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theFuture
ofScience
andEthics
Rivista scientifica a cura del Comitato Etico
della Fondazione Umberto Veronesi
Volume 6 ■ 2021 ■ ISSN 2421-3039theFuture ofScience andEthics
theFuture
ofScience
andEthics
Rivista scientifica
del Comitato Etico
della Fondazione Umberto Veronesi
ISSN 2421-3039
ethics.journal@fondazioneveronesi.it
Via Solferino, 19
20121, Milano
Comitato di direzione and Political Science, UK); Gilda
Ferrando (Università degli Studi di
Direttore Genova); Giuseppe Ferraro (Univer-
Marco Annoni (Consiglio Nazionale sità degli Studi di Napoli Federico
delle Ricerche-CNR e Fondazione II); Giovanni Maria Flick (Presidente
Umberto Veronesi) emerito della Corte costituzionale);
Nicole Foeger (Austrian Agency for
Condirettori Research Integrity-OeAWI, Vienna,
Cinzia Caporale (Consiglio Naziona- e Presidente European Network for
le delle Ricerche-CNR) Research Integrity Offices – ENRIO);
Carlo Alberto Redi (Università degli Tommaso Edoardo Frosini (Universi-
Studi di Pavia, Accademia dei Lincei) tà degli Studi Suor Orsola Beninca-
Silvia Veronesi (Fondazione Umber- sa, Napoli); Filippo Giordano (Libera
to Veronesi) Università Maria Ss. Assunta-LUM-
SA, Roma); Giorgio Giovannetti (Rai
Direttore responsabile − Radiotelevisione Italiana S.p.A.);
Donatella Barus (Fondazione Um- Vittorio Andrea Guardamagna (Isti-
berto Veronesi) tuto Europeo di Oncologia-IEO);
Antonio Gullo (Università degli Studi
di Messina); Henk ten Have (Duque-
Comitato Scientifico sne University, Pittsburgh, PA, USA);
Roberto Andorno (University of Zuri- Massimo Inguscio (Università Cam-
ch, CH); Vittorino Andreoli (Psichiatra pus Bio-Medico di Roma); Giuseppe
e scrittore); Elisabetta Belloni (Diret- Ippolito (Direttore scientifico IRCCS
tore generale del Dipartimento delle Istituto Nazionale per le Malattie In-
informazioni per la sicurezza); Mas- fettive Lazzaro Spallanzani, Roma);
simo Cacciari (Università Vita-Salute Michèle Leduc (Direttore Institut fran-
San Raffaele, Milano); Stefano Ca- cilien de recherche sur les atomes
nestrari (Università di Bologna); Car- froids-IFRAF e Presidente Comité
lo Casonato (Università degli Studi di d'éthique du CNRS, Parigi); Seba-
Trento); Roberto Cingolani (Ministro stiano Maffettone (LUISS Guido Car-
della Transizione Ecologica); Carla li, Roma); Luciano Maiani (Sapienza
Collicelli (Consiglio Nazionale delle Università di Roma); Elena Mancini
Ricerche-CNR); Gherardo Colom- (Consiglio Nazionale delle Ricer-
Volume 6 ■ 2021
bo (già Magistrato della Repubblica che-CNR); Vito Mancuso (Teologo e
italiana, Presidente Casa Editrice scrittore); Alberto Martinelli (Univer-
Garzanti, Milano); Giancarlo Comi sità degli Studi di Milano); Armando
(Direttore scientifico Istituto di Neu- Massarenti (ilSole24Ore); Roberto
rologia Sperimentale, IRCCS Ospe- Mordacci (Università Vita-Salute San
dale San Raffale, Milano); Gilberto Raffaele, Milano); Paola Muti (Eme-
Corbellini (Sapienza Università di rito, McMaster University, Hamilton,
Roma); Lorenzo d'Avack (Università Canada); Ilja Richard Pavone (Con-
theFuture degli Studi Roma Tre); Giacinto del- siglio Nazionale delle Ricerche-C-
ofScience la Cananea (Università degli Studi NR); Renzo Piano (Senatore a vita);
andEthics di Roma Tor Vergata); Sergio Della Alberto Piazza (Emerito, Università
Sala (The University of Edinburgh, degli Studi di Torino); Riccardo Pie-
UK); Andrea Fagiolini (Università trabissa (IUSS Pavia); Tullio Pozzan
4 degli Studi di Siena); Daniele Fa- (Università degli Studi di Padova);
nelli (London School of Economics Francesco Profumo (Politecnico diTorino); Giovanni Rezza (Direttore berto Defez (Responsabile del labo-
Generale della Prevenzione sanita- ratorio di biotecnologie microbiche,
ria presso il Ministero della Salute); Istituto di Bioscienze e Biorisorse del
Gianni Riotta (Princeton Universi- CNR di Napoli); Domenico De Masi
ty, NJ, USA); Carla Ida Ripamonti (Sociologo e Professore emerito di
(Fondazione IRCCS Istituto Nazio- Sociologia del lavoro, Sapienza Uni-
nale dei Tumori-INT, Milano); Mar- versità di Roma); Giorgio Macellari
celo Sánchez Sorondo (Cancelliere (Chirurgo Senologo Docente di Bio-
Pontificia Accademia delle Scienze); etica, Scuola di Specializzazione in
Angela Santoni (Sapienza Università Chirurgia di Parma); Telmo Pievani
di Roma); Pasqualino Santori (Presi- (Professore di Filosofia delle Scienze
dente Comitato di Bioetica per la Ve- Biologiche, Università degli Studi di
terinaria e l'Agroalimentare CBV-A, Padova); Giuseppe Remuzzi (Diret-
Roma); Paola Severino Di Bene- tore dell'Istituto di Ricerche Farma-
detto (Vicepresidente LUISS Guido cologiche Mario Negri IRCCS); Luigi
Carli, Roma); Elisabetta Sirgiovanni Ripamonti (Medico e Responsabile
(Sapienza Università di Roma); Gui- Corriere Salute, Corriere della Sera);
do Tabellini (Università Commerciale Alfonso Maria Rossi Brigante (Presi-
Luigi Bocconi, Milano); Chiara Tonelli dente Onorario della Corte dei Conti)
(Università degli Studi di Milano);
Elena Tremoli (Università degli Studi Comitato editoriale
di Milano e Direttore scientifico IRC-
CS Centro Cardiologico Monzino, Caporedattore
Milano); Riccardo Viale (Università Roberta Martina Zagarella (Consiglio
Milano Bicocca e Herbert Simon So- Nazionale delle Ricerche-CNR)
ciety); Luigi Zecca (Consiglio Nazio-
nale delle Ricerche-CNR) Redazione
Giorgia Adamo (Consiglio Nazionale
Sono componenti di diritto del delle Ricerche-CNR); Marco Arizza
Comitato Scientifico della rivista (Consiglio Nazionale delle Ricer-
i componenti del Comitato Etico che-CNR); Rosa Barotsi (Università
della Fondazione Umberto Vero- Cattolica del Sacro Cuore); Fede-
nesi: Carlo Alberto Redi, Presidente rico Boem (University of Twente);
(Professore di Zoologia e Biologia Andrea Grignolio Corsini (Consiglio
Volume 6 ■ 2021
della Sviluppo, Università degli Stu- Nazionale delle Ricerche-CNR);
di di Pavia); Giuseppe Testa, Vice- Chiara Mannelli (Columbia Universi-
presidente (Professore di Biologia ty, NY, USA e Università di Torino);
Molecolare, Università degli Studi di Paolo Maugeri (Campus IFOM-IEO);
Milano e Human Technopole); Giulia- Clio Nicastro (ICI Berlin Institute for
no Amato, Presidente Onorario (Giu- Cultural Inquiry); Annamaria Parola
dice Costituzionale, già Presidente (Fondazione Umberto Veronesi); El-
del Consiglio dei ministri); Cinzia vira Passaro (Università degli Studi
Caporale, Presidente Onorario (Co- dell'Insubria); Maria Grazia Ros- theFuture
ordinatore del Centro Interdiparti- si (Universidade Nova de Lisboa); ofScience
mentale per l'Etica e l'Integrità nella
Ricerca del CNR); Guido Bosticco
Chiara Segré (Fondazione Umberto
Veronesi); Virginia Sanchini (Univer-
andEthics
(Giornalista e Professore presso il sità degli Studi di Milano)
Dipartimento degli Studi Umanistici,
Università degli Studi di Pavia); Ro- Progetto grafico: Gloria Pedotti
5Volume 6 ■ 2021
theFuture
ofScience
andEthics
6Volume 6 ■ 2021
RECENSIONI
SOMMARIO
Consulta Scientifica del Cortile dei Gentili
PANDEMIA E GENERATIVITÀ. BAMBINI E
ADOLESCENTI AI TEMPI DEL COVID
di Mons. Carlo Maria Polvani 134
Anna Maria Bruzzone
CI CHIAMAVANO MATTI.
ARTICOLI VOCI DAL MANICOMIO (1968-1977)
di Anna Poma 138
• IL 'GREEN PASS' ALLA LUCE DELL'ARTICOLO 32
DELLA COSTITUZIONE: ALCUNE BREVI
Maya J. Goldenberg
CONSIDERAZIONI
VACCINE HESITANCY: PUBLIC TRUST,
di Federico Gustavo Pizzetti 10
EXPERTISE, AND THE WAR ON SCIENCE
di Teresa Gavaruzzi e Alessandra Tasso 142
• ANTROPOCENE, PANDEMIA, GIUSTIZIA
INTERGENERAZIONALE: L'ETICA PUBBLICA AL
CROCEVIA FRA INCLUSIONE ED ESCLUSIONE DEL Antonella Ficorilli
FUTURO NUOVI TERRITORI PER L'ETICA NELLA
di Ferdinando G. Menga 22 RICERCA SCIENTIFICA
di Matteo Galletti 146
• LA VITA UMANA COME BENE DISPONIBILE
di Giorgio Macellari 32 Agnese Collino
LA MALATTIA DA 10 CENTESIMI. STORIA
• GEOETICA: UN'ETICA PER LA RELAZIONE DELLA POLIO E DI COME HA CAMBIATO
TRA GLI ESSERI UMANI E LA TERRA LA NOSTRA SOCIETÀ
di Silvia Peppoloni e Giuseppe Di Capua 42 di Donatella Barus 150
• WHY DO WE NEED RANDOMIZED CONTROLLED Armando Massarenti e Antonietta Mira
TRIALS? MEDICAL SCANDALS AND THE LA PANDEMIA DEI DATI. ECCO IL VACCINO
EVOLUTION OF DRUG REGULATION di Cinzia Caporale 152
di Mattia Andreoletti 54
Laura Pepe
• MICROETHICS FOR HEALTHCARE DATA SCIENCE: LA VOCE DELLE SIRENE. I GRECI E L'ARTE
ATTENTION TO CAPABILITIES IN SOCIOTECHNICAL DELLA PERSUASIONE
SYSTEMS di Mauro Serra 156
di Mark Graves e Emanuele Ratti 64
Alessandro Bilotta e Dario Grillotti
• LA BIOETICA COME PROFESSIONE E L'EXPERTISE LA FUNZIONE DEL MONDO.
IN MATERIA BIOETICA: RIFLESSIONI PEDAGOGICHE
SULLO SVILUPPO DI UN CURRICULUM DI MASTER UNA STORIA DI VITO VOLTERRA
DI SECONDO LIVELLO IN BIOETICA E SCIENZE di Sandra Lucente 160
SOCIALI IN AMBITO ANGLOSASSONE
di Silvia Camporesi 74 Sara Garofalo
SBAGLIANDO NON SI IMPARA. PERCHÉ
FACCIAMO SEMPRE LE SCELTE SBAGLIATE
IN AMORE, SUL LAVORO E NELLA VITA
QUOTIDIANA
DOCUMENTI DI ETICA E BIOETICA di Andrea Grignolio Corsini 164
• LA FIGURA DELL'ESPERTO IN BIOETICA
Comitato Nazionale per la Bioetica86
Commenti di NORME EDITORIALI 168
• Marianna Gensabella e Lucio Romano 94
• Demetrio Neri 98 CODICE ETICO 169
• IL TEMPO DELLA RICERCA. COMPRENDERE LA I COMPITI DEL COMITATO ETICO
SCIENZA PER SUPERARE L'EMERGENZA COVID-19 DELLA FONDAZIONE VERONESI 172
Comitato Etico Fondazione Umberto Veronesi 102
Commenti di
theFuture
• Raffaella Campaner e Marina Lalatta Costerbosa 112
• Federica Russo 116
ofScience
• Daniele Fanelli 120
• Gianluca Attademo 124
• SCIENCE FOR PEACE 2021:
IL DIRITTO E IL DOVERE DI VACCINARSI 128
andEthicsArticoli Why do we need randomized controlled trials? Medical scandals and the evolution of drug regulation Perché abbiamo bisogno degli studi randomizzati e controllati? Scandali medici e l'evoluzione della regolamentazione farmaceutica MATTIA ANDREOLETTI mattia.andreoletti@gmail.com AFFILIAZIONE Università Vita-Salute San Raffaele
Why do we need
SOMMARIO ABSTRACT randomized
controlled trials?
Perché abbiamo bisogno degli Why do we need Randomized
studi randomizzati e controllati Controlled Trials (RCTs)? So
(RCT)? Finora, le risposte a que- far, the answers to this question Articoli
sta domanda si sono concentrate have mostly focused on the vir-
principalmente sulle loro virtù met- tues of the methodological design.
dologiche. In breve, abbiamo biso- Roughly, we need RCTs because
gno degli RCT perché questi sono they are the best way to assess
il modo migliore per valutare la drugs safety and efficacy. But this
sicurezza e l'efficacia dei farmaci. answer is just partially satisfactory
Ma questa risposta è solo parzial- since it does not explain why, in the
mente soddisfacente, non spiega first place, we want to test drugs
infatti perché mai vogliamo testa- before they can be marketed, and
re i farmaci prima che possano why we want to do it in such a rig-
essere commercializzati e perché orous way. Here I clarify that the
vogliamo farlo in modo così rigo- reasons that brought about the
roso. In questo articolo analizzo le emergence of RCTs as the 'gold
ragioni che hanno portato gli RCT standard' of clinical research are
a diventare il 'gold standard' della the outcome of the interaction of
ricerca clinica. Tali ragioni sono il historical, organizational, and, ul-
risultato dell'interazione di preoc- timately, socio-political concerns.
cupazioni storiche, organizzative Focusing on the history of drug
e socio-politiche. Concentrando- regulation in the United States, I
mi sulla storia della regolamenta- argue that changes and reforms
zione dei farmaci negli Stati Uniti, were implemented in response to
sostengo che i cambiamenti e le major pharmaceutical scandals,
riforme sono stati attuati in rispo- and not only in response to the
sta a grandi scandali farmaceuti- real epistemic needs put in place
ci, e non solo in risposta alle reali by developments in drug research.
esigenze epistemiche emerse con More specifically, I show that scan-
gli sviluppi della ricerca farmaceu- dals played a crucial role in trigger-
tica. Nello specifico, mostro che gli ing reforms in drug regulation, and
scandali hanno giocato un ruolo hence in shaping the methodology
cruciale nell'innescare una serie of contemporary clinical research.
di riforme della regolamentazione
dei farmaci, e quindi nel plasmare
la metodologia della ricerca clinica
contemporanea.
KEYWORDS
PAROLE CHIAVE
Medicine
Medicina
Clinical trials
Studi clinici
Drug regulation
Regolamentazione dei farmaci
Pharmacology
Farmacologia
Scandals
Scandali
Volume 6 ■ 2021
theFuture
ofScience
andEthics
DOI: 10.53267/20210105
55Why do we need 1. INTRODUCTION debates on the adoption of new reg-
randomized ulatory standards. As the historian
controlled trials? Nowadays the medical-scientific of medicine, Marcia Meldrum put it:
community agrees that a Random- «the RCT is a dynamic methodol-
ized Control Trials (RCT) is the best ogy, and its present and future are
Articoli research design to evaluate the effi- informed by its history» (Meldrum,
cacy of medical treatments in a spe- 2000).
cific population. Conventionally, the
term 'treatment' refers to many kinds Historically, the link between scan-
of interventions: diagnostic, screen- dals and policies in Western democ-
ing, health education, etc. However, racies is nothing new: many sociol-
RCTs are systematically and exten- ogists and political scientists have
sively adopted in drug research and discussed it for decades (Butler &
testing, as they are the last phase Drakeford, 2003; Thompson, 2000)1.
of a mandatory threefold process, In general, a scandal is defined as
which is strictly regulated by trans- an event, often regarded as moral-
national laws. Of course, RCTs did ly wrong, which causes public out-
not come out of the blue, nor did the rage. While it is clear that scandals
rules that had made them compulso- play a crucial role in the general po-
ry. In this article, I dig into the histo- litical scenario, it is quite uncharted
ry of randomized controlled trials to whether these events could have an
bring out and make clear the reasons impact in other fields, such as clini-
why they became the gold standard cal research. In what follows, I show
for drug testing and regulation. More that scandals played a crucial role in
specifically, I argue that pharmaceu- triggering reforms in drug regulation,
tical scandals played a crucial role in and hence in shaping the methodolo-
the development of drug regulations, gy of contemporary clinical research.
forcing regulators to acknowledge
the weak points of previous stan- 2. THE GREAT AMERICAN FRAUD
dards and to consider more robust
alternatives, ranging from laboratory In the last decades of the nineteenth
tests to RCTs. The historical inves- century, laboratory science had a
tigation of the evolution of method- great boost thanks to the develop-
ological concepts is instrumental to ment of many basic research fields
warrant our claim (Schickore, 2011). such as chemistry, physiology, and
Why do we need RCTs? So far, the microbiology. These scientific ad-
answers to this question have mostly vancements ended up in what his-
focused on the virtues of this meth- torian of medicine Charles Rosen-
odological design. Roughly, we need berg (Rosenberg, 1997) has called
RCTs because they are the best way a 'therapeutic revolution', that is, the
to assess drugs safety and efficacy. discovery of a noticeable number of
But this answer is just partially sat- effective therapeutic agents. Phy-
isfactory since it does not explain sicians and patients were deeply
why, in the first place, we want to affected by this 'revolution', as they
test drugs before they can be mar- came across a continuously increas-
keted, and why we want to do it in ing number of new drugs.
such a rigorous way. Here I clarify
that the reasons that brought about However, physicians realized soon
the emergence of RCTs as the 'gold that many drugs did not contain any
standard' of clinical research are the active ingredient, but pharmaceu-
outcome of the interaction of histor- tical companies promoted inactive
ical, organizational, and, ultimately, drugs in the same way as the ones
socio-political concerns. with real and active compounds.
With this regard, for instance, Sam-
In order to bridge this explanatory uel Hopkins Adams, an American
gap, I suggest focusing on the his- investigative journalist (a muckrak-
Volume 6 ■ 2021
tory of drug regulation in the United er), in 1905 coined the expression
States (Gaudillière & Hess, 2013; «The Great American Fraud ». In
Marks, 2000; Temin, 1980, 1985). As discussing therapeutic reforms, the
I argue, changes and reforms were market plays a contingent yet signifi-
implemented in response to major cant role, much as scientific progress
pharmaceutical scandals, and not in does. Indeed, at a certain point, the
response to the real epistemic needs medical scientific community had to
put in place by developments in drug face «a novel intellectual and politi-
theFuture research. Moreover, if this is true, cal problem» (Marks, 2000): how to
ofScience then one should evaluate the epis- foster even further the increasing
andEthics temic import of experimental designs scientific progress in the laboratories
also to the extent to which they could while protecting the patients and the
prevent scandals. Considering the market from fake and potentially un-
56 historical and socio-political context safe drugs. In other words, there was
is particularly relevant for the recent a need to tell apart effective and inef-fective drugs without discrediting the ingredients labeled or advertised Why do we need
entire scientific enterprise. by the manufacturer. Moreover, the randomized
law did not allow anyone to screen controlled trials?
The American Medical Association drugs and control for potential frauds
(AMA) made the first effort towards before their placing on the market:
a more rational approach to pharma- it was remedial but not preventive. Articoli
ceutical therapeutics. In the spring The meaning and the exact enforce-
of 1905, the AMA established the ment of the 1906 Act were indeed
Council on Pharmacy and Chemis- questionable. In 1912, to counter this
try, which had the task of investigat- flaw, the U.S. Congress enacted the
ing the medicines advertised in the Sherley Amendment that prohibited
pages of the Journal of the associa- explicitly false therapeutic claims.
tion (JAMA). The work of the Council However, in the following years, the
was to review the scientific evidence consequences of the new law were
supporting a drug and deliberate on practically nil since it was still hard to
its quality. In practice, the scientific prove something regarding the thera-
evidence was often scarce and then peutic effects of the drug through lab-
the deliberation of the council reflect- oratory tests alone. Yet, the necessi-
ed «a curious mixture of judgments ty to investigate in a more systematic
[…] and opinions» (Marks, 2000). way a method to test for drug efficacy
When the council's assessment was was made clearer only a few years
a matter of laboratory tests, to reveal later, when some scandals emerged.
whether the drug contained an active
known ingredient, the decision was One of the most striking was the case
quite easy. However, pharmaceuti- of Banbar, an old patent medicine
cal companies also developed drugs advertised as a cure for diabetes.
containing ingredients that could The drug was not dangerous per se,
be tested in a laboratory but whose since it contained just inactive ingre-
beneficial properties were complete- dients like milk, sugar, and a grass
ly unknown. In these murky cases, plant known as 'equisetum'. Nonethe-
the deliberation was more difficult or less, it was obviously life-threatening
even impossible. In these latter cas- for those who rejected insulin, which
es, extra-scientific considerations, had become a standard treatment
such as the track record of the com- shortly after its discovery in 1922.
panies, played a major role in the de- Meanwhile, in 1927, the Bureau of
cision-making process. Chemistry's name was transformed
into the 'Food, Drug, and Insecticide
As just mentioned, since clinical ev- Administration', then abbreviated to
idence was scarce or even missing, the current version (FDA). In the 30s
the Council relied mostly on the ex- the 'new' FDA accused the producer
pertise of academic clinicians, but of Banbar of fraud and took to court
then often bumped into a divergence all the evidence about the death of
of opinions. Hence, they warned patients who had refused to take in-
that their approval for the biological sulin to get Banbar. In its defense, the
purity of the compounds did not im- producer of the drug took to the court
ply clinical efficacy. In many cases, testimonial letters, which consumers
laboratory tests could not address had written thanking him. Those let-
the question of efficacy. Take for in- ters were sufficient to demonstrate
stance glandular extracts (e.g., red to the court his bona fides about the
bone marrow, ovarian, parotid gland efficacy of the drug. So, the FDA did
extracts) that were common on the not get the authorization to seize the
market in the early 1900s. Labels product that remained on the market
reported the exact chemical compo- (Junod, 2008).
sition, and this could be easily tested
in the labs. However, it was unclear This case clearly illustrates the ma-
what all those extracts did: labora- jor limits of the 1906 Act: it was more
Volume 6 ■ 2021
tory tests were not sufficient for that about basic chemical quality con-
question. trol (the drug had the ingredients it
claimed it had) to protect consumers
Nonetheless, the U.S. Government from frauds, rather than addressing
in 1906 passed the first key legisla- more relevant epistemic needs such
tion to control the drug market: the as safety and efficacy. These would
Pure Food and Drug Act. The new come in the following decades when
law gave to the Bureau of Chemis- new scandals made it unavoidable.
try (the predecessor to the FDA) in theFuture
the Department of Agriculture the 3. THE 1938 FOOD, DRUG, AND ofScience
legal power to seize adulterated or COSMETIC ACT andEthics
misbranded products (Junod, 2008).
But it assumed the same standards In the wake of Banbar and oth-
of the Council: laboratory tests to er minor scandals, people started 57
check whether a drug contained the being more and more suspiciousWhy do we need of pharmaceutical companies and of the 1938 Act. Another major ac-
randomized the drug trade. In those years, two complishment was the overcoming
controlled trials? books became very popular and in- of the 'fraud flaw' of the 1906 Act:
fluential among the public opinion: the FDA could now remove from the
100,000,000 Guinea Pigs: Dangers market unsafe drugs without having
Articoli in Everyday Foods, Drugs, and to prove that there was the intent of
Cosmetics by Arthur Kallet and F.J fraud on the part of the producer.
Schilnk, and American Chambers
of Horrors: the truth about food and Soon the new Act was put to the
drugs by Ruth deForest Lamb. The test. In the spring of 1938 British
authors harshly criticized the FDA researchers had discovered a new
and the government for their failure sulfonamide compound (2-para-ami-
in protecting people from the abuses nobenzene pyridine), apparently bet-
and the frauds of drug companies. ter than every other sulfa drug. Ex-
They pointed out all the weaknesses perimental tests in mice showed low
of the 1906 Act, asking for an imme- toxicity, few adverse side effects, and
diate update. Instead, at the very be- more beneficial effects than its pre-
ginning, the FDA reacted vindicating decessors. In October 1938, Merck
the success of all its activities. & Company, an American company,
applied for the FDA approval of sulp-
Meanwhile, the pharmaceutical mar- hapyridine for the treatment of pneu-
ket was growing fast. In the 1930s, monia, for which there was no effec-
more than a hundred companies tive therapy yet. The FDA requested
were manufacturing drugs containing the opinion of the experts and cli-
sulphanilamide, a 'wonder' antibacte- nicians who had the opportunity to
rial compound used to cure strepto- test the experimental drug. Some of
coccal infections. The company S. them were reporting adverse events,
E. Massengill started the production some did not. On the drug's efficacy,
of a syrup-type sulphanilamide using the data were even more unconvinc-
diethylene glycol, an extremely toxic ing: the drug had been administered
solvent. The syrup was then placed only to a few patients with pneumo-
on the market, without any tests nia and it was still too early to judge
in animals or humans, causing at its efficacy. Therefore, many sceptics
least 106 documented deaths (Wax, were advising the FDA to keep the
1995). However, under the 1906 Act, application on hold since they were
the FDA could only prosecute Mas- concerned about the risk-benefit
sengill for misbranding. The subse- balance. They were also concerned
quent public outrage prompted Con- about the lack of data on the effects
gress to pass a new set of laws: the of sulphapyridine on other infectious
1938 Food, Drug and Cosmetic Act. diseases for which it might be pre-
The 1938 Act required companies to scribed.
inform the FDA of their intention to
put a new drug on the market. On The FDA had adopted the view that
the one hand, the FDA was given the the expert judgment of qualified clin-
power to ask for «adequate tests by ical investigators should prevail over
all methods reasonably applicable the opinion of regular clinicians. But
to show whether or not the drug is in case of disagreement among the
safe» (Greenberg, 1999). The major former, the debate would not be
concern of regulators in the 1938 Act settled by the methodological supe-
was the safety of the drugs, whereas riority of their respective tests, but
they did not nearly consider the prob- through the majority rule.
lem of evaluating the efficacy, which
of course they soon bumped into. On Despite the pressure of the press,
the other hand, the 1938 Act did not asking for fast approval of the drug,
make FDA approval a prerequisite and despite the incoming winter, a
for market access. time when cases of pneumonia were
Volume 6 ■ 2021
more frequent, the FDA kept collect-
It is worth focusing on the kind of ing and reviewing data and experts'
'adequate tests' required by the FDA opinions until the deadline provided
as proof of drug safety. Although for in the statute. In March 1939 the
these tests remained unspecified in FDA decided to 'not deny' (it is worth
the act, the regulators adopted the noting that, officially, the act did not
same standards already advocated allow the FDA to approve a drug, but
by the AMA's Council on Pharmacy just gave to the agency the power to
theFuture and Chemistry: laboratory analysis deny a request) the applications for
ofScience and experts' evaluation. Moreover, sulphapyridine, provided that man-
andEthics animal tests, even if not formally re- ufacturers explicitly reported on the
quired, were systematically request- labels and in advertising that the
ed by the FDA, and soon became a drug had to be used «under close,
58 sort of gold standard for drug safety. continuous observation of a quali-
This was one of the major novelties fied practitioner of medicine» (Marks,2000). This is because some doubts of natural random variability might Why do we need
remained about the efficacy of the be limited. What statistics could of- randomized
drug. As noted by Theodore Klumpp, fer to clinical researchers was an controlled trials?
by then chief of the Drug Division experimental design that permitted
in the FDA: «While a few investiga- to control for biological variability
tors recommended that the drug be and chance regardless of previous Articoli
withheld from the market such rec- knowledge. Generally, this break-
ommendations upon analysis do not through is credited to the genius of
appear to rest upon considerations a British statistician and biologist, Sir
of the intrinsic safety or danger of Roland Aylmer Fisher (1890-1962).
the drug. Principally those workers
were concerned with the orderly Fisher had been dealing with bio-
development of medical scientific logical variability since 1919 when
knowledge, concerning the thera- he began to work as a statistician at
peutic efficacy of the drug» (Marks, the agricultural experimental station
2000). The sulphapyridine was soon in Rothamsted. Fisher had to find a
replaced by a more powerful drug, reliable method to solve some practi-
penicillin, so the extent of the FDA's cal problems in agricultural research:
decision is not clear. But regarding Which varieties of seeds are better?
safety, 'adequate tests', laboratory Which fertilizer? Which crop rotation
analysis and experts' judgment gave system is best? Simple comparisons
the impression to perform that task cannot provide a reliable answer.
well. At least, it seemed so. Suppose that you observe a 10 per-
cent difference in yields between two
What was clear among the medical varieties: is it due to a real difference
community, at that point, was that in the quality of the seeds or to plot
the standards adopted by the FDA conditions? One way to answer this
were far from being able to check is to rely on experience: an expert
for efficacy. Drug evaluation was farmer could tell that a 10 percent
left to the judgments and opinions difference is never due to plot con-
of experts, which was considered ditions alone. Nonetheless for Fish-
superior to regular clinical judgment, er, this strategy was far from being
and the medical community thought scientific since it relied entirely on
to be reliable at least in spotting experts' knowledge (i.e., subjective).
adverse effects. However, another Moreover, it would not be feasible if
scandal soon undermined that belief such previous knowledge were not
and forced the FDA to reconsider its available to anyone. Another option
regulations and standards. Develop- would be to replicate the experience
ments outside the medical field con- many times, but this is rarely possi-
verged to make it possible. ble in agricultural practice. Fisher
calculated that it would require ap-
4. METHODOLOGICAL INNOVA- proximately five hundred years to
TIONS find that such a 10 percent difference
is due to chance alone.
Physicians had been dealing with
the variability of biological phenom- So, Fisher proposed to set up a new
ena for centuries. They were always experimental design, dividing the
aware of the fundamental role of experimental plots into strips to in-
chance in medical observations: the crease the number of observations
natural course of the disease, spon- in a single experiment. This way he
taneous remissions, and response to reduced the variability of the effects
treatments were considerably differ- due to other factors than a quality
ent in each patient. Clinical measure- difference between grains. In oth-
ment was not as uniform as laborato- er words, he increased the sample
ry tests. Therefore, physicians relied size of the experiment. But the most
only on their experience to handle crucial innovation was to sow grain
Volume 6 ■ 2021
uncertainty. This was the case also in strips in random order. The ran-
in comparative experiments. Indeed, domization of the plots ensured that
knowledge of the variance of the dis- all the possible perturbing factors
eases, and potential perturbing fac- were equally distributed among all
tors, could be exploited to perform the strips.
comparative studies, trying to reduce
the chance to a minimum. Of course, According to Fisher randomization is
the management of chance was con- crucial not just for controlling for con-
sidered fundamental for any com- founders, but also for the calculation theFuture
parative experiment. Therefore, their of the probability of finding a given ofScience
quality depended on the experience difference between the experimental andEthics
of the researcher. Still, this approach treatments, as illustrated by the fa-
had serious limitations because mous thought experiment of the lady
physicians' knowledge of both con- tasting tea (Salsburg, 2002), which 59
founding factors and the magnitude however cannot be discussed here.Why do we need Yet, Fisher's direct influence on bi- that will soon become fundamental:
randomized ological and medical communities a control group, the random alloca-
controlled trials? was negligible. It was Bradford Hill, tion of patients, and standardized
a British statistician working on med- non-qualitative criteria to assess
ical topics, who exported Fisher's ex- outcome. In the U.S., the Public
Articoli perimental design to drug testing in Health Serviced (PHS) organized a
the 1940s. Historians of medical sta- research study on streptomycin to
tistics have argued, time and again, treat tuberculosis. PHS researchers
that British physicians did not grasp did not want to make the mistakes
the statistical rationale of random- of their predecessors, so they strict-
ization (Armitage, 1982; Chalmers, ly controlled the trial funding and the
2011). There was instead a wide- limited amount of streptomycin avail-
spread concern among British doc- able made it necessary to arrange
tors about the many ways in which comparative experiments to produce
personal biases could spoil the eval- the best knowledge most efficiently.
uation of novel therapies.
To control for the allocation bias, the
They found in the randomized al- study design included the random-
location of treatment a device that ization of treatments. PHS research-
could neutralize the personal beliefs ers' main concern was to avoid
of investigators as to who would ben- individual decisions of physicians,
efit most from the therapy. Allocation especially those who were already
bias occurs when the allocation of convinced of the beneficial effects of
subjects to study groups is jeopar- streptomycin. That is also why PHS
dized by the preferences of the ex- researchers planned to conduct the
perimenters (e.g., the healthiest or entire study in a double-blind fash-
youngest patients receive the exper- ion, but they failed to convince the
imental treatment). Randomization involved physicians. Nonetheless,
can easily succeed in neutralizing the study produced reliable and un-
this bias. However, many other bi- contested results in favor of strep-
ases can occur in a comparative ex- tomycin. However, it employed only
periment. For instance, participants' descriptive statistics, there was no
preferences can still spoil the result, use of statistical tests of significance.
conditioning the evaluation of the
outcomes. If physicians want to favor On the other side of the Atlantic, in
the drug under testing, they could 1947, the British Medical Research
report better outcomes for the exper- Council was conducting a very sim-
imental drug and so could patients ilar trial, which became known as the
as well. That is why we need another 'first RCT' ever, since it employed for
de-biasing method, such as blinding the first time a standardized method
the allocation of treatments to physi- for statistical inference. The scientist
cians and patients. Indeed, compar- in charge was Sir Austin Bradford
ative controls, such as blind assess- Hill, a relevant actor in the history of
ment, are similarly instrumental for medicine. In a series of papers on
the coming into being of RCTs (see medical statistics, published in the
Kaptchuk, 1998; Shapiro & Shapiro, prestigious journal The Lancet, he
2000). And randomization is an es- defended the relevance of random-
sential part of blinding procedures. ization and controls to ensure the ob-
jectivity of a study. Bradford Hill ar-
Despite their merits, it took more than gued that the primary experimenter's
a decade to implement both Fisher's aim is «to ensure beforehand that,
approach and controls in medicine: as far as possible, the control and
the first randomized controlled trial, treated groups are the same in all
with significance testing and blind relevant respects» (Yoshioka, 1998).
assessment, took place in Britain in Moreover, randomization was crucial
1947. It would take one more decade to ensure the objective assessment
Volume 6 ■ 2021
to spread among physicians and two of treatments since it removed per-
more decades to transform it into sonal responsibility from the clinician
a regulatory standard (Byar et al., in selecting which patients would
1976). benefit. These two ideas shaped the
rationale behind the design of the
5. HOW RANDOMIZED CONTROL- MRC trial. The trial enrolled 107 pa-
LED TRIALS BECAME THE GOL- tients randomized in two groups: 55
DEN STANDARD assigned to the experimental group
theFuture receiving streptomycin and the stan-
ofScience In the years after the war, some dard of care (bed rest) and 52 to
andEthics breakthroughs in clinical trials design the control group receiving only bed
were achieved in two independent rest. The radiologists who interpret-
studies of streptomycin. For the first ed x-ray chest exams were blind to
60 time, researchers introduced in trials' the allocation of the treatments. After
design a standardized set of controls 6 months there were only 4 deathsin the streptomycin group, whereas children with phocomelia, a terrible Why do we need
there were 15 in the control. Inves- congenital disorder involving limbs randomized
tigators considered that difference malformations, leading to prema- controlled trials?
statistically significant, «the probabil- ture death. In the U.S, the German
ity of it occurring by chance is less company reached an agreement
than one in a hundred» (“Streptomy- with Richardson-Merrell to market Articoli
cin Treatment of Pulmonary Tubercu- the drug, and this latter applied for
losis”, 1948). For the first time both a approval with the FDA in 1961 when
method for minimizing allocation bias evidence of thalidomide side effects
and statistical evaluation of collected started to be reported. Of course,
data were employed in a clinical trial. both the German and the American
Therefore, Hill's trial became a mile- companies denied the link between
stone and influenced an entire gen- the cases of phocomelia and their
eration of physicians. product. As part of the approval pro-
cess, the drug was then distributed
Certainly, these trials had both a to many physicians in the U.S for
great and important weight in the testing purposes. At the FDA, one of
history of medicine and clinical re- the physicians reviewing thalidomide
search, i.e., the exclusion of subjec- approval, Frances Oldham Kelsey,
tive judgments from drug testing and decided to withhold it asking for more
evaluation. The new methodological clinical tests because of emerging
standard provided indeed a more ob- evidence of serious adverse effects.
jective and scientific tool to appraise Unfortunately, the testing drug sam-
therapeutic innovations, rather than ples still caused 17 reported cases
relying on conflicting judgments. of phocomelia, but Kelsey's decision
Yet, despite its initial success, the was indeed a great and fortunate
randomized controlled experimental one and it has secured her a place
design was integrated into drug reg- in history.
ulation more than a decade later, in
the aftermath of further pharmaceu- So, under public pressure and after a
tical scandals. rushed discussion, in 1962 the Con-
gress passed a new pharmaceutical
In 1959, U.S. Senator Estes Kefau- regulatory framework, inspired by
ver held hearings on the drug indus- Kelsey's precautionary attitude. First,
try. His main concern was the exorbi- it introduced a system of control by
tant profit margins of pharmaceutical FDA over clinical experimentation,
companies. The companies justified assigning an IND (Investigational
their profits with the high costs of New Drug) status to experimental
research since many drugs failed drugs, and nullifying this status if
during drug development. The hear- clinical trial protocols were not meth-
ings generated important evidence odologically sound or patients' rights
documenting the poor quality of clin- were not respected. Second, it re-
ical research supporting the market- moved the 'automatic' approval by
ing of many drugs. It revealed to the default after 60 days: drugs needed
public what all the experts already a 'positive' approval by the FDA to
knew: most of the clinical research enter the market. And third, above
was just rubbish. Kefauver's hear- all, it required 'substantive evidence'
ing placed drug regulation on the top of effectiveness based on 'well-con-
of the agenda of U.S politics, but it trolled studies', in addition to the
was another tragedy to trigger both pre-clinical demonstration of safety.
the enactment of the Kefauver-Harris The lawmakers left the task of bet-
1962 Amendments of the 1938 Act ter specifying the meaning of those
and the subsequent Investigational expressions to FDA experts and offi-
New Drug Regulations in 1963. cers, who saw the minimum standard
in 'randomized controlled trials'.
The story of thalidomide is notorious.
Volume 6 ■ 2021
It was a quite popular drug in Europe Moreover, the 1963 IND rules shaped
and especially in Western Germany, somehow the 3-phases structure of
where it was manufactured by phar- drug testing, the form DF 1571 list-
maceutical company Chemie Grü- ed for the first time three phases of
nenthal since 1957 and marketed as trials. The testing of a new drug is
Contergan. The drug was prescribed indeed a complicated and time-con-
to treat a great number of various suming process, and it is usually
symptoms, mostly psychological as divided into three phases. Phase 1
anxiety or tension. But it was also trials are the first human studies of theFuture
often administered to many preg- a new drug. They usually require few ofScience
nant women to alleviate nausea and healthy volunteers and are designed andEthics
sickness. This was the beginning of to obtain preliminary information on
a tragedy for thousands of women drug safety, including side effects
around the world. Indeed, those who and dosing. Phase 2 studies involve 61
had taken thalidomide gave birth to a small number of diseased people,Why do we need and they are designed to further losophers of science have long dis-
randomized assess adverse effects and to offer cussed the limits of RCTs to support
controlled trials? initial data on drug efficacy. Phase 3 causal claims (see e.g., Cartwright,
trials (i.e., RCTs) are reserved for ex- 2010, 2011) and have proposed sev-
perimental drugs which have shown eral alternatives which might better
Articoli at least some evidence of effective- suit this aim. However, if the main
ness in the previous. They include aim of regulatory trials is not epistem-
many patients (several hundred to ic (i.e., warranting causal claims), but
several thousand) and are designed rather political (i.e., protecting people
to gather enough information on from pharmaceutical catastrophes),
safety and effectiveness to allow an then we should also assess how
adequate assessment of a risk/ben- RCTs perform in achieving this latter
efit ratio for the drug. goal. With regard to this, RCTs may
have performed quite well so far,
This division provides additional evi- since [in the last decades] we did not
dence to support my claim that RCTs assist to any thalidomide-like scan-
become the gold standard in medical dal. Therefore, it seems that there
research because they better serve is not a real need for alternatives.
the political goals of regulators, com- Moreover, as some scholars have
pared to animal experiments and suggested, despite the epistemic lim-
experts' judgment. Indeed, it is the itations in assessing causality RCTs
design of phase 3 trials that makes have led mostly to accurate regulato-
it possible to objectively assess the ry decisions, if for instance their ac-
safety and efficacy of a drug, all the curacy is defined in terms of market
previous phases are pointless to this withdrawals (see Andreoletti & Teira,
epistemic aim. However, as it was al- 2019). So far, RCTs have served at
ready clear at that time, RCTs were best the goals of regulators.
quite challenging and demanding
experiments requiring many patients FUNDING
to allow correct statistical inferences.
As Donald Mainland noted in the The author thanks the Italian Minis-
'60s: «the method of controlled trials try of Education, University, and Re-
is still in its infancy; that, although search for supporting this work with
the principles are simple, the art is a PRIN grant: Progetti di Ricerca di
extremely difficult» (Mainland, 1960). Rilevante Interesse Nazionale-Ban-
do 2017 Prot. 201743F9YE.
Intuitively, running big experiments in
humans can raise a medical scandal
as well, exposing many individuals to NOTES
a potentially toxic drug. This possi-
bility would result in an even bigger 1. Carpenter (Carpenter, 2010) and
scandal than thalidomide, making Porter (Porter, 2020) are partial re-
the fears of early critics of the phar- markable exceptions. Hutchinson
maceutical industry true: turning peo- (Hutchison, 2016) has also made a
ple into guinea pigs. Therefore, the similar point but focusing on nursing
early phases were introduced to pro- practice.
vide preliminary evidence of safety,
before exposing many patients to the
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Volume 6 ■ 2021
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