct 2015)

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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, …)

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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

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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

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Thank You

Questions?