Transcript document

Defining Off-Label
Marketing of Prescription Drugs
Conduct Likely to Trigger Government Scrutiny
Antonia F. Giuliana
March 31, 2011
Off-Label Drug Settlements 2004-2010
1
Drug(s) at
Issue1
Settlement
Amount
Time Period for
Alleged Conduct
U.S. Attorney’s
Office
Applicable
Law(s)
Date
Company
May
2004
Pfizer
Parke-Davis
Warner-Lambert
Neurontin
$430M
1995 – 2001
D.Mass.
FCA
FDCA
Dec.
2005
Eli Lilly
Evista
$36M
1998
S.D.Ind.
FDCA
Aug.
2006
Schering
Claritin*
K-Dur*
Temodar
Intron A
$435M
1998-2001
D.Mass.
FCA
FDCA
Oct.
2006
Intermune
Actimmune
$37M
2002 – 2003
N.D.Cal.
FCA
FDCA
Apr.
2007
Pfizer
Pharmacia &
Upjohn Co.
Genotropin
$35M
2000 – 2003
D.Mass.
AKS
Sep.
2007
Cell Therapeutics
Trisenox
$11M
2001 – 2005
W.D.
Wash.
FCA
FDCA
Apr.
2007
Medicis
Loprox
$10M
2001 – 2004
D.Kan.
FCA
Drugs with * did not involve off-label conduct.
2
Off-Label Drug Settlements 2004-2010 (cont’d)
1
Drug(s) at
Issue1
Settlement
Amount
Time Period for
Alleged Conduct
U.S. Attorney’s
Office
Applicable
Law(s)
Date
Company
July
2007
Jazz
Orphan Medical
Xyrem
$20M
2005
E.D.N.Y.
FCA
FDCA
Sep.
2007
BMS Apothecon
Abilify
Serzone*
Others*
$515M
2002 - 2005
D.Mass
S.D.Fla.
FCA
FDCA
Mar.
2008
Otsuka
Abilify
$4M
2002 – 2005
D.Mass
S.D.Fla.
FCA
FDCA
Sep.
2008
Cephalon
Actiq
Gabitril
Provigil
$425M
2001 – 2006
E.D.Pa.
FCA
FDCA
Jan.
2009
Eli Lilly
Zyprexa
$1,400M
1999 – 2003
E.D.Pa.
FCA
FDCA
Sep.
2009
Pfizer
Pharmacia & Upjohn
Co.
Bextra
Geodon
Zyvox
Lyrica
$2,300M
2002 – 2005
D.Mass
E.D.Pa.
E.D.Ky.
FCA
FDCA
Apr.
2010
AstraZeneca
Seroquel
$520M
2001 – 2006
E.D.Pa.
FCA
Drugs with * did not involve off-label conduct.
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Off-Label Drug Settlements 2004-2010 (cont’d)
Drug(s) at
Issue1
Settlement
Amount
Time Period for
Alleged Conduct
U.S. Attorney’s
Office
Applicable
Law(s)
Date
Company
Apr.
2010
Ortho-McNeilJanssen
Topamax
$81M
2002 – 2007
D.Mass.
FCA
FDCA
May
2010
Novartis Vaccines
TOBI
$73M
2001 – 2006
N.D.Cal.
FCA
Sep.
2010
Allergan
Botox
$600M
2000 – 2005
N.D.Ga.
FCA
FDCA
Sep.
2010
Forest Labs.
Celexa
Lexapro
Levothroid*
$313M
1998 – 2005
D.Mass.
FCA
FDCA
Sep.
2010
Novartis
Trileptal
Diovan*
Sandostatin*
Exforge*
Tekturna*
Zelnorm*
$423M
2000 – 2004
E.D.Pa.
FCA
FDCA
Dec.
2010
Elan
Esai
Zonegran
$214M
2000 – 2005
D.Mass.
FCA (Elan &
Esai)
FDCA (Elan)
Dec.
2010
Kos Pharm.
Advicor
Niaspan*
$41M
2002 – 2006
M.D.La.
FCA
AKS
1
Drugs with * did not involve off-label conduct.
4
Off-Label Settlements:
Statistics by U.S. Attorney’s Offices
U.S.
Attorney’s
Office
Total
Settlement
Value
Total # of
Settlements
Total # of
Settlements
$100M+
Misdemeanor
Pleas
Deferred
Prosecution
Agreements
Initiated
by Qui
Tam Suit
D. Mass.
$4,300M
9
6
5
3
0
9
8
E.D. Pa.
$2,800M
4
4
0
4
0
4
4
N.D. Ga.
$600M
1
1
0
1
0
1
1
N.D. Cal.
$110M
2
0
0
0
1
2
1
M.D. La.
$41M
1
0
0
0
1
1
0
S.D. Ind.
$36M
1
0
0
1
0
0
0
E.D.N.Y.
$20M
1
0
1
0
0
1
1
W.D. Wash.
$11M
1
0
0
0
0
1
1
D. Kan.
$10M
1
0
0
0
0
1
1
TOTAL:
$7,928M
21
11
6
9
2
20
17
Felony
Pleas
CIAs
5
Off-Label Settlement Statistics
 The government settled 21 drug cases between 2004 and 2010.
 95% of the government’s investigations in these cases were initiated
by a qui tam complaint.
 Companies were required to enter into Corporate Integrity
Agreements (“CIAs”) in 81% of the cases.
 Criminal pleas were made in 72% of the cases.
 felony pleas were made in 29% of cases
 misdemeanor pleas were made in 43% of cases
 52% of the settlements were in excess of $100 million each.
6
Recent Government Interventions
Wyeth/Rapamune (E.D. Pa. Oct. 2010)
 In October 2010, the DOJ intervened in a whistleblower suit
accusing Wyeth of marketing Rapamune, a kidney transplant drug,
for off-label uses.
 The relators, former sales representatives of Wyeth, allege that
Wyeth targeted African Americans, a high risk patient group.
 The relators allege that Wyeth targeted two hospitals with mostly
African-American patients – Philadelphia’s Einstein Medical
Center and New York’s SUNY Downstate Medical Center.
 Wyeth is also accused of offering off-label studies, abstracts,
and lists of studies to use when marketing Rapamune for offlabel usage.
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Recent Government Interventions (cont’d)
Wyeth/Rapamune (E.D. Pa. Oct. 2010)
 The relators claim that Wyeth paid kickbacks to doctors and
hospitals in the form of donations, grants, and speaker fees to
prescribe Rapamune for off-label uses.
 The relators’ complaint does not include factual allegations after
2007.
8
Recent Government Interventions (cont’d)
Abbott/Depakote (W. Va. Feb. 2011)

In February 2011, the DOJ moved to intervene in a qui tam suit brought by
three former employees accusing Abbott of marketing Depakote, an antiseizure drug, for off-label uses such as dementia and behaviors seen in
Alzheimer’s patients.

The relators allege:

Company gave its sales representatives materials requiring them to
encourage nursing homes to use Depakote for off-label uses.

Company failed to disclose that certain favorable articles about
Depakote were written by doctors who were paid by the company.

Company offered sales force bonuses and incentives for off-label
promotion.
9
Recent Government Interventions (cont’d)
Abbott/Depakote (W. Va. Feb. 2011)
 Other allegations by relators:
 Company disguised seminars for doctors that were actually
sessions for discussion of off-label uses.
 Company paid doctors to prescribe Depakote off-label.
 Company trained its sales representatives to avoid being
detected when promoting off-label uses.
 No allegations after 2008.
10
Recent Subpoenas
 On February 11, 2011, Cephalon announced that it received a
subpoena requesting documents relating to Fentora, a drug to treat
cancer pain, in connection with an investigation conducted by the
U.S. Postal Service Office and the Civil Division of the U.S.
Attorney’s Office for the Eastern District of Pennsylvania.
 On February 16, 2011, NovoNordisk announced that it received a
subpoena requesting documents relating to the company’s
marketing practices for its diabetes drugs Novolog, Levemir, and
Victoza from the U.S. Attorney’s Office for the District of
Massachusetts.
11
Pipeline for Off-Label Investigations & Cases

In January 2011, the DOJ and HHS released the following statistics about
sealed qui tam cases, including cases involving off-label marketing:

As of January 4, 2011, there were 1,341 qui tam cases under
investigation awaiting an intervention decision by the government.

885 (or 66%) of cases allege health care fraud.

867 (or 98%) of health care fraud cases involve Medicare or
Medicaid.

DOJ/HHS declined to disclose how many sealed qui tam cases
involve off-label marketing allegations, but revealed generally that
180 cases allege fraud in connection with the pricing and
marketing of pharmaceuticals.

Many of the 180 pricing and marketing cases make allegations
against multiple pharmaceutical manufacturers.
12
Conduct Likely to Trigger an
Off-Label Investigation by the DOJ
 95% of the off-label investigations that resulted in
settlements from 2004 to 2010 were initiated by the filing
of a qui tam complaint under the False Claims Act.
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#1. Target Vulnerable Population
(Children, Elderly, or Institutionalized Patients)
 Marketing an anti-depressant that was approved only for adult
depression for treatment of children and adolescents.
 Promoting an atypical anti-psychotic that was approved only for
adult use for pediatric use and to treat dementia-related psychosis in
elderly patients.
 Promoting an atypical anti-psychotic drug for treatment that was
approved only for adult use to treat elderly, pediatric, and adolescent
patients in long term fare facilities and prisons.
14
#2. Target Doctors Who Do Not Normally
Treat Patients for Any On-Label Use
 Company instructed its sales representatives to sell an antiinflammatory drug to market the drug for pre- and post-operative
pain to orthopedic surgeons, podiatrists, oral surgeons, and “anyone
that used a scalpel for a living” even though the drug was not
approved to treat the acute pain of surgery.
 Sales representatives marketed an anti-epilepsy drug by calling on
psychiatrists and promoting the drug for anxiety and other
psychiatric indications.
 Sales representatives promoted an atypical anti-psychotic drug
approved only for adult use to child psychiatrists, nursing homes,
and pediatric specialists.
15
#3. Misrepresent or Conceal Study
Results Concerning Off-Label Uses
 Company publicized the positive results of a study of an antidepressant drug in adolescents while failing to tell doctors about a
similar study that had negative results. Company submitted both
studies confidentially to FDA and FDA rejected pediatric approval for
the drug based on the negative study. Negative study did not
become public until the New York Times published an article about it
several years later.
 Company promoted an anti-epilepsy drug as effective for treating
bipolar disease even though a study demonstrated that a placebo
worked as well or better than the drug.
 Company promoted a biological drug for treatment of a lung disease
despite a clinical trial that failed to establish statistically significant
evidence for such treatment.
16
#4. Promote Drug for an Off-Label
Use that FDA Has Rejected
 Company promoted an osteoporosis drug for reducing the risk of
breast cancer, even after FDA rejected the company’s proposed
labeling for this use.
 Company promoted an anti-depressant drug as a treatment for
adolescent depression after FDA denied approval for this indication.
 Company marketed an anti-inflammatory drug for acute pain,
including the pain of surgery, even though FDA declined to approve
drug for this indication because of safety concerns.
 Company promoted anti-epilepsy drug as effective for use as the
sole drug (monotherapy) for epileptic seizures, even though FDA
rejected this use.
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#5. Ignore FDA Letter Instructing Company
to Cease Off-Label Promotion of Drug
 FDA first approved the company’s narcolepsy drug to treat
excessive daytime sleepiness associated with narcolepsy, then
expanded the label to include excessive sleepiness associated with
sleep apnea and shift work sleep disorder. From 2001 to 2006, the
company promoted the drug as a non-stimulant for the treatment of
sleepiness, tiredness, decreased activity, lack of energy, and
fatigue, despite a 2002 letter from FDA instructing company to
cease such promotion.
18
#6. Drug Has Serious Adverse Effects, For Which
“Black Box” Warning May Have Been Issued
 FDA mandated that an atypical anti-psychotic drug carry a “black
box” warning concerning its use in the treatment of dementia-related
psychosis. The company allegedly created a specialized long term
care sales force that called almost exclusively on nursing homes,
where dementia-related psychosis is far more prevalent than onlabel uses for schizophrenia or bipolar disorder.
 Company allegedly knew that significant weight gain and obesity
were adverse side effects of its atypical anti-psychotic drug and that
weight gain and obesity were factors in causing hyperglycemia and
diabetes. Despite written caution from FDA, the company continued
to promote those adverse events as therapeutic benefits, particularly
in the elderly.
19
#6. Drug Has Serious Adverse Effects, For Which
“Black Box” Warning May Have Been Issued (cont’d)
 FDA approved a fentanyl product, a strong and highly addictive
narcotic manufactured as a lollipop, for use only in opiod-tolerant
cancer patients. Company allegedly promoted the drug for noncancer patients to use for such maladies as migraine headaches,
sickle-cell pain crises, and injuries. Company also allegedly
promoted the drug for use in patients who were not yet opiodtolerant, and for whom the drug could have life-threatening results.
 Company marketed two anti-depressant drugs for use in children
even after FDA issued “black box” warning that the drugs could
cause suicidal thinking in children.
20
#7. Drug Is Later Withdrawn from
Market Due to Serious Adverse Effects
 FDA approved anti-epilepsy drug for treatment of partial seizures.
The company allegedly promoted the drug as a remedy for anxiety,
insomnia, and pain. Following reports of seizures in patients taking
the drug who did not have epilepsy, FDA required the company to
send a warning letter to doctors advising the on the connection
between off-label use and the risk of seizures. The company then
ceased promotion of the drug.
 Company’s anti-inflammatory drug was withdrawn from the market
after 3 ½ years at FDA’s request due to cardiovascular risk issues.
21
#8. Off-Label Promotion
Accompanied by Kickbacks
 Company allegedly paid doctors to prescribe anti-depressant drugs.
The remuneration included “cash payments disguised as grants or
consulting fees, expensive meals and lavish entertainment,”
including tickets to St. Louis Cardinal and Red Sox games, a $1,000
gift certificate to a gourmet French restaurant, Broadway theater
tickets, and a deep sea fishing trip for a doctor and his family.
 Company allegedly used “sham” consulting agreements to pay
doctors between $500 and $1000 to attend dinners and conferences
where off-label uses of its drug were discussed. These meetings
were held at expensive resorts and restaurants. Doctors who wrote
large numbers of prescriptions for off-label uses were asked to
speak at various events for additional financial bonuses.
22
#8. Off-Label Promotion
Accompanied by Kickbacks (cont’d)
 Company allegedly offered and paid doctors, other medical
professionals, physician groups, and managed care organizations
money, free travel, grants, honoraria, and other valuable goods and
services to get them to prescribe certain drugs. Two doctors
proposed they would endorse the use of the company’s products in
exchange for a series of payments. In 4 ½ years, one doctor wrote
4,130 prescriptions for the company’s products.
 Company allegedly offered to make excess payments of several
million dollars on a distribution contract to a subsidiary of a
pharmacy benefit manager, in the expectation of obtaining improved
formulary positioning and improved formulary ancillary benefits from
that pharmacy benefit manager for the company’s drug products.
23
#9. Use of CMEs and Similar Programs
to Influence Prescribing Behaviors
 Company allegedly used advisory boards, consultant meetings, and
other forums to promote drug for unapproved uses and dosages.
Company used these meetings to invite doctors to serve as
“consultants,” but the goal was to develop them to be “advocates” on
behalf of the company.
 An “advocate,” as one company slide set explained, provides a
solid and positive product message, rather than just presenting
“balanced information, not advocating one product over the
other.” The slide set demonstrated with sports images how the
doctors were to be developed into advocates who could rise
from the “Farm League” to ultimately be on the company’s “All
Star Team.”
24
#9. Use of CMEs and Similar Programs
to Influence Prescribing Behaviors (con’t)
 Company allegedly sponsored “independent medical education”
events on off-label uses of a drug with extensive input from the
company regarding topics, speakers, content, and participants.
 Company allegedly misled the medical community beforehand
about the content, as well as the lack of independence from the
company’s influence, of many of these educational events.
 In at least one instance, when unfavorable remarks were
proposed by a speaker, the company offset the negative impact
by “planting” people in the audience to ask questions
highlighting the benefits of the drug.
25
#9. Use of CMEs and Similar Programs
to Influence Prescribing Behaviors (con’t)
 Company allegedly funded continuing medical education programs,
through millions of dollars in grants, to promote off-label uses of its
drugs.
 Company allegedly retained medical professionals to speak to doctors
during peer-to-peer sessions about off-label uses.
 Company allegedly used “medical liaisons” who represented
themselves, often falsely, as scientific experts on a particular disease,
to promote off-label uses of a drug. Doctors were paid to attend
“consultants meetings” in which doctors received a fee for attending
expensive dinners or conferences during which presentations about offlabel uses were made. These events included lavish weekends and
trips to Florida, the 1996 Atlanta Olympics, and Hawaii. There was
allegedly little or no consulting provided by the doctors.
26
#9. Use of CMEs and Similar Programs
to Influence Prescribing Behaviors (con’t)
 Company allegedly directed physician workshops and dinners
focused on off-label uses, paid doctors to attend “advisory boards”
promoting off-label uses, and created an “independent” online
education organization to stimulate increased off-label use.
 Company allegedly made a series of payments to two doctors in the
form of a “sponsorship” of continuing medical education classes
conducted by the doctors.
 Company allegedly promoted an anti-epilepsy drug for off-label
psychiatric uses through its “Doctor-for-a-Day” program. Using this
program, the company hired outside doctors to join sales
representatives in their visits to the offices of health care providers
and to speak at meetings and dinners about prescribing the drug for
unapproved uses and doses.
27
#9. Use of CMEs and Similar Programs
to Influence Prescribing Behaviors (con’t)
 Company allegedly organized a “market research summit” during
which off-label uses for an osteoporosis drug were discussed.
Company also organized “consultant meetings” for doctors who
prescribed the drug during which unapproved uses were discussed.
 Company allegedly engaged doctors to give promotional speaker
programs on off-label uses and to conduct studies on such use.
28
#10. Conduct Demonstrating Intent to
Engage in Unlawful Off-Label Promotion
 Sales force created “sham physician requests” from physicians for
medical information in order to send unsolicited information to
physicians about unapproved uses of drugs.
 Sales force promoted, drafted, and distributed proposed physician
standing orders and hospital wide protocols and pain pathways that
called for unapproved uses of drugs.
 Sales representatives were trained to prompt or bait questions by
doctors in order to promote drug for unapproved uses.
29
#11. Top Level Management Involved
in Off-Label Promotion Strategy
 Management allegedly created marketing materials to promote a
drug for off-label uses, trained its sales force to “disregard the law,”
and directed its sales personnel to promote the drug for off-label
uses. Management specifically trained the sales force on how to
respond to doctors’ concerns about off-label uses of the drug and
how to continue to promote the drug for off-label conditions.
 Company’s marketing team positioned the drug for unapproved uses
and commissioned market research to test its sales materials.
 Strategic marketing plans and promotion material generated by
management show company’s intent to expand the market by
promoting drug for unapproved uses.
30
#12. Problematic Promotional Activities
at Company’s National Sales Meeting
 Promotional activities at a company’s national sales meetings are of
particular interest to the government when conducting off-label
investigations (and other investigations concerning the marketing
and pricing of drugs).
 If problematic marketing activities occur at a company’s national
sales meeting, the government may argue that such problematic
activities were not isolated events, but rather were widespread
activities that were part of the company’s national marketing plan.
31
#12. Problematic Promotional Activities
at Company’s National Sales Meeting (cont’d)
Example

Drug X was officially launched at a national sales meeting for sales representatives in
2002. During this meeting, the sales force was given a vivid message of how to
promote Drug X for the “power” position.

Sales representatives were inundated with displays of music, light shows, acrobats,
and dancers.

The marketing managers led the entire audience in thrusting their fists into the air
(the marketing symbol of Drug X) and pounding them against their upraised hands in
unison to symbolize the power of Drug X and to “Power Up” the sales force.

Ultimately, simulated large steel doors crash down on the stage, and Drug X’s fist
symbol crashed through the doors.

According to the government, the events from the launch demonstrate the sales
frenzy that accompanied the launch of Drug X as the company strove to make the
drug reach blockbuster status.
32
#13. Ghostwriting Articles About Off-Label Uses
 Company allegedly initiated, funded, and sometimes drafted or paid
vendors to draft articles about its drug for unapproved uses without
appropriately disclosing the company’s role.
 Company allegedly recruited doctors to serve as authors of articles
that were ghostwritten by medical literature companies and about
studies the doctors in question did not conduct. Company allegedly
uses these studies and articles as the basis for promotional
messages about unapproved uses of the drug.
33
#14. Teach Doctors How to Get
Reimbursed for Off-Label Use
 Company allegedly doubled the size of its reimbursement team to
assist doctors in obtaining payment for off-label uses and:
 Held workshops to teach doctors and their office staff how to bill
for off-label uses;
 Conducted detailed audits of doctors’ billing records to
demonstrate how they could make money by prescribing the
drug; and
 Operated a Reimbursement Hotline which provided a wide array
of free on-demand services to doctors for off-label uses.
34
#15. Exploit On-Label
Indication to Grow Off-Label Sales
 Company allegedly exploited its on-label cervical dystonia (CD)
indication to grow off-label pain and headache (HA) sales.
 Company allegedly developed the “CD/HA Initiative” as a
“rescue strategy” in the event of negative results from its clinical
trials to ensure continued expansion into the pain and headache
markets.
 Company allegedly claimed that cervical dystonia was
“underdiagnosed” and that doctors could diagnose cervical
dystonia based on headache and pain symptoms, even when
the doctor “doesn’t see any cervical dystonia.”
35
#16. Sales Force Quotas Cannot
Be Met Without Off-Label Use
 Company structured its sales quotas and bonuses in such a way
that sales representatives could reach their sales goals only if they
promoted and sold the drugs for off-label uses.
 Sales representatives were given sales quotas for the amount of a
drug that had to be purchased in their districts, without regard to
whether those sales were on or off-label.
 Because sales representatives were judged on a competitive
basis, they would have been negatively affected if they did not
capture off-label sales but their colleagues did.
 Sales numbers substantially above quota resulted in significant
bonuses annually.
36
#17. Majority of Sales Come From Off-Label Use
 57% of sales for an anti-inflammatory drug were off-label.
 The “vast majority” of sales for a biological drug were attributable to
off-label prescriptions.
 78% of sales for an anti-epilepsy drug were off-label.
37
#18. Drug Achieves Blockbuster Status During
Period of Alleged Off-Label Marketing
 In the early 2000s, the company was one of the drug industry’s biggest
success stories. It was a small specialty pharmaceutical company that
licensed an anti-depressant drug and turned it into a blockbuster drug.
 In the fiscal year ending March 2002, the drug’s sales were greater
than $1 billion and accounted for 69% of the company’s total
revenue.
 The drug lost patent protection in 2004 causing much of its sales to
vanish.
 The company then introduced a new improved anti-depressant
drug.
 The new drug was the company’s #1 product with sales of $2.3
billion in 2008.
38
Contact
Antonia F. Giuliana
PARTNER
Litigation
Phone: (212) 808-7941
[email protected]