Molecular Interventions 4:60-61 (2004) © 2004 American Society of
Pharmacology and Experimental Therapeutics
Beyond the Bench
The Drug that Came in from the Cold Rebecca
Anderson
The Constant Gardener. John le Carré. New York: Simon &
Schuster; 2000. 480 pages. $28.00. ISBN: 0743215052
John le Carré, best known as the author of post–World War II spy
novels, has a masterful knack for portraying global conflict through
the lives of ordinary people. With the passing of the cold war, le
Carré has turned to the pharmaceutical industry as the alternative
setting for his latest novel. A major Swiss pharmaceutical firm,
Karel Vita Hudson (KVH), is running clinical trials on Dypraxa, an
experimental drug being tested on African tuberculosis patients. KVH
has engaged an African health care conglomerate, the House of
ThreeBees (Bell, Barker, and Benjamin), to foot one-quarter of the
research and development costs in exchange for the exclusive import
and distribution rights to Dypraxa in Africa.
At the center of The Constant Gardener is Justin Quayle, a
low-profile career diplomat in the British Foreign Service Office in
Nairobi, whose wife had been compiling, prior to her untimely
death, information concerning the clinical trials of Dypraxa in
Africa. Justin had admired Tessa Quayle’s humanitarian spirit
and her legal mind, but he knows little about her lawyerly probing
into the deaths of patients who had participated in the drug
trials. In a journey that encompasses Kenya, Poland, Britain,
Italy, Germany, and Canada, Justin carries us along as he searches
not for European spies—the typical fare of previous le Carré
fiction—but rather for answers to the questions Tessa had been
investigating: Was the drug being tested properly for efficacy? Was
it safe? Were patients adequately informed? And most importantly,
were ThreeBees and KVH conspiring to conceal adverse drug events?
Indeed, Tessa’s persistent and vocal prodding had threatened to
generate quite unfavorable publicity.
Le Carré has woven an interesting and entertaining tale of
intrigue, typical of his spy novels, which include the best sellers,
The Spy Who Came in from the Cold, Smiley’s People, and
Tinker, Tailor, Soldier, Spy. In this instance, le Carré
presents a rarely exposed and at times unsettling perspective
on drug development, and he has clearly done his homework. The
development of Dypraxa and its pharmacological characteristics
are presented in believable detail, beginning with the discovery
of Dypraxa, in Poland, by two physicians on leave from the University
of Leipzig. During their sabbatical, they demonstrate preliminary
clinical efficacy before KVH acquires the rights to develop and
market the drug.
In a scenario typical of many drugs, Dypraxa performs well in
preclinical studies (e.g., no mutagenicity and a long half-life
in rats), but subsequent clinical testing reveals isolated incidents
of liver failure, internal bleeding, dizziness, and blurred
vision secondary to possible optic nerve damage. Nevertheless,
Dypraxa meets regulatory requirements for approval in Germany,
Poland and Russia, as well as certification for use by the World
Health Organization, and KVH is keen to continue the clinical
testing and secure registration of the drug in the most lucrative
pharmaceutical markets of North America and Europe. Thus, the
pursuit of a blockbuster drug forms the backdrop for the plot
played out by KVH, ThreeBees, Tessa and, ultimately, Justin.
Le Carré discusses a number of activities and issues that real
pharmaceutical teams often confront during clinical development. He
portrays the need to obtain informed consent from patients before
treatment, the necessity of rewriting protocols due to the appearance
of adverse events, and the importance of excluding women of
childbearing age under certain treatment conditions. The author also
touches on real-life social concerns, such as the possible coercion
of needy patients, the solicitation of favorable reports and
testimonials by opinion leaders, and the ghostwriting of such
testimonials by sponsoring pharmaceuticals firms themselves. The
reader is also exposed to some of the realities of biomedical
publishing, such as the difficulty of communicating negative data in
premier medical journals, the potential for censorship of unpopular
data by biased peer reviewers, and the use of confidentiality
agreements that can prevent company employees and their associates
from communicating research findings.
In positing adverse reactions to the drug, le Carré is careful to
explain that Dypraxa is not a bad drug; it is simply being
administered improperly. The author points out that insufficient work
has been done to characterize its pharmacokinetics, the extent of
drug-drug interactions, and the disposition of the drug in patients
who are already very sick. In this regard, le Carré highlights a
scenario quite common in real drug development. The pressure to enter
Phase III trials often compels companies to gloss over—or omit
entirely—key Phase II studies whose purpose is to establish optimal
dose schedules and define critical inclusion and exclusion criteria.
Regulatory agencies, including the FDA, in fact persistently
emphasize the need to collect sufficient clinical data on
pharmacokinetics, concomitant medications, and comorbidities prior to
Phase III. When this advice is not heeded, patients in the targeted
therapeutic population may die from drug overdose, or may die from
their disease because they are underdosed. In The Constant
Gardener, profit is the motive behind KVH’s decision to
continue clinical trials, despite serious adverse events.
Le Carré puts a human face on this situation. We see drug
development through the eyes of patients and their advocates,
including Dr. Lara Emrich, one of the physicians who originally
discovered Dypraxa. We become acquainted with patients who willingly
submit to experimental treatment, full of hope and trust that
Dypraxa is the miracle that will cure them. When one such patient
dies, the impact of le Carré’s fictional account is much
greater than we might have experienced simply by reading data entries
from an actual Case Report Form and a Serious Adverse Event Report.
Dr. Emrich is portrayed as a compassionate research scientist whose
attempts to proceed cautiously, with scientific rigor, are
undermined. To her, financial rewards should be secondary to patient
welfare and good clinical practice.
As for KVH, le Carré’s portrait of the drug company is indirect,
established rather unsympathetically through the skeptical eyes of
patient advocates. However, the practices attributed to KVH do not
appear to be out of line with real-life pharmaceutical R&D
activities. KVH met or exceeded the regulatory requirements for
clinical safety and efficacy necessary to achieve market approval in
three countries. It is not uncommon to adjust clinical protocols, as
the fictional company appears to do, when adverse events are
observed, in order to ensure safety. Similarly, pharma companies
often seek the endorsement of key opinion leaders, as does KVH, as a
way of encouraging the medical community to use a new drug. Finally,
confidentiality agreements are standard practice in the
pharmaceutical industry; they are designed to protect the huge
financial investment that underlies drug development and to control
disclosure of data about drugs that are still under development.
Still, Tessa Quayle and Dr. Emrich view KVH’s efforts with
skepticism, convinced that maximizing profits is overriding other
important concerns. However, Le Carré is careful to avoid a blanket
condemnation, and concedes, "...Not all pharmaceutical companies are
careless and greedy." In addition, his plot positions a corrupt
distributor, ThreeBees, as the scapegoat for most of the clinical
sins.
There are few faults in le Carré’s plot line. Tuberculosis is a
major unmet medical challenge in the third world, but it is hard to
imagine that any major pharma company would consider a drug like
Dypraxa to be a blockbuster. The market for tuberculosis drugs in
industrialized nations is not large. Furthermore, the presumed
advantage of Dypraxa is the promise of reducing treatment to a few
weeks, when in fact most blockbusters depend on chronic treatment to
sustain revenues. Also, although many drug companies are increasingly
conducting clinical trials in Africa, it is unlikely that they would
depend so heavily on African clinics to collect definitive efficacy
data. Despite the large patient base for tuberculosis studies, the
logistics for monitoring studies in Africa is complicated and too
costly for most pharma companies.
The Constant Gardener exposes the reader to a variety of the
facets of real-life drug development: basic research and drug
discovery, clinical trials, patients and health advocates, and
the financial ramifications. In the real world of pharmaceuticals,
the cloak-and-dagger dilemmas of the novel’s hero are rare.
However, the novel does much to reveal drug development as a
high-stakes business that evokes passions from a variety of
perspectives, and le Carré’s ability to touch on moral issues is
evident in the tale of a naïve, bereaved husband; his protagonist
serves as a compelling vehicle to present a very personalized
perspective on drug development. It is a perspective that we should
keep in mind as we develop new drugs. In this regard, The Constant
Gardener is both interesting and thought provoking.
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