Principles and Practice of Clinical Research

753 Pages·2012·14.201 MB·English

Chapter 1
A Historical Perspective on
Clinical Research
John I. Gallin
NationalInstitutesofHealthClinicalCenter,Bethesda,Maryland
Chapter Outline
TheEarliestClinicalResearch 1 NineteenthCentury 6
GreekandRomanInfluence 2 TwentiethCenturyandBeyond 12
MiddleAgesandRenaissance 2 Acknowledgment 13
SeventeenthCentury 3 SummaryQuestions 13
EighteenthCentury 4 References 13
If I have seen a little further it is by standing on the shoulders THE EARLIEST CLINICAL RESEARCH
ofgiants.
dSirIsaacNewton,1676 Medical practice and clinical research aregrounded in the
beginnings of civilization. Egyptian medicine was domi-
The successful translation of a basic or clinical obser- nantfromapproximately2850BCto525BC.TheEgyptian
vation into a new treatment of disease is rare in an inves- Imhotep,whosenamemeans“hewhogivescontentment,”
tigator’s professionallife, butwhenit occurs, thepersonal lived slightly after 3000 BC and was the first physician
thrill is exhilarating and the impact on society may be figure to rise out of antiquity.2 Imhotep was a known
substantial. The following historical highlights provide scribe, priest, architect, astronomer, and magician (medi-
a perspective of the continuum of the clinical research cineandmagicwereusedtogether);heperformedsurgery,
endeavor. These events also emphasize the contribution practiced some dentistry, extracted medicine from plants,
thatclinicalresearchhasmadetoadvancesinmedicineand and knew the position and function of the vital organs.
public health. Imhotep likely provided the first description of cancer in
In this chapter, and throughout the book, a broad defi- oneofhis48clinicalcasereports.Incase45,hereported,
nition of clinical research from the Association of Amer- “If you examine (a case) having bulging masses on (the
ican Medical Colleges Task Force on Clinical Research is breast) and you find that they have spread over his breast;
used.1 This taskforcedefined clinical research as ifyouplaceyourhandupon(the)breast(and)findthemto
“acomponentofmedicalandhealthresearchintended becool,therebeingnofeveratallthereinwhenyourhand
to produce knowledge essential for understanding human feelshim;theyhavenogranulations,containnofluid,give
disease, preventing and treating illness, and promoting rise to no liquid discharge, yet they feel protuberant to
health. Clinicalresearchembraces a continuum of studies your touch you say concerning him: ‘This is a case of
involving interaction with patients, diagnostic clinical bulging masses I have to contend with.’ Bulging tumors
materials or data, or populations, in any of these cate- of the breast mean the existence of swellings on the
gories: disease mechanisms; translational research: clin- breast, large, spreading, and hard; touching them is like
icalknowledge;detection;diagnosisandnaturalhistoryof touching a ball of wrappings, or they may be compared
disease;therapeuticinterventionsincludingclinicaltrials; with unripe hemat fruit, which is hard and cool to the
prevention and health promotion; behavioral research; touch.”3
health services research; epidemiology; and community- Evidence also shows that ancient Chinese medicine
based and managedcare-based research.” included clinical studies. For example, in 2737 BC, Shen
1
PrinciplesandPracticeofClinicalResearch.DOI:10.1016/B978-0-12-382167-6.00001-1
2012PublishedbyElsevierInc.
2 Principles andPracticeofClinicalResearch
Nung, the putative father of Chinese medicine, experi- and the patient suffers as if he has pus inside, only less severe
mented with poisons and classified medical plants,4 and I. and more protracted. One can recognize that it is not pus but
Yin(1176e1123BC),afamousprimeministeroftheShang water.ifyouputyourearagainstthechestyoucanhearitseethe
dynasty,describedtheextractionofmedicinesfromboiling insidelikesourwine.9
plants.5
Hippocratesalsodescribedtheimportanceofcleanlinessin
Documents from early Judeo-Christian and Eastern
the management ofwounds. Hewrote, “If water was used
civilizations provide examples of a scientific approach to
forirrigation,ithadtobeverypureorboiled,andthehands
medicine and the origin of clinical research. In the Old
andnails ofthe operator were tobe cleansed.”10
Testament, written from the 15th century BC to approxi-
Hippocrates used the Greek word for “crab,” karkinos,
mately the 4th century BC,6 a passage in the first chapter
to describe cancer. The tumor, with its clutch of swollen
of the Book of Daniel describes a comparative “protocol”
bloodvesselsaroundit,remindedHippocratesofacrabdug
of diet and health. Daniel described the preferred diet of
inthe sand with its legs spread ina circle.11
legumes and water made for healthier youths compared
Hippocrates’ teachings remained dominant and
with the king’srich foodand wine:
unchallenged until the time of Claudius Galen of Per-
ThenDanielsaidtothesteward. gamum (ca. 130e200 AD), the physician to the Roman
“Testyourservantsfortendays;letusbegivenvegetablestoeat Emperor Marcus Aurelius.12 Galen was one of the first
andwatertodrink.Thenletyourappearanceandtheappearance individuals to utilize animal studies to understand human
oftheyouthswhoeattheking’srichfoodbeobservedbyyou,and disease. By experimenting on animals, he was able to
accordingtowhatyouseedealwithyourservants. describe the effects of transection of the spinal cord at
So he harkened to them in this matter; and tested them for ten different levels. According to Galen, health and disease
days. reflected the balance of four humors (blood, phlegm,
At the end of ten days it was seen that they were better in black bile, and yellow bile), and veins contained blood
appearance and fatter in flesh than all the youths who ate the and the humors, together with some spirit.12 Inflamma-
king’srichfood.Sothestewardtookawaytheirrichfoodandthe tion, described by Galen as a red, hot, and painful
winetheyweretodrink,andgavethemvegetables.” distention, was attributed to excessive blood. Tubercles,
Daniel1:11e16 pustules, catarrh, and nodules of lymph, all cool, boggy
andwhite,wereattributedtoexcessesoflymph.Jaundice
The ancient Hindus excelled in early medicine, especially
was an overflow of yellow bile. Cancer was attributed to
insurgery.Sushruta,thefatherofIndiansurgery,residedin
black bile as was melancholia, the medieval term for
the court of the Gupta kings in about 600 BC and wrote
depression. Thus cancer and depression were closely
medical texts about surgery, the most famous being Sus-
intertwined.13
hruta Samhita, an encyclopedia of medical learning. In
addition,thereisevidenceofIndianhospitalsinCeylonin
437 BC and137 BC.7 MIDDLE AGES AND RENAISSANCE
In the Middle Ages, improvements in medicine became
GREEK AND ROMAN INFLUENCE evident,andtheinfrastructureforclinicalresearchbeganto
develop. Hospitals and nursing, with origins in the teach-
Although early examples of clinical research predate the
ings of Christ,14 became defined institutions (although the
Greeks,Hippocrates(460e370BC)isconsideredthefather
beginnings of hospitals can be traced to the ancient Bab-
of modern medicine, and he exhibited the strict discipline
yloniancustomofbringingthesickintothemarketplacefor
requiredof aclinical investigator.
consultation, and the Greeks and Romans had military
His emphasis on the art of clinical inspection, observa-
hospitals).
tion,anddocumentationestablishedthescienceofmedicine.
The Persian al-Razi (865e925) discovered the use of
In addition, as graduating physicians are reminded when
alcohol as an antiseptic and wrote the first treatise on
theytaketheHippocraticoath,heprovidedphysicianswith
pediatrics, as well as more than 180 books and articles.15
high moral standards. Hippocrates’ meticulous clinical
Persian scientists emphasized the importance of meth-
records were maintained in 42 case records.8 These case
odology, and Ibn al-Haytham (Alhazen) wrote his Book
studies describe, among other maladies, malarial fevers,
of Optics, for which he is regarded as the father of
diarrhea, dysentery, melancholia, mania, and pulmonary
optics.16 The surgical needle was invented and described
edemawithremarkableclinicalacumen.
by Abu al-Qasim al-Zahrawi in his Al-Tasrif in the year
Onpulmonary edema, hewrote the following:
1000.17 The Iraqi surgeon Ammar ibn Ali al-Mawsili
Water accumulates; the patient has fever and cough; the respi- invented the first injection syringe in the 9th century
rationisfast;thefeetbecomeedematous;thenailsappearcurved using a hollow glass tube and suction to extract and
Chapter | 1 AHistoricalPerspectiveonClinicalResearch 3
removecataractsfrompatients’eyes.18 Bythe1100sand SEVENTEENTH CENTURY
1200s, hospitals were being built in England, Scotland,
Studiesofbloodbeganinthe17thcentury.WilliamHarvey
France, and Germany.
(1578e1657) convincingly described the circulation of
Early progress in pharmacology can be linked to the
bloodfromtheheartthroughthelungsandbacktotheheart
Crusades and the development of commerce. Drug trade
and then into the arteries and back through the veins.24
became enormously profitable during the Middle Ages.
Harveyemphasizedthatthearteriesandveinscarriedonly
Drugs were recognized as the lightest, most compact, and
one substance, the blood, ending Galen’s proposal that
most lucrative of all cargoes. Records of the customhouse
at the port of Acre (1191e1291) show a lively traffic in veinscarriedablendofmultiplehumors.(Ofcourse,today
aloes,benzoin,camphor,nutmegs,andopium.19Influences weknowthatbloodcontainsmultiplecellularandhumoral
elements, so to some extent Galen was correct.) The
ofArabicpharmacyandcontactoftheCrusaderswiththeir
famous architect Sir Christopher Wren (1632e1723),
Muslim foes spread the knowledge of Arabic pharmaceu-
originally known as an astronomer and anatomist
ticalsandgreatlyenhancedthevalueofdrugsfromtheFar
East.ThePersianIbnSina-Avicenna(980e1037),aleader (Figure 1-3), in 1656 assembled quills and silver tubes as
cannulasandusedanimalbladderstoinjectopiumintothe
in pharmacy, philosophy, medicine, and pharmacology,
veinsofdogs.25 Thefirst well-documentedtransfusionsof
wrote The Canon of Medicine, which describes seven
blood into humans were done in 1667 by Richard Lower
conditions for “the recognition of the strengths of the
and Edmund King in London26 and were mentioned in
characteristics of medicines through experimentation”:
Pepys’diary.27
ensuringtheuseofpuredrugs,testingthedrugforonlyone
disease, use of control groups, use of dose escalation,
requirement of long-term observation, requirement of
reproducible results, and requirement of human over
animal testing.20
Documentation through case records is an essential
feature of clinical research. Pre-Renaissance medicine of
the 14th and 15th centuries saw the birth of “Consilia” or
medicalcasebooks,consistingofclinicalrecordsfromthe
practice of well-known physicians.21 Hippocrates’
approachofcasestudiesdeveloped1700yearsearlierwas
reborn,particularlyintheBologneseandPaduanregionsof
Italy.Universitiesbecameimportantplacesofmedicinein
Paris, Bologna, and Padua.
Clinical research remained mostly descriptive, resem-
bling today’s natural history and disease pathogenesis
protocols.In1348,GentiledaFoligno,aPaduanprofessor,
described gallstones.21 Bartolomeo Montagna (1470), an
anatomist, described strangulated hernia, operated on
lachrymal fistula, and extracted decayed teeth.21
TheRenaissance(1453e1600)representedtherevival
of learning and the transition from medieval to modern
conditions; many great clinicians and scientists pros-
pered.Atthistime,manyoftheancientGreekdictumsof
medicine, such as Galen’s four humors, were discarded.
Perhaps the most important anatomist of this period was
LeonardodaVinci(1453e1519)(Figure1-1).22DaVinci
created more than 750 detailed anatomic drawings
(Figure 1-2). In 1533, Andreas Vesalius, at age 19, was
beginning his incredible career as an anatomist. His
dissections and recordings of the human anatomy recor-
ded in detailed plates and drawings of patients with
cancer failed to note black bile in any cancer, regardless
of the organ involved, and provided the basis for dis-
FIGURE1-1 LeonardodaVinciself-portrait(redchalk);Turin,Royal
missing Galen’s theory of the role of black bile in
Library.(FromDaVinciL.CopyrightinItalybytheInstituteGeografic
cancer.23 DeAgostiniS.p.A.-Novara.NewYork:Reymal&Company;1956,Figure1.)
4 Principles andPracticeofClinicalResearch
FIGURE1-3 ChristopherWren’sdrawingofthebrainshowsblood
vesselsdiscoveredbyThomasWillis.(FromKnoeffR.Bookreviewof
SoulMadeFlash:DiscoveyoftheBrainandHowItchangedtheWorldby
C.Zimmer.Nature2004;427:585.)
FIGURE 1-2 Example of anatomic drawing by Leonardo da Vin-
ci.Trunk of female human body, with internal organs seen as though
ventralsideweretransparent.(FromDaVinciL.CopyrightinItalybythe
Institute Geografic DeAgostini S.p.A.-Novara. New York: Reymal &
Company;1956,p.369.)
The 17th century also brought the first vital statistics,
which were presented in Graunt’s book Natural and
Political Observations Mentioned in a Following Index,
and Made Upon the Bills of Mortality.28 In this book of
comparative statistics, population and mortality statistics
were compared for different countries, ages, and sexes in
rural and urban areas. Use of data on mortality among
groups would have major importance in future clinical
studies.
EIGHTEENTH CENTURY
The 18th century brought extraordinary advances in the
biological sciences and medicine. At the end of the 17th
century, Antony van Leeuwenhoek of Delft (1632e1723)
invented the microscope. Although he is best known for
using his microscope to provide the first descriptions of
protozoaandbacteria,Leeuwenhoekalsoprovidedthefirst
description of striated voluntary muscle, the crystalline
structure of the lens, red blood cells, and spermatozoa
(Figures 1-4and 1-5).29
FIGURE1-4 AntonyvanLeeuwenhoek.(FromDobellC.Antonyvan
Modern clinical trials can be recognized in the 1700s.
LeeuwenhoekandHisLittleAnimals.NewYork,Dover:ACollectionof
Scurvy was a major health problem for the British Navy.
WritingsbytheFatherofProtozoologyandBacteriology;1960[Original
William Harvey earlier had recommended lemons to treat workpublishedin1932.].)
Chapter | 1 AHistoricalPerspectiveonClinicalResearch 5
0*0
PHILOSOPHICAL
TRANSACTIONS.
For the Months of Jng*Ji and Stftemttr.
Stftemt. 21. 1674,
The CONTENTS.
llxnfatictl Qtftrtfttutt firna «#r. Leeuwcnboeck, «fotf
Blood, Milk, Bones, tkt Brain, Spitle, Coticula, Sweat,
Fact, Teares 5 ummtmutei t» t** Letttrs to the PaUfitr.
An AtuHit tf* ntttkU Ctfe if* Dropfy, mfoktn fir Grt-
vibtk* at+yt**g W*mt* ^ imftrttAh* Lttnttd Ptyfoi*
MI* Holland. jfa4tt*at,f three E»hr LDE SE-
CRET IQKE JN-IM.ALI Ctgtutt, 4»tb. Gall.
Co'e, At D. IF. Ertfmi BtrthiM SELECT A
GEO eX£ fR \CA. III. LOG ICJ, fat An
CritoUi; f * Gtllit* i» iMnnu* Strmutem vtrfc SUM
A*t*u&o*rfait *p* tke Latin Verfon, mult by C. S. of the
Pbil.TranUflions*/' J. 1665.1666.1667.
l OtftnnttoKfr** e^C Leeowrahoeck, u#tr»-
*7 Blood, Milk, Bones, /fc Bnio,SpitIe,36^ Cuticula,^.
MmmmtiUAk tkt JUt Obfervtr i» tin fMjbtr in *
Letttr, lUteljUK r. 1674,
Sir,
FIGURE1-6 JamesLind.
Y Ours of 14* of Mrit\a& was mywelcome to roe j
Wheocelnnd«ftoodwitfj great cooteotfneot, that my
Microfcopical Cooxnookatiom badnot been nnaocepoble co
The 18th century saw great progress in the area of
yoaaod yoor Philofophkal Frkndr; wUcb hath encouraged
R ** surgery. A remarkable succession of teachers and their
studentsledthesestudies.PercivalPottofSt.Bartholomew’s
FIGURE1-5 TitlepagefromLeeuwenhoek’spaper,“Microscopical
Hospital described tuberculosis of the spine, or Pott’s
Observations.”(FromDobellC.AntonyvanLeeuwenhoekandHisLittle
Animals. New York, Dover: A Collection of Writings by the Father of disease.31 John Hunter, Pott’s pupil, was the founder of
ProtozoologyandBacteriology;1960[Originalworkpublishedin1932.].) experimental and surgical pathology and was a pioneer in
comparative physiology and experimental morphology.
Hunter described shock, phlebitis, pyremia, and intussus-
scurvybutarguedthatthetherapeuticeffectwasaresultof ception and reported major findings of inflammation,
the acid in the fruit. James Lind (Figure 1-6), a native of
Scotland and a Royal Navy surgeon, conducted a clinical
trial in 1747 to assess this hypothesis by comparing three
therapies for scurvy (Table 1-1).30 Twelve sailors with TABLE1-1 TreatmentofScurvybyJamesLind
classicscurvyweredividedintosixgroupsoftwoeach,all
Treatmentarm Cured pValuea
givenidenticaldiets;thevariousgroupsweresupplemented
with vinegar, dilute sulfuric acid, cider, seawater, and Sulfuricacid 0/2 >0.05
a nutmeg, garlic, and horseradish mixture, along with two
Vinegar 0/2 >0.05
oranges andone lemon daily.
Sulfuric acid, vinegar, seawater, cider, and the physi- Seawater 0/2 >0.05
cian’s remedy had no benefit. Two sailors receiving citrus Cider 0/2 >0.05
fruit avoided scurvy. Although not significant because of
Physicians 0/2 >0.05
sample size, this early clinical study formed the basis for
successful avoidance of scurvy with citrus fruit. Studies Citrusfruit 2/2 >0.05
with sulfuric acid, vinegar, and cider excluded acid as aComparedtopatientsinthefiveareasofthetrial;noplacebogroup.
alikelyexplanationforthebeneficialeffectofcitrusfruit.
6 Principles andPracticeofClinicalResearch
gunshot wounds, and surgical diseases of the vascular seesthreeorfourmildcasesbutnevertwothatareserious
system.31 Hunter’s student Edward Jenner (1749e1823)31 and dangerous; that in a word one never truly has that
introduced vaccination as a tool to prevent infectious illness twice in life.”36 Thus, Voltaire recognized natural
diseases (Figure 1-7).32 Jenner was aware that dairymaids immunitytosmallpox,whichwasanimportantconceptfor
who had contracted cowpox through milking did not get future vaccinology. In 1721, Cotton Mather demonstrated
smallpox. In 1798, Jenner conceived of applying this thatvariolationprotectedcitizensoftheAmericancolonies
observationonagrandscaletopreventsmallpox.33 inMassachusetts,37and,in1777,GeorgeWashingtonused
Jenner was not the first to conceive of the idea of variolation against smallpox to inoculate the Continental
inoculation for smallpox. For example, the Chinese had Armydthe first massive immunization of a military
thoughtofthisearlier,andSirHansSloanehaddonesmall group.38 Jenner was the first to try vaccination on a large
studies in 1717 using variolation (inoculating healthy scale using scabs from cowpox to protect against human
people with pus from blisters obtained from patients with smallpox andwasthefirsttouseexperimentalapproaches
smallpox).34 In addition, James Jurin published several to establish the scientific basis for vaccination. Jenner
articles between 1723 and 1727 comparing death from transformed a local country tradition into a viable
naturalsmallpoxinpeoplewhohadnotbeeninoculatedvs. prophylactic principle. Jenner’s vaccine was adopted
those who had been inoculated. Jurin showed that death quicklyinGermanyandtheninHolland,Denmark,therest
occurredinfiveofsixsubjectsinthefirstgroupcompared ofEurope, andthe United States.
with one in 60 in the latter,35 providing one of the first The 1700s were also the time when the first known
studies using mortality as a critical clinical end point. In blinded clinical studies were performed. In 1784
1734, Voltaire wrote, “The Cirassians [a Middle Eastern acommissionofinquirywasappointedbyKingLouisXVI
people] perceived that of a thousand persons hardly one of France to investigate medical claims of “animal
wasattackedtwicebyfullblownsmallpox;thatintruthone magnetism”or“mesmerism.”Thecommission,headedby
Benjamin Franklin and consisting of such distinguished
members as Antoine Lavoisier, Jean-Sylvain Bailly, and
Joseph-Ignace Guillotin, had as a goal to assess whether
reported effects of this new healing method were due to
“real” force or to “illness of the mind.” Among the many
tests performed, blindfolded people were told that they
were either receiving or not receiving magnetism when in
fact, at times, the reverse was happening. Results showed
thatstudysubjectsfelteffectsofmagnetismonlywhenthey
were told thattheyreceivedmagnetism andfelt no effects
when they were not told this, whether or not they were
receivingtreatment.39Thiswasthebeginningoftheuseof
blinded studies inclinical research.
The 18th century provided the first legal example that
physicians must obtain informed consent from patients
before performing a procedure. In an English lawsuit,
Slater vs. Baker & Stapleton, two surgeons were found
liable for disuniting a partially healed fracturewithout the
patient’s consent.40 This case set an important precedent
described by the court: “Indeed it is reasonable that
apatientshouldbetoldwhatisabouttobedonetohimthat
hemaytakecourageandputhimselfinsuchasituationas
toenable him toundergothe operation.”
NINETEENTH CENTURY
Inthefirstdaysofthe19thcentury,BenjaminWaterhouse,
aHarvardprofessorofmedicine,broughtJenner’svaccine
totheUnitedStates,andby1802thefirstvaccineinstitute
FIGURE 1-7 Edward Jenner (painting by Sir Thomas Lawrence).
wasestablishedbyJamesSmithinBaltimore,Maryland.In
(FromGarrisonFH.HistoryofMedicine.Philadelphia:Saunders;1917.
Reprinted1963.) 1813 this led to the establishment of a national vaccine
Chapter | 1 AHistoricalPerspectiveonClinicalResearch 7
agency by the Congress of the United States under the childbed shouldneverbe attended by physicians who have
direction of James Smith.41 beenconductingpostmortemsectionsoncasesofpuerperal
Jenner’s vaccination for smallpox was followed by fever;thatthediseasemaybeconveyedinthismannerfrom
other historic studies in the pathogenesis of infectious patient to patient, even from a case of erysipelas; and that
diseases. In the mid-1800s, John Snow (1813e1858), an washing the hands in calcium chloride and changing the
anesthesiologist by training, performed the classic studies clothesafterleavingapuerperalfevercasewaslikelytobe
that determined how cholera was spread in contaminated a preventive measure. Holmes’ essay stirred up violent
water. Snow’s studies, which included the first use of opposition by obstetricians. However, he continued to reit-
statistical mapping, identified contaminated water as the erate his views, and in 1855 in a monograph, Puerperal
source of cholera. For his work, John Snow is widely Fever as a Private Pestilence, Holmes noted that
considered tobe the father of modern epidemiology.42 Semmelweis,workinginViennaandBudapest,hadlessened
The French physician Pierre Charles Alexandre Louis the mortality of puerperal fever by disinfecting the hands
(1787e1872) realized that clinical observations on large withchlorideoflimeandthenailbrush.45
numbers of patients were essential for meaningful clinical IgnazPhilippSemmelweis(1818e1865)performedthe
research.Hepublishedclassicalstudiesontyphoidfeverand most sophisticated preventive clinical trial of the 19th
tuberculosis, and his research in 1835 on the effects of century,whichestablishedtheimportanceofhandwashing
bloodlettingdemonstratedthatthe benefitsclaimedfor this to prevent the spread of infection (Figure 1-9).46
popular mode of treatment were unsubstantiated.43 On Semmelweis,aHungarianpupil,becameanassistantinthe
February 13, 1843, one of Louis’students, Oliver Wendell first obstetric ward of the Allgemeines Krankenhaus in
Holmes (1809e1894), the father of the great Justice Viennain1846.Semmelweiswastroubledbythedeathrate
Holmes, read his article, “On the Contagiousness of
Puerperal Fever,”44 to the Boston Society for Medical
Improvement (Figure 1-8). Holmes stated that women in
FIGURE1-8 OliverWendellHolmes.(FromGarrisonFH.Historyof FIGURE1-9 IgnazPhilippSemmelweis.(FromGarrisonFH.History
Medicine.Philadelphia:Saunders;1917.Reprinted1963,p.435) ofMedicine.Philadelphia,Saunders,1917,Reprinted1963,p.436.)
8 Principles andPracticeofClinicalResearch
associated with puerperal or “childbed” fever. From 1841 nineteenthcenturythatwerecriticalinthedevelopmentof
to 1846, the maternal death rate from puerperal sepsis modernsurgery.In1865,aScottishsurgeonnamedJoseph
averaged approximately 10%, and in some periods was as Lister recognized the importance of keeping surgical
highas50%,intheFirstMaternityDivisionoftheVienna wounds clean and wrote “.that the decomposition in the
GeneralHospital.Incontrast,theratewasonly2or3%in injured part might be avoided.by applying as a dressing
the Second Division, which was attended by midwives somematerialcapableofdestroyingthelifeofthefloating
rather than physicians. The public knew the disparity, and particles.” Based on the observation that carbolic acid
women feared being assigned to the First Division. cleansedrawstorage,Listerbegantoapplycarbolicacidto
Semmelweis became frustrated by thismystery and began wounds with great success, establishing the importance of
to study cadavers offevervictims. In 1847, his friend and antisepsisin the operating room.48
fellow physician Jakob Kolletschka died after receiving The work of Holmes and Semmelweis on the impor-
a small cut on the finger during an autopsy. The risk of tanceofhandwashingopenedthedoorforPasteur’swork
minor cuts during autopsies was well known, but on the germ basis of infectious diseases. Louis Pasteur
Semmelweis made the further observation that Kolletsch- (1822e1895) was perhaps the most outstanding clinical
ka’sdeathwascharacteristicofdeathfrompuerperalfever. investigator of the 19th century (Figure 1-10). He was
He reasoned that puerperal fever was “caused by convey- trained in chemistry. His fundamental work in chemistry
ance to the pregnant women of putrid particles derived led to the discovery of levo and dextro isomers. He then
from living organisms, through the agency of the exam- studied the ferments of microorganisms, which eventually
ining fingers.” In particular, he identified cadaveric matter led him to study the detrimental causes of three major
from the autopsy room, with which midwives had no
contact,as the source ofthe infection.
In 1847 Semmelweis insisted that all students and
physiciansscrubtheirhandswithchlorinatedlimebefore
entering the maternity ward, and during 1848, the
mortality rate on his division dropped from 9.92% to
1.27%. Despite his convincing data, colleagues rejected
Semmelweis’ findings and accused him of insubordina-
tion. The dominant medical thinking at the timewas that
high mortality in the charity hospital was related to the
poor health of impoverished women, despite the differ-
ences between control (no chlorinated lime hand
washing) and experimental (washing with chlorinated
lime) divisions. Without any opportunity for advance-
ment in Vienna, Semmelweis returned to his home in
Budapest and repeated his studies with the same results.
In 1861, he finally published The Etiology, Concept, and
Prophylaxis of Childhood Fever.46 Although Holmes’
workantedatedSemmelweisbyfiveyears,thesuperiority
of Semmelweis’ observation lies not only in his experi-
mental data but also in his recognition that puerperal
feverwasabloodpoisoning.TheobservationsofHolmes
and Semmelweis represent a critical step for medicine
and surgery.
In addition to the discovery of the importance of hand
washing,thefirstwell-documenteduseofetherforsurgery
(1846) by William Thomas Green Morton, a Boston
dentist,withDr.JohnCollinsWarrenasthesurgeonatthe
Massachusetts General Hospital, occurred during the 19th
FIGURE1-10 LouisPasteur. OneoftheremarkablefactsaboutPasteur
century.47 The discovery of anesthesia led to the dissocia- was his triumph over a greatphysicalhandicap. In1868at age 46, just
tion of pain from surgery, allowing surgeons to perform after completing his studies on wine, he had a cerebral hemorrhage.
prolonged operations. Oliver Wendell Holmes is credited Althoughhismindwasnotaffected,hewasleftwithpartialparalysisofhis
with proposing the words anesthetic and anesthesia.47 leftside, which persisted for theremainderofhis life. Thisphotograph,
takenafterhewasawardedtheGrandCrossoftheLegionofHonorin1881,
Recognition of the importance of hand washing and the
givesnohintofhisinfirmity.(FromHaagensenCD,LloydEB.AHundred
discovery of anesthetics were essential findings of the YearsofMedicine.NewYork:SheridanHouse;1943,p.116)
Chapter | 1 AHistoricalPerspectiveonClinicalResearch 9
industries in France: wine, silk, and wool. Pasteur discov- anthrax, which was later used by Pasteur to develop
eredthegermbasisoffermentation,whichformedthebasis a vaccine, and he established Koch’s postulates to prove
of the germ theory of disease.49 He discovered Staphylo- that an infectiousagent causesdisease (Figure 1-11).49
coccus pyogenes as a cause of boils and the role of Strep- ThestudiesofPasteurandKochwereperformedduring
tococcus pyogenes in puerperal septicemia. In other the same period as the work of the Norwegian Gerhard
studies, he carried forward Jenner’s work on vaccination Armauer Hansen (1841e1912). In 1874, based on epide-
and developed approaches to vaccine development using miologic studies in Norway, Hansen concluded that
attenuation of a virus for hydrophobia (rabies) and inacti- Mycobacteriumlepraewasthemicroorganismresponsible
vation ofa bacterium for anthrax. for leprosy. Hansen’s claim was not well received, and in
Thework ofPasteur was complemented by the studies 1880, in an attempt to prove his point, he inoculated live
ofRobertKoch(1843e1910),whomadecriticaltechnical leprosy bacilli intohumans,includingnursesand patients,
advancesinbacteriology.Kochwasthefirsttouseagaras without first obtaining permission. One of the patients
a culture medium, and he introduced the Petri dish, pour brought legal action against Hansen. The court, in one of
plates, and blood agar to make bacterial culture and iden- the early cases demonstrating the importance of informed
tification easy and widely available. Koch cultured the consent in clinical research, removed Hansen from his
tubercle bacillus and identified the causative agent for position as director of Leprosarium No. 1, where the
experimentshadtakenplace.However,Hansenretainedhis
position as chief medical officer for leprosy50 and later in
his life received worldwide recognition for his life’s work
on leprosy.
In the same era, Emil von Behring (1854e1917)
demonstrated in 1890 that inoculation with attenuated
diphtheria toxins in one animal resulted in production of
FIGURE 1-11 Robert Koch. His career in research began in 1872,
whenhiswifegavehimamicroscopeasabirthdaypresent.Hewasthen28
yearsold,performinggeneralpracticeinasmalltowninSilesia.Thiswas
anagriculturalregionwhereanthraxwascommonamongsheepandcattle,
anditwasinthemicroscopicstudyofthisdiseaseinrabbitsthatKoch FIGURE1-12 EmilvonBehring.(FromHirschJG.Hostresistanceto
made his first great discovery of the role of anthrax bacilli in disease. infectious diseases: a centennial. In: Gallin JI, Fauci AS, editors.
(FromHaagensenCD,LloydEB.AHundredYearsofMedicine.NewYork: Advances in Host Defense Mechanisms: Vol. 1. Phagocytic Cells. New
SheridanHouse;1943,p.132) York:RavenPress;1982,p.7)
10 Principles andPracticeofClinicalResearch
a therapeutic serum factor (antitoxin) that could be deliv-
ered to another, thus discovering antibodies and establish-
ing a role for passiveimmunization. On Christmas Eve of
1891,thefirstsuccessfulclinicaluseofdiphtheriaantitoxin
occurred.49 By 1894, diphtheria antiserum became
commercially available as a result of Paul Ehrlich’s work
establishing methods of producing high-titer antisera.
Behring’s discovery of antitoxin was the beginning of
humoral immunity, and in 1901 Behring received the first
NobelPrize.KochreceivedthePrizein1905(Figure1-12).
The Russian scientist Elie Metchnikoff (1845e1916)
discoveredtheimportanceofphagocytosisinhostdefense
againstinfectionandemphasizedtheimportanceofcellular
components of host defense against infection.51 Paul
Ehrlich (1854e1915) discovered the complement system
andassertedtheimportanceofthehumoralcomponentsof
hostdefense.In1908,MetchnikoffandEhrlichsharedthe
Nobel Prize (Figures1-13 and1-14).
At the end of the 19th century, studies of yellow fever
increased awareness of the importance of the informed
consent process in clinical research. In 1897, Italian bacte-
riologist GiuseppeSanarelli announced that hehad discov-
eredthebacillusforyellowfeverbyinjectingtheorganism
into five people. William Osler was present at an 1898 FIGURE 1-14 Paul Ehrlich. (From Hirsch JG. Host resistance to
infectious diseases: a centennial. In: Gallin JI, Fauci AS, editors.
Advances in Host Defense Mechanisms: Vol. 1. Phagocytic Cells. New
York:RavenPress,1982,p.9.)
FIGURE1-13 ElieMetchnikoffinhis40s.(FromTauberAI,Chernyak
L. Metchnikoff and the Origins of Immunology. New York: Oxford
UniversityPress;1991,Figure5.) FIGURE1-15a WilhelmConradRo¨ntgen.