Transcript Vitally Important to the Practice of Medicine

Off-Label Communications and the Public Health
Presentation to the Pharmaceutical Compliance Forum
November 8, 2007
Paul E. Kalb, M.D., J.D.
With appreciation for the contributions of
Joan McPhee and Alan Bennett of Ropes & Gray and
Dan Troy of Sidley Austin
Overview
1. Introduction
2. Off-Label Prescribing is Lawful, Common and
Vitally Important to the Practice of Medicine
3. Many Government Policies and Practices
Encourage Off-Label Prescribing
4. Open Communication of Clinical Trial Data is
Essential to Public Health
5. Criminalizing the Dissemination of Truthful,
Non-Misleading Scientific Data Threatens
Public Health
2
1. Introduction
3
Disconnect Between FDA-Approved Labeling
and State of the Art Medical Practice
• FDA-Approved Labeling of Drug Products Often
Represents an Incomplete or Even Inaccurate
Picture of the Current State of Medical
Knowledge.
“Science moves faster than the FDA.”
Peter Barton Hutt, former FDA General Counsel
FDA Seeks to Add Drugs’ New Uses to Labels,
Washington Post, Mar. 29, 1994
4
Disconnect Between FDA-Approved Labeling
and State of the Art Medical Practice
• Many of the most beneficial uses for approved
drugs are discovered in the post-FDA approval
stage.
• There is often a substantial time lag between
scientific discoveries and FDA approval:
– FDA approval of supplemental drug applications takes an
average of more than two years
– By the time of approval for a new use of a drug, two-thirds
of medical journal articles regarding that use have already
been published
– New uses are recognized in U.S. Pharmacopoeia – Drug
Information an average of 2½ years before FDA approval
5
Disconnect Between FDA-Approved Labeling
and State of the Art Medical Practice
• Many medically accepted off-label uses never
become FDA-approved uses
– There is frequently no rational economic incentive to seek
supplemental approval for new uses late in a drug’s patent
life
– For certain diseases, it may be difficult, if not impossible, to
find patients willing to participate in the large, randomized
clinical trials required to obtain FDA approval for a new use
6
2. Off-Label Prescribing is Lawful,
Common, and Vitally Important to
the Practice of Medicine
7
Off-Label Prescribing is Lawful, Common and
Vitally Important to the Practice of Medicine
• Physicians may lawfully prescribe FDAapproved drugs for any use consistent with
available scientific data and appropriate medical
practice
“[A] physician may, as part of the practice of medicine, lawfully prescribe a
different dosage for his patient, or may otherwise vary the conditions of use
from those approved in the package insert.”
37 Fed. Reg. 16503 Aug. 15, 1972
8
Off-Label Prescribing is Lawful, Common and
Vitally Important to the Practice of Medicine
• The FDA has no jurisdiction over the practice of
medicine:
“FDA does not have the authority [under the FDCA provisions] to control decisions
made by qualified healthcare practitioners to prescribe products for conditions other
than those described in FDA-approved professional labeling, or to otherwise regulate
medical or surgical practice.”
FDA Guidance for Industry on Development of Risk
Minimization Action Plans, March 2005
“The physician is responsible for making the final judgment as to which, if any, of the
available drugs his patient will receive in the light of the information contained in their
labeling and other adequate scientific data available to him.”
37 Fed. Reg. 16504 Aug. 15, 1972
9
Off-Label Prescribing is Lawful, Common and
Vitally Important to the Practice of Medicine
• DOJ has affirmed that the FDA has no
jurisdiction over the practice of medicine:
“DoJ recognizes that once a drug has been approved by FDA for a medical
condition, a health care practitioner may lawfully prescribe the drug for any
use, regardless of whether FDA has determined that drug to be safe and
effective for that use.”
Assistant US Attorney General Peter Keisler, November, 2004
10
Off-Label Prescribing is Lawful, Common and
Vitally Important to the Practice of Medicine
• Prescribing drugs off-label is extremely common:
How often do you prescribe drugs for off-label
indications?
More than 40% of the time
30% - 40% of the time
20% - 30% of the time
10% - 20% of the time
5% - 10% of the time
Less than 5% of the time
Don’t know/not sure
9%
12%
17%
19%
18%
18%
7%
Daniel Klein, Alexander Tabarrok,Do Off-Label Practices Argue Against FDA Efficacy
Requirements?,Independent Institute, April 16, 2003
11
Off-Label Prescribing is Lawful, Common and
Vitally Important to the Practice of Medicine
• Off-label prescribing is pervasive in the practice
of oncology:
– 60% of oncologists report that they frequently prescribe
medications off-label
– More than half of all cancer patients have received an anticancer drug for an off-label use
– Nearly every type of cancer is treated with off-label
regimens
– Roughly 95% of all oncology drugs are used off-label
The Rationale for Off-Label Prescriptions, 12(3) Johns Hopkins Medical Letter: Health After 50 (May 2000);
General Accounting Office, Report to the Chairman, Comm. On Labor and Human Resources, U.S. Senate,
Off-Label Drugs: Reimbursement Policies Constrain Physicians in Their Choice of Cancer Therapies 20, 27
(1991); American Society of Clinical Oncology Daily News (May 14, 2001).
12
Off-Label Prescribing is Lawful, Common and
Vitally Important to the Practice of Medicine
• The need to address the risk of not treating patients
leads to extensive off-label prescribing in oncology:
“The labeling of anticancer products frequently presents an incomplete or even
inaccurate picture of the current state of medical knowledge. For virtually every cancer
drug, appropriate medical dosage differs from the terms on the product labeling.”
John R. Durant, M.D., Executive Vice President, American Society of Clinical Oncology, 1998
“The off-label uses of approved drugs have been an important tool for advancing the
treatment of cancer.”
American Society of Clinical Oncology, 2003
“[I]n some cases, if you didn’t use the drug in the off-label way, you’d be guilty
of malpractice.”
M. Roy Schwarz, Vice President for Science and Education, American Medical Association
13
Off-Label Prescribing is Lawful, Common and
Vitally Important to the Practice of Medicine
• Lack of pediatric indications on drug labels
leads to off-label prescribing:
“Because most of the drugs currently marketed for administration by
prescription do not have pediatric dosing information as part of the label,
clinicians are faced with the dilemma of either using drugs without much
information to support them or depriving their patients of potentially effective
and sometimes lifesaving therapy.”
American Academy of Pediatrics, Off Label Uses of Drugs in Children, September 1999
• According to FDA estimates, nearly 80% of all
drugs prescribed for children are prescribed offlabel
Jenette Restivo, Pediatric Drug Testing Enters Infancy Nature Medicine 9(6),
June 2003, at 631
14
Off-Label Prescribing is Lawful, Common and
Vitally Important to the Practice of Medicine
• Off-label prescribing is also common in
psychiatry:
– One study found high percentages of off-label
prescriptions in the psychiatric field:
• 75% of anti-seizure medications
• 66% of antipsychotic medications
• 25% of antidepressant medications
Chain Drug Review, 48(1), Nov. 24, 2003
15
Off-Label Prescribing is Lawful, Common and
Vitally Important to the Practice of Medicine
• Off-label prescribing is common in psychiatry for
numerous reasons:
– Patients are often treated based on their symptoms rather
than a specific diagnosis
– Psychiatry patients often have disorders for which no drug
has an indication
– Even when a drug does have an indication for a particular
disorder, patients often fall outside the labeled age or
demographic group
– Patients often fail to respond to labeled products, and
experimentation and adaptation is necessary
– Off-label prescriptions are often necessary to address
adverse side effects associated with many psychiatric
drugs
16
Off-Label Prescribing is Lawful, Common and
Vitally Important to the Practice of Medicine
• The FDA has recognized that off-label
prescribing is necessary and valuable in the
practice of medicine:
“FDA recognizes that. . . off-label uses of approved products are appropriate,
rational and accepted medical practice.”
“FDA knows that there are important off label uses of approved drugs.”
William B. Schultz, FDA Deputy Commissioner of Policy (1996, 2004)
17
Off-Label Prescribing is Lawful, Common and
Vitally Important to the Practice of Medicine
• FDA recognizes off-label usage may be the
standard of care:
– FDA’s Oncologic Drugs Advisory Committee (ODAC)
rejected accelerated approval of Marqibo in December
2004
– Cited Rituxan as an available therapy, recognizing the
widespread off-label use of Rituxan in the treatment of
both front-line and refractory aggressive Non-Hodgkin's
Lymphoma
18
Off-Label Prescribing is Lawful, Common and
Vitally Important to the Practice of Medicine
• The courts recognize the value of off-label uses
to the proper practice of medicine:
“Off-label
use is widespread
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essential
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to more stringently
enforce
its statutory
authorityand
to 288
prosecute
misbranding.”
Off-label
use of medical
devices
“is United
an accepted
necessary
corollary
of
States v. Caputo,
F. Supp. 2d 912
(N.D. Ill. 2003)
the FDA’s mission to regulate in this area without directly interfering with the
practice of medicine.”
Washington Legal Foundation v. Henney 56 F. Supp. 2d 81, [201] (D.D.C. 1999)
Buckman Co. v. Plaintiffs’ Legal Committee, 531 U.S. at 351 n.5
Buckman Co. v. Plaintiffs’ Legal Committee, 531 U.S. 341, 350 (2001)
19
Off-Label Prescribing is Lawful, Common and
Vitally Important to the Practice of Medicine
• The AMA has also affirmed the importance of
off-label prescribing:
“The prevalence and clinical importance of prescribing drugs for unlabeled uses are
substantial…. Thus, the prescribing of drugs for unlabeled uses is often necessary for
optimal patient care.”
1997 AMA Annual Meeting
“The AMA affirms that a physician may lawfully use an FDA-approved drug for an
unlabeled indication when such use is based upon sound scientific evidence and sound
medical opinion.”
AMA Policy 120.988
“Up-to-date, clinically appropriate medical practice at times requires the use of
pharmaceuticals for ‘off-label’ indications as distinct from the specific approved
indication(s) from the US Food and Drug Administration. . .”
AMA House of Delegates, Resolution 820, “Off-Label Use of
Pharmaceuticals,” September 21, 2005
20
3. Many Government Policies and
Practices Encourage Off-Label
Prescribing
21
Many Government Policies and Practices
Encourage Off-Label Prescribing
• The Government supports the appropriate offlabel usage of oncology drugs:
“Off-label use of drugs is widespread in cancer treatment for several reasons.
… Some cancer drugs are found to be effective against a variety of tumor
types. … Cancer chemotherapy often involves the use of multiple drugs. …
Cancer treatment is always evolving.”
National Cancer Institute, Q&A Off-Label Drugs, posted December 31, 1999
22
Many Government Policies and Practices
Encourage Off-Label Prescribing
• The National Cancer Institute recognized offlabel indications of Rituxan as standard of care
– Front Line Aggressive Adult Non-Hodgkin’s Lymphoma:
“Standard treatment options: … 1. CHOP plus rituximab”
– Indolent, Noncontiguous Stage II/III/IV Adult Non-Hodgkin’s Lymphoma:
“Standard treatment options: … 1. Rituximab may be considered as first line
therapy”
– Stage I, II, III, and IV Chronic Lymphocytic Leukemia:
“Treatment options: … 2. Rituximab, and anti-CD20 monoclonal antibody.”
National Cancer Institute website, www.cancer.gov
23
Many Government Policies and Practices
Encourage Off-Label Prescribing
“The publication of results from the
Multiple Outcomes of Raloxifene
Evaluation, or MORE trial, which show that
the osteoporosis prevention drug
raloxifene (Evista®) reduced the
incidence of breast cancer in
postmenopausal women with
osteoporosis, brings additional peerreviewed data to the body of evidence
that supports the rationale for the Study
of Tamoxifen and Raloxifene (STAR).”
24
Many Government Policies and Practices
Encourage Off-Label Prescribing
• Government policy on use of antipsychotics in
nursing homes validates off-label usage:
– CMS State Operations Manual recognizes a number of
antipsychotic drugs for use for residents without
psychological issues
– Recognizing use as “necessary to maintain or improve the
residents functional status”
25
Many Government Policies and Practices
Encourage Off-Label Prescribing
Medicare State
Operations Manual,
Appendix PP at F329 42
C.F.R § 483.25
26
Many Government Policies and Practices
Encourage Off-Label Prescribing
• Medicare federal coverage policy:
– Medicare policy guidance specifically includes, as eligible
for coverage, off-label uses supported by recognized
compendia or peer-reviewed medical journals
The Social Security Act defines a “medically accepted indication” for use of a drug to be any FDAapproved use, as well as other uses if- the drug has been approved by the FDA, and
(i) the use is supported by certain compendia; or
(ii) the use is medically accepted based on supportive clinical evidence in certain peerreviewed medical literature.
Social Security Act § 1861(t)(1)
“FDA approved drugs used for indications other than what is indicated on the official label
may be covered under Medicare if the carrier determines the use to be medically
accepted, taking into consideration the major drug compendia, authoritative medical
literature and/or accepted standards of medical practice.”
Medicare Benefit Policy Manual (CMS Pub. 100-2) Chapter 15 §50.4.2
27
Many Government Policies and Practices
Encourage Off-Label Prescribing
• Medicaid federal coverage policy:
“The term ‘medically accepted indication’ means any use
for a covered outpatient drug which is approved under the
Federal Food, Drug, and Cosmetic Act, or the use of which
is supported by one or more citations included or approved
for inclusion in any of the compendia described in section
(G)(1)(b)(i).”
Social Security Act § 1927 (G)(1)(b)(i)
28
Many Government Policies and Practices
Encourage Off-Label Prescribing
• Edmonds v. Levine:
– In federal court in Florida, plaintiffs seeking coverage for
off-label uses on Neurontin challenged a state policy that
to be "supported by” Drugdex compendium, the efficacy of
a drug had to be demonstrated in two randomized,
controlled clinical trials
– Magistrate judge granted plaintiffs’ motion, and required
reimbursement for 54 off-label uses of Neurontin
“The court direct[s] the defendant to stop applying the ‘Neurontin Policy’
effective July 2004, and provide coverage for off-label uses of Neurontin
which are cited in one of the Congressionally approved compendia.”
Edmonds v. Levine, 2006 WL 453911, at *2 (S.D. Fla. 2006)
29
4. Open Communication of Clinical
Trial Data is Essential to Public
Health
30
Open Communication of Clinical Trial
Data is Essential to Public Health
• The FDA has acknowledged the importance of
access to information regarding off-label uses:
The “principle for the FDA is that the very latest information that can be
of value to physicians, pharmacists, and patients must be made
available as soon as possible. Frequently, unlabeled use information is
extremely important.”
Stuart J. Nightingale, FDA Associate Commissioner for Health Affairs,
Unlabeled Uses of Approved Drugs, 26 Drug. Info. J. 141,145 (1992).
31
Failure to Communicate Clinical Trial Data is a
Major Public Health Problem
• President’s Cancer Panel affirms that the
sharing of clinical information is important:
“Disseminating prompt, accurate information in usable formats to community health care
providers and the public about cancer prevention and treatment advances is a critical step in
the translation - the link between an intervention's development and its adoption in clinical
practice."
President's Cancer Panel, 2004-2005 Annual Report, at 65.
“Simply put, we are not applying what we know – interventions demonstrated to be
efficacious and validated through the clinical trials process – nearly well enough, quickly
enough, or widely enough.”
The National Cancer Program: Assessing Past,
Charting the Future, 1999 Annual Report
"To achieve the ultimate goal of dissemination - enabling individuals and organizations to
adopt evidence-based approaches that will help reduce the risk and burden of cancer specific education and communication needs of the public, health care professionals, and
research community must be met.”
President's Cancer Panel, 2004-2005 Annual Report, at ix.
32
Open Communication of Clinical Trial
Data is Essential to Public Health
• The AMA has affirmed the importance of access
to accurate information regarding off-label uses:
“It is imperative that physicians have access to accurate and
unbiased information about unlabeled uses of prescription
drugs.... Dissemination of independently derived scientific
information about unlabeled uses by manufacturers to
physicians can help physicians have access to the latest,
scientifically credible information.”
1997 AMA Annual Meeting
33
Open Communication of Clinical Trial
Data is Essential to Public Health
• Access to scientific information regarding offlabel uses is of particular importance outside of
urban areas of academic medical excellence:
Physicians outside of major urban areas “have very little time to pursue
information; therefore, information must be immediately accessible,
concise, high quality, presynthesized, and up-to-date.”
Dee and Blazek, Information Needs of the Rural Physician: A Descriptive Study,
Bull Med Libr. Assoc 81(3), July 1993, at 263.
34
Open Communication of Clinical Trial
Data is Essential to Public Health
“[I]t is well-documented that physicians rely upon
the [pharmaceutical] industry for much of their drug
information.”
Spiller and Wymer, Physicians’ Perceptions and Uses of Commercial Drug
Information Sources: An Examination of Pharmaceutical Marketing to Physicians,
Health Marketing Quarterly Vol. 19(1) (2001), 94
35
Open Communication of Clinical Trial
Data is Essential to Public Health
• 73% of the physicians surveyed in a 2001 study
found information from pharmaceutical sales
representatives to be useful to their practice:
– 57% of physicians in the study found sales reps to be a
“somewhat useful” source of information.
– 16% of physicians found sales reps to be “extremely
useful.”
Spiller and Wymer, Physicians’ Perceptions and Uses of Commercial Drug
Information Sources: An Examination of Pharmaceutical Marketing to Physicians,
Health Marketing Quarterly Vol. 19(1) (2001), 96
36
Open Communication of Clinical Trial
Data is Essential to Public Health
• Industry-wide movement towards sharing of
clinical trial data, particularly after GSK NY
settlement regarding full disclosure of clinical
trial data:
“This settlement holds GSK to a new standard of disclosure
about studies concerning its drugs, a standard that helps to
ensure that doctors and patients have access to all
scientifically sound information so doctors can prescribe
appropriate medication for their patients.”
NY AG Elliott Spitzer
37
5. Criminalizing the Dissemination
of Truthful, Non-Misleading
Scientific Data Threatens Public
Health
38
Federal Prosecutors are Pursuing the Dissemination
of Off-Label Information as Criminal and Civil Misconduct
• Federal prosecutors are prosecuting off-label
dissemination as a federal crime
• Some cases have been resolved by criminal
pleas and the payment of substantial fines
– No adjudications on the merits
• Numerous other cases are currently under
investigation
39
Federal Prosecutors are Pursuing the Dissemination
of Off-Label Information as Criminal and Civil Misconduct
• In these cases and investigations, the
government has pursued criminal off-label
charges through two distinct legal theories under
the Federal Food Drug and Cosmetic Act:
– Misbranding “no adequate directions for use” 21 U.S.C.
§§ 331(a), 352(f)
– Unapproved new drug, 21 U.S.C. §§ 331(d), 355
• Neither theory of criminality requires false or
misleading representations or other inherently
wrongful conduct
40
Federal Prosecutors are Pursuing the Dissemination
of Off-Label Information as Criminal and Civil Misconduct
Off-label
On-label
Truthful,
NonMisleading
Untruthful
or
Misleading
“Early” or “emerging” data are not inherently
misleading. Context is critical.
41
Federal Prosecutors are Pursuing the Dissemination
of Off-Label Information as Criminal and Civil Misconduct
• Criminal prosecution for the truthful, nonmisleading off-label communications raises
numerous concerns:
-Statutory:
While false and misleading statements are expressly prohibited by the Food, Drug and
Cosmetic Act, truthful, non-misleading statements are not, raising doubt as to whether the
more general prohibition on introduction of goods into interstate commerce without
“adequate directions” or introducing “new drugs” without FDA approval can be interpreted
to prohibit truthful, non-misleading statements.
-Constitutional:
There is serious doubt about whether the Government may criminalize the dissemination
of truthful, non-misleading scientific information.
-Policy:
Criminalizing truthful, non-misleading scientific speech carries the substantial risk of
chilling investment in off-label research, dissemination of truthful, non-misleading off-label
information, support for scientific meetings, and support for CME.
All of this negatively impacts public health.
42
Federal Prosecutors are Pursuing the Dissemination
of Off-Label Information as Criminal and Civil Misconduct
“[W]e need to ask whether or not it is helpful for attorneys that are
part of the United States government to be criminalizing people
who are conveying to doctors truthful, non misleading scientific
information that, in many cases, the government’s own scientists
are themselves developing. It seems to me that activities to
criminalize the dissemination of truthful, non-misleading
information about new uses for existing drugs, especially in fields
marked by rapid medical advance like cancer, has the potential to
greatly impede the ability of patients to access the latest therapies
based on the most up-to-date medical evidence.”
Scott Gottlieb, M.D., FDA Deputy Commissioner
(December 2006)
43
Federal Prosecutors are Pursuing the Dissemination
of Off-Label Information as Criminal and Civil Misconduct
• The Government is also pursuing off-label
promotion civilly, primarily under the False
Claims Act
• Legally uncertain and unsettled
• Nonetheless, a substantial threat
• Amplifies policy concerns about suppression of
truthful, non-misleading scientific information
44
Solutions?
1. Continue to clarify the FDA rules distinguishing
between impermissible off-label promotion and
permissible scientific exchange.
2. Establish clear guidelines for investigation and
prosecution of off-label cases. Ask:
A. Whether conduct conforms with FDA “safe harbor?”
B. Whether communications are truthful and nonmisleading?
C. Whether patients are helped or harmed?
D. Whether FDA approved process has been undermined?
45
THE END
46