Institutional Corruption
and
Off-Label Drug Use
Marc A. Rodwin, J.D., Ph.D.
Professor of Law,
Suffolk University Law School
V8
[email protected]
WebWeb page: http://www.law.suffolk.edu/faculty/directories/faculty.cfm?InstructorID=48
.SSRN: http://papers.ssrn.com/sol3/cf_dev/AbsByAuth.cfm?per_id=625249
Outline
What is Institutional Corruption?
How Might Pharmaceutical Policy be Institutionally
Corrupted?
Inappropriate Off-Label Drug Use as an Example of
Institutional Corruption
• What is off-label drug use?
• What is the incidence of off-label drug use?
• Is Off-Label Drug Use Inappropriate?
• What Drives Off-label Drug Use?
A Proposal to Manage Off-Label Drug Use by
Targeting Institutional Corruption.
Lawrence Lessig. Two Conceptions of ‘Corruption.’
Republic, Lost: How Money Corrupts Congress – and a
Plan to Stop It. Twelve-Hackette Book Group, 2011.
Institutional Corruption:
Widespread or systemic practices, usually legal,
that undermine an institution’s objectives,
integrity or effectiveness.
• A metaphor for institutional corruption:
magnetic deviation. A compass arrow is
supposed to point towards magnetic north. But
if a magnet approaches the compass it draws the
arrow away from the true north.
Working Definition:
“Institutional corruption is manifest when there is
a systemic and strategic influence which is legal,
or even currently ethical, that undermines the
institution’s effectiveness by diverting it from its
purpose or weakening its ability to achieve its
purpose, including, to the extent relevant to its
purpose, weakening either the public’s trust in that
institution or the institution’s inherent
trustworthiness.”
• “Systematic and strategic influence”
– Focus on influence/ inefficiencies that are
systematic
• “Which is legal or even currently ethical”
– Distinguish IC from traditional illegal
corruption, e.g., bribes, kickbacks, violation of
governing rule.
• “Undermines the institution’s
effectiveness”
– Key is the effects of behaviors
• “By diverting it from its purpose”
– Assumes institution has clear purpose
• including, when relevant, weakening the
public’s trust
– Sometime public trust is necessary to achieve
its purpose.
• “Or weakening the institution’s inherent
trustworthiness”
– Separate from whether the institution is trusted.
Should the institution be trusted?
• A key source of institutional corruption is improper
dependence by the institution or its key actors on the
actions of third parties that have fundamentally different
interests.
• Dependence Corruption. Improper dependencies can
both displace the mission of an institution and weaken
its functioning.
• The House of Representatives is supposed to be
“dependent on the people alone.”
• However, Congressional representatives depend on
campaign contributions to get elected. Campaign
contributions in turn come in large part from industries
and wealthy individuals who stand to profit from laws
and regulations that emanate from Washington.
Example: Today, Congress is dependent on a
tiny fraction of wealthy donors; a mere .01
percent of the population gives more than
$10,000 in any election cycle. “The tiniest
fraction of the one percent have the effective
power to block reform desired by the 99-plus
percent.”
• Candidates cannot win in the general
election unless they are s/elected in the
election of campaign funders.
III) Institutional Corruption
and Pharmaceutical Policy
• The health care system’s improper
dependency on pharmaceutical firms
displaces some policy goals and
compromises the attainment of others.
• Six Kinds of Institutional Corruption from
Improper Dependency on Pharmaceutical
firms:
Dependency on Drug Firms
Dependency on Drug Firms
(4) To market drugs only for approved uses.
– However, manufacturer earns more money when MDs
prescribe off-label.
(5) to provide information on the risks of drugs once they are
marketed.
– However, it is imprudent to rely mainly on manufacturers to
warn about the risks of their products.
(6) to supply information on drugs to physicians and to finance
continuing medical education and other professional activities.
– However, manufacturers supply information and donate money
in order to sell their products, and that compromises the integrity
of these activities.
Drug Firm Influence on
•
•
•
•
•
•
•
Research on risks and benefits of drug
The FDA
CME
Key Opinion Leaders
Clinical practice guidelines
Physicians clinical judgments (through
marketing)
Patient association policies
What Is Off-Label Prescribing?
• FDA requires that drug labels reflect safety/ effectiveness data
from clinical trials submitted to FDA in NDA. Clinical trials
test a drug for a particular therapeutic purpose, dose &
population.
• Off-label Prescribing: Prescribing drugs in ways that deviate
from the uses specified in the FDA-approved drug label,
package insert, and marketing authorization.
OxyContin Label
Procrit Label
Procrit Package Insert
Procrit Medication Guide
Off-Label Prescribing
Prescribing a drug for:
• Therapeutic purpose other than the one approved by the FDA;
• To treat patients in a different age cohort or gender than the
population on which it was tested; or
• Using a different dose than approved,
• For a different duration of use,
• For a different mode of administration than indicated on label
Off-Label Marketing v. Off-Label Rx
FDA regulates marketing of drugs, but does not regulate
physician prescribing. In principle, MDs can prescribe drug for
any purpose.
Why do physicians prescribe off-label?
Can prescribing off-label ever be justified?
• Yes - If reasonable evidence suggests that the benefit of offlabel use will outweigh the risks, that declining to treat the
condition poses even greater dangers than the off-label
prescription does, and that there is no adequate alternative
therapy
The Limits of On-Label Prescribing
Clinical trials conducted to support an application to market
a new drug often do not provide information about the
drug’s effect on significant segments of the population.
Research protocols typically excludes:
•
•
•
•
children
pregnant women
patients with additional complicating medical conditions
the elderly
To What Extent Do Physicians
Prescribe Off-Label?
David Radley, Dartmouth Med. School, estimates:
• approximately 21 percent of uses for commonly
prescribed medicines are off-label.
• For some drug classes, up to half of all
prescriptions are off-label
D. C. Radley, S. N. Finkelstein, and R. S. Stafford, “Off-Label Prescribing among OfficeBased Physicians,” Archives of Internal Medicine 166(9). 2006: 1021-1026.
Common Practice Areas in Which Drugs are
Used Off-Label
• Oncology
• Pain management and palliative care
• Anticonvulsants
• Anti-asthmatics
• Psychiatric medications
Chemotherapy Off-Label Uses
• 33% of treatments are used for off-label purposes. (GAO
study)
• 50% of oncology drugs are used for off-label purposes.
(American Society of Clinical Oncology)
• 50 to 75 % of oncology drugs are used for off-label purposes.
(David Radley)
Off-Label Drugs: Reimbursement Policies Constrain Physicians in Their Choice of Cancer Therapies,
Report to the Chairman, Committee on Labor and Human Resources, U.S. Senate (1991).
S. G. Poole and M. J. Dooley, “Off-Label Prescribing in Oncology,” Supportive Care in Cancer 12(5).
2004: 302-305
Populations with High
Off-Label Use
• Pediatric population: 80% of uses are offlabel
• Rare diseases: 90% of uses off-label
How Often is Off-Label Prescribing Justified?
• About 15% of all drug uses lack scientific
support for efficacy.
• More than 70% of off-label uses lack
significant scientific support.
Off-labels uses that most frequently lack
scientific support
• Psychiatric treatments
• Allergy treatments
Examples of Justified Off-Label Prescribing
1) Extend a drug’s use to therapeutic problems similar to those addressed
in clinical trials.
Examples:
• An antibiotic that combats certain infections and microorganisms may
also be used to treat infections caused by other microorganisms.
• The FDA approved Imatinib to treat advanced chronic myeloid
leukemia. Imatinib targets enzymes called tyrosine kinases, which are
overexpressed in the cells of patients with this type of cancer. Other
cancers also involve abnormally high levels of tyrosine kinases, so
physicians sometimes prescribe Imatinib in those cases.
2) When well-designed peer-reviewed studies suggest a drug can be
beneficial for certain off-label uses.
Why is Off-Label Prescribing
a Problem?
• Unmanaged off-label drug use undermines the FDA’s
mission to regulate the drug market in order to protect
patients from dangerous and ineffective drug therapies.
• It also compromises the medical ideal that physicians
should prescribe medications based on a careful evaluation
of the risks and benefits.
What Drives Off-Label Prescribing?
• Physicians demand the right to prescribe off-label.
• Insurers that reimburse such prescriptions make it
feasible for patients to purchase the drugs.
• The lack of controls over off-label prescribing makes it
easy to do.
• MAINLY--Pharmaceutical firms’ incentive to increase
sales drives this practice.
Institutional Corruption
•
“Systematic and strategic influence”
•
“Which is legal or even currently ethical”
•
“Undermines the institution’s effectiveness”
•
“By diverting it from its purpose”
•
Including, weakening the public’s trust”
•
“Or weakening the institution’s inherent
trustworthiness”
•
Improper dependencies can both displace the
mission of an institution and weaken its functioning.
The Problem
• Drug firms have incentives to maximize their sale of drugs,
even for off-label uses, despite the risk of legal penalties for
violating the law.
•
Some practices to promote off-label drug use are protected
by the 1st Amendment.
•
Some off-label uses are reasonable so its difficult to stop the
practice even when it is not reasonable.
•
Drug firms lack incentives to evaluate the effectiveness and
safety of off-label drug use.
•
We lack tools to track the incidence of off-label drug use and
to study its causes and effects
Misalignment between incentives for drug
firms profits and goals of evidence-based
medicine and public health
• We depend on drug firms to produce evidence
regarding the safety and effectiveness of off-label
uses, but they lack incentives to fund any wellcontrolled studies of off-label uses.
• We depend on drug firms to promote sales and
supply information in ways that promote
evidence-based medicine and public health goals
while these firms have an incentive to maximize
sales regardless of how drugs are used.
Role of Insurers
Insurers sometimes Limit off-label prescribing:
• Through contracts that exclude treatment that is
experimental or not medically necessary
• By requiring MDs to justify off-label prescriptions
Insurers usually pay for drugs if compendia report there is
evidence of effectiveness.
• Medicaid programs often required to cover drugs listed in
compendia.
• Medicare reimburses hospitals for off-label uses if drugs are
listed in certain compendia.
• < 25% of Medicare/ Medicaid drug benefit managers say
they DO NOT reimburse off-label uses.
• Most insurers don’t ask doctors the purpose for which they
prescribe or require prior authorization for reimbursement.
Compendia
Compendia vary in conclusions on off-label uses.
• Process by which compendia make decisions is opaque
• Relations between drug firms and compendia unclear
• Conflicts of interest AHRQ White Paper: Potential
Conflicts of Interest in the Production of Drug Compendia,
2009
Leading Compendia
• DRUG-DEX,
• Am Hospital Formulary Service Drug Information
• Unites States Pharmacopoeia Dispensing Information
• American Hospital Formulary Service Drug Information
• American Medical Association Drug Evaluations
• U.S. Pharmacopoeia Dispensing Information
• The Agency for Healthcare Research Quality
• The Medical Letter
• National Disease and Therapeutic Index
How to Manage Off-Label Prescribing
1) The Usual Recommendations
• Increased enforcement to prevent illegal marketing;
• Stronger sanctions for illegal off-label marketing:
o Higher financial penalties;
o Criminal prosecutions;
• Additional prohibitions;
• Disclosure of physician-pharma financial ties;
• Restrictions on physician-pharma financial ties;
• Education on appropriate prescribing.
How to Manage Off-Label Prescribing, cont’d
2) Problems with the Usual Recommendations
• Legal enforcement is costly and uncertain;
• 1st Amend. protects some promotion deemed to be speech;
• Paying fines is acceptable cost of doing business;
• Disclosure of CI often does not change conduct;
• Restrictions on pharma-MD financial ties is difficult;
• Educational programs have limited impact and are
overshadowed by pharma marketing.
20 firms Paying the Most Penalties 1991-July, 2012
GlaxoSmithKline
$7.56 Billion
Bristol-Myers Squibb
$789 M
Pfizer
$2.96 B
Mylan
$707 M
Johnson &
$2.3 B
Serono
$704 M
Merck
$1.86 B
Purdue
$620 M
Abbott
$1.82 B
Allergan
$600 M
Eli Lilly
$1.71 B
Daiichi Sankyo
$500 M
Schering-Plough
$1.34 B
Cephalon
$425 M
AstraZeneca
$954 Million
Boehringer Ingelheim
$329 M
Tap Pharma
$875 M
Forest Laboratories
$315 M
Johnson
Total Federal Pharma Settlements
7- 2012 - 2014
25 settlements: $4.97 Billion:
Pfizer and
Wyeth
Par
Pharma
Endo
DFB
Pharma
Wyeth
Boehringer Amgen
Igelheim
Orthofix
Ranbaxy
Astellas
Pfizer
Genzyme
Shire
Sanofi
CareFusion
Victory
Pharma
Johnson &
Johnson
Pfizer
Teva
Teva
Amgen
Abbott
RxAmerica C.R Bard
Amedisys
A New Approach to Managing
Off-Label Prescribing
1) Track off-label prescriptions.
2) Finance evaluation of off-label prescription safety
and effectiveness.
1) End pharmaceutical incentives to sell off-label
prescriptions.
1) Track Off-Label Prescriptions
• Data will allow setting priorities for evaluation of new
uses, targeting education, enforcement, and public
information.
• Physicians should be required to indicate on each
prescription the purpose for which the drug is
prescribed.
• Provide codes for patient’s principal diagnostic and
symptoms, age and gender.
• Condition reimbursement on providing this information.
What Off-Label Data Can Reveal
• Which patient populations use drugs off-label.
• For what circumstances/ purposes drugs are used offlabel.
• In what situations doctors prescribe off-label despite
evidence of high risks or low therapeutic value.
• Which doctors frequently prescribe off-label without
scientific support.
2) Finance Evaluation of Off-Label Drug Use
• Manufacturers are already required to monitor drug safety
after they receive marketing approval.
• When off-label prescriptions exceed a threshold, we should
evaluate the safety & efficacy of unapproved uses.
• Because manufacturers profit from off-label sales even
though only authorized to market drugs for FDA-approved
uses, it is reasonable to require them to finance the
evaluation of off-label uses.
3) End Pharmaceutical Incentives to
Sell Off-Label Prescriptions
• Reimburse manufacturer only for the marginal
cost of producing a drug when it is prescribed for
off-label use.
• Manufacturers will cease promoting and will
even discourage off-label prescribing when it
increases their costs but not their profits.
Rationale:
• Manufacturers have knowledge of off-label
sales and affect physicians’ prescribing.
• It might not be the manufacturers’ fault that a
physician prescribes a drug off-label, but the
FDA grants market exclusivity - with
resulting monopoly profits - only to allow
selling for approved uses.
• Allowing firms to profit from off-label
prescribing undermines the purpose of FDA
marketing authorization.
Need to Change Pharma
Reimbursement
Problem: manufacturers generally sell drugs in bulk to wholesalers and
do not know at time of sale how the drug will be prescribed.
Solution: Adjust manufacturer compensation after the Rx is filled
when we have data on off-label sales volume.
• Drug firms would forfeit income from off-label sales.
• Drug firms would pay excess off-label sale profits into a
government-supervised fund used to evaluate off-label uses and
promote drug safety.
• We will need to review mfg. production costs to determine marginal
cost of production. For a model, see Medicare hospital cost
reporting.
Rooting Out Institutional Corruption
to Manage Inappropriate Off-Label Drug Use
Rodwin, Marc A. 2013. “Rooting Out Institutional
Corruption to Manage Inappropriate Off-Label Drug
Use” J. of Law, Medicine & Ethics 4(3): 654-64.
http://papers.ssrn.com/sol3/papers.cfm?abstract_id=
2292037
Marc A. Rodwin is Professor of Law at Suffolk Univ. Law School, Boston, MA.
His research focuses on health law and policy and pharmaceutical issues,
medical ethics, and regulation.
He is the author of Conflicts of Interest and the Future of Medicine: The United
States, France and Japan (Oxford, 2011); Medicine, Money & Morals:
Physicians' Conflicts of Interest (Oxford, 1993). He is editor of the symposium
on Institutional Corruption and Pharmaceutical Policy, Journal of Law, Medicine
& Ethics 2013. 41(3).
• email: [email protected].
• Faculty web page: https://www.suffolk.edu/law/faculty/MarcRodwin.php
• SSRN web link to publications: http://papers.ssrn.com/sol3/results.cfm
CONFLICTS OF INTEREST AND THE FUTURE OF MEDICINE
The United States, France, and Japan
By Marc A. Rodwin
As most Americans know, conflicts of interest riddle the US health care system. They result from
physicians practicing medicine as entrepreneurs, from physicians' ties to pharma, and from investorowned firms and insurers' influence over physicians' medial choices. These conflicts raise questions
about physicians' loyalty to their patients and their professional and economic independence. The
consequences of such conflicts of interest are often devastating for the patients--and society--stuck in
the middle.
In Conflicts of Interest and the Future of Medicine, Marc Rodwin examines the development of these
conflicts in the US, France, and Japan. He shows that national differences in the organization of medical
practice and the interplay of organized medicine, the market, and the state give rise to variations in the
type and prevalence of such conflicts. He then analyzes the strategies that each nation employs to cope
with them.
Unfortunately, many proposals to address physicians' conflicts of interest do not offer solutions that
stick. But drawing on the experiences of these three nations, Rodwin demonstrates that we can mitigate
these problems with carefully planned reform and regulation. He examines a range of measures that
can be taken in the private and public sector to preserve medical professionalism--and concludes that
there just might be more than one prescription to this seemingly incurable malady.
ISBN: 978-0-19-933043-0 | September 2013 | Paperback | 256 pp.
Drug Firm Influence on
•
•
•
•
•
•
•
Research on risks and benefits of drug
The FDA
CME
Key Opinion Leaders
Clinical practice guidelines
Physicians clinical judgments (through
marketing)
Patient association policies