1,000 PEER REVIEWED REPORTS AND STUDIES ON VACCINES

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VACCINE

Peer Review

The History Of The Global Vaccination Program

In 1000 Peer Reviewed Reports And Studies

1915-2015

A Jeff Prager Publication

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“Dissent is crucial for the advancement of science.

Disagreement is at the heart of peer review and is important for uncovering

unjustifed assumptions, fawed methodologies and problematic reasoning.”

I. de Melo-Martín and K. Intemann, Division of Medical Ethics, Department of Public Health, Weill Cornell Medical College, New York, USA

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“the harm from vaccines has seriously exceeded the beneft of disease prevention”

Dr. Harold Buttram

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“No batch of vaccine can be proved safe before it is given to children”

Surgeon General of the United States, Leonard Scheele, addressing an AMA convention in 1955

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“The only safe vaccine is a vaccine that is never used”

Dr. James A. Shannon, National Institutes of Health

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“Immune challenges during early development,

including those vaccine-induced, can lead to permanent

detrimental alterations of the brain and immune function.

Experimental evidence also shows that simultaneous administration

of as little as two to three immune adjuvants can overcome genetic

resistance to autoimmunity. In some developed countries, by the time

children are 4 to 6 years old, they will have received a total of

126 antigenic compounds along with high amounts of

aluminum adjuvants through routine vaccinations.

According to the US Food and Drug Administration, safety assessments for vaccines

have often not included appropriate toxicity studies because vaccines have not been

viewed as inherently toxic. Taken together, these observations raise plausible concerns

about the overall safety of current childhood vaccination programs.”

From the Journal Lupus, February 2012 by Lucija Tomljenovic & CA Shaw, Neural Dynamics Research Group

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Over the past 35 years, patients have suffered from a largely hidden epidemic of side effects from drugs that usu- ally have few offsetting benefts. The pharmaceutical industry has corrupted the practice of medicine through its

infuence over what drugs are developed, how they are tested, and how medical knowledge is created. Since 1906,

heavy commercial infuence 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 benefts; and

the creation of a National Drug Safety Board.

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 misrepresent evidence about

new drugs; distort the medical literature; and misrepresent products to prescribing physicians. We focus on the

consequences for patients: millions of adverse reactions. After defning institutional corruption, we focus on evi- dence that it lies behind the epidemic of harms and the paucity of benefts.

It is our thesis that institutional corruption has occurred at three levels. First, through large-scale lobbying and

political contributions, the pharmaceutical industry has infuenced Congress to pass legislation that has compro- mised 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 turning to industry-paid “user fees” since

1992 has biased funding to limit the FDA’s ability to protect the public from serious adverse reactions to drugs

Institutional Corruption of Pharmaceuticals

and the Myth of Safe and Effective Drugs

Donald W. Light

Rowan University, School of Osteopathic Medicine

Harvard University – Edmond J. Safra Center for Ethics

Joel Lexchin

York University

Jonathan J. Darrow

Harvard Medical School

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.

~ June 1, 2013 ~

Journal of Law, Medicine and Ethics, 2013, Vol. 14, No. 3:590-610

Abstract

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that have few offsetting advantages. Finally, industry has commercialized the role of physi- cians and undermined their position as independent, trusted advisers to patients.

Institutional Integrity: The Baseline of Corruption

If “corruption” is defned 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 democratically elected representatives should be dedicated solely to

the best interests of the people they represent. According to seminal essays on institutional

corruption by Dennis Thompson and Larry Lessig, this baseline of integrity is corrupted

because elections are not publicly funded. As a result, congressional representatives must

constantly raise funds from a tiny percent of the population and respond to their priorities.

This dependency corruption creates an “economy of infuence,” even if individual actors

are well-intentioned. 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 infuence, not money, affecting decisions. These are the ends of continua, and

there is a need to recognize degrees of corruption in between.

Special interests also infuence members of Congress to make legal what has been illegal 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.

Just as a proper electoral democracy is devoted to the public good, health care systems are

founded on the moral principles of benefcence, nonmalefcence (“ frst, do no harm”), re- spect for autonomy, and the just distribution of scarce resources. Based on these principles,

health care workers are obliged to use the best medical science to relieve suffering and

pain, treat illness, and address risks to health. The institutional corruption of health care

consists of deviations from these principles.

The major patent-based research pharmaceutical companies also nominally commit them- selves to improving health and relieving suffering. For example, Merck promises “to pro- vide innovative, distinctive products that save and improve lives … and to provide investors

with a superior rate of return.” Pfzer is dedicated “to applying science and our global re- sources 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 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 busi- ness model to maximize profts on scores of drugs with clinically minor additional benefts.

Physician commitment to better health is compromised as the industry spends billions to

create what Lessig calls a “gift economy” of interdependent reciprocation. New research

fnds that truly innovative new drugs sell themselves in the absence of such gift-economy

marketing.

Regulators such as the FDA and the Environmental Protection Agency arise when unregu- lated competition 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. Through a series of legislative enact- ments, 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 suffcient test- ing for serious risks, and inadequately guarding the public from harmful side effects. These

distortions serve commercial interests well and public health poorly.

For the past 50 years, patent-based research companies have objected to the FDA’s gate- keeping function as being too rigid and too slow. They have claimed that an obsessive con- cern about safety has undermined patient access to drugs that could save lives or reduce the

burdens of ill health. This message is increasingly being accepted by the FDA.

Flooding the Market with Drugs of Little Beneft

In response to the emphasis by pharmaceutical companies, their lobbyists, and their trade

association — the Pharmaceutical Research Manufacturers of America (PhRMA) — on the

high risk and cost of research and development (R&D), Congress has authorized billions in

taxpayer contributions to support R&D, exemptions from market competition, and special

privileges. Patents, of course, can be found in all industries, but lobbyists for the pharma- ceutical industry have successfully pressured Congress to provide several forms of market

protection beyond patents.

Therapeutic Value of Drugs Marketed in France, 2002-2011

The industry measures “innovation” in terms of new molecular entities (NMEs), but most

NMEs provide at best minor clinical advantages over existing ones and may lawfully be

approved by the FDA even if they are inferior to previously approved drugs. The prepon- derance of drugs without signifcant therapeutic gain dates back at least 35 years. From the

mid-1970s through the mid-1990s, multiple assessments have found that only 11 to 15.6

percent of NMEs provide an important therapeutic gain. Millions of patients beneft from

the one out of six drugs that are therapeutically signifcant advances; but most R&D dollars

are devoted to developing molecularly different 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 thera- peutic merits.

An analysis of data from the National Science Foundation by Donald Light and Joel Lex- chin indicates that patent-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. The 25 percent of

revenues spent on promotion is about 19 times more than the amount spent on discovering

new molecules. In short, the term “R&D” as used by industry primarily means “develop- ment” 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

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new drug product or new indication approved in France. From 1981 to 2001, it found that

about 12 percent offered therapeutic advantages.But in the following decade, 2002- 2011,

as shown in Figure 1, only 8 percent offered some advantages and nearly twice that many

— 15.6 percent – were judged to be more harmful than benefcial. A mere 1.6 percent of- fered substantial advantages. 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. 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 eventually being approved but from fewer new drugs being clinically superior. The

number of products put into trials has actually increased as the number of clinically supe- rior drugs has decreased. These facts provide evidence that companies are using patents

and other protections from market competition primarily to develop drugs with few if any

new therapeutic benefts and to charge infated prices protected by their strong IP rights.

Despite the small number of clinically superior drugs, sales and profts have soared as suc- cessful marketing persuades physicians to prescribe the much more costly new products

that are at best therapeutically equivalent to established drugs. Both an American and a Ca- nadian study found that 80 percent of the increase in drug expenditures went to paying for

these minor-variation new drugs, not for important advances. 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.

Almost a decade ago, Jerry Avorn, a widely respected pharmacoepidemiologist and author

of a book on the risks of drugs, described how the big pharmaceutical companies exploited

patents and concluded that “[l]aws designed to encourage and protect meaningful inno- vation had been turned into a system that rewarded trivial pseudo-innovation even more

proftably than important discoveries.” He also noted that efforts in Congress to introduce

a “reasonable pricing clause” that would refect large taxpayer contributions to new drugs

were defeated by industry lobbyists.

An Epidemic of Harmful Side Effects

Most new drugs approved and promoted since the 1970s lack additional clinical advantag- es over existing drugs and — as with all drugs — they have been accompanied by harmful

side effects. A systematic review of the 39 methodologically strongest studies performed in

the U.S. between 1964 and 1995 examined patients who were hospitalized due to a serious

adverse drug reaction (ADR) or who experienced an ADR while in the hospital.

The review found that 4.7 percent of hospital admissions were due to serious reactions from

prescription drugs that had been appropriately prescribed and used. In addition, 2.1 percent

of in-hospital patients who received correctly prescribed medications experienced a serious

ADR, for a total of 6.8 percent of hospital patients having serious ADRs. Applying this 6.8

percent hospital ADR rate to the 40 million annual admissions in U.S. acute care hospitals

indicates that up to 2.7 million hospitalized Americans each year have experienced a seri- ous adverse reaction. Of all hospitalized 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

signifcantly increase the totals.

An analysis conducted in 2011, based on a year of ADRs reported to the FDA, came to sim- ilar conclusions: Americans experienced “2.1 million serious injuries, including 128,000

patient deaths.”

Other studies reveal that one in every fve NMEs eventually caused enough serious harm

in patients to warrant 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.

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 hospitaliza- tion, about 81 million side effects are currently experienced every year by the 170 million

Americans who use pharmaceuticals. Groups such as pregnant women, elderly patients,

and those who are taking multiple medications are especially at risk. Most of these medi- cally minor adverse reactions are never brought to clinical attention, but even minor reac- tions can impair productivity or functioning, lead to falls, and cause potentially fatal motor

vehicle accidents.

Contributors to More Harm and Less Beneft

Are the adverse side effects we have just been describing simply the “price of progress or

an unavoidable risk of drug therapy?” In fact, evidence suggests that commercial distor- tions of the review process and aggressive marketing contribute to both undermining be- nefcence as health care’s raison d’être and to the epidemic of harm to patients.

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 ineffective medicines (medicines that may delay truly

useful treatments). At that time, lobbyists — paid from drug profts — argued that even

bills to require accurate listing of secret ingredients would destroy the industry. These lob- byists had managed 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 enforce- ment.

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 manufacturers to prove to the FDA

that drugs were safe before being allowed to sell them. The companies’ two trade associa- tions launched “well-choreographed screams of protest” and letter-writing campaigns to

mislead Congress and to distort its mission to protect its constituents from harm. Employ- ees of drug makers wrote to Congress, arguing that requiring companies to make honest

claims about safe drugs would put thousands out of work. The FDA staff wanted the legis- lation 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. Public response trumped industry lobbyists and Congress

passed the 1938 law, requiring that drugs be safe but leaving it to companies to decide how

to defne and test for safety.

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For the next 25 years, drugs were approved within 180 days unless the FDA objected,

based on the companies’ tests and reports of safety. Some companies “tested” their prod- ucts by sending samples out to providers for feedback, keeping no records of the results,

and denying serious harms when reported by doctors. Daniel Carpenter, the author of a

book considered to be a defnitive work on the politics of the FDA, has detailed how the

FDA staff dedicated themselves to enforcing the rules and developing better criteria for

safety and effcacy. 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.

In his review of new pharmaceutical products in the 1940s and 1950s, Dr. Henry Dowling,

an AMA senior offcer and expert, found that companies launched 200-400 a year but only

three on average were clinically useful. 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 physicians could then give to their patients

— a two-stage economy of reciprocation. In effect, through political pressure and lobby- ing, companies minimized the role of the FDA as the protector of public health for its frst

56 years.

Following the 1962 amendments, propelled to passage by the thalidomide tragedy, the

FDA commissioned the National Research Council, as part of the National Academy of

Sciences, to review the effectiveness of all 2820 drugs (available in 4350 different ver- sions) approved between 1938 to 1962. Companies were required to submit substantial

evidence of effectiveness. The review concluded that seven percent of the drugs reviewed

were completely ineffective for every claim they made and a further 50 percent were only

effective for some of the claims made for them. 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 guidance document, are today “marketed illegally without

required FDA approval.”

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 effcacy before a drug can

be approved, three key features of the modern drug-testing system actually work for indus- try profts 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 effective treatments, and the use of surrogate or substitute end points,

rather than actual effects on patients’ health. Noninferiority trials that merely show that

the product is not worse than another drug used to treat the same condition by more than

a specifed margin are accepted, rather than requiring superiority trials. Silvio Garattini,

founder of the Mario Negri Institute for Pharmacological Research, points out that placebo

and noninferiority trials violate international ethical standards and provide no useful infor- mation for prescribing.

Second, allowing companies to test their own products has led them — as rational eco- nomic actors — to design trials in ways that minimize detection and reporting of harms

and maximize evidence of benefts. Furthermore, clinical trials for new drugs are designed

to test primarily for effcacy and generally are not able to detect less common adverse

events.

Industry-friendly rules allow companies to exclude those patients most likely to have ad- verse reactions, while including those most likely to beneft, so that drugs look safer and

more effective than they are in practice. Approvals based on scientifcally compromised

trials underlie the large number of heavily marketed new drugs with few or no new thera- peutic benefts to offset their under-tested risks of harm.

Third, companies have created what can be characterized as the trial-journal pipeline be- cause companies treat trials and journals as marketing vehicles. They design trials to pro- duce results that support the marketing profle for a drug and then hire “publication plan- ning” teams of editors, statisticians, and writers to craft journal articles favorable to the

sponsor’s drug. 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 ar- ticles discussing non-commercially funded clinical trials. Yet, journal approval is deemed

to certify what constitutes medical knowledge. Published papers legitimate the pharmaceu- tical 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 confdentiality about those re- sults. Positive results are sometimes published twice — or even more often — under dif- ferent guises. This further biases meta-analyses — 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.”

For decades, the FDA has kept silent about these practices and about the discrepancies

between the data submitted to the FDA by companies and the fndings published in jour- nal articles, to the detriment of patients but much to the beneft 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 flled by company-shaped “evidence” that misleads physi- cians to prescribe drugs that are less safe and effective than indicated by evidence that the

FDA possesses.

PDUFA: Confict-of-Interest Payments

In 1992, after years of underfunding and cuts in the 1980s that contributed to drug re- view times ballooning from 6 to 30 months, Congress passed the Prescription 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. 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.

In return for paying user fees, companies required the FDA to guarantee that it would re- view priority applications within six months and standard applications 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 serious adverse reactions, a 10.9-

percent increase in hospitalizations, and a 7.2-percent increase in deaths. Now, 20 years

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later, what Carpenter calls “corrosive capture” has set in — a weakened application of regulatory tools and

a cultural capture of rhetoric about saving lives by getting new drugs to patients more quickly.

For the FDA, the reduction in review time combined with the fear that missing review deadlines will jeop- ardize continued PDUFA funding has also led to an increase in “up against the wall” approvals as review

deadlines approach. Carpenter and his colleagues 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.

These detailed studies corroborate what FDA staff told the Offce of the Inspector General, 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.”

The 1998 withdrawal of fve drugs, used by 19.8 million Americans, prompted critical refection. Three

distinguished physicians were struck by how little information had been gathered about the harmful side

effects of these drugs before they were withdrawn. 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, effcacy, and toxicity of drugs” after FDA approval.

To compensate for the FDA’s failures, 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 Evaluation 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 offcials’ 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 address- ing adverse reactions as a major cause of death.

In 1997, a year before these fve withdrawals, Congress had passed PDUFA II and companies had insisted

that none of the fees collected be spent on post-market surveillance or on drug-safety programs. PDUFA

II, III, IV, and V and related legislation provided the FDA with steeply increasing user fees but included

lower criteria for approval, mandated that an industry representative be on FDA scientifc advisory com- mittees, lowered barriers to promotional efforts by companies, and required FDA offcers to consult and

negotiate with industry on the agency’s goals and plans.

Offsetting the harms associated with PDUFA I’s shortened approval framework are several tools created

in PDUFA III through V for detecting, managing, and raising awareness of risks such as the Sentinel sys- tem and the Risk Evaluation and Mitigation Strategies; but there is no clear evidence these are reducing

the epidemic of harms. 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 Offce of Drug Safety and the $7.5

million provided for the FDA’s advertising enforcement arm are tiny in comparison to the more than $690

million in user fees that fow to the FDA each year. 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, perpetuating 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 fve to one in three. 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 effects by independent review

groups. Refecting 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, priority review … to get

critical and innovative medicines to market more rapidly.” Quicker reviews and less evidence of clinical

beneft have rewarded the hidden business model of developing still more drugs with minor benefts.

The FDA’s obligation to serve the public is being corroded by pressures to serve the companies it regu- lates. As for post-market surveillance — “the single most important function…for protecting the public

against the dangers of harmful drugs” — 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 maximizes the number of patients exposed to risks from the

roughly 25 to 40 new NMES approved annually.

Field studies fnd that most drug representatives do not discuss adverse side effects. Although the law

requires companies to submit some marketing materials for review, Congress and the FDA allocate only

a small budget and staff to review about 75,000 submissions a year for false or misleading information.

Further, the small stream of letters ordering that inaccuracies be corrected is subject to a review process

that delays their reaching the companies.

Marketing for unapproved or “off-label” uses worsens the balance of harm and beneft and undermines

the purpose of testing to show that a drug is effective and safe for a specifc use. While trying drugs for

new uses is clinically important, especially for certain populations such as children and cancer patients, 75

percent of off-label prescribing is neither supported by sound evidence nor accompanied by an organized

means for gathering such evidence. 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.”

A 15-month investigation by the Committee on Government Reform of the U.S. House of Representatives

found “a growing laxity in FDA’s surveillance and enforcement procedures, a dangerous decline in regula- tory vigilance, and an obvious unwillingness to move forward even on claims from its own feld offces.”

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.

Read the rest: https://app.box.com/s/5414zf7lufhtwf3czjfo9msafnoz6ht5 or: http://ethics.harvard.edu/news/institutional-corruption-and-pharmaceutical-policy

Direct from author: https://www.academia.edu/6750219/Institutional_Corruption_and_the_Myth_of_Safe_and_Effective_Drugs