ArticlePDF Available

Institutional Corruption of Pharmaceuticals and the Myth of Safe and Effective Drugs

Authors:

Abstract and Figures

Over the past 35 years, patients have suffered from a largely hidden epidemic of side effects from drugs that usually have few offsetting benefits. The pharmaceutical industry has corrupted the practice of medicine through its influence over what drugs are developed, how they are tested, and how medical knowledge is created. Since 1906, heavy commercial influence has compromised congressional legislation to protect the public from unsafe drugs. The authorization of user fees in 1992 has turned drug companies into the FDA's prime clients, deepening the regulatory and cultural capture of the agency. Industry has demanded shorter average review times and, with less time to thoroughly review evidence, increased hospitalizations and deaths have resulted. Meeting the needs of the drug companies has taken priority over meeting the needs of patients. Unless this corruption of regulatory intent is reversed, the situation will continue to deteriorate. We offer practical suggestions including: separating the funding of clinical trials from their conduct, analysis, and publication; independent FDA leadership; full public funding for all FDA activities; measures to discourage R&D on drugs with few, if any, new clinical benefits; and the creation of a National Drug Safety Board.
Content may be subject to copyright.
Electronic copy available at: http://ssrn.com/abstract=2282014
590 journal of law, medicine & ethics
Institutional
Corruption of
Pharmaceuticals
and the Myth of
Safe and Eective
Drugs
Donald W. Light, Joel Lexchin,
and Jonathan J. Darrow
Institutional corruption is a normative concept of
growing importance that embodies the systemic
dependencies and informal practices that distort
an institution’s societal mission. An extensive range of
studies and lawsuits already documents strategies by
which pharmaceutical companies hide, ignore, or mis-
represent evidence about new drugs; distort the medi-
cal literature; and misrepresent products to prescribing
physicians.1 We focus on the consequences for patients:
millions of adverse reactions. After defining institutional
corruption, we focus on evidence that it lies behind the
epidemic of harms and the paucity of benefits.
It is our thesis that institutional corruption has
occurred at three levels. First, through large-scale
lobbying and political contributions, the pharmaceu-
tical industry has influenced Congress to pass legis-
lation that has compromised the mission of the Food
and Drug Administration (FDA). Second, largely as a
result of industry pressure, Congress has underfunded
FDA enforcement capacities since 1906, and turn-
ing to industry-paid “user fees” since 1992 has biased
funding to limit the FDAs ability to protect the public
from serious adverse reactions to drugs that have few
osetting advantages. Finally, industry has commer-
cialized the role of physicians and undermined their
position as independent, trusted advisers to patients.
Institutional Integrity: The Baseline
of Corruption
If “corruption” is defined as an impairment of integrity
or moral principle, then institutional corruption is an
institution’s deviation from a baseline of integrity. In
the case of Congress, integrity demands that demo-
cratically elected representatives should be dedicated
solely to the best interests of the people they repre-
sent. According to seminal essays on institutional cor-
ruption by Dennis Thompson and Larry Lessig,2 this
baseline of integrity is corrupted because elections are
not publicly funded. As a result, congressional rep-
resentatives must constantly raise funds from a tiny
percent of the population and respond to their priori-
ties. This dependency corruption creates an “economy
Donald W. Light, Ph.D., is a fellow for 2012-2013 at the
Edmond J. Safra Center for Ethics at Harvard University
in Cambridge, MA. He received his Ph.D. in sociology from
Brandeis University and is a professor of comparative health
policy at Rowan University, School of Osteopathic Medicine.
Joel Lexchin, M.Sc., M.D., has been teaching health policy
for 12 years at York University in Toronto, ON. He received his
M.D. from the University of Toronto in 1977 and since 1988
has been an emergency physician at the University Health
Network in Toronto. Jonathan J. Darrow, J.D., M.B.A.,
LL.M., S.J.D., is a research fellow at Harvard Medical School
and a lecturer on law at Bentley University in Waltham, MA.
He received his S.J.D. from Harvard in 2013.
Electronic copy available at: http://ssrn.com/abstract=2282014
institutional corruption and the pharmaceutical industry fall 2013 591
Light, Lexchin, and Darrow
of influence,” even if individual actors are well-inten-
tioned.3 Lessig’s examples portray how secrecy and
rationalizations disguise distortions in the democratic
process and mission.
The concept of institutional corruption highlights
numerous distinctions — between what is legal and
illegal; between good people doing bad things, not
bad people doing bad things; between influence, not
money, aecting decisions. These are the ends of con-
tinua, and there is a need to recognize degrees of cor-
ruption in between.4 Special interests also influence
members of Congress to make legal what has been ille-
gal or else to game the rules, thereby blurring the line
between legal and illegal as well as making it hard to
determine the law’s intent.5
Just as a proper electoral democracy is devoted to
the public good, health care systems are founded on
the moral principles of beneficence, nonmaleficence
(“first, do no harm”), respect for autonomy, and the
just distribution of scarce resources.6 Based on these
principles, health care workers are obliged to use the
best medical science to relieve suering and pain,
treat illness, and address risks to health. The institu-
tional corruption of health care consists of deviations
from these principles.
The major patent-based research pharmaceuti-
cal companies also nominally commit themselves to
improving health and relieving suering. For exam-
ple, Merck promises “to provide innovative, distinctive
products that save and improve lives…and to provide
investors with a superior rate of return.7 Pfizer is ded-
icated “to applying science and our global resources to
improve health and well-being at every stage of life.
Pharmaceutical companies continuously emphasize
how deeply society depends on their development of
innovative products to improve health. But in fact,
these companies are mostly developing drugs that are
mostly little better than existing products but have the
potential to cause widespread adverse reactions even
when appropriately prescribed. This deviation from
the principles of health care by institutions allegedly
dedicated to health care is institutional corruption. We
present evidence that industry has a hidden business
model to maximize profits on scores of drugs with clin-
ically minor additional benefits.8 Physician commit-
ment to better health is compromised as the industry
spends billions to create what Lessig calls a “gift econ-
omy” of interdependent reciprocation.9 New research
finds that truly innovative new drugs sell themselves
in the absence of such gift-economy marketing.10
Regulators such as the FDA and the Environmen-
tal Protection Agency arise when unregulated com-
petition is perceived to cause serious harm to society
and government regulation is needed to address the
problem. The FDA was founded to protect the public’s
health from the fraudulent cures peddled in the 19th
century.11 Through a series of legislative enactments,
often in response to a drug disaster, the pharmaceuti-
cal regulatory side of the FDA has acquired ever-wider
responsibilities to ensure that new drugs do more good
than harm. Institutional corruption consists of distor-
tions of these responsibilities, such as approving drugs
that are mostly little better than existing medications,
failing to ensure sucient testing for serious risks, and
inadequately guarding the public from harmful side
eects. These distortions serve commercial interests
well and public health poorly.
For the past 50 years, patent-based research compa-
nies have objected to the FDAs gatekeeping function
as being too rigid and too slow. They have claimed that
an obsessive concern about safety has undermined
patient access to drugs that could save lives or reduce
the burdens of ill health.12 This message is increasingly
being accepted by the FDA.
Flooding the Market with Drugs
of Little Benefit
In response to the emphasis by pharmaceutical com-
panies, their lobbyists, and their trade association
— the Pharmaceutical Research Manufacturers of
Through a series of legislative enactments, often in response to a drug disaster,
the pharmaceutical regulatory side of the FDA has acquired ever-wider
responsibilities to ensure that new drugs do more good than harm. Institutional
corruption consists of distortions of these responsibilities, such as approving drugs
that are mostly little better than existing medications, failing to ensure sucient
testing for serious risks, and inadequately guarding the public from harmful side
eects. These distortions serve commercial interests well and public health poorly.
592 journal of law, medicine & ethics
SYMPOSIUM
America (PhRMA) — on the high risk and cost
of research and development (R&D), Congress
has authorized billions in taxpayer contribu-
tions to support R&D, exemptions from market
competition, and special privileges.13 Patents,
of course, can be found in all industries, but
lobbyists for the pharmaceutical industry have
successfully pressured Congress to provide sev-
eral forms of market protection beyond patents.
The industry measures “innovation” in terms
of new molecular entities (NMEs), but most
NMEs provide at best minor clinical advan-
tages over existing ones and may lawfully be
approved by the FDA even if they are inferior
to previously approved drugs. The preponder-
ance of drugs without significant therapeutic
gain dates back at least 35 years. From the mid-
1970s through the mid-1990s, multiple assess-
ments have found that only 11 to 15.6 percent of
NMEs provide an important therapeutic gain.14
Millions of patients benefit from the one out
of six drugs that are therapeutically significant
advances; but most R&D dollars are devoted to
developing molecularly dierent but therapeutically
similar drugs, which tends to involve less risk and cost
for manufacturers. These drugs are then sold through
competition based on brand name, patent status, and
newness, rather than on their therapeutic merits. An
analysis of data from the National Science Foundation
by Donald Light and Joel Lexchin indicates that pat-
ent-based pharmaceutical companies — often deemed
by Congress, the press, the public, and themselves to
be “innovative” — in fact devote only 1.3 percent of
revenues, net of taxpayer subsidies, to discovering new
molecules.15 The 25 percent of revenues spent on pro-
motion is about 19 times more than the amount spent
on discovering new molecules.16 In short, the term
“R&D” as used by industry primarily means “devel-
opment” of variations rather than the path-breaking
“research” that onlookers might like to imagine.
The independent drug bulletin, La revue Prescrire,
analyzes the clinical value of every new drug product
or new indication approved in France. From 1981 to
2001, it found that about 12 percent oered therapeu-
tic advantages.17 But in the following decade, 2002-
2011, as shown in Figure 1, only 8 percent oered
some advantages and nearly twice that many — 15.6
percent – were judged to be more harmful than ben-
eficial.18 A mere 1.6 percent oered substantial advan-
tages. Assessments by the Canadian advisory panel to
the Patented Medicine Prices Review Board and by
a Dutch general practice drug bulletin have come to
similar conclusions.19 No comparable review has been
done in the United States on the 229 NMEs approved
by the FDA between 2002 and 2011.
This decrease does not come from the “innovation
crisis” of fewer new molecules entering trials or even-
tually being approved but from fewer newdrugs being
clinically superior.20 The number of products put into
trials has actually increased as the number of clini-
cally superior drugs has decreased.21 These facts pro-
vide evidence that companies are using patents and
other protections from market competition primarily
to develop drugs with few if any new therapeutic ben-
efits and to charge inflated prices protected by their
strong IP rights.
Despite the small number of clinically superior
drugs, sales and profits have soared as successful mar-
keting persuades physicians to prescribe the much
more costly new products that are at best therapeuti-
cally equivalent to established drugs.22 Both an Amer-
ican and a Canadian study found that 80 percent of
the increase in drug expenditures went to paying for
these minor-variation new drugs, not for important
advances.23 Companies claim that R&D costs are
“unsustainable.” But over the past 15 years, revenues
have increased six times faster than has investment in
R&D.24
Almost a decade ago, Jerry Avorn, a widely respected
pharmacoepidemiologist and author of a book on the
risks of drugs, described how the big pharmaceuti-
cal companies exploited patents and concluded that
“[l]aws designed to encourage and protect meaning-
ful innovation had been turned into a system that
Figure 1
Therapeutic Value of Drugs Marketed in France,
2002-2011*
institutional corruption and the pharmaceutical industry fall 2013 593
Light, Lexchin, and Darrow
rewarded trivial pseudo-innovation even more profit-
ably than important discoveries.25 He also noted that
eorts in Congress to introduce a “reasonable pricing
clause” that would reflect large taxpayer contributions
to new drugs were defeated by industry lobbyists.
An Epidemic of Harmful Side Eects
Most new drugs approved and promoted since the
1970s lack additional clinical advantages over exist-
ing drugs and — as with all drugs — they have been
accompanied by harmful side eects. A systematic
review of the 39 methodologically strongest studies
performed in the U.S. between 1964 and 1995 exam-
ined patients who were hospitalized due to a serious
adverse drug reaction (ADR) or who experienced an
ADR while in the hospital.26 The review found that
4.7 percent of hospital admissions were due to seri-
ous reactions from prescription drugs that had been
appropriately prescribed and used. Inaddition, 2.1
percent of in-hospital patients who received cor-
rectly prescribed medications experienced a serious
ADR, fora total of 6.8 percent of hospital patients
having serious ADRs.27 Applying this 6.8 percent
hospital ADR rate to the 40 million annual admis-
sions in U.S. acute care hospitals indicates that up
to 2.7 million hospitalized Americans each year have
experienced a serious adverse reaction. Of all hos-
pitalized patients, 0.32 percent died due to ADRs,
which means that an estimated 128,000 hospitalized
patients died annually, matching stroke as the 4th
leading cause of death. Deaths and serious reactions
outside of hospitals would significantly increase the
totals.
An analysis conducted in 2011, based on a year of
ADRs reported to the FDA, came to similar conclu-
sions: Americans experienced “2.1 million serious
injuries, including 128,000 patient deaths.28 Other
studies reveal that one in every five NMEs eventu-
ally caused enough serious harm in patients to war-
rant a severe warning or withdrawal from the market.
Of priority drugs that were reviewed in slightly more
than half the normal time, at least one in three of them
caused serious harm.29
The public health impacts are even greater when
milder adverse reactions are taken into account. Given
estimates that about 30 ADRs occur for every one that
leads to hospitalization, about 81 million side eects
are currently experienced every year by the 170 mil-
lion Americans who use pharmaceuticals.30 Groups
such as pregnant women, elderly patients, and those
who are taking multiple medications are especially at
risk. Most of these medically minor adverse reactions
are never brought to clinical attention, but even minor
reactions can impair productivity or functioning,
lead to falls, and cause potentially fatal motor vehicle
accidents.31
Contributors to More Harm and Less Benefit
Are the adverse side eects we have just been describ-
ing simply the “price of progress or an unavoidable
risk of drug therapy?”32 In fact, evidence suggests
that commercial distortions of the review process and
aggressive marketing contribute to both undermining
beneficence as health care’s raison d’être and to the
epidemic of harm to patients.33
Distorting, Limiting, and Circumventing Safety
Regulations
Since at least the 1890s, the public has clamored for
Congress to regulate contaminated or adulterated
foods and harmful or ineective medicines (medicines
that may delay truly useful treatments).34 At that time,
lobbyists — paid from drug profits — argued that even
bills to require accurate listing of secret ingredients
would destroy the industry. These lobbyists had man-
aged to have earlier bills sent to die in the Committee
on Manufactures until President Roosevelt intervened
to secure passage of the 1906 Food and Drug Act,
which still only required that statements on labels be
true and provided no budget for enforcement.
Work on what would become the 1938 food and
drug law began in 1933 with a bill that would prohibit
misstatements in advertising and require manufac-
turers to prove to the FDA that drugs were safe before
being allowed to sell them.35 The companies’ two trade
associations launched “well-choreographed screams
of protest” and letter-writing campaigns to mislead
Congress and to distort its mission to protect its con-
stituents from harm. Employees of drug makers wrote
to Congress, arguing that requiring companies to
make honest claims about safe drugs would put thou-
sands out of work. The FDA sta wanted the legisla-
tion passed but were stopped by threats of prosecution
if they campaigned for it. Then a manufacturer added
diethylene glycol (antifreeze) to a sulfa drug to make
a sweet-tasting elixir and children started dying. Pub-
lic response trumped industry lobbyists and Congress
passed the 1938 law, requiring that drugs be safe but
leaving it to companies to decide how to define and
test for safety.
For the next 25 years, drugs were approved within
180 days unless the FDA objected, based on the com-
panies’ tests and reports of safety. Some companies
“tested” their products by sending samples out to pro-
viders for feedback, keeping no records of the results,
and denying serious harms when reported by doc-
tors.36 Daniel Carpenter, the author of a book consid-
ered to be a definitive work on the politics of the FDA,
594 journal of law, medicine & ethics
SYMPOSIUM
has detailed how the FDA sta dedicated themselves
to enforcing the rules and developing better criteria
for safety and ecacy. But as Malcolm Salter, at the
Harvard Business School emphasizes, companies
institutionalize corruption by getting legislative and
administrative rules shaped to serve their interests,
either directly or by crafting rules in ways they can
game.37
In his review of new pharmaceutical products in the
1940s and 1950s, Dr. Henry Dowling, an AMA senior
ocer and expert, found that companies launched
200-400 a year but only three on average were clini-
cally useful.38 Physicians, swamped with far more
drugs than they could know much about, relied on
sales reps to brief them, entertain them, and leave an
ample supply of free samples as gifts that the physi-
cians could then give to their patients — a two-stage
economy of reciprocation.39 In eect, through political
pressure and lobbying, companies minimized the role
of the FDA as the protector of public health for its first
56 years.
Following the 1962 amendments, propelled to pas-
sage by the thalidomide tragedy, the FDA commis-
sioned the National Research Council, as part of the
National Academy of Sciences, to review the eec-
tiveness of all 2820 drugs (available in 4350 dierent
versions) approved between 1938 to 1962. Companies
were required to submit substantial evidence of eec-
tiveness. The review concluded that seven percent of
the drugs reviewed were completely ineective for
every claim they made and a further 50 percent were
only eective for some of the claims made for them.40
Although the FDA has acted to remove many of these
ineffective drugs from the market, some pre-1962
drugs are — more than 50 years later — still under-
going review and are among the “several thousand
drug products” that, according to a 2011 FDA guid-
ance document, are today “marketed illegally without
required FDA approval.41
Regulatory capture begins with the dependency
corruption of Congress, which passes the regulations
and provides the funding for agencies to protect the
public. While the 1962 amendments ushered in the
modern era of testing for safety and ecacy before a
drug can be approved,42 three key features of the mod-
ern drug-testing system actually work for industry
profits and against the development of safe drugs that
improve health.
First, three criteria used by the FDA contribute to
the large number of new drugs approved with few
therapeutic advantages. New drugs are often tested
against placebos rather than against established eec-
tive treatments, and the use of surrogate or substi-
tute end points, rather than actual eects on patients’
health.43 Noninferiority trials that merely show that
the product is not worse than another drug used to
treat the same condition by more than a specified
margin are accepted, rather than requiring superior-
ity trials.44 Silvio Garattini, founder of the Mario Negri
Institute for Pharmacological Research, points out
that placebo and noninferiority trials violate interna-
tional ethical standards and provide no useful infor-
mation for prescribing.45
Second, allowing companies to test their own prod-
ucts has led them — as rational economic actors —
to design trials in ways that minimize detection and
reporting of harms and maximize evidence of ben-
efits.46 Furthermore, clinical trials for new drugs are
designed to test primarily for ecacy and generally
are not able to detect less common adverse events.
Industry-friendly rules allow companies to exclude
those patients most likely to have adverse reactions,
while including those most likely to benefit, so that
drugs look safer and more eective than they are in
practice.47 Approvals based on scientifically compro-
mised trials underlie the large number of heavily mar-
keted new drugs with few or no new therapeutic ben-
efits to oset their under-tested risks of harm.
Third, companies have created what can be charac-
terized as the trial-journal pipeline because compa-
nies treat trials and journals as marketing vehicles.
They design trials to produce results that support the
Regulatory capture begins with the dependency corruption of Congress,
which passes the regulations and provides the funding for agencies to protect
the public. While the 1962 amendments ushered in the modern era of testing
for safety and ecacy before a drug can be approved, three key features
of the modern drug-testing system actually work for industry profits
and against the development of safe drugs that improve health.
institutional corruption and the pharmaceutical industry fall 2013 595
Light, Lexchin, and Darrow
marketing profile for a drug and then hire “publication
planning” teams of editors, statisticians, and writers to
craft journal articles favorable to the sponsor’s drug.48
Articles that present the conclusions of commercially
funded clinical trials are at least 2.5 times more likely
to favor the sponsor’s drug than are the conclusions in
articles discussing non-commercially funded clinical
trials.49 Yet, journal approval is deemed to certify what
constitutes medical knowledge. Published papers
legitimate the pharmaceutical products emerging
from the R&D pipeline and provide the key marketing
materials.
Furthermore, companies are much less likely to
publish negative results, and they have threatened
researchers who break the code of secrecy and con-
fidentiality about those results.50 Positive results are
sometimes published twice — or even more often —
under dierent guises. This further biases meta-anal-
yses — a method of statistically combining the results
of multiple studies — and clinical guidelines used for
prescribing. The result is “a massive distortion of the
clinical evidence.51 For decades, the FDA has kept
silent about these practices and about the discrepan-
cies between the data submitted to the FDA by com-
panies and the findings published in journal articles,
to the detriment of patients but much to the benefit
of the companies. In sum, testing and FDA criteria
approval provide little or no information to clinicians
on how to prescribe new drugs, a vacuum filled by
company-shaped “evidence” that misleads physicians
to prescribe drugs that are less safe and eective than
indicated by evidence that the FDA possesses.
PDUFA: Conflict-of-Interest Payments
In 1992, after years of underfunding and cuts in the
1980s that contributed to drug review times balloon-
ing from 6 to 30 months, Congress passed the Pre-
scription Drug User Fee Act (PDUFA), authorizing the
FDA to collect “user fees” from drug companies that
would allow it to hire 600 more reviewers and thereby
speed up drug review.52 Supporters claimed that fees
would increase incentives for innovation and improve
health; but aside from clearing the backlog of NMEs
waiting for approval, industry fees have not increased
innovation as measured by clinically superior drugs.53
In return for paying user fees, companies required
the FDA to guarantee that it would review priority
applications within six months and standard appli-
cations within 12 months of submission. Shortened
review times led to substantial increases in serious
harms. An in-depth analysis found that each 10-month
reduction in review time — which could take up to 30
months — resulted in an 18.1-percent increase in seri-
ous adverse reactions, a 10.9-percent increase in hos-
pitalizations, and a 7.2-percent increase in deaths.54
Now, 20 years later, what Carpenter calls “corrosive
capture” has set in — a weakened application of regu-
latory tools and a cultural capture of rhetoric about
saving lives by getting new drugs to patients more
quickly.55
For the FDA, the reduction in review time com-
bined with the fear that missing review deadlines
will jeopardize continued PDUFA funding has also
led to an increase in “up against the wall” approvals
as review deadlines approach. Carpenter and his col-
leagues found that “the probability of a drug approved
in the two months before the deadline receiving a new
black-box warning (the most serious safety warning
that the FDA can issue) is 3.27 times greater than a
drug approved at some other time” and the likelihood
of a drug being withdrawn from the market because of
serious adverse events is 6.92 times greater.56
These detailed studies corroborate what FDA sta
told the Oce of the Inspector General,57 namely, that
concerns arising near the end of the review period
are not adequately addressed, that needed meetings
with advisory committees are not held, and that label
warnings and contraindications are hastily written.
As a result, there are “tens of thousands of additional
hospitalizations, adverse drug reactions, and deaths.58
The 1998 withdrawal of five drugs, used by 19.8 mil-
lion Americans, prompted critical reflection. Three
distinguished physicians were struck by how little
information had been gathered about the harmful side
eects of these drugs before they were withdrawn.59
They attributed inaction to the FDA’s lack of interest
in safety, lack of funds, and to “the lack of a proactive,
comprehensive and independent system to evaluate
the long-term safety, ecacy, and toxicity of drugs”
after FDA approval. To compensate for the FDA’s fail-
ures, they called for an independent National Drug
Safety Board — akin to the National Transportation
Safety Board that investigates each plane crash and
holds public meetings — so that the same part of the
FDA that approves drugs, the Center for Drug Evalu-
ation and Research (CDER), would not later be asked
to decide whether that drug should be restricted or
withdrawn. In other words, public health would not
depend on FDA ocials’ willingness to admit their
own mistakes. Such an independent board should
establish an active monitoring system and gather
comparative data across a given therapeutic class so
it could provide objective information and develop
better strategies for addressing adverse reactions as a
major cause of death.
In 1997, a year before these five withdrawals, Con-
gress had passed PDUFA II and companies had
insisted that none of the fees collected be spent on
596 journal of law, medicine & ethics
SYMPOSIUM
post-market surveillance or on drug-safety programs.
PDUFA II, III, IV, and V and related legislation pro-
vided the FDA with steeply increasing user fees but
included lower criteria for approval, mandated that an
industry representative be on FDA scientific advisory
committees, lowered barriers to promotional eorts
by companies, and required FDA ocers to consult
and negotiate with industry on the agency’s goals and
plans.60
Osetting the harms associated with PDUFA I’s
shortened approval framework are several tools cre-
ated in PDUFA III through V for detecting, manag-
ing, and raising awareness of risks such as the Sentinel
system and the Risk Evaluation and Mitigation Strate-
gies; but there is no clear evidence these are reducing
the epidemic of harms.61 These tools are inadequate
to counterbalance the increase in risks — let alone to
improve safety. The additional $10 million of funding
provided by PDUFA III for the Oce of Drug Safety
and the $7.5 million provided for the FDA’s advertis-
ing enforcement arm are tiny in comparison to the
more than $690 million in user fees that flow to the
FDA each year.62 In sum, PDUFA allocates user fees
overwhelmingly to ensure speedy review of new drug
applications while leaving safety and enforcement
dependent on grossly inadequate funding, perpetuat-
ing a history of underfunding safety.
Granting priority status to more drugs further
increases the number of drugs reviewed in the
shortest time and the chance of a major safety issue
increases from one drug in five to one in three.63
Between 1999 and 2008, the FDA gave priority review
status to almost 47 percent (114 of 244) of new drug
applications, more than four times the proportion of
drugs found to have superior clinical eects by inde-
pendent review groups.64 Reflecting the cultural and
corrosive capture of the FDA, its Commissioner said
recently that “an increasing number of treatments are
being approved under the agency’s fast-track, prior-
ity review…to get critical and innovative medicines
to market more rapidly.65 Quicker reviews and less
evidence of clinical benefit have rewarded the hidden
business model of developing still more drugs with
minor benefits.
Post-Marketing Surveillance
Large and growing user fees, with a sunset expira-
tion every five years and a threat of nonrenewal that
would severely cripple the FDA, have intensified the
classic principal-agent conflict.66 Marcia Angell, for-
mer editor-in-chief of the New England Journal of
Medicine, observed that, “[i]n eect, the user fee act
put the FDA on the payroll of the industry it regulates
[and]…has drastically changed the way it operates.67
The FDA’s obligation to serve the public is being cor-
roded by pressures to serve the companies it regulates.
As for post-market surveillance — “the single most
important function…for protecting the public against
the dangers of harmful drugs”68 — it is put largely in
the hands of the manufacturers and the FDA Center
for Drug Evaluation and Research (CDER), the part of
the FDA that companies pay to review their new drug
applications.
After approval, aggressive marketing of new drugs
to doctors for both approved and unapproved uses
before good safety information is available maxi-
mizes the number of patients exposed to risks from
the roughly 25 to 40 new NMES approved annually.69
Field studies find that most drug representatives do
not discuss adverse side eects.70 Although the law
requires companies to submit some marketing mate-
rials for review, Congress and the FDA allocate only a
small budget and sta to review about 75,000 submis-
sions a year for false or misleading information.71 Fur-
ther, the small stream of letters ordering that inaccu-
racies be corrected is subject to a review process that
delays their reaching the companies.72
Marketing for unapproved or “o-label” uses wors-
ens the balance of harm and benefit and undermines
the purpose of testing to show that a drug is eective
and safe for a specific use.73 While trying drugs for
new uses is clinically important, especially for certain
Marketing for unapproved or “o-label” uses worsens the balance of harm
and benefit and undermines the purpose of testing to show that a drug is
eective and safe for a specific use. While trying drugs for new uses is clinically
important, especially for certain populations such as children and cancer
patients, 75 percent of o-label prescribing is neither supported by sound
evidence nor accompanied by an organized means for gathering such evidence.
institutional corruption and the pharmaceutical industry fall 2013 597
Light, Lexchin, and Darrow
populations such as children and cancer patients, 75
percent of o-label prescribing is neither supported
by sound evidence nor accompanied by an organized
means for gathering such evidence.74 Companies
retain leading experts to expand use, broaden clinical
guidelines, and conduct small, short sham trials that
companies get published and hand out to their physi-
cian-customers as “evidence.75
A 15-month investigation by the Committee on
Government Reform of the U.S. House of Represen-
tatives found “a growing laxity in FDA’s surveillance
and enforcement procedures, a dangerous decline in
regulatory vigilance, and an obvious unwillingness
to move forward even on claims from its own field
oces.76 The resulting 2006 report also documented
a 53.7-percent decline in warning letters. Since then,
FDA leadership has shifted to talking about being a
“partner” with industry to get more drugs to patients
more quickly. For the reasons we explained above, the
proportion of new products with clinical advantages
seems to have moved from about 1 in 8 down to 1 in 12,
while the proportion with serious harms has gone up
from 1 in 5 towards 1 in 3 as the number of drugs given
priority status increases.
Restoring Institutional Integrity
for Safer Drugs
Many concerned experts have suggested ways to
reduce conflicts of interest and improve the safety and
eectiveness of drugs.
First, while research companies play important roles
in discovering and developing superior drugs, they
should play no role in testing them.77 Over the years,
expert bodies and prominent scientists have called for
an independent institute to test drugs because com-
mercial trials were so poor, biased, and conflicted.78
Yet this bedrock reform has never been accomplished,
as the industry’s lobbying of Congress and its contri-
butions to Congressional campaigns have soared.79
Second, the FDA needs new leadership to restore
public trust and build a new culture focused on safety
through enforcement of its existing rules. Hearings
through the 1960s and 1970s documented how fre-
quently the FDA fails to adhere to its own rules and
protocols.80
Third, user fees must end, and the FDA must be
entirely funded by taxpayers-as-consumers. The FDA
should be entirely clear about whom it serves.
Fourth, while approval criteria should allow for a
sucient number of therapeutically equivalent drugs
in a class to give clinicians a range of choices,81 they
should also require patient-relevant evidence of supe-
riority. Limiting the number of drugs in the same
therapeutic class worked successfully in Norway but
was stopped when Norway harmonized its regulatory
requirements with those of the European Union in
1995.82 Non-inferiority trials should be allowed only if
one can ethically justify entering patients into a trial in
which there can be no benefit for them.83 All adverse
events, including those occurring among subjects who
drop out, must be reported with follow-up for two
years.
Fifth, Congress needs to restore trust by creating a
National Drug Safety Board with adequate powers,
funds, and mandates to independently investigate and
report on drug safety issues. The creation of this board
would support the position that all data related to how
drugs and vaccines aect people are a public good and
that access to this data is a human right. Both the
inadequacy of pre-approval safety testing and the lack
of systematic post-approval monitoring need urgent
attention.84
None of this is likely to happen until third-party
payers, politicians, and the people decide they want to
stop paying so much for so many drugs of little value
and then for treating the millions harmed by those
drugs. Nor is it likely until the campaign to restore
institutional integrity to Congress through funding
elections by the 99 percent, rather than by the one
percent, is successful.85
Acknowledgements
This article was partially supported by the Edmond J. Safra Center
for Ethics (Light, Darrow) and by the Escher project (T6-202), a
project of the Dutch Top Institute Pharma (Light). The funders
had no role in the concept, research, or drafting of this paper. The
authors alone conceived of the paper, conducted the research, and
drafted and revised the paper. They appreciate helpful comments
and suggestions from the editor of the special issue, Marc Rodwin.
References
1. J. Lexchin et al., “Pharmaceutical Industry Sponsorship and
Research Outcome and Quality: Systematic Review,BMJ 326,
no. 31 (2003): 1167-1170; M. A. Steinman et al., “Characteris-
tics and Impact of Drug Detailing for Gabapentin,PLoS Medi-
cine 4, no. 4 (2007): 743-751; K. P. Hill et al., “The ADVAN-
TAGE Seeding Trial: A Review of Internal Documents,” Annals
of Internal Medicine 149, no. 4 (2008): 251-258; J. S. Ross
et al., “Guest Authorship and Ghostwriting in Publications
Related to Rofecoxib,JAMA 299, no. 15 (2008): 1800-1812;
S. Sismondo, “How Pharmaceutical Industry Funding Aects
Trial Outcomes: Causal Structures and Responses,Social Sci-
ence & Medicine 66, no. 9 (2008): 1909-1914; G. Spurling et
al., “Information from Pharmaceutical Companies and the
Quality, Quantity and Cost of Physicians’ Prescribing: A Sys-
temiatic Review,PLoS Medicine 7, no. 10 (2010): e1000352;
J. Lexchin, “Those Who Have the Gold Make the Evidence:
How the Pharmaceutical Industry Biases the Outcomes of
Clinical Trials of Medications,Science and Engineering Eth-
ics 18, no. 2 (2012): 247-261; S. Vedula, T. Li, and K. Dicker-
sin, “Dierences in Reporting of Analyses in Internal Comany
Documents Versus Published Trial Reports: Comparisions in
Industry-Sponsored Trials in O-Label Uses of Gabapentin,
PLoS Medicine 10, no. 1 (2013): e1001378.
598 journal of law, medicine & ethics
SYMPOSIUM
2. D. Thompson, “Two Concepts of Corruption,” in Working
Papers (Edmond J. Safra Center for Ethics: Harvard Univer-
sity, 2010); L. Lessig, Republic, Lost: How Money Corrupts
Congress - and a Plan to Stop It (New York: Twelve/Hachette,
2011); D. Thompson, Ethics in Congress: From Individual to
Institutional Corruption (Washington, D.C.: Brookings Insti-
tution, 1984); see also L. Lessig, “Institutional Corruptions,
in Research in Action Working Papers, Edmond J. Safra Cen-
ter for Ethics (Cambridge, MA: Research in Action Working
Papers, Edmond J. Safra Center for Ethics, Harvard University,
2013). Quotations are from Republic, Lost.
3. See Republic, Lost, supra note 2, at 285.
4. D. W. Light, “Strengthening the Theory of Institutional Cor-
ruptions: Broadening, Clarifying, Measuring,” in Research in
Action Working Paper, L. Lessig and M. Somos, eds. (Edmond
J. Safra Center for Ethics: Harvard University, 2013).
5. M. Salter, “Lawful but Corrupt: Gaming and the Problem of
Institutional Corruption in the Private Sector,” in Harvard
Business School Working Papers (Boston: Harvard Business
School, 2009).
6. T. Beauchamp and J. Childress, Principles of Bioethical Ethics,
5th ed. (New York: Oxford University Press, 2001); R. Gillon,
“Medical Ethics: Four Principles Plus Attention to Scope,BMJ
309, no. 6948 (1994): 184.
7. See Purposeful Identity, “Merck & Company,available at
<http://www.purposefulidentity.com/values-mission-value-
drivers-vision/mission-statement-2011/Merck-Healthcare-
Support-Services-industry-104.html> (last visited June 20,
2013). Missions of Pfizer and other companies can be found at
the website as well.
8. JFor a discussion of the misalignment between market incen-
tives and public health goals, and ways to address that prob-
lem, see M.-A. Gagnon, “Corruption of Pharmaceutical Mar-
kets: Addressing the Misalignment of Financial Incentives and
Public Health,Journal of Law, Medicine & Ethics 41, no. 3
(2013): 571-580. See also in JLME 41, no. 3 (2013): M. Rod-
win, “Five Un-Easy Pieces to Pharmaceutical Policy Reform,
581-589, and S. Sismondo, “Key Opinion Leaders and the Cor-
ruption of Medical Knowledge: What the Sunshine Act Will
and Won’t Cast Light On,” 635-643.
9. See Republic, Lost, supra note 2, at 107-116.
10. M. King and P. Bearman, “Conflict of Interest Policies and
the Diusion of Stimulant, Antidepressant, and Antipsychotic
Medications,” in American Sociological Association (New York
City: Yale University School of Management, 2013).
11. J. H. Young, The Toadstool Millionaires: A Social History of
Patent Medicines in America before Federal Regulation (Princ-
eton, NJ: Princeton University Press, 1961); P. J. Hilts, Pro-
tecting America’s Health: The FDA, Business and One Hundred
Years of Regulation (New York: Alfred A. Knopf, 2003).
12. See Hilts, supra note 11; J. Zelenay, “The Prescription Drug
User Fee Act: Is a Faster Food and Drug Administration
Always a Better Food and Drug Administration?” Food and
Drug Law Journal 60, no. 2 (2005): 261-338.
13. M. Angell, The Truth About the Drug Companies: How They
Deceive Us and What to Do About It (New York: Random
House, 2004); J. Avorn, Powerful Medicines: The Benefits,
Risks, and Costs of Prescription Drugs (New York: Knopf,
2004); M. Goozner, The $800 Million Pill: The Truth Behind
the Cost of New Drugs (Berkeley: University of California Press,
2004).
14. D. Light and J. Lexchin, “Pharmaceutical R&D - What Do We
Get for All That Money?” BMJ 344, no. 7869 (2012): e4348.
15. D. W. Light and J. Lexchin, “Foreign Free Riders and the High
Price of US Medicines,BMJ 331, no. 7522 (2005): 958-960;
National Science Foundation, “Research and Development in
Industry: 1999” (Arlington: March 2002).
16. M.-A. Gagnon and J. Lexchin, “The Cost of Pushing Pills: A
New Estimate of Pharmaceutical Promotion Expenditures in
the United States,PLoS Medicine 8, no. 1 (2008): 1-5.
17. Prescrire Editorial Sta, “Drugs in 2001: A Number of Ruses
Unveiled, Prescrire International 11, no. 58 (2002): 58-60.
18. Prescrire Editorial Sta, “New Drugs and Indications in 2011,
Prescrire International 21, no. 126 (2012): 106-110.
19. J. Lexchin, “International Comparison of Assessments of Phar-
maceutical Innovation,Health Policy 105, nos. 2-3 (2012):
221-225.
20. See Light and Lexchin, supra note 14.
21. E. O’Reilly, “IND Preparation and Maintenance,” Duke Trans-
lational Medicine Institute, available at <http://tracs.unc.edu/
docs/regulatory/IND_Presentation-IND_Preparation_and_
Maintenance-Best_Practices.ppt> (last visited June 20, 2013);
E. Schmid and D. Smith, “Is Declining Innovation in the Phar-
maceutical Industry a Myth?” Drug Discovery Today 10, no. 15
(2005): 1031-1039.
22. M. A. Steinman et al., “Narrative Review: The Promotion of
Gabapentin: An Analysis of Internal Industry Documents,
Annals of Internal Medicine 145, no. 4 (2006): 284-293; M.
Hoffman, “Pharmaceutical Detailing Is Not for Everyone,
Journal of Legal Medicine 33, no. 3 (2012): 381-397; G.
Spurling et al., “Information from Pharmaceutical Companies
and the Quality, Quantity and Cost of Physicians’ Prescrib-
ing: A Systemiatic Review,PLoS Medicine 7, no. 10 (2010):
e1000352; see also S. Sah and A. Fugh-Berman, “Physicians
under the Influence: Social Psychology and Industry Market-
ing Strategies,Journal of Law, Medicine & Ethics 41, no. 3
(2013): 665-672.
23. See Avorn, supra note 13, at Chapter 13; S. G. Morgan et al.,
“’Breakthrough’ Drugs and Growth in Expenditure on Prescrip-
tion Drugs in Canada,BMJ 331, no. 7520 (2005): 815-816.
24. See Light and Lexchin, supra note 14.
25. See Avorn, supra note 13, at 205, 197-216.
26. J. Lazarou, B. H. Pomeranz, and P. N. Corey, “Incidence of
Adverse Drug Reactions in Hospitalized Patients,Journal of
American Medical Association 279, no. 15 (1998): 1200-1205.
27. Other recent studies find similar rates of harm. C. van der
Hooft et al., “Adverse Drug Reaction Related Hospitalizations,”
Drug Safety 29, no. 2 (2006): 161-168; M. Pirmohamed et al.,
Adverse Drug Reactions as Cause of Admission to Hospital:
Prospecive Analysis of 18,820 Patients,BMJ 329, no. 7456
(2004): 15-19.
28. ISMP, “QuarterWatch,” T. J. Moore, M. R. Cohen, and C. D.
Furberg, eds. (Horsham, PA: Institute for Safe Medication
Practices, 2012).
29. J. Lexchin, “New Drugs and Safety: What Happened to New
Active Substances Approved in Canada between 1995 and
2010?” Archives of Internal Medicine 172, no. 21 (2012):
1680-1681.
30. Kaiser Family Foundation, Prescription Drug Trends, 2010.
31. T. Moore, Prescription for Disaster (New York: Simon & Schus-
ter, 1998); A. Goodnough and K. Zezima, “Drivers on Prescrip-
tion Drugs: Dangerous, but Hard to Convict,New York Times,
July 25, 2010.
32. See Avorn, supra note 13.
33. M.-A. Gagnon and J. Lexchin, “The Cost of Pushing Pills: A
New Estimate of pharmaceutical promotion expenditures
in the United States,PLoS Medicine 5, no. 1 (2008); K.
Applbaum, “Getting to Yes: Corporate Power and the Creation
of a Psychopharmaceutical Blockbuster,Culture, Medicine
and Psychiatry 33, no. 2 (2009): 185-215; K. Applbaum, “Is
Marketing the Enemy of Pharmaceutical Innovation?” Hast-
ings Center Report 39, no. 4 (2009): 13-17. For excellent over-
views of how dependency corruption compromises the medical
profession’s duty to make patients as healthy as they can be,
see M. Rodwin, “Conflicts of Interest, Institutional Corruption,
and Pharma: An Agenda for Reform,Journal of Law, Medi-
cine & Ethics 40, no. 3 (2012): 511-522; M. Rodwin, “Reform-
ing Pharmaceutical Industry-Physician Financial Relation-
ships: Lessons from the United States, France, and Japan,
Journal of Law, Medicine & Ethics 39, no. 4 (2011): 662-670.
34. See Young, supra note 11; Hilts, supra note 11.
35. See Hilts, supra note 11, at 79-90.
36. Id., at 151-156.
institutional corruption and the pharmaceutical industry fall 2013 599
Light, Lexchin, and Darrow
37. Salter, supra note 5; M. Salter, Short-Termism at Its Worst,
Edmond J. Safra Center for Ethics Working Paper No. 5,
2013, available at <http://papers.ssrn.com/sol3/papers.
cfm?abstract_id=2247545> (last visited June 20, 2013); M.
Salter, Innovation Corrupted: The Origins and Legacy of
Enron’s Collapse (Cambridge, MA: Harvard University Press,
2008); D. Carpenter, Reputation and Power: Organizational
Image and Pharmaceutical Regulation at the FDA (Princeton:
Princeton University Press, 2010).
38. See Hilts, supra note 11, at Chap. 8. This is about what Pre-
scrire has found since 1981 (Figure 1).
39. See Republic, Lost, supra note 2, at 107-116.
40. See Hilts, supra note 11, at Chap. 11.
41. Food and Drug Administration, “Guidance for FDA Sta and
Industry: Marketed Unapproved Drugs: Compliance Policy
Guide,” September 19, 2011, at 3, 10-11.
42. See Hilts, supra note 11; Carpenter, supra note 37.
43. Id. (Hilts); J. Abraham, Science, Politics and the Pharmaceuti-
cal Industry (London: Routledge, 1995); M. Rodwin, “Inde-
pendent Clinical Trials to Test Drugs: The Neglected Reform,”
St. Louis Law Review 6, no. 113 (2012): 113-166.
44. U.S. Government Accounting Oce, “New Drug Approvals:
FDA Needs to Enhance its Oversight of Drugs Approved on
the Basis of Surrogate Endpoints,” Washington, D.C., 2009; J.
Avorn, “Approval of a Tuberculosis Drug Based on a Paradoxi-
cal Surrogate Measure,JAMA 309, no. 13 (2013): 1349-1350.
45. S. Garattini and V. Bertele, “Non-Inferiority Trials Are Unethi-
cal Because They Disregard Patients’ Interests,The Lancet
370, no. 9602 (2007): 1875-1877.
46. S. Garattini and V. Bertele, “Ecacy, Safety, and Cost of New
Anticancer Drugs,BMJ 325, no. 7358 (2002): 269-271; S.
Garattini and V. Bertele, “Ethics in Clinical Research,” Jour-
nal of Hepatology 51, no. 4 (2009): 792-797; S. Garattini and
V. Bertele, “Europe’s Opportunity to Open Up Drug Regula-
tion,BMJ 340, no. 30 (2010): 842-843; J. A. Fisher, Medical
Research for Hire: The Political Economy of Pharmaceutical
Clinical Trials (New Brunswick: Rutgers University Press,
2009); J. A. Fisher, “United States Private-Sector Physicians
and Pharmaceutical Contract Research: A Qualitative Study,
PLoS Medicine 9, no. 7 (2012): e1001271; L. McGoey, “On the
Will to Ignorance in Bureaucracy,Economy and Society 36,
no. 2 (2007): 212-235.
47. M. Zimmerman, J. Mattia, and M. A. Posternak, “Are Subjects
in Pharmacologocal Treatment Trials of Depression Represen-
tative of Patients in Routine Clinical Practice,American Jour-
nal of Psychiatry 159, no. 3 (2002): 469-473; J. Travers et al.,
“External Validity of Randomised Controlled Trials in Asthma:
To Whom Do the Resuls of the Trials Apply?” Thorax 62, no. 3
(2007): 219-223.
48. K. Applbaum, “Is Marketing the Enemy of Pharmaceutical
Innovation?” The Hasting Center Report 39, no. 4 (2009):
13-17; S. Sismondo, “Ghost Management,PLoS Medicine 4,
no. 9 (2007): 1429-1433; see Sismondo, supra note 8; B. Hart,
A. Lundh, and L. Bero, “Eect of Reporting Bias on Meta-
Analyses of Drug Trials: Reanalysis of Meta-Analyses,” BMJ
344, no. 7838 (2012): d7202; Lexchin (2012), supra note 1.
49. A. Lundh et al., “Industry Sponsorship and Research Outcome
(Review),” Cochrane Database of Systematic Reviews no. 12
(2012).
50. D. Rennie, “When Evidence Isn’t: Trials, Drug Companies
and the FDA,Journal of Law and Policy 15, no. 3 (2007):
991-1012; S. Prakash, “Did Merck Try to Censor Vioxx Crit-
ics?” National Public Radio, June 9, 2005; S. Prakash, “Con-
flicted Safety Panel Let Vioxx Study Continue,” National Public
Radio, June 8, 2006; B. Goldacre, Bad Pharma: How Drug
Companies Mislead Doctors and Harm (London: Faber &
Faber, 2012).
51. See Rennie, supra note 50, at 1001.
52. See Zelenay, supra note 12.
53. B. Munos, “Lessons from 60 Years of Pharmaceutical Inno-
vation,Nature Reviews Drug Discovery 8, no. 12 (2009):
959-968.
54. M. K. Olson, “Are Novel Drugs More Risky for Patients Than
Less Novel Drugs?” Journal of Health Economics 23, no. 6
(2004): 1135-1158.
55. D. Carpenter, “Corrosive Culture? The Dueling Forces of
Autonomy and Industry Influence in FDA Pharmaceutical
Regulation,” in Preventing Regulatory Capture: Social Influ-
ence and How to Limit It, D. Carpenter and D. Moss, eds.,
(New York: Cambridge University Press, 2013): at Chap. 6; M.
Hamburg, “Innovation, Regulation, and the FDA,New Eng-
land Journal of Medicine 363, no. 23 (2010): 2228-2232. For
telling details, see Rodwin, supra note 43, and M. Rodwin,
“Drug Advertising, Continuing Medical Education, and Physi-
cian Prescribing: An Historical Review and Reform Proposal,
Journal of Law, Medicine & Ethics 38, no. 4 (2010): 807-815.
56. D. Carpenter et al., “The Complication of Controlling Agency
Time Discretion: FDA Review Deadlines and Postmarket Drug
Safety,American Journal of Political Science 56, no. 1 (2012):
98-114.
57. U.S. Oce of the Inspector General, FDA’s Review Process for
New Drug Applications: A Management Review, 2003.
58. See Carpenter, supra note 56, at 99.
59. A. Wood, C. M. Stein, and R. Woosley, “Making Medicines
Safer - The Need for an Independent Drug Safety Board,New
England Journal of Medicine 339, no. 25 (1998): 1851-1854;
see also Hilts, supra note 11; T. Moore, Deadly Medicine: Why
Tens of Thousands of Heart Patients Died in America’s Worst
Drug Disaster (New York: Simon & Schuster, 1995).
60. See Zelenay, supra note 12.
61. On REMS, see S. Walker, “Maximizing REMS Potential,”
Drug Topics 156, no. 9 (2012). On the Sentinel system, see J.
Racoosin et al., “FDA’s Sentinel Initiative: Active Surveillance
to Identify Safety Signals,” in B. L. Strom, S. E. Kimmel, and
S. Hennessy, eds., Pharmacoepidemiology (New York: Wiley
Online Library, 2012); N. Savage, “Digging for Drug Facts,
Communications of the ACM 55, no. 10 (2010). On AERS, see
S. Weiss-Smith, “The FDA Drug Safety Surveillance Program:
Adverse Event Reporting Trends,Archives of Internal Medi-
cine 171, no. 6 (2011): 591-593.
62. See 21 U.S.C. § 379h(b)(1)(A) (2013).
63. See Lexchin, supra note 29. The poorer safety record for pri-
ority drugs cannot be explained by the importance of the dis-
eases they treat or the mechanisms by which they work.
64. Prescrire Editorial Sta, supra note 18.
65. R. Weissman, “From FDA, a Warning,Boston Globe, March
16, 2013, at B5.
66. See Zelenay, supra note 12.
67. M. Angell, “Taking Back the FDA,” Boston Globe, February 26,
2007.
68. See Rennie, supra note 50, at 1006; T. Lemmens, “Pharmaceu-
tical Knowledge Governance: A Human Rights Perspective,
Journal of Law, Medicine & Ethics 41, no. 1 (2013): 163-184.
69. H. Brody and D. W. Light, “The Inverse Benefit Law: How
Drug Marketing Undermines Patient Safety and Public
Health,American Journal of Public Health 101, no. 3 (2011):
399-404; D. Healy, Pharmageddon (Berkeley: University of
California Press, 2012); see Goldacre, supra note 50.
70. B. Mintzes et al., “Pharmaceutical Sales Representatives and
Patient Safety: A Comparative Prospective Study of Information
Quality in Canada, France and the United States,” Journal of
General Internal Medicine (forthcoming 2013); Prescrire Edito-
rial Sta, “15 Years of Monitoring and One Simple Conclusion:
Don’t Expect Sales Representatives to Help Improve Healthcare
Quality,Prescrire International 15, no. 84 (2006): 154-159.
71. U.S. Government Accounting Office, “Prescription Drugs:
FDA’s Oversight of the Promotion of Drugs for Off-Label
Uses,” Washington, D.C., 2008; M. Kiester, “DDMAC submis-
sions,” FDA, available at <http://www.fda.gov/downloads/
Drugs/DevelopmentApprovalProcess/FormsSubmissionRe-
quirements/ElectronicSubmissions/UCM246563.pdf> (last
visited June 20, 2013).
72. D. Nguyen et al., “Changes in FDA Enforcement Activities Fol-
lowing Changes in Federal Administration: The Case of Regu-
600 journal of law, medicine & ethics
SYMPOSIUM
latory Letters Released to Pharmaceutical Companies,” BMC
Health Services Research 13 (2013): 27.
73. S. Krumholz and D. Egilman, “Study of Neurontin: Ittrate to
Eect, Profile of Safety (STEPS) Trial: A Narrative Account of
a Gabapentin Seeding Trial,Archives of Internal Medicine 171,
no. 12 (2011): 1100-1107.
74. T. Eguale et al., “Drug, Patient, and Physician Characteris-
tics Associated with O-Label Prescribing in Primary Care,”
Archives of Internal Medicine 172, no. 10 (2012): 781-788; D.
C. Radley, S. N. Finkelstein, and R. S. Staord, “O-Label Pre-
scribing among Oce-Based Physicians,Archives of Internal
Medicine 166, no. 9 (2006): 1021-1026.
75. For more detail, see Rodwin (2012), supra note 33, and M.
A. Rodwin, “Rooting Out Institutional Corruption to Manage
Inappropriate O-Label Drug Use,Journal of Law, Medicine
& Ethics 41, no. 3 (2013): 654-664.
76. H. Waxman, “Prescription for Harm: The Decline in FDA
Enforcement Activity,” in Special Investigations Division
(Washington, D.C.: Committee on Government Reform, U.S.
House of Representatives, 2006).
77. See Rennie, supra note 50; Rodwin, supra note 43.
78. Id. (Rodwin), at 130-159.
79. See Open Secrets, available at <http://www.opensecrets.org/
lobby/indusclient.php?id=H04> (last visited June 20, 2013).
80. See Rodwin, supra note 43; Abraham, supra note 43; J. Abra-
ham and C. Davis, “Deficits, Expectations, and Paradigms in
British and American Drug Safety Assessment,” Science Tech-
nology Human Values 32, no. 4 (2007): 399-431; J. Abraham,
“Drug Evaluation and the Permisive Principle,Social Studies
of Science 39, no. 4 (2009): 569-598.
81. R. Warburton, “What Do We Gain from the Sixth Coronary
Heart Disease Drug?” BMJ 327, no. 7426 (2003): 1237-1238.
82. M. Dukes and I. Lunde, “The Regulatory Control of Non-Ste-
roidal Anti-Inflammatory Agents,European Journal of Clini-
cal Pharmacology 19, no. 1 (1981): 3-10.
83. See Garattini and Bertele, supra note 45.
84. M. Rodwin and J. Abramson, “Clinical Trial Data as a Pub-
lic Good,” JAMA 308, no. 9 (2012): 87 1-872; supra note 68;
R. Duijnhaven et al., “Number of Patients Studied Prior to
Approval to New Medicines: A Database Analysis,PLoS Medi-
cine 10, no. 3 (2013): e1001407.
85. See Republic, Lost, supra note 2, at Part IV.
... Critical social science scholarship has explored the pharmaceutical industry's power across a range of health, social, political, economic, and scientific spheres (e.g. Abraham, 2008;Busfield, 2006;Light et al., 2013). In this scholarship, a particular concern has been the industry's strategic management of financial relations with other health actors, especially health professionals (Sismondo, 2013), patient organizations (Rose, 2013), and regulators and policymakers (Lexchin and O'Donovan, 2010), for the purpose of influencing them and their environment, often out of public sight. ...
... At the same time, several researchers have maintained that payment disclosure alone cannot solve larger underlying problems of the 'institutional corruption' of medicine (Light et al., 2013), namely, 'that the pharmaceutical industry has a disproportionate influence on medical opinion, which weakens medicine's ability to promote individual and public health in ways that are independent of the industry' (Sismondo, 2013: 636). Furthermore, it has been noted that many of the larger payments that companies make to physicians are primarily intended not to affect their prescriptions, but rather to purchase their influence on other physicians (Sismondo, 2013), meaning that studies tend to underestimate the effects of these payments (Winn et al., 2021). ...
... The first strand is situated within broader scholarship on the pharmaceutical industry that is concerned with industry power over research, innovation, regulation, and medical practice (e.g. Busfield, 2006;Davis and Abraham, 2013;Dumit, 2012;Fierlbeck et al., 2021;Fisher, 2008;Light et al., 2013;Mirowski and Van Horn, 2005). A key insight from this work is that power may not be visible to most, both because power is actively concealedas in the case of the 'ghost management' of science and prescribers (Sismondo, 2007) and because it is often normalized or hegemonic as in the case of the industry's financial relations with and influence over many health system actors (Sismondo, 2017). ...
Article
Full-text available
How corporations surveil and influence consumers using big data tools is a major area of research and public debate. However, few studies explore it in relation to physicians in the USA, even though they have been surveilled and targeted by the pharmaceutical industry since at least the 1950s. Indeed, in 2010, concerns about the pharmaceutical industry's undue influence led to the passing of the Physician Sunshine Act, a unique piece of transparency legislation that requires companies to report their financial ties to physicians and teaching hospitals in a public database. This article argues that while the Sunshine Act has clearly helped expose important commercial influences on both prescribing and the scale of industry involvement with physicians, it has also, paradoxically, fuelled further commercial surveillance and marketing. The article casts new light on innovative pharmaceutical marketing approaches and the key role of data brokers and analytics companies in the identification, targeting, managing, and surveillance of physicians. We place this analysis within the political economies of the pharmaceutical industry, surveillance-based marketing, and transparency, and argue that policies to promote increased transparency must be tightly tied to policies that impede the commodification and use of transparency data for surveillance and marketing purposes.
... This kind of co-opting of the medical infrastructure by industry through an education programme appears novel, though the process very much recalls tactics used in other areas of healthcare. 50 Similar to how others identified a kind of 'ghost authorship' 15 51 that facilitates the promotion of industry messaging through medical research, we saw a parallel kind of authorship vacuum among these policy and training documents, including specifically in the regulatory and industry documents. This absence both elides individual responsibility for industry promotion on the part of regulatory and sometimes professional leaders and also gives space for industry to gain credibility on the shoulders of medical institutional authority. ...
Article
Full-text available
Objectives Pharmaceutical industry involvement in medical education, research and clinical practice can lead to conflicts of interest. Within this context, this study examined how the ‘Suboxone Education Programme’, developed and delivered by a pharmaceutical company as part of a federally regulated risk management program, was presented as a solution to various kinds of risks relating to opioid use in public documents from medical institutions across Canada. Setting These documents were issued during the Canadian opioid crisis, a time when the involvement of industry in health policy was being widely questioned given industry’s role in driving the overprescribing of opioid analgesics and contributing to population-level harms. Design A critical discourse analysis of 69 documents collected between July 2020 and May 2021 referencing the Suboxone Education Program spanning 13 years (2007–2021) from medical, nursing and pharmacy institutions sourced from every Canadian province and territory. Discursive themes were identified through iterative and duplicate analyses using a semistructured data extraction instrument. Results Documents characterised the Programme as addressing iatrogenic risks from overprescribing opioid analgesics, environmental risks from a toxic street drug supply and pharmacological risks relating to the dominant therapeutic alternative of methadone. The programme was identified as being able to address these risks by providing mechanisms to surveil healthcare professionals and to facilitate the prescribing of Suboxone. Medical institutions legitimised the Suboxone Education Programme by lending their regulatory, epidemiological and professional authority. Conclusions Addressing risk is considered as a central, moral responsibility of contemporary healthcare services. In this case, moral imperatives to address opioid crisis-related risks overrode other ethical concerns regarding conflicts of interest between industry and public welfare. Failing to address these conflicts potentially imperils efforts of mitigating population health harms by propagating an important driving force of the opioid crisis.
... A recent study has shown that nearly 90 percent of new drugs do not perform better than existing options. 13 There is an ethical cost to be considered when devoting financial resources and effort to create new drugs that are inferior to existing treatments and have not led to changes to clinical practice. While the FDA claims to follow the bioethical principles of beneficence and nonmaleficence, its choice of approving treatments through placebo controls, despite the existence of standard interventions, counters these guidelines. ...
Article
Full-text available
Photo by Diana Polekhina on Unsplash ABSTRACT Randomized placebo-controlled trials are often used in clinical research, though there are ethical concerns regarding their use. The Food and Drug Administration (FDA) has rejected international stances on placebo-controlled trial use in favor of the bioethical principles of autonomy, beneficence, nonmaleficence, and justice. The FDA permits placebo-controlled trials in three circumstances: when there are no established treatments available when their use would be of negligible harm to the patient, and when there are compelling reasons for their use. However, in some cases, the FDA’s approval of placebo-controlled trials violates bioethical principles. Ultimately, the FDA should overhaul its practices regarding the use of placebo-controlled trials. INTRODUCTION Randomized placebo-controlled clinical trials (PCTs) are considered the most rigorous method of understanding the efficacy of an intervention and, as a result, are widely used in clinical research.[1] However, there are ethical concerns regarding placebo controls, including their use in the study of deadly diseases or when effective treatments already exist, though poor oversight and lax rules have largely permitted PCT research, even under those conditions.[2] The FDA prefers PCTs for most interventional research and considers them essential to test the efficacy of drugs. Between 2006-2011, 40 percent of FDA-approved clinical trials used a placebo alone for comparison. The FDA has been lagging in altering its policies regarding PCTs, only advising against PCT research in select oncological cases for the first time in 2019 in a nonbinding guidance. It is our belief that the FDA should change its approach and prohibit the use of placebo controls in clinical trials where effective treatments already exist. l. Brief History of PCTs and the FDA In contemporary research practices, PCTs are used to evaluate whether an intervention is effective by comparing it to a control group that received a treatment designed to have no real effect (placebo). Throughout the 20th century there have been numerous bioethical tragedies, including but not limited to the Holocaust and the Tuskegee Syphilis Study.[3] These and other transgressions have become an impetus for establishing ethical research standards preventing human exploitation in the name of science. The Declaration of Helsinki, adopted in 1964, a nonbinding instrument, restricts the use of PCTs. Clause 33 of the Declaration of Helsinki states that new medical interventions should be tested against previously demonstrated interventions and placebos should be used only if there is no existing intervention with narrow exceptions. Clause 33 says the effectiveness of a new intervention must be tested against those of the best current proven intervention (s), except in the following circumstances: Where no proven intervention exists, the use of placebo, or no intervention, is acceptable; or Where for compelling and scientifically sound methodological reasons the use of any intervention less effective than the best proven one, the use of placebo, or no intervention is necessary to determine the efficacy or safety of an intervention and the patients who receive any intervention less effective than the best proven one, placebo, or no intervention will not be subject to additional risks of serious or irreversible harm as a result of not receiving the best proven intervention. Extreme care must be taken to avoid abuse of this option.[4] The FDA has largely ignored this and deemed placebo controls the gold standard, stating that “PCTs are necessary to control for placebo effect of investigational medicinal product.”[5] The FDA has even refused to approve drugs that are tested against established treatments instead of against placebos, notably atenolol.[6] By stretching the “methodological” exception and failing to define harm reasonably, the FDA does not meet the spirit behind Helsinki’s conditions for allowing PCTs. When the Declaration of Helsinki was revised in 2000 to increase restrictions, the Director of Medical Policy for the FDA’s Center for Drug Evaluation and Research considered it “unpardonable” and abandoned any compliance with it in 2008.[7] The FDA’s past statements and actions have supported its belief that drug approval hinges on the use of placebos. While the FDA has rejected the Declaration of Helsinki’s stance on placebos, it has remained faithful to the guidelines of other bioethical codes such as the International Ethical Guidelines for Biomedical Research Involving Human Subjects and the Council for International Organization of Medical Science’s guidelines for biomedical research involving human subjects. The International Ethical Guidelines for Biomedical Research Involving Human Subjects permits PCTs if the consequences are negligible, when methodologically advantageous, and when responses have been historically erratic.[8] The Council for International Organization of Medical Science’s guidelines for biomedical research involving human subjects echoed the Declaration of Helsinki in guideline 11, stating that a “‘placebo may be used: When there is no effective intervention; when withholding an established, effective intervention would expose to, at most temporary discomfort, or delay in relief symptoms; when use of an established, effective intervention as comparator would not yield scientifically reliable results and the use of the placebo would not add risk of serious or irreversible harm to subjects.”[9] The Belmont Report notes three ethical principles: beneficence, respect for persons (autonomy), and justice. The Common Rule requires IRBs for human research and reflects principles noted in the Belmont Report. The Belmont Report covers three applications of its principles: Informed consent, selection of research subjects, and risk-benefit assessments.[10] In 1979, Beauchamp and Childress established the four principles approach to bioethics including autonomy, beneficence, nonmaleficence, and justice. While PCTs were not mentioned in these reports, the principles in them permit placebo controls as long as subjects are informed of the risks of participating and risks are minimized. The FDA has since followed that approach. These guidelines have made PCTs ethically ambiguous, and there are moral counterpoints to be made. ll. FDA-PCT Conditions The FDA has permitted PCT use under three conditions. The first condition is when there is no proven intervention for the medical condition under the study. This means treatment has either not been found for a disease or has not yet been translated into clinical practice and is not controversial. The second condition is when there is negligible harm to the patient from delaying or forgoing an available treatment. In this scenario, a placebo is not suspected to cause damage and the available treatment is meant for mild conditions that pose low-risk adverse effects, which is said to justify its use. The final condition is when there are compelling methodologic reasons for the use of the placebo. This scenario is for situations where outcomes fluctuate for complex reasons making other research methods likely to be unreliable. This condition for PCT use is also justified when it is not possible to administer the intervention to the experimental group because of economic, social, or administrative factors, in which case it is believed to be better to have results of some kind than none at all.[11] We will argue each condition is unethical to the current degree it is practiced. lll. Condition One: Lack of Established Treatment Placebo use in cases where no established treatment exists would not typically be considered unethical. However, placebos continue to be used in numerous clinical trials approved by the FDA, many of which already have standard interventions.[12] In addition, the lack of head-to-head drug trials, in favor of placebo, has had no benefit on clinical guidelines and practices. The direct comparison of drugs in head-to-head trials gives physicians and buyers a better understanding of the effectiveness of a drug and allows for the creation of more robust clinical guidelines. Instead, under the PCT model, the market is saturated with a plethora of drugs to choose from. While each one may be better than placebo, it can be difficult to understand how each treatment compares to another, which may be harmful to patients. A recent study has shown that nearly 90 percent of new drugs do not perform better than existing options.[13] There is an ethical cost to be considered when devoting financial resources and effort to create new drugs that are inferior to existing treatments and have not led to changes to clinical practice. While the FDA claims to follow the bioethical principles of beneficence and nonmaleficence, its choice of approving treatments through placebo controls, despite the existence of standard interventions, counters these guidelines. lV. Condition Two: Negligible Harm from Delayed Treatment The International Ethical Guidelines for Biomedical Research Involving Human Subjects argues that placebos are acceptable if there is only “temporary discomfort or a delay in relief of symptoms,” a stipulation that the FDA follows. However, what constitutes temporary is arbitrary, as there is no absolute reference of time prescribed, nor is there a defined proportion relative to total life expectancy available. For example, many patients in trials for terminal illnesses have a limited therapeutic window and a reduced life expectancy, so they value time differently from someone with a non-terminal illness. Additionally, there is no consensus of what constitutes harm when withholding treatment; placebos are often used in trials for major depressive disorder, yet this population has statistically higher rates of self-harm and suicide without treatment compared to the general population.[14] Serious risks can be incurred due to a placebo intervention by not offering experimental treatment, without excusing the psychological harm withholding a treatment may have on a patient should it be unblinded. Nevertheless, the FDA has used the umbrella term of “temporary discomfort” to justify the widespread use of PCTs, but the vagueness of this language results in human suffering. V. Condition Three: Compelling Methodological Reasoning Finally, the FDA authorizes placebo use in cases where for compelling scientifically sound methodological reasons, the use of placebo is necessary to determine the efficacy or safety of an intervention, and the parties who receive placebo or no treatment will not be subject to any risk of serious or irreversible harm. The condition includes cases where PCT is believed to be necessary to demonstrate efficacy, such as in trials of psychoactive drugs where evidence is inconsistent due to disease heterogeneity and demonstrating equivalence to an established treatment is insufficient. There are also arguments that PCTs, while not necessary, may be beneficial in generating socially valuable knowledge. However, whether a placebo control demonstrates efficacy is not sufficient to justify its use. When considering the ethical use of PCTs, investigators must weigh the social value gained against the risks of no treatment in the control. Unfortunately, the risk-benefit analysis is often controversial. For example, in 2001, the FDA initially responded positively to a placebo-controlled trial of Surfaxin in infants with acute respiratory distress syndrome in Latin America. However, the trial was deemed exploitative by a public watch group when it was revealed that the drug was already FDA-approved in the United States, and the manufacturer of that drug was undertaking another study with the same drug in Europe without any placebos. To justify withholding treatment from a vulnerable population in a developing country, the manufacturer stated that they would be providing a drug that would otherwise be unavailable to many participants, and the risks would be compensated by upgrades to the host country’s medical infrastructure. Despite the FDA’s initial approval and the manufacturer’s attempt to quell public outcry, objections by the public led to the removal of the placebo arm from the trial. While the FDA believes there may be methodologically compelling reasons to utilize PCTs, they have demonstrated a lack of judgment necessary to balance the gains against their inherent losses, requiring the public to step in. CONCLUSION Based on the ambiguous bioethical guidelines that the FDA follows, and the moral justifications described in this paper, its preference of PCTs is unethical. We suspect the overreliance of PCTs has resulted in harm to research participants and the general population, which is why the FDA should change its policy. We propose that PCTs be used only for diseases that lack an established treatment, as decreed by Clause 33 of the Declaration of Helsinki. Other measures that would satisfy Clause 33, the Belmont Report, and the Common Rule are the use of large retrospective observational trials for comparison rather than a prospective placebo group. Ultimately, it is ethically necessary that the FDA modify its practices regarding drug approval and more stringently scrutinize PCTs as well as adopt more favorable approaches to other comparative models. Acknowledgments We sincerely thank Dr. Gregory James Smith, JD, DBE for his patience and guidance in both the research and writing of this paper. - [1] Simmonds A. Ethics of placebo-controlled trials in developing countries: The Search for Standards and Solutions. The Morningside Review. https://journals.library.columbia.edu/index.php/TMR/article/view/5507. Published May 1, 2011. Accessed April 21, 2022; Millum J, Grady C. The ethics of placebo-controlled trials: Methodological Justifications. Contemporary Clinical Trials. 2013;36(2):510-514. doi:10.1016/j.cct.2013.09.003; Center for Drug Evaluation and Research. Institutional Review Boards (IRBs) and Protection of Human Subjects in Clinical Trials. U.S. Food and Drug Administration. https://www.fda.gov/about-fda/center-drug-evaluation-and-research-cder/institutional-review-boards-irbs-and-protection-human-subjects-clinical-trials. Published September 11, 2019. Accessed April 21, 2022. [2] Keränen T, Halkoaho A, Itkonen E, Pietilä A-M. Placebo-controlled clinical trials: How trial documents justify the use of randomisation and Placebo. BMC Medical Ethics. 2015;16(1). doi:10.1186/1472-6939-16-2; Feifel D. The use of placebo-controlled clinical trials for the approval of psychiatric drugs: part I-statistics and the case for the "greater good.” Psychiatry (Edgmont). 2009;6(3):41-43; van der Graaf R, Rid A. Placebo-controlled trials, ethics of. International Encyclopedia of the Social & Behavioral Sciences. 2015:164-173. doi:10.1016/b978-0-08-097086-8.11011-6; Ibrahim MS, Ovosi JO, Bello-Ovosi BO. Randomized controlled trials: Ethical and scientific issues in the choice of placebo or active control. Annals of African Medicine. 2017;16(3):97-100. doi:10.4103/aam.aam_211_16; Sorscher S, AbuDagga A, Almashat S, Carome M, Wolfe S. Placebo-only-controlled versus active-controlled trials of new drugs for nine common life-threatening diseases. Open Access Journal of Clinical Trials. 2018;Volume 10:19-28. doi:10.2147/oajct.s156054; Mezher M. FDA finalizes guidance on placebos and blinding for cancer trials. Regulatory Affairs Professionals Society (RAPS). http://www.raps.org/news-and-articles/news-articles/2019/8/fda-finalizes-guidance-on-placebos-and-blinding-fo. Published August 28, 2019. Accessed April 21, 2022. [3] WMA Declaration of Helsinki – ethical principles for medical research involving human subjects. The World Medical Association. http://www.wma.net/policies-post/wma-declaration-of-helsinki-ethical-principles-for-medical-research-involving-human-subjects/. Published July 9, 2018. Accessed April 21, 2022. [4] WMA Declaration of Helsinki, Clause 33. [5] Ovosi JO, Ibrahim MS, Bello-Ovosi BO. Randomized controlled trials: Ethical and scientific issues in the choice of placebo or active control. Ann Afr Med. 2017;16(3):97-100. doi:10.4103/aam.aam_211_16; Rothman KJ, Michels KB. The continuing unethical use of placebo controls. New England Journal of Medicine. 1994;331(6):394-398. doi:10.1056/nejm199408113310611 [6] Rothman KJ, Michels KB. The Continuing Unethical Use of Placebo Controls. New England Journal of Medicine.1994;331(6):394-98. doi:10.1056/nejm199408113310611 [7] Hollon T. FDA uneasy about placebo revision. Nature Medicine. 2001;7(1):7-7. doi:10.1038/83389 [8] International Ethical Guidelines for Biomedical Research Involving Human Subjects. Geneva: CIOMS; 1993. https://cioms.ch/wp-content/uploads/2017/01/WEB-CIOMS-EthicalGuidelines.pdf. Accessed April 21, 2022. [9] Ovosi JO, Ibrahim MS, Bello-Ovosi BO. Randomized controlled trials: Ethical and scientific issues in the choice of placebo or active control. Ann Afr Med. 2017;16(3):97-100. doi:10.4103/aam.aam_211_16 [10] The Belmont Report Ethical Principles and Guidelines for the Protection of Human Subjects of Research. Washington, D.C: U.S. Government Print. Off; 1978. Accessed April 21, 2022. Office for Human Research Protections (OHRP); Federal Policy for the Protection of Human Subjects ('Common Rule'). HHS.gov. https://www.hhs.gov/ohrp/regulations-and-policy/regulations/common-rule/index.html. Published June 16, 2021. Accessed April 21, 2022. [11] Millum J, Grady C. The ethics of placebo-controlled trials: Methodological justifications. Contemporary Clinical Trials. 2013;36(2):510-514. doi:10.1016/j.cct.2013.09.003; Center for Drug Evaluation and Research. Institutional Review Boards (IRBs) and Protection of Human Subjects in Clinical Trials. U.S. Food and Drug Administration. https://www.fda.gov/about-fda/center-drug-evaluation-and-research-cder/institutional-review-boards-irbs-and-protection-human-subjects-clinical-trials. Published September 11, 2019. Accessed April 21, 2022. [12] Center for Drug Evaluation and Research. New drug therapy approvals 2020. U.S. Food and Drug Administration. https://www.fda.gov/drugs/new-drugs-fda-cders-new-molecular-entities-and-new-therapeutic-biological-products/new-drug-therapy-approvals-2020#first-in-class. Published January 8, 2021. Accessed April 21, 2022. [13] Light DW, Lexchin J, Darrow JJ. Institutional corruption of pharmaceuticals and the myth of safe and effective drugs. Journal of Law, Medicine & Ethics. 2013;41(3):590-600. doi:10.1111/jlme.12068 [14] Lahey T. The ethics of clinical research in low- and middle-income countries. Ethical and Legal Issues in Neurology. 2013:301-313. doi:10.1016/b978-0-444-53501-6.00025-1
... This arrangement has a corrosive influence on the workings of Congress as a whole, incentivizing the members of Congress to abandon their constitutional duties to voters in favor of representing the interests of their largest donors (Lessig, 2014(Lessig, , 2015. Similarly, there are a number problematic dependencies between medical practice and research and the pharmaceutical industry (Fields, 2013;Gray, 2013;Light et al., 2013;Rodwin, 2012Rodwin, , 2013. Within the United States, the medical community relies primarily on for-profit pharmaceutical companies to research, develop, and distribute new medicines. ...
Article
Full-text available
This article argues that criminal justice scholars should import the theory of institutional corruption from political science to make sense of a distinct set of problems in the criminal justice system. To make this argument, this article examines the case of Ferguson, Missouri. In Ferguson, the city’s mandate to maximize revenue generation had a corrosive effect on the day-to-day policies and practices of both the Ferguson Police Department and the municipal court, leading to aggressive policing, excessive fines, and a number of unfair and unconstitutional practices. Framed as a problem of institutional corruption, the case of Ferguson is emblematic of a broader set of issues in criminal justice institutions involving policies and practices that are legal but rife with corrupting incentives. Such problems demand further scrutiny from criminal justice scholars and practitioners alike.
... The pharmaceutical industry has corrupted the practice of medicine through its influence over what drugs are developed, how they are tested, and how medical knowledge is created. Meeting the needs of the drug companies has taken priority over meeting the needs of patients" [86]. Dark triad refers to the constellation of narcissism, machiavellianism, and psychopathy -'The malevolent side of human nature' [87]. ...
Article
Full-text available
Health may not be a perfect balance point but efforts can be made to maintain the health in a perfect homeostatic range. Disrupted homeostasis is the underlying issue of all the diseases. Larger and longer the deviations of the body from homeostatic conditions, poorer the ability to regain the original functions will be. George E Billman stated 'Homeostasis: The Underappreciated and Far Too Often Ignored Central Organizing Principle of Physiol-ogy'. Lack of clinical diagnosis and treatments on the basis of homeostasis could lead to public health damage, disingenuous medical curriculum, and eventually iatrogenic pseudoscience. Ivan Illich criticized iatrogenesis caused by treatments, health policies, medicalization of life and eradication of autonomous coping skills during illnesses. Antonovsky distinctly stated that the salutogenesis was not limited by the disciplinary borders of one profession but rather an interdisciplinary approach and a question of bringing coherence between disciplines and realise what connects them through the people's ability to comprehend the whole situation and the capacity to use the resources available [called as sense of coherence-SOC] to move in a health promoting direction. Prevention or healing of homeostatic disturbances obviously need interdisciplinary approach of various medical specializations including Physiotherapy. Intensifying impeccable prophylaxis, clinical applications and public health policies on the basis of homeostasis need in-depth and persistent emphasis on 'Homeostaticology', 'Iatrogenicology' and 'Salutogenicology'.
... A mere 1.6% offered substantial advantages" (Light et al., 2013, p. 592;Prescrire Editorial Staff, 2012. Similar results were found in reviews of drugs in Canada and the Netherlands (Light et al., 2013;Prescrire Editorial Staff, 2012). Additionally, a Cochrane review that examined 743 RCTs found that almost half of the new treatments were actually worse than established ones (Djulbegovic et al., 2012). ...
Article
Full-text available
Evaluation of primary health care and improvement of the services provided Primary health care (PHC) is a central pillar of health systems internationally, based on the view of health as a universal and socially established right. The PHC services in Greece have been characterized over time by disintegration, and inefficiency, high levels of fragmentation and inequality, in terms of their access to the general population and geographical distribution, with incomplete implementation of the state health system. The recent, ongoing financial crisis, coupled with economic policies to reduce health expenditures, have exacerbated these problems and magnified the systematic weaknesses of PHC in Greece, as reflected by population health indicators, the financial burden of patients and the deteriorating quality of the services provided. These social inequalities in health, which developed in previous years, were intensified by the COVID-19 pandemic, which further highlighted the need to improve the health services provided and to promote a public health development strategy. Reform of PHC based on systematic evaluation can be a way of responding to its chronic weaknesses and meeting the urgent health needs of the population emanating from the crisis situation and the turbulent economic environment. Although several attempts have been made over the years to develop and implement a PHC system, these have been fragmented, and initiated from a technocratic perspective, diminishing the role of evaluation to a financial tool. The main characteristic of systematic evaluation should be continuous repetition of a circular process, consisting of collection of information, evaluation, and formulation of proposals for improvement and change. This process will support the universality of care and establish health as a social good, but it presupposes interdisciplinary and inter-professional cooperation, with the active involvement of patients. Αξιολόγηση της πρωτοβάθμιας φροντίδας υγείας και βελτίωση των παρεχόμενων υπηρεσιών Περίληψη στο τέλος του άρθρου
Article
The relationships between innovation and firm misconduct have received little attention. We contribute to advancing understanding of misconduct in several ways. First, we find support for previous research on firm misconduct that finds that strain can contribute to unethical firm behavior. Theoretically, our contribution provides evidence in support of the novel idea that strain that results from innovation deficits promotes misconduct. We also contribute to the growing literature on ethical organizational cultures by providing evidence linking weak ethical cultures in the pharmaceutical industry with increased harm to patients. A large body of non-quantitative literature argues that many pharmaceutical firms engage in misconduct in order to promote sales and overcome innovation deficits. We find support for the conclusion that misconduct constitutes a substitute for all measurable categories of drug innovation.
Article
Background: The Prescription Drug User Fee Act (PDUFA) is due for reauthorization in 2022. Beyond creating the user fee program which now generates a majority of the Food and Drug Administration (FDA) Human Drugs Program budget, PDUFA has made numerous additional changes to FDA policy during its 29-year history. FDA's budgetary dependence on user fees may advantage the industry in negotiating favorable policy changes through PDUFA. Methods: The full texts of all prior PDUFA reauthorization bills and all submitted public comments and meeting minutes for the 2022 reauthorization were reviewed. Provisions affecting FDA regulatory authority and processes were identified. Findings: PDUFA legislation has instituted a broad range of changes to FDA policy, including evidentiary standards for drug approval, accelerated pathways for approval, industry involvement in FDA decision-making, rules regarding industry information dissemination to providers, and market entry of generic drugs. Negotiations over the 2022 reauthorization suggest that industry priorities include increased application of real-world evidence, regulatory certainty, and increased communication between FDA and industry during the drug application process. Conclusions: The need for PDUFA reauthorization every 5 years has created a recurring legislative vehicle through which far-ranging changes to FDA have been enacted, reshaping the agency's interactions and relationship with the regulated industry. The majority of policy changes enacted through PDUFA legislation have favored industry through decreasing regulatory standards, shortening approval times, and increasing industry involvement in FDA decision-making. FDA's budgetary dependence on the industry, the urgency of each PDUFA reauthorization's passage to maintain uninterrupted funding, and the industry's required participation in PDUFA negotiations may advantage the industry.
Preprint
Full-text available
We know palliative care in the US is underutilized. Little understood is why palliative care is rarely offered in the US, and that the efficacy and safety of palliative care is often better than that of drugs and medical procedures
Article
Full-text available
Data indicate that the widely touted “innovation crisis” in pharmaceuticals is a myth. The real innovation crisis, say Donald Light and Joel Lexchin , stems from current incentives that reward companies for developing large numbers of new drugs with few clinical advantages over existing ones Since the early 2000s, industry leaders, observers, and policy makers have been declaring that there is an innovation crisis in pharmaceutical research. A 2002 front page investigation by the Wall Street Journal reported, “In laboratories around the world, scientists on the hunt for new drugs are coming up dry . . . The $400 billion a year drug industry is suddenly in serious trouble.”1 Four years later, a US Government Accounting Office assessment of new drug development reported that “over the past several years it has become widely recognized throughout the industry that the productivity of its research and development expenditures has been declining.”2 In 2010, Morgan Stanley reported that top executives felt they could not “beat the innovation crisis” and proposed that the best way to deal with “a decade of dismal R&D returns” was for the major companies to stop trying to discover new drugs and buy into discoveries by others.3 Such reports continue and raise the spectre that the pipeline for new drugs will soon run dry and we will be left to the mercies of whatever ills befall us.4 The constant production of reports and articles about the so called innovation crisis rests on the decline in new molecular entities (defined as “an active ingredient that has never been marketed . . . in any form”5) since a spike in 1996 that resulted from the clearance of a backlog of applications after large user fees from companies were introduced (fig 1⇓). This decline ended in …
Article
Background: Clinical research affecting how doctors practice medicine is increasingly sponsored by companies that make drugs and medical devices. Previous systematic reviews have found that pharmaceutical-industry sponsored studies are more often favorable to the sponsor's product compared with studies with other sources of sponsorship. A similar association between sponsorship and outcomes have been found for device studies, but the body of evidence is not as strong as for sponsorship of drug studies. This review is an update of a previous Cochrane review and includes empirical studies on the association between sponsorship and research outcome. Objectives: To investigate whether industry sponsored drug and device studies have more favorable outcomes and differ in risk of bias, compared with studies having other sources of sponsorship. Search methods: In this update we searched MEDLINE (2010 to February 2015), Embase (2010 to February 2015), the Cochrane Methodology Register (2015, Issue 2) and Web of Science (June 2015). In addition, we searched reference lists of included papers, previous systematic reviews and author files. Selection criteria: Cross-sectional studies, cohort studies, systematic reviews and meta-analyses that quantitatively compared primary research studies of drugs or medical devices sponsored by industry with studies with other sources of sponsorship. We had no language restrictions. Data collection and analysis: Two assessors screened abstracts and identified and included relevant papers. Two assessors extracted data, and we contacted authors of included papers for additional unpublished data. Outcomes included favorable results, favorable conclusions, effect size, risk of bias and whether the conclusions agreed with the study results. Two assessors assessed risk of bias of included papers. We calculated pooled risk ratios (RR) for dichotomous data (with 95% confidence intervals (CIs)). Main results: Twenty-seven new papers were included in this update and in total the review contains 75 included papers. Industry sponsored studies more often had favorable efficacy results, RR: 1.27 (95% CI: 1.17 to 1.37) (25 papers) (moderate quality evidence), similar harms results RR: 1.37 (95% CI: 0.64 to 2.93) (four papers) (very low quality evidence) and more often favorable conclusions RR: 1.34 (95% CI: 1.19 to 1.51) (29 papers) (low quality evidence) compared with non-industry sponsored studies. Nineteen papers reported on sponsorship and efficacy effect size, but could not be pooled due to differences in their reporting of data and the results were heterogeneous. We did not find a difference between drug and device studies in the association between sponsorship and conclusions (test for interaction, P = 0.98) (four papers). Comparing industry and non-industry sponsored studies, we did not find a difference in risk of bias from sequence generation, allocation concealment, follow-up and selective outcome reporting. However, industry sponsored studies more often had low risk of bias from blinding, RR: 1.25 (95% CI: 1.05 to 1.50) (13 papers), compared with non-industry sponsored studies. In industry sponsored studies, there was less agreement between the results and the conclusions than in non-industry sponsored studies, RR: 0.83 (95% CI: 0.70 to 0.98) (six papers). Authors' conclusions: Sponsorship of drug and device studies by the manufacturing company leads to more favorable efficacy results and conclusions than sponsorship by other sources. Our analyses suggest the existence of an industry bias that cannot be explained by standard 'Risk of bias' assessments.
Book
When regulations (or lack thereof) seem to detract from the common good, critics often point to regulatory capture as a culprit. In some academic and policy circles it seems to have assumed the status of an immutable law. Yet for all the ink spilled describing and decrying capture, the concept remains difficult to nail down in practice. Is capture truly as powerful and unpreventable as the informed consensus seems to suggest? This edited volume brings together seventeen scholars from across the social sciences to address this question. Their work shows that capture is often misdiagnosed and may in fact be preventable and manageable. Focusing on the goal of prevention, the volume advances a more rigorous and empirical standard for diagnosing and measuring capture, paving the way for new lines of academic inquiry and more precise and nuanced reform.
Article
Modern government offers few if any agencies more powerful, more watched, or more pressured than the U.S. Food and Drug Administration (FDA). Rough estimates suggest that the FDA regulates more than one quarter of U.S. gross domestic product, with primary responsibilities for food, pharmaceuticals and medical devices, cosmetics, and, since 2009, tobacco products. Over a wide range of these products – drugs, medical devices, food additives, and certain tobacco products – the FDA has expansive gatekeeping power: the congressionally mandated task of deciding whether the products in question can be marketed at all. Gatekeeping power has many facets. Gatekeeping can be used to protect the public or provide it with false confidence; create market-wide confidence in new products; enhance or stifle innovation (often both); snow and guile consumers into thinking that poor, unsafe products are safer and better than they are; and hone the production, dosage, and information about drugs to help doctors and patients optimize their use. If ever there were a plausible prima facie case for capture, a gatekeeping regulator like the FDA would seem to provide it. In its governance of pharmaceuticals, the FDA regulates a vast industry, one that supplies a global market approaching $1 trillion in size. Given its size and its historical connections to science and technology, this industry possesses broad economic, political, and cultural power. When Samuel Huntington and Marver Bernstein wrote about the potential capture of regulatory agencies in the 1950s and 1960s, it was with just such an agency-industry relationship in mind (although neither wrote about the FDA). Large industries like these would seem to be primed to limit entry and preserve market access for themselves. And when George Stigler looked for examples of when “regulation is acquired by the industry,” he found his examples among entry-limiting regulation: weight limits for trucks (shaped by the lobbying of railroads and farmers) and occupational licensing (in which those with market power limit the entry of their potential competitors, restraining supply and inflating equilibrium price).
Article
Background: Internal documents from the pharmaceutical industry provide a unique window for understanding the structure and methods of pharmaceutical promotion. Such documents have become available through litigation concerning the promotion of gabapentin (Neurontin, Pfizer, Inc., New York, New York) for off-label uses. Purpose: To describe how gabapentin was promoted, focusing on the use of medical education, research, and publication. Data Sources: Court documents available to the public from United States ex. rel David Franklin vs. Pfizer, Inc., and Parke-Davis, Division of Warner-Lambert Company, mostly from 1994-1998. Data Extraction: All documents were reviewed by 1 author, with selected review by coauthors. Marketing strategies and tactics were identified by using an iterative process of review, discussion, and re-review of selected documents. Data Synthesis: The promotion of gabapentin was a comprehensive and multifaceted process. Advisory boards, consultants meetings, and accredited continuing medical education events organized by third-party vendors were used to deliver promotional messages. These tactics were augmented by the recruitment of local champions and engagement of thought leaders, who could be used to communicate favorable messages about gabapentin to their physician colleagues. Research and scholarship were also used for marketing by encouraging "key customers" to participate in research, using a large study to advance promotional themes and build market share, paying medical communication companies to develop and publish articles about gabapentin for the medical literature, and planning to suppress unfavorable study results. Limitations: Most available documents were submitted by the plaintiff and may not represent a complete picture of marketing practices. Conclusion: Activities traditionally considered independent of promotional intent, including continuing medical education and research, were extensively used to promote gabapentin. New strategies are needed to ensure a clear separation between scientific and commercial activity.
Article
Background: The incidence of adverse drug reaction (ADR)-related hospitalisations has usually been assessed within hospitals. Because of the variability in results and methodology, it is difficult to extrapolate these results to a national level. Objectives: To evaluate the incidence and characteristics of ADR-related hospitalisations in The Netherlands in 2001. Methods: We conducted a nationwide study of all hospital admissions in 2001. Data were retrieved from a nationwide computer database for hospital discharge records. All acute, non-planned admissions to all Dutch academic and general hospitals in 2001 were included in the study (n = 668 714). From these admissions we selected all hospitalisations that were coded as drug-related, but intended forms of overdose, errors in administration and therapeutic failures were excluded. Hence, we extracted all ADR-related hospitalisations. We compared age, sex and the risk of a fatal outcome between patients admitted with ADRs and patients admitted for other reasons, as well as the most frequent main diagnoses in ADR-related hospitalisations and which drugs most frequently caused the ADRs. In addition, we evaluated to what extent these ADRs were reported to the Netherlands Pharmacovigilance Centre Lareb for spontaneous ADR reporting. Results: In 2001, 12 249 hospitalisations were coded as ADR related. This was 1.83% of all acute hospital admissions in The Netherlands (95% CI 1.80, 1.86). The proportion increased with age from 0.8% (95% CI 0.75, 0.85) in the
Article
To combat institutional corruption, we need to distinguish it clearly from individual corruption. Individual corruption occurs when an institution or its officials receive a benefit that does not serve the institution and provides a service through relationships external to the institution under conditions that reveal a quid pro quo motive. Institutional corruption occurs when an institution or its officials receive a benefit that is directly useful to performing an institutional purpose, and systematically provides a service to the benefactor under conditions that tend to undermine procedures that support the primary purposes of the institution. Institutional corruption does not receive the attention it deserves partly because it is so closely (and often unavoidably) related to conduct that is part of the job of a responsible official, the perpetrators are often seen as (and are) respectable officials just trying to do their job, and the legal system and public opinion are more comfortable with condemning wrongdoing that has a corrupt motive. Yet institutional corruption, which is usually built into the routines and practices of organizations, is usually more damaging to the institution and society than individual corruption, which in advanced societies typically consists of isolated acts of misconduct with effects limited in time and scope.