Hensley pdd presentation final draft 14 feb13

Off-Label Promotion and

x Brett Hensley, Pharm.D.1st Year Medical Information Fellow

Janssen Scientific Affairs, LLCFebruary 14, 2013

Outline Off-label drug use (OLDU) background

Off-label promotion in the pharmaceutical industry

United States v. Caronia: Off-label promotion and free speech

Discussion

Off-Label Drug Use

Background, Benefits, and Risks

Off-Label Drug Use1

OLDU definition: Prescribing currently available and

marketed medications for an indication that has never received FDA approval

OLDU also applies to: Patient population Dosage Dosage form

1. Wittich CM, et al. Mayo Clin Proc. 2012;87(10):892-99.

Common Reasons for OLDU1

• Medication not studied in a specific population Different

Populations

• Any treatment that is logical and available for a life-threatening or terminal condition

Life-threatening Conditions

• Medication may have FDA approval but others in the same class do not

o ARBs in heart failureSame Drug Class

Similar Pathological Conditions

• Two conditions with similar pathological or physiological conditions

o Diabetes and metabolic syndrome

1. Wittich CM, et al. Mayo Clin Proc. 2012;87(10):892-99.

How Common is OLDU?2

79%

15%6%

Database of 725 million prescriptions

On-label (FDA approved)

Off-label with little or no scientific evidence

Off-label with strong scien-tific evidence

21% OLDU

2. Radley DC, et al. Arch Intern Med. 2006;166(9):1021-26.

Inappropriate OLDU2

Most likely to be used off-label without strong evidence: Atypical antipsychotics Antidepressants

725 million prescriptions



OLDU: 21%

Poor or no scientific support:

73%


Top Therapy Classes Used Off-Label2


Psyc

hiat

ric T

hera

pies

Antia

sthm

atics

Allegy

The

rapi

es

Cardi

ac T

hera

pies

Dyspe

psia

The

rapi

es

Antico

nvul

sant

s0

10

20

30

4040.1

24.428.5

11.216.3

7.7

18.0 17.714.7

9.5 7.0 6.6

On-label use Off-label use

Nu

mb

er

of

Uses (

Million

s)

Other OLDU studies Adults

Antidepressant, anticonvulsant, and antipsychotic OLDU is high and more prevalent with age3

Intensive care unit: 36.2% OLDU rate (N=5,237 prescriptions)4

Children Pediatric hospital:

78.9% taking at least one OLDU at discharge (N=355,409 patients)5

Pediatric emergency department: 26.2% OLDU rate (N=6,675 prescriptions)6

3. Chen H, et al. J Clin Psychiatry. 2006;67(6):972-982.4. Lat I, et al. J Crit Care. 2011;26(1):89-94.5. Phan H, et al. Pediatr Emerg Care. 2010;26(6):424-30.6. Qureshi ZP, et al. Arch Intern Med. 2011;171(8):785-787.

Physician knowledge of FDA-approved indication & evidence base for medications7

Survey 599 primary care physicians and 600 psychiatrists 14 drug-indication pairs varying in:

FDA-approval status Levels of supporting evidence

Results Correctly identified FDA-approval status: 55% Believed at least one drug-indication pair with uncertain

or no supporting evidence was FDA-approved: 41% Conclusion

Need more effective methods to inform physicians about the evidence base (or lack thereof) for drugs prescribed off-label

7. Chen DT, et al. Pharmacoepidemiol Drug Saf. 2009;18:1094–100.

Public Perceptions of OLDU8

2006 nation-wide poll 50% of respondents believed that drugs could be

prescribed only for an FDA-approved use

Nearly two thirds of respondents believed that, except for clinical trials, OLDU should be completely prohibited

8. http://www.harrisinteractive.com/news/printerfriend/index.asp?NewsID1126

http://www.harrisinteractive.com/news/printerfriend/index.asp?NewsID1126

OLDU Advantages OLDU Disadvantages

Allows for clinical innovation, especially for patients who do not respond to standard treatments

May diminish public expectation for evaluation of drug safety and efficacy

May be the only available option for uncommon conditions or for patient populations that have not been studied

Less industry incentive to perform clinical trials

Allows physicians to adopt new practices based on emerging evidence

May have unrecognized safety and efficacy problems (prescribed without sufficient scientific evidence)

Increases return on investment for pharmaceutical companies

Promotes use of drugs in populations for which they have not been tested

Potential to improve on the standard of care

Third party payers may not cover medications for off-label uses

OLDU Pros & Cons9

9. http://www.eurekalert.org/pub_releases/2009-08/uocm-ouo081809.php

http://www.eurekalert.org/pub_releases/2009-08/uocm-ouo081809.php

Off-Label Promotion in the Pharmaceutical Industry

Regulation and Settlements

Off-Label Promotion Regulations10

Food, Drug, and Cosmetic Act (FDCA) 1938 U.S.C. 21 §§301-97

FDA Modernization Act (FDAMA) 1997 Allowed manufacturers to:

Distribute peer-reviewed articles and book chapters Sponsor independent continuing medical education programs

describing uses of products beyond the approved indications

FDA Draft Guidance FDA’s Good Reprint Practices Guidance 2011 FDA’s Guidance on Responding to Unsolicited Requests

for Off-Label Information 2011

10. http://www.fda.gov/RegulatoryInformation/Legislation/default.htm

http://www.fda.gov/RegulatoryInformation/Legislation/default.htm

Off-Label Promotion Settlements

$13 Billion

Off-Label Promotion Whistleblower Study11

Complaints filed in US federal fraud cases that contained allegations of off-label marketing January 1996–October 2010 41 complaints from 18 cases

Three non–mutually exclusive goals Unapproved diseases (35/41, 85%) Unapproved disease subtypes (22/41, 54%) Unapproved drug doses (14/41, 34%)

Of the four non–mutually exclusive types of marketing practices, “Prescriber-related” was #1 (41/41, 100%) Distorted presentation of supporting evidence (31/41,

76%)

11. Kesselheim AS, et al. PLoS Med. 2011;8(4):e1000431.

United States v. Caronia

Off-Label Promotion and Free Speech

Background Defendant: Alfred Caronia

Former Specialty Sales Consultant for Orphan Medical, Inc. (now Jazz Pharmaceuticals, LPC)

Convicted of conspiracy to introduce a misbranded drug into interstate commerce (2008) Promoting Xyrem® (sodium oxybate) for off-label use

in violation of the Federal Food, Drug, and Cosmetic Act (FDCA)

12. http://www.kslaw.com/imageserver/KSPublic/library/publication/ca122012.pdf

http://www.kslaw.com/imageserver/KSPublic/library/publication/ca122012.pdf

Xyrem® (sodium oxybate)12

Central nervous system depressant Indications:

Cataplexy in narcolepsy Excessive daytime sleepiness (EDS) in narcolepsy

Oral Solution Black Box Warnings:

Respiratory depression Schedule III controlled substance and is the

sodium salt of gamma hydroxybutyrate (GHB), a Schedule I controlled substance

Only available via patient/prescriber enrollment in a restricted distribution program

Cost: $2,333.20 per bottle13. Xyrem [package insert]. Palo Alto, CA: Jazz Pharmaceuticals, Inc; 2002.

Evidence13

The government obtained two tape-recorded conversations in which Caronia and another physician promoted Xyrem® for unapproved indications and subpopulations Muscle disorders Chronic pain Daytime fatigue Restless legs syndrome Fibromyalgia Parkinson’s disease Patients under 16



Charges13

1. Conspiracy to introduce a misbranded drug into interstate commerce in violation of 21 U.S.C. §§ 331(a) and 333(a)(2)

a. Knowingly and intentionally conspired to introduce the drug into interstate commerce when the drug was misbranded

b. Marketed the drug with others for medical indications that were FDA approved when he knew and believed that the drug did not contain adequate directions for and warnings against such uses

2. Introducing a misbranded drug into interstate commerce in violation of 21 U.S.C. §§ 331(a) and 333(a)(2)



Appeal13

The First Amendment does not permit the government to criminalize truthful and non-misleading promotion of an FDA-approved drug for off-label uses where the promoted use itself is not illegal and others are permitted to engage in the same type of speech.



2nd Circuit U.S. Court of Appeals13

Overturned Caronia’s conviction (2-1 vote) December 3, 2012

OLDU is not prohibited Denying the truthful off-label promotion by a

particular class of speakers would not directly further the government’s goals of: Preserving the efficacy and integrity of the FDA’s drug

approval process Reducing patient exposure to unsafe and ineffective

drugs



Sorrell v. IMS Health, Inc. (2011)13

Vermont law that prohibited: Drug manufacturers from using prescriber-identifiable

information for marketing or promoting a prescription drug without the prescriber’s consent

Law ruled to be unconstitutional “Speech in aid of pharmaceutical marketing is a form of

expression protected by the Free Speech Clause of the First Amendment.”

The Court found that the law imposed restrictions on: Content-based (marketing) speech Speaker-based (pharmaceutical manufacturers) speech



Applying Sorrell v. IMS Health, Inc13

FDA’s restrictions on off-label speech are Content-based: permits speech about approved

uses but prohibits speech about unapproved uses Speaker-based: prohibits pharmaceutical

manufacturers from speaking but allows others to speak

“Prohibiting off-label promotion by a pharmaceutical manufacturer while simultaneously allowing off-label use ‘paternalistically’ interferes with the ability of physicians and patients to receive potentially relevant treatment information.”



Central Hudson Gas & Electric Corp. v. Public Service Commission of New York13

Applying the Central Hudson test

The speech in question must concern lawful activity and must not be misleading in order to be protected by the First Amendment.

The government interest asserted to justify the restriction on speech must be substantial.

The restriction must directly advance the governmental interest “to a material degree.”

The restriction must be “narrowly drawn” and not more extensive than necessary to serve the government interest.



Dissent13

2nd Circuit Judge Debra Ann Livingston The government used Caronia’s speech as

evidence of motive or intent

Prohibition on off-label promotion directly advanced a substantial government interest and was narrowly tailored to further that interest

Decision undermines federal regulation that has existed for almost a century



Proceed with Caution13

Ruling does not prevent enforcement action based on misleading off-label speech

Government may use off-label speech as evidence of intent or conspiracy to misbrand Multi-level investigations Civil suits

Ruling limited to the 2nd Circuit Court New York, Connecticut, and Vermont FDA did not appeal the decision



Future Implications14

FDA may revise regulatory guidance such as: FDA’s Good Reprint Practices Guidance FDA’s Guidance on Responding to Unsolicited

Requests for Off-Label Information

FDA must expand or clarify opportunities for sharing truthful, non-misleading information with the medical community about OLDU Citizen Petition to “clarify FDA regulations and policies

governing certain communications and activities relating to new uses of marketed products.” (2011)

OLDU approval process or “safe harbor”

14. http://www.elsevierbi.com/publications/rpm-report/9/3/the-consequences-of-emcaroniaem-impact-on-fdas-offlabel-regulation

http://www.elsevierbi.com/publications/rpm-report/9/3/the-consequences-of-emcaroniaem-impact-on-fdas-offlabel-regulation

http://www.elsevierbi.com/publications/rpm-report/9/3/the-consequences-of-emcaroniaem-impact-on-fdas-offlabel-regulation

Summation Despite the benefits of OLDU for drug manufacturers

and patients, studies show a deficiency in scientific evidence to support OLDU in many cases.

The decision in US v. Caronia has the potential to profoundly impact how the FDA regulates off-label drug promotion. The FDA must clarify many ambiguities in its regulations.

As industry pharmacists, we should continue to advocate for the responsibility to provide quality, unsolicited, off-label scientific evidence to HCPs about our products.

References1. Wittich CM, Brukle CM, Lanier WL. Ten common questions (and their

answers) about off-label drug use. Mayo Clin Proc. 2012;87(10):892-99.

2. Radley DC, Finkelstein SN, Stafford RS. Off-label prescribing among office-based physicians. Arch Intern Med. 2006;166(9):1021-26.

3. Chen H, Reeves JH, Fincham JE, Kennedy WK, Dorfman JH, Martin BC. Off-label use of antidepressant, anticonvulsant, and antipsychotic medications among Georgia Medicaid enrollees in 2001. J Clin Psychiatry. 2006;67(6):972-982.

4. Lat I, Micek S, Janzen J, Cohen H, Olsen K, Haas C. Off-label medication use in adult critical care patients. J Crit Care. 2011;26(1):89-94.

5. Phan H, Leder M, Fishley M, Moeller M, Nahata M, Off-label and unlicensed medication use and associated adverse drug events in a pediatric emergency department. Pediatr Emerg Care. 2010;26(6):424-30.

6. Qureshi ZP, Liu Y, Sartor O, Chu YH, Bennett CL. Enforcement actions involving Medicaid fraud and abuse, 1996-2009. Arch Intern Med. 2011;171(8):785-787.

7. Chen DT, Wynia MK, Moloney RM, Alexander GC. U.S. physician knowledge of the FDA-approved indications and evidence base for commonly prescribed drugs: results of a national survey. Pharmacoepidemiol Drug Saf. 2009;18:1094–100.

8. U.S. adults ambivalent about the risks and benefits of off-label prescription drug use. HarrisInteractive Web site. http://www.harrisinteractive.com/news/printerfriend/index.asp? News ID1126. Accessed January 25, 2013.

9. Alexander, GC. Off-label use: Oft not evidence based. http://www.eurekalert.org/ pub_releases/2009-08/uocm-ouo081809.php. Accessed January 25, 2013.

10. U.S. Food and Drug Administration. Regulatory Information. http://www.fda.gov/ RegulatoryInformation/Legislation/default.htm. Accessed January 25, 2013.

11. Kesselheim AS, Mello MM, Studdert DM. Strategies and Practices in Off-Label Marketing of Pharmaceuticals: A Retrospective Analysis of Whistleblower Complaints. PLoS Med. 2011;8(4):e1000431.

12. King & Spalding Client Alert. Second circuit vacates off-label promotion conviction on first amendment grounds in U.S. v. Caronia http://www.kslaw.com/imageserver/KSPublic/library/ publication/ca122012.pdf. Accessed January 30, 2013.

13. Xyrem [package insert]. Palo Alto, CA: Jazz Pharmaceuticals, Inc; 2002.

14. Elsevier Business Intelligence. The consequences of Caronia: Impact on FDA’s off-label regulation. http://www.elsevierbi.com/publications/rpm-report/9/3/the-consequences-of-emcaroniaem-impact-on-fdas-offlabel-regulation. Accessed January 31, 2013.

References

Acknowledgements Seema Patel, Pharm.D.

Freddy Jimenez, J.D.

Roxanne McGregor-Beck, EMBA

Vishal Patel, Pharm.D. (BMS)

Open Forum: Points for Discussion How do you feel about the US v. Caronia

appellate court decision?

How do you think the court’s decision will affect the pharmaceutical industry and/or the FDA?

Should there be an approval process for off-label promotion?

Feedback

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