The NEW ENGLA ND JOURNAL of MEDICINE

Perspective july 19, 2012

2 0 0 TH ANNIVERSARY AR TICLE

Two Centuries of Assessing Drug Risks

Jerry Avorn, M.D.

T he history of medicine is largely the story of

medicines a continuing tale of unfolding
risks and benefits. Yet the medical world into which
the Journal was born in 1812 did not systematically
assess the side effects of treat-
ments in relation to the good
they did. Often, there was no
understanding of the causal link-
age between adverse events and
the therapies that led to them.
The mixed bag that was the eras
pharmacopoeia is illustrated in the
first article of the Journals first
issue, Remarks on Angina Pec-
toris, in which John Warren de-
scribes a patient with acute car-
diac ischemia who was ordered
to take opium and aether, or the
fetid gums; to bathe the feet in
warm water; and under the direc-
tion of a physician, to lose a little
blood. . . . The nitrate of silver
was prescribed in solution. To-
bacco rounded out the regimen
(1812; see box for cited Journal
articles). There was no systematic
approach for determining which
treatments could be effective with
an acceptable level of risk and
which were merely toxic.
This confusion is illustrated by
an 1814 article on arsenic noting
that in the treatment of herpetic
affections, the beneficial effects
of the remedy are not apparent
until after its use has been some-
time discontinued a perfect
method for confounding assess-
ment of efficacy (in this case nil)
with side effects. The author de-
scribes a patient in whom arsenic
treatment was stopped when it
caused the skin eruptions that
are a hallmark of its toxicity
(1814a). The lesions subsided af-
ter the arsenic was discontinued,
a primitive but commonsensical
basis for attributing causality to
drug-induced pathology. Not so
fast, warned the expert, a Dr.
Kinglake. Under such circum-
stances, it is natural enough for
the patient to deny the medicine
any share in the cure, attributing
the benefit rather to the discon-
tinuance than the efficacy of the
remedy. In reality, he explained,
the arsenic had had a high stim-
ulating effect that prevent[ed]
its beneficial operation from be-
ing observable. This arsenical
excitement was mistook for an
unaltered continuance of the orig-
inal affliction. Treat on through
the signs and symptoms of toxic
effects for up to 3 months,
Kinglake recommended. The Jour-
nals own commentator wisely not-
ed, we cannot divest ourselves of
apprehension that [such continu-
ing treatment] may lay the foun-
dation of subsequent irreparable
mischief, and should by no means
recommend its general employ-
ment to such an extent.
That same year, a case report

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PERSPE C T I V E Two Centuries of Assessing Drug Risks

cases, that continuance of mer-

Historical Journal Articles Cited.
cury [is] proper. For although
New England Journal of Medicine and Surgery, and the Collateral Branches of Science this devastating syndrome could
1812. Warren J. Remarks on angina pectoris. 1:1-11. be caused by an incautious use of
1814a. Intelligence: Arsenic. 3:96. mercury, it could also be pro-
1814b. Description of a disease produced by the use of mercury. 3:120-6. duced in an aggravated form by a
Boston Medical and Surgical Journal too early removal of the mineral
1906. Pure Food and Drugs Act. 155:363. (1814b).
New England Journal of Medicine The Journals clinical descrip-
1937a. Miscellany: Patent medicines and seafoods get special attention in food tions of adverse drug effects were
and drug report. 216:34-5.
often detailed and apt, but there
1937b. When to lock the stable. 217:960.
was little capacity to weigh these
1938a. Christian HA. Food, drug, and cosmetic control. 218:92.
downsides of therapies against
1938b. WheelerLea Act. 218:846.
their usefulness. When the Journal
1938c. Grabfield GP. The relation of newer drugs to public health. 218:911-4.
1962. Mellin GW, Katzenstein M. The saga of thalidomide neuropathy to embry-
was launched, the systematic use
opathy, with case reports of congenital anomalies. 267:1184-92. of randomized, controlled trials
2000. Bombardier C, Laine L, Reicin A, et al. Comparison of upper gastrointestinal was still more than 130 years in
toxicity of rofecoxib and naproxen in patients with rheumatoid arthritis. 343: the future; it did not become
1520-8.
standard until after World War II.
2005a. Bresalier RS, Sandler RS, Quan H, et al. Cardiovascular events associated
with rofecoxib in a colorectal adenoma chemoprevention trial. 352:1092-102.
Attribution of drug-induced syn-
2005b. Curfman GD, Morrissey S, Drazen JM. Expression of concern: Bombardier dromes to a cause was therefore
et al., Comparison of upper gastrointestinal toxicity of rofecoxib and naproxen often confused and occasionally
in patients with rheumatoid arthritis. 353:2813-4. counterproductive. At the end of
2006. Curfman GD, Morrissey S, Drazen JM. Expression of concern reaffirmed. the Journals first century of pub-
354:1193.
lication, the dean of Harvard Med-
2007. Nissen SE, Wolski K. Effect of rosiglitazone on the risk of myocardial infarc-
tion and death from cardiovascular causes. 356:2457-71. ical School summed up the risk
2008a. Schneeweiss S, Seeger JD, Landon J, Walker AM. Aprotinin during coronary- benefit situation neatly: I firmly
artery bypass grafting and risk of death. 358:771-83. believe that if the whole materia
2008b. Shaw AD, Stafford-Smith M, White WD, et al. The effect of aprotinin on medica could be sunk to the bot-
outcome after coronary-artery bypass grafting. 358:784-93. tom of the sea, it would be all the
2008c. Fergusson DA, Hbert PC, Mazer CD, et al. A comparison of aprotinin and
lysine analogues in high-risk cardiac surgery. 358:2319-31.
better for mankind, and all the
2010. Woodcock J, Sharfstein JM, Hamburg M. Regulatory action on rosiglitazone
worse for the fishes.1
by the U.S. Food and Drug Administration. 363:1489-91. Appreciation of this imbalance
2011a. Zarin DA, Tse T, Williams RJ, Califf RM, Ide NC. The ClinicalTrials.gov results between toxicity and benefit was
database update and key issues. 364:852-60. not widely shared by his medical
2011b. Behrman RE, Benner JS, Brown JS, McClellan M, Woodcock J, Platt R. contemporaries, but it caught the
Developing the Sentinel System a national resource for evidence develop-
ment. 364:498-9. attention of their patients. By the
turn of the 20th century, the pro-
liferation of patent medicines
from Dublin commented on the an acrimonious lymph, and des- had become a national scandal.
difficulty of determining whether quamation so severe that large Manufacturers were not even re-
a particularly florid syndrome was pieces of the hand will come quired to reveal their products
an adverse drug effect, a new un- off, so entire as to resemble a contents, and certainly not to en-
related disease, or most prob- glove. Appropriately, the article sure their safety and efficacy. In
lematic the consequence of was titled Description of a dis- the Journal, the debate became a
stopping medication too early. The ease produced by the use of mer- battle between those concerned
patient, who been treated with cury. Helpfully, the report point- with patient safety and benefit and
mercury, developed a dramatic ed out that The cure of this a powerful industry intent on pro-
skin eruption, fever to 108F, disease is very simple. It consists, tecting its profitability and auton-
tachycardia to 130 beats per min- first, in removing the exciting omy from government control.
ute, headache, nausea, convul- cause and then its effects. But A 1906 issue reported the view
sions, blisters that discharged the author thought, in some of H.W. Wiley, who headed a com-

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PERSPECTIVE
mission working on the Pure Food
and Drugs Act, which would lay
the groundwork for todays Food
and Drug Administration (FDA).
In an apparent bow to political
reality, Wiley said his commission
desired to have the new law go
into operation with the least pos-
sible disturbance to business and
with the least possible inconven-
ience to the [patent medicine]
manufacturers and dealers of the
country (1906).
Initially, the FDAs pharmaceu-
tical jurisdiction was limited to
requiring manufacturers to accu-
rately label the contents of their
products, whose main active in-
gredient was often alcohol or an
opiate. The agency had no author-
ity to require that products be safe
(which came 32 years later) or
effective (which came 23 years af-
ter that). For decades more, thera-
peutics continued to be dominat-
ed by useless nostrums that
posed potentially great risks. A
1937 article quotes FDA chief
W.G. Campbell railing against
patent medicines that claimed to
cure cancer, tuberculosis, diabetes,
pneumonia, influenza, gallstones,
glomerulonephritis, and venereal
disease products, he com-
plained, that have no value what-
ever in the treatment of those
conditions. The firms resorting
to this sort of business find shel-
ter, at least temporarily, in the
requirement that the Government
must prove fraud, and in the in-
adequate manpower of the Admin-
istration, which must cover the
coast lines and State borders with
a corps of inspectors numbering
less than 100 (1937a).
A major movement to prevent
medication-induced illness took
shape in 1937, propelled as
most important drug-safety devel-
opments have been by a crisis.
More than 100 children had been
n engl j med 367;3 nejm.org july 19, 2012
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Two Centuries of Assessing Drug Risks
fatally poisoned by the Massen-
gill companys preparation of the
new antimicrobial sulfanilamide
(see photo) dissolved in diethyl-
ene glycol, a solvent known to be
lethal. An enraged public de-
manded that the FDA be given
the right to require that manufac-
turers prove their products were
not toxic before they could be sold.
A Journal editorial placed the
sulfa disaster in the context of
other drug-induced tragedies:
deaths and blindness caused by
dinitrophenol, fatal hepatotoxic ef-
fects from cinchophen, and acute
and chronic poisoning . . . from
the improper use of thyroid and
radium preparations. Perhaps,
the editorialist suggested, the
boyish enthusiasm with which
we accept nearly anything new,
The Lethal Sulfanilamide Preparation That
Killed More Than 100 Children in 1937.
and swallow hook, line, and sink-
er of the printed page, may be
again tempered with that calm
appraisal of the facts that has so
long been considered a heritage
of the medical fraternity (1937b).
As reaction to the Massengill
massacre grew, G. Philip Grab-
field of Peter Bent Brigham Hos-
pital and Harvard Medical School
noted that Under the present
law the only liability of this firm
lies in connection with use of the
word elixir, which is defined as
an alcoholic solution. In other
words, the firm cannot be indict-
ed for manslaughter but only for
misbranding. Selling a poison-
ous medication was not yet ille-
gal. He continued, It was
shown in 1930 that the toxicity
of diethylene glycol was approxi-
mately that of wood alcohol. Ap-
parently, this mixture was dis-
tributed for sale not only without
being tested but without even a
casual investigation of the litera-
ture on the part of its makers.
This ghastly experience indicates
. . . the crying need for adequate
legislation to control the market-
ing of all medicinal substances
(1938c).
Grabfield argued that deficits
in physicians knowledge contrib-
uted to the drug-safety problem,
noting that the teaching of phar-
macology and preventive medi-
cine is deficient in most schools.
After graduation it should become
the concern of the legally consti-
tuted health authorities to keep
the physicians under their juris-
diction continually conscious of
these pitfalls of therapeutics. . . .
Education, continuous and unre-
mitting, is the only practicable
method of breaking down the
hold that proprietary medicine
has upon the medical and lay
public. Criticizing the weakness
of the proposed 1938 amend-
ments to the law defining the
FDAs authority, and observing
that as much is spent in the
United States for patent medi-
cines as for all other types of
medical service combined, he
noted, eliminating the waste of
money on patent medicines might
almost make unnecessary the pro-
vision of additional facilities for
the medically indigent (1938c).
195
PERSPE C T I V E Two Centuries of Assessing Drug Risks

Control of pharmacologic tox- omide debacle led to major legis- stroke (2005a). Accumulating evi-
icity was to be joined in the new lative reforms, this time giving dence clarified that the VIGOR
legislation with control of informa- the FDA the power to require findings on myocardial infarction
tional toxicity the outrageous drug manufacturers to demon- were not attributable to a cardio-
and often completely untenable strate effectiveness as well as protective effect of naproxen but to
claims made in promoting drugs. nontoxicity. a cardiotoxic effect of rofecoxib.
But industry pushback was in- The Journal played a central Follow-up publications drew atten-
tense. In a 1938 letter to the edi- role in two prominent drug-safe- tion to other important problems
tor, Henry Christian of Peter Bent ty developments of the 21st cen- with the depiction of adverse
Brigham Hospital exhorted phy- tury, involving the cyclooxygen- events in that trial, including the
sicians to agitate for stronger ase-2 inhibitor rofecoxib (Vioxx) selective omission of key adverse
laws to protect patients: Remem- and the oral hypoglycemic agent events caused by the sponsors
ber that powerful interest in the rosiglitazone (Avandia). Accord- drug and an earlier cutoff date
drug and food trades fight for recording side effects
against restrictive laws; they that cast the product in an
are well organized; so there unfavorable light (myocardial
is great need that every phy- infarctions) than for those
sician express himself to revealing its clinical advan-
those who make our laws in tage (gastrointestinal bleeding
Washington (1938a). This events). This selective report-
concern was echoed in an ing prompted the editors to
editorial criticizing the new write two Expressions of
drug-safety law: Why was Concern about the report-
such a bill written and ap- ing of risk data in that trial
proved? The proper answer (2005b, 2006).
seems to be that powerful Recent years have seen
business interest of the trade An Early 20th-Century Ad Featuring Drugs from the growth of a new mecha-
in drugs and cosmetics saw Bayer, Including Heroin for Coughs and Aspirin. nism for the study of ad-
in this method an escape verse drug events: court ac-
from the more effective provi- ing to the pivotal study promot- tion forcing the release of raw
sions of a different bill that ing rofecoxib, the Vioxx Gastro- clinical trial data held by the
would have given the FDA stronger intestinal Outcomes Research companies that funded the stud-
authority to monitor promotional (VIGOR) trial (2000), patients ies.2 Years after publication of the
claims (1938b). given that drug had significantly original Vioxx studies, such re-
The next major drug-safety fewer episodes of gastrointesti- analyses of their underlying trial
event, the thalidomide disaster, nal bleeding than those taking reports have found clear evidence,
came nearly a quarter-century lat- naproxen. The authors also re- from 3 years before the drugs
er, when pregnant women who ported an incidental finding: withdrawal, of an increased risk
took the heavily promoted seda- naproxen users had one fourth as of cardiovascular death,3 as well
tiveantinauseant gave birth to many myocardial infarctions as as evidence that its gastroprotec-
children with crippling limb- patients in the rofecoxib group. tive advantage for most patients
reduction malformations (1962). They speculated that the cause was greatly overstated.4 The ad-
Before the drugdefect associa- was a cardioprotective antiplate- vent of mandatory adverse-event
tion was understood, this epi- let effect of naproxen. reporting at ClinicalTrials.gov is
demic of congenital anomalies The VIGOR article became likely in the coming years to pro-
afflicted more than 10,000 chil- notorious, for several reasons. In vide an additional means of en-
dren worldwide, but very few in 2004, another randomized trial suring more timely detection of
the United States, where an astute of rofecoxib was stopped early drug-safety problems (2011a).
FDA medical officer had prevent- because the drug, as compared Rofecoxib became another
ed the drugs approval. Like the with placebo, nearly doubled the milestone in the punctuated evo-
sulfanilamide tragedy, the thalid- risk of myocardial infarction and lution of drug-safety science and

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PERSPECTIVE Two Centuries of Assessing Drug Risks

policy. In the wake of its with- based review of records from lished (2008c), aprotinin was with-
drawal, influential reports from thousands (or millions) of pa- drawn from routine use; it has
the Institute of Medicine and the tients, combined with advanced since been reintroduced in Europe
Government Accountability Of- pharmacoepidemiologic methods, and Canada.
fice, along with Congressional to accurately quantify the rates Thus, two centuries after the
hearings, questioned how a drug of specific adverse effects. These Journal cited experts recommend-
that nearly doubled the risk of tools permit assessment of risk ing that physicians treat through
myocardial infarction or stroke in relation to a drugs benefits. the side effects of arsenic and mer-
could have been used by more For example, in 2008, the Journal cury therapy, the assessment of
than 20 million Americans over published two observational stud- drug risks has become consider-
5 years without that risk being ies designed to determine wheth- ably more sophisticated. Through
widely appreciated. The debate er using the procoagulant apro- out this history, the study and
highlighted the inadequacy of the tinin (Trasylol) in cardiac surgery management of this inevitable
FDAs reliance on spontaneously increased the risk of thrombotic aspect of therapeutics have in-
reported adverse events as a volved a complex interplay of
main method of ongoing clinical practice, pharmacolo-
drug-safety surveillance. In gy, epidemiology, policy, and
the resulting FDA Amend- politics. Greater access to
ments Act of 2007, Congress data and the application of
required the FDA to develop a modern information technol-
near-real-time surveillance ogy and sophisticated epide-
system capable of scanning miologic approaches are fi-
the electronic records of nally providing a valuable
more than 100 million Amer- and potentially lifesaving way
icans by 2012. This Sentinel to balance the good that
System is now operational medications can do against
(2011b). the harm that they some-
The past two decades have A 1915 Journal Ad Promoting Radium to Treat Arthritis. times cause.
also seen the widespread ap- Disclosure forms provided by the author
plication of newer quantitative events. Scanning the records of are available with the full text of this arti-
cle at NEJM.org.
methods for analyzing drug more than 88,000 patients given
risks. In a meta-analysis of pub- aprotinin or a comparator agent, From Harvard Medical School and the Divi-
sion of Pharmacoepidemiology and Phar-
licly available data from the clini- the two teams of investigators macoeconomics, Department of Medicine,
cal trials of rosiglitazone, Nissen found a significant increase in the Brigham and Womens Hospital both in
and Wolski reported a 43% in- risk of death associated with apro- Boston.
crease in the incidence of myo- tinin, after adjustment for under- 1. Holmes OW. Lecture on drugs. In: Bartlett
cardial infarction among patients lying differences between the J, ed. Bartletts familiar quotations. 10th ed.
randomly assigned to receive that groups (2008a, 2008b). The larger Boston: Little, Brown, 1919.
2. Kesselheim AS, Avorn J. The role of litiga-
drug versus several comparators of the two studies had been fund- tion in defining drug risks. JAMA 2007;297:
(2007). This finding, initially con- ed by the drugs manufacturer to 308-11.
Madigan D, Sigelman DW, Mayer JW, Fur-
tested by rosiglitazones manu- inform an FDA advisory commit- 3. berg CD, Avorn J. Under-reporting of cardio-
facturer, was similar to results of tee meeting, but the company vascular events in the rofecoxib Alzheimers
analyses conducted by both the didnt provide its findings in time disease studies. Am Heart J 2012. DOI:
company and the FDA, which for inclusion in those delibera- 10.1016/j.ahj.2012.05.002.
4. Graham DY, Jewell NP, Chan FKL. Rofe-
had not previously been made tions, and the committee deter- coxib and clinically significant upper and
public. The drug was effectively mined that there wasnt enough lower gastrointestinal events revisited based
removed from the market in late information to warrant withdraw- on documents from recent litigation. Am J
Med Sci 2011;342:356-64.
2010 (2010). ing the drug from the market. 5
5. Harris G. F.D.A. says Bayer failed to reveal
The latest development affect- However, when these articles and drug risk study. New York Times. September
ing our understanding of drug findings from a randomized trial 30, 2006.
DOI: 10.1056/NEJMp1206652
risks is the use of a computer- with similar results were pub- Copyright 2012 Massachusetts Medical Society.

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