Some of the most important methods for preventing bias in

modern clinical trials have a peculiar history. Masked assess-

ment with placebo control seems to have appeared first during
tests led by Benjamin Franklin in 1784 to investigate unorthodox
claims of healing by animal magnetism or mesmerism. People
were blindfolded and told that they were or were not receiving
magnetism, when the reverse was true, and were given sham
treatments of mesmerised water.
1
Similar methods were used
to test claims of higher mesmeric phenomena such as thought-
reading and precognition.
2
Two-hundred years later, the same
methodology is still used to assess controversial claims in para-
psychology, a subdiscipline of experimental psychology, that
uses controlled laboratory techniques to examine claims of psychic
abilities. Recent problems noted with the conduct of clinical
trials suggest that although the two fields have diverged, para-
psychology might now have something to offer in the design of
orthodox medical research.
Problems with allocation concealment
In some clinical trials, patients have been allocated to interven-
tions in such a way that clinicians could predict or control what
the next eligible patient will receive, for example, by allocating
patients in alternating order, or by drawing marbles out of a bag
without appropriate precautions to prevent sampling until the
favoured option is drawn. It is well established that treatment
estimates are biased in such trials in comparison with trials in
which allocations are concealed.
3
This is presumably because
clinicians can assign their favoured treatment to particular patients
by giving allocations out of sequence, or manipulating whether
or when certain patients enter the trial, resulting in baseline
risk factor imbalance. Trialists have attempted to deal with the
problem by concealing allocations from clinicians until assign-
ment. Although centralized randomization offers a relatively
secure method of concealment, it still appears much more
common for trialists to attempt to conceal allocations at the trial
sites.
4
However, there are many anecdotes, such as those docu-
mented by Schulz,
5
of trial clinicians attempts to breach such
concealment. The methods described include holding envelopes
containing allocations up to a light bulb, deciphering the allocation
sequence by examining the appearance of the tablets in the
sequentially numbered medication containers, and rifling through
the principal investigators filing cabinet.
As in clinical trials, parapsychologists testing claims of
extrasensory perception must also conceal material from people
who would like to know its contents; a typical parapsychology
experiment consists of concealing a random sequence of symbols
from a participant who attempts to guess it. Particularly when
testing participants such as Uri Geller who make strong claims
about their psychic abilities, experimenters must defend against
cheating so that any positive results from the study can be taken
seriously.
6
This is not a trivial problem in parapsychology. People
have such strong opinions about psychic claims that some
laboratories have been infiltrated by performance magicians
posing as psychics to attempt to trick the experimenters and
discredit their methods.
7
Spies, magicians, and envelopes
The literature that parapsychologists draw upon to conceal
adequately their materials is (sometimes deliberately) obscure and
mostly unknown to clinical trialists, but it has much to say
about methods commonly used for allocation concealment used
in trials. Sealed, opaque envelopes are an interesting case in
point. As any reader of junior detective novels will know,
envelopes with water-soluble glue on the flaps can be steamed
open. Military intelligence specialists have also long known this,
as documented in the CIA Flaps and Seals Manual.
8
The Manual
is essentially a spies handbook of how to get into and out of
other peoples envelopes without their knowledge. In addition
to the more pedestrian methods of tampering with flaps, it
includes, for example, a section on how to use carbon tetra-
chloride, which is highly toxic, to open envelopes sealed with
sellotape without detection and without killing yourself. There
are also sections on how to set booby traps to detect whether
someone has opened and resealed an envelope in transit, such
as leaving a section of the flap unglued which the interceptor
might seal completely after opening. Further sections describe
methods for detecting booby traps, for example by examining
an envelope under ultraviolet light to detect the use of more
than one type of glue on the flap.
Parapsychology also draws on the expertise of the commercial
security industry concerning concealment materials. Some
IJE vol.32 no.6 International Epidemiological Association 2003; all rights reserved. International Journal of Epidemiology 2003;32:943944
DOI: 10.1093/ije/dyg285
Spies, magicians, and Enid Blyton: how they
can help improve clinical trials
Julie Milton
Accepted 30 June 2003
Keywords Random allocation, randomized controlled trials/st[Standards]
Department of Social Medicine, University of Bristol, Canynge Hall, White-
ladies Road, Bristol BS8 2PR, UK. E-mail: j.milton@bristol.ac.uk
943

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References
1
Kaptchuk T. Control of observer biases: masking (blinding) and
placebos. In: Chalmers I, Milne I, Trhler U (eds). Controlled Trials from
History. www.rcpe.ac.uk/controlled_trials. Accessed 19 June 2002.
2
Kaptchuk TJ. Intentional ignorance: a history of blind assessment and
placebo controls in medicine. Bull Hist Med 1998;72:389433.
3
Jni P, Egger M. Allocation concealment in clinical trials [Letter].
JAMA 2002;288:240708.
4
Milton J, Logan S, Gilbert R, Pindoria S, Higgins JPT. Investigation of
baseline risk factor imbalance in randomised controlled trials that attempt
allocation concealment at the trial site. Submitted for publication.
5
Schulz KF. Subverting randomization in controlled trials. JAMA
1995;274:145658.
6
Milton J, Wiseman R. Guidelines for Extrasensory Perception Research.
Hatfield, UK: University of Hertfordshire Press, 1997.
7
Randi J. The Project Alpha experiment: Part 1. The first two years.
Skeptical Inquirer 1983;7:2433.
8
Harrison JM. CIA Flaps and Seals Manual. Boulder, CO: Paladin Press,
1975.
9
Morris RL. What psi is not: the necessity for experiments. In Edge HL,
Morris RL, Palmer J Rush JH (eds). Foundations of Parapsychology:
Exploring the Boundaries of Human Capability. Boston: Routledge and
Kegan Paul, 1986, pp. 70110.
10
Sample I. Letter of the law. New Scientist 16 December 2000.
944 INTERNATIONAL JOURNAL OF EPIDEMIOLOGY
companies manufacture special, tamper evident security
envelopes to protect against industrial espionage or blackmail
concerning sensitive information in transit. Many such
envelopes are made out of plastics that deform or stain if
solvents are used to attack the glue on the flap. Some envelopes
can be opened surreptiously by freezing, which makes the glue
brittle and cracked, enabling the flap to be lifted easily and
the contents of the envelope to be examined. The contents can
be replaced in the envelope, and the flap placed back down. As
the envelope returns to room temperature the glue melts and
reseals the envelope. Many security envelopes are therefore
made from materials that show evidence of having been
subjected to extremes of temperature.
In order to protect against another weakness of ordinary
envelopestheir transparency if placed in front of an intense
light source, as noted by some of Schulzs
5
respondentssome
commercial security envelopes are lined with black plastic.
The use of plastic also protects against the use of special wetting
agents, which can render transparent envelopes made out of
quite thick paper. This technique has long been used by
magicians to simulate psychic powers on stage. For example, a
magician might ask a member of the audience to draw a picture
on a sheet of paper without letting him or her see it, to seal the
picture in an opaque envelope, and pass it to the magician, who
then describes its contents without opening it. One of the
many ways of doing this trick involves the magician unobtrus-
ively applying a wetting agent to the envelope from a small vial
through a tube to a flesh-coloured sponge attached to his or
her finger. The surface becomes temporarily transparent, enab-
ling the contents of the envelope to be read, and the wetting
agent evaporates quickly, leaving little trace.
9
A company in
the US has recently exploited this principle to develop a spray
that allows law enforcement agencies to inspect covertly
suspect packages that might contain bombs, without opening
them.
10
Tamper-evident envelopes manufactured by specialist security
firms are commercially available and could be used in clinical trials,
though trialists should choose their materials carefully. Products
change often, offer varying degrees of protection against inter-
ference and, even if described as being tamper evident, have not
necessarily been subjected to testing. For example, some security
envelopes appropriately use solvent-resistant glue on the flaps
but use water-soluble glue on the seals. Trial investigators con-
cerned about security can find a range of potentially useful and
currently available materials by using search terms such as tamper
evident on the internet, but should obtain sample materials and
conduct their own tests on them before making a choice.
Conclusions
Trial clinicians without special knowledge or training are
unlikely to go to some of the more extreme and colourful
lengths described here. However, several of the methods are
either common knowledge or easily re-invented and do not
require unusual equipment or materials. The general point to
be taken from the expertise in these other fields is that if
envelopes, and other on-site concealment methods, are used in
trials they should incorporate appropriate security measures
and be adequately tracked through the trial to prevent
premature opening. Concealment methods should be described
in much more detail than is usual in trial reports so that readers
can assess their adequacy. Inexpensive centralized randomization
is becoming more widely available and obviates many of these
problems. While on-site concealment continues to be used,
however, clinical researchers might do well to consider spies
and magicians when designing their trials.
KEY MESSAGES
Some important aspects of clinical trial methodology have their historical basis in investigations of paranormal
phenomena.
The methodology of such investigations has continued to develop, drawing upon little-known literatures in fields
such as performance magic, and military and industrial espionage.
Some material from these fields suggest ways in which randomized trials may be better protected against
clinicians attempts to breach allocation concealment.

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