OPDP Enforcement Letters Update - Mitigate Compliance Risks that Lead to FDA Warning Letters 2016

Alan BergstromExecutive Director, Commercial Regulatory AffairsDaiichi Sankyo, Inc.

CBI 16th Off-Label Guidelines SummitJune 22-23, 2016

OPDP Enforcement Letters UpdateMitigate Compliance Risks that lead to FDA Warning Letters

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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What is Off-Label Information

•HCPs can lawfully use or prescribe products for uses or indications not described in approved labeling.

•FDCA and regulations prohibit a manufacturer from introducing new drugs or devices into interstate commerce for a use that FDA has not determined to be safe and effective

•Statements that promote a drug or device for uses other than those approved by FDA may be used as evidence of a new use.

•Introducing a product into commerce for such a new intended use would generally violate the law.

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So What’s the Worst That Can Happen?

OPDP issues a letterReputationSales

But then perhaps…

DOJ

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Notable Off-Label Settlements

•Settled for $321 million (criminal) and $628 million (civil) involving off-label promotion of VIOXX

• DoJ press release announcing the settlement specifically refers to Warning Letter issued in Sept 2001

•Promotional audio conferences June 2000 in which VIOXX was promoted for unapproved uses and unapproved dosing regimens.

• …effective in terms of treating patients with rheumatoid arthritis.• …safe and effective for …prevention of cancer and invasive cancer, and for the

treatment • …COX-2 seems to be able to interfere with programmed cell death. Therefore

you get this increased cell growth which allows polyps to form, cancer and then invasive cancer. And by blocking COX-2 you can actually prevent the development of colon polyps, cancer and invasive cancer.

• …within one or two pills acute attacks of gout were being shut down.• …potential uses of these drugs, the most exciting right now I guess in two areas,

one is Alzheimer’s disease…

Merck 12/16/2011

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Notable Off-Label Settlements

• Settled for $485 million (criminal) and $1.72 billion (civil) for off-label prescribing of Risperdal, Invega, and Natrecor

• Creation of written sales aids for Janssen’s ElderCare sales force • Promoted use of Risperdal to treat symptoms of anxiety, agitation,

depression, hostility and confusion in elderly dementia patients• The indication for Risperdal was for the management of the manifestations

of psychotic disorders• Clinical studies did not include sufficient numbers of patients aged 65 and

over• After seeking advisory comment from DDMAC on the promotion of

Risperdal in the geriatric population

Johnson & Johnson 11/4/2013

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Recent OPDP Letters re Off-label use

•2010, 48 Untitled Letters or Warning Letters were issued. 3 were for unapproved new uses.

•2011, 31 letters total, of which 3 were unapproved new uses.

•2012, 28 letters total, 2 for unapproved new uses

•2013, 24 letters total, 3 for unapproved new uses

•2014, 9 total letters, 1 for unapproved new use

•2015, 9 total letters, 2 for unapproved new uses

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•Amgen 5/24/2010 - oral statements at ASHP that VECTIBIX is a first-line therapy which is an unapproved use

•Forest 4/28/2011 - oral statements by a sales rep that SAVELLA is approved for fibromyalgia and useful in back pain and mood disorder

•Ortho-McNeil, Janssen 8/26/2011- Oral statements at ASHP that NUCYNTA is effective in Diabetic Peripheral Neuropathic Pain

•Sunovion 12/14/2011-Oral statements to an HCP about ongoing studies for use of LATUDA in bipolar disorder

Oral Statements by Sales Reps

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•Merck 2/28/2012-oral statements by a physician speaker at promotional event suggesting SAPHRIS was safe and effective for an unapproved use

Oral Statements by Speaker

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• Kadmon Pharmceuticals 11/18/2013 – Intro Letter for RIBASHERE RibaPak which made unsubstantiated claims, omitted material facts, and promoted for an intended new use

• Amgen 11/19/2013 – Direct Mailer for ARANESP which promoted for a broader range of patients or conditions, made unsubstantiated efficacy claims, omitted material facts and promoted for intended new use

• Covis Pharmaceuticals 12/9/2013 –Physician Letter for LANOXIN which omitted and minimized risk, made misleading superiority claims, claims for a broader range of patients or conditions, and promoted for an intended new use

Letters and Direct Mailers

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•Slate Pharmaceuticals WARNING Letter 3/24/2010 - website and consumer video for TESTOPEL which promoted treatments for depression, ED, T2DM, mood disorders, loss of sexual interest, and for increased muscle mass and bone strength

•Novartis WARNING Letter 4/21/2010 – website which promoted GLEEVEC for neoadjuvant therapy prior to surgery

•Gilead Sciences 6/27/2014 – Sponsored link for VIREAD which promoted for an intended new use, omitted risk information, and failed to present required established name.

•Luitpold Pharmaceuticals 1/29/2015 – video segment which promoted INJECTAFER for an intended new use, minimized risk, omitted material facts, and made misleading claims

•Discovery Laboratories 3/5/2015 – website for SURFAXIN which made unsubstantiated superiority claims and promoted for an intended new use

Websites, Consumer Video, and Sponsored Links

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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•5 Oral Statements, 2 letters, 1 Direct Mailer, 1 Sponsored Link, 2 video, 3 websites•Omission/minimization of or failure to communicate risk – 11 letters•Unsubstantiated efficacy/superiority – 7 letters•Misleading superiority – 2 letters•Omits material facts – 4 letters

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Exparel (bupivacaine liposome injectable suspension) Warning Letter (Issued Sept 2014,rescinded Dec 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 consistent with FDA-approved labeling, indication, population, condition

• 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

OPDP Enforcement Letters Update - Mitigate Compliance Risks that Lead to FDA Warning Letters 2016

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