ETHICAL DILEMMAS ENCOUNTERED DURING CLINICAL DRUG TRIALS
George K Daikos, M.D.
Professor of Medicine (Emeritus), Athens University Medical School
E-mail:daik@otenet.gr

ABSTRACT

            We are fortunate to live in an era when medicine is making important progress in the diagnosis and treatment of many diseases, which have plagued mankind for centuries. The pace of progress is really staggering. New potent drugs are introduced continuously. The evaluation of their efficacy and safety is an arduous and costly process that involves laboratory work, animal studies and human trials. Someone must take a new drug first hence, human experimentation is unavoidable.

            Over the years, principles and rules have been introduced to guarantee respect for the individual.  In our present state of knowledge, randomised clinical trials are necessary. They aim not only at the actual patient’s treatment, but also to serve future patients who will need the drug. We should appreciate that conscientious people have established an ethical basis for the proper conduct of RCTs. Individual investigators in basic science, in institutions, and the pharmaceutical companies, all contribute to a common end - the production of useful drugs. Most of us are involved in clinical trials.

The present review has discussed briefly some of the ethical dilemmas encountered during the clinical trial process in order to encourage the exercise of more humane medicine.

INTRODUCTION

Clinical trials and especially controlled randomized trials are fundamental to the advancement of evidence-based medicine. It is widely accepted that, if the evidence does not support a new treatment, a diagnostic method, or another practices, they should not be accepted as good, scientific medicine.
Open, that is not controlled, observations are seen as subject to bias and hence cannot contribute to evidence-based medicine.
It is most interesting that the Hippocratic corpus, contains a passage that talks about Evidence-based medicine: 

“ Do not rely on conclusions that result from mere reasoning,
but (rely) on evidence.  Arguments in the form of plain rhetorics
are false and easily defeated. Therefore you should stick to the
facts and scrutinize them , if you are going to acquire faultless
capability, which we call Medicine”.
Hippokrates Parangeliai , (Recommendations), 2 ¹

The present paper will discuss, some of the ethical dilemmas encountered during the conduct of clinical drug trials. The controlled randomized trials that are required for the approval of the distribution of a drug, should prove its efficacy and safety.  The agent chosen for comparison (the control) preferably should be a placebo or an older active drug. The new agent must be shown to be pharmacologically equal to, or more active than the control.  The patients, who are assigned to the control arm of placebo, will remain without treatment for the duration of the trial.  For decades now observers have asked whether it is ethical to leave an individual without treatment for the observation period, and thus risk a worsening of the disease.

Historical

The antimicrobial chemotherapy was neither discovered nor its benefits established based on clinical trials.  Under modern systems of regulatory control, sulfonamides and penicillin would not have been approved for human use. One could also cite many other examples of major therapeutic advances that have not followed the path of randomized clinical trials ( RCT).

The Medical Research Council (UK) instituted the first controlled clinical trial during the investigation of the treatment of Tuberculosis (1948) ². That study led to the formation of the first protocols for co-operative studies designed to recruit a statistically significant number of patients. Cancer chemotherapy and large scale (multicenter) studies followed later in an analogous manner. Following the same protocol, the combination of related active agents led to real progress in cancer chemotherapy.

The ignoble Tuskegee Syphillis Study.( “America’s Nuremberg”)

On the occasion of the 50^th anniversary of the introduction of the Nuremberg Code, Wolinsky has drawn the attention of ethicists and the medical profession to the Tuskegee Syphilis Study, which otherwise might have been overlooked^2a.  In Macon County, Alabama ³, the US Public Health Service (USPHS) placed 431 black agriculture laborers, who had seropositive latent syphilis, in a prospective study for the purpose of observing the natural history of the disease.

The investigation sought to determine whether syphilis caused cardiovascular lesions more frequently than neurological damage and whether the course of the infection  followed a different cause in blacks than in whites.

Participants were only observed, they were not treated. The study began in 1932, at a time when only bismuth and salvarsan were available for the treatment of Syphilis. The only explanation the USPHS gave the patients was that the study was meant to “cure their bad blood”.  These individuals were recruited to the trial by the offer of food and other small gifts.

USPH officials supervised the study, taking care that these poor people received no treatment. In order to recruit more people the health service associated itself with the prestigious Tuskegee Institute in the area.

The study, which was a crude and ruthless human experimentation, continued through 1972, well beyond 1947 when penicillin was proven as the best and most effective treatment for syphilis. The same year (1947) the code of Nuremberg was introduced and accepted by all nations as the ethical standard for all human investigations; among other things, it required the investigators to obtain an informed consent from all participants.

This ignoble experiment was revealed by a reporter in Washington Post in 1972.

As the Houston historian, James Jones ⁴, noted in his comments on the behavior of the USPH investigators, even as evidence was accumulating, concerning the benefits of penicillin the patients were pressed to continue without any treatment because such investigation was “ a never-again-to be repeated-opportunity”!

In 1997 President Clinton was obliged to offer a formal apology for this ignoble affair, but the government granted no compensation to the survivors, despite the efforts of a volunteer lawyer.

In October 1998, the Barbican Center (London) ⁵, presented a theatrical work with the title “Miss Evers’ Boys”, that told the story through the tragic life of four artists-participants in the study.  Despite her friendship and sympathy for the four artists, the nurse (Miss Evers) co-operated fully with the health authorities as she helped to oversee the program.  This theatrical work is used for teaching in some US medical schools.

 Patent Rights  vs. Patients’ Rights.

The high price of modern drugs which places them beyond the reach of citizens in a great part of the world, was one of the main themes of the last International AIDS Congress (July 2000) in Durban, South Africa.

In the developed world, treatment with a combination of drugs (HAART), which costs about $ 10.000 to $15.000 US a year, can change AIDS to a more chronic disease (always fatal). In the developing countries, where 95% of people infected with HIV are living, treatment even with a single drug is impossible because of its cost.  Thirteen years after its circulation, Zidovudine, the first anti-HIV drug, is still very expensive for most patients.  The patent for this drug will expire in more than 4 years, that is, in 2005.   

The patent for some antiretroviral drugs is held by a public agency (e.g. NIH), but this agency has granted the right of production and commercial exploitation to pharmaceutical companies.

The prices the manufacturers have set for USA, a rich country that does not impose price restrictions, may be viewed as unreasonably high.  Unfortunately for most of the 34-36 million people with HIV the drug industry continues to demand high prices, for these essential drugs.  Countries, like India, Thailand and Brazil, have broken the patents and, using a different process of production, are producing cheaper drugs under their generic names. It is alleged that the pharmaceutical industry and the western governments are exerting a strong pressure on poorer countries not to purchase these cheaper AIDS drugs.  The international aid group, “Medecins sans frontières”, has put this ethical dilemma appropriately when it delcared “Access to health care and to medical progress as a human right is a challenge that AIDS poses to the humanity”^{6, 7}.

Contemporary Systems of Clinical Drug Research.

The development of a new drug costs approximately $300 to 600 million dollars. 

70% of the money for clinical trials come from the pharmaceutical Industry, the rest from NIH, or other government sources.  During the last 10 years, new types of clinical networks for drug investigation have been developed, such as the Contract Research Organizations, (CRO) and the Site Management Organizations (SMO) which have changed entirely the process of data acquisition. 

Such organizations specialize in a fast recruitment of the proper number of patients, who will agree by written consent to be subjects in the assessment of the new treatment. For each day that government approval is delayed the industry loses approximately $ 1.3 mil. The policies of academic centers impose delays on the recruitment of patients, especially for controlled clinical trials that require at least twice as many patients.  Organizations such as CRO’s and SMO’s, which sometimes are organized by the industry themselves, have at their disposal investigator-designers, clinicians, and statisticians, and often are able to collect large numbers of patients in a short time.  They work through community general practitioners, who are paid by case and often do not inform their own patients that they are participants in a clinical trial.  This new trend has developed quickly and is creating new problems, even in academic centers and in large hospitals ⁸.

Conflict of interest arises because well-known physicians are co-operating with pharmaceutical industries, either as consultants or investigators, while at the same time holding university or government positions.  Many also have financial interest, as stockholders, or through other mechanisms.  The subject has drawn much attention lately. The New England Journal of Medicine, in its November 30, 2000, issue had two special articles^9,10on such conflicts of interest - an editorial ¹¹and a Sounding Board article ¹².  Their authors found that only one out of 20 centers observed guidelines, such as the one proposed by Harvard University that requires physicians to abstain from industry activities.  These observers suggest that scientist investigators, especially clinicians should remain scientifically and ethically beyond and above conflicts of interest.

On the other hand, to counteract industry intrusion and to regain lost ground many academic centers have created their own networks of clinical trials, like Columbia University with Cornell University and New York Presbyterian Hospital. Also the Pittsburgh Clinical Research Network. With support of the industry and NIH, these institutions, as a reaction to intrusion of the “for profit” organizations, arrange the co-operation of academic investigators and community practitioners, in the recruitment of the patients.

Publication of Scientific findings  

The findings of these clinical trials accumulate in the data bases of the pharmaceutical companies that are developing the drugs and, if the results are not favorable, they may not publish their findings.  The firms’ marketing departments are interested mainly in FDA approval, while the scientists are looking forward to publication in peer-reviewed journals of prestige. Usually, upon accepting the assignment to conduct a clinical trial, the investigator signs a restrictive contract and agrees, for a given time interval, not to publish the results, without the approval of the industry.  Those that have dared to publish, against the will of the industry, have lived through a bitter experience ^13,14.

The  non-writing author -non-author writer syndrome, or briefly “ guest-ghost syndrome, is a growing phenomenon, particularly in the commercial sector, where community-physician investigators have little interest in authorship.

A “ghostwriter” is a professional medical writer who is given the data by the pharmaceutical company, or CRO, in order to write the paper. His name does not appear in the paper, while the investigators are cited as the authors.  Usually the ghostwriter adds an interpretation favorable to the manufacturer’s product.  The “guest  author” is a clinical investigator who appears as the author, without having written the paper or having analyzed the  data ^{15, 16}.

In the September 13, 2001 issue of New England Journal of Medicine an important editorial deals with  the problems of publication of the results of clinical trials. “Sponsorship, Authorship and Accountability”¹⁷is signed by the editors of 12 Medical Journals (  including : F. Davidoff of Annals of Int. Med., Catherine DeAngelis of JAMA,  J.Drazen of NEJM, J. Hoey of Canadian Med. Ass. Journal , Liselotte Hojgaard, Danish  Med. Ass.J, Richard Horton of  Lancet, Sheldon Kotzin, Medline/Index Medicus, et.al.)

The editors felt compelled to make clear statements in order to protect the independent investigator in publishing his/her results free from the pressures of the sponsors. They state: “As editors of general medical journals,we recognize that the publication of clinical research findings in respected peer-reviewed journals is the ultimate basis for most treatment decisions.. We are concerned that the current intellectual environment in which some clinical research is conceived , study subjects are recruited , and the data are analyzed and reported (or not reported) may threaten this precious objectivity.. Patients participate in clinical trials for altruistic reasons- that is, to advance the standard of care..  as editors, we strongly oppose contractual agreements that deny investigators the right to examine the data independently or submit a manuscript for publication without first obtaining the consent of the sponsor”

Registering All Clinical Trials – Reporting negative Results.

 Another difficult subject is the premature interruption of a clinical trial because of negative results, that remain unpublished.  Observers have proposed that the scientific community establish a registry of all clinical trials, no matter what stage, which will be accessible electronically. NIH has already set up such a registry (www. clinical trials.gov/), which for the moment displays data from trials supported by NIH, but not those supported by the industry. It is expected that industry data will follow soon. Earlier, British publishers set up a registry (www.controlled trials.com/).The Cochrane collaboration had also organized a systematic registry, but thus far only of the finished trials.

Ioannidis and Lau ¹⁸have recently assessed the amount of the space allocated to the incidence, severity, and nature of adverse events in published reports of 192 randomised controlled trials. Reporting  of adverse events was considered adequate in only 39% of the trials.

Recruitment of study patients.

There is a heavy demand for clinical trial participants because the number of drugs in the pre-clinical phase is growing.  Lancet in an editorial ¹⁹ commented recently on an important study conducted by the Office of Inspector General of USA, (OIG) and entitled “Recruiting human subjects, pressures in industry-sponsored clinical research”²⁰ where the need is emphasized for strict controls on the recruitment of participants for clinical trials.  Physicians are paid considerable amounts of money to collect patients and to open their records so that the companies can select those they want.  Often such patients are not aware that they are being assigned as participants in a trial.  

On the other hand, physicians often become sidetracked when advertisements in the press or messages of other mass media addressed to the patients describe a new wonder drug and as a consequence, people demand that their doctors included them in the trial of the promising substance²¹. The advertisement of over-the-counter drugs has become big business and, as a consequence, the public is conditioned to accept experimental drugs.

Physician – Pharmaceutical Industry Relationships.

 It is true that industry is the greatest contributor to drug development. It applies biological knowledge to produce products that are useful drugs. It does so for profit of course, but it is important that it does it. Research, development and marketing are intertwined and not easy to separate them. Marketing often has the greatest influence in decision making²².

These departments use every legal means to keep physicians happy, because they are the ones who prescribe the drugs.  As Marcia Angel, then editor of The New England Journal of Medicine,²³noted among other things:“Traveling around the world to appear at industry-sponsored symposiums has much more to do with marketing than with technology transfer”.

Many non-investigator physicians are offered complimentary travel to the international symposia and Congresses during which they are offered special dinners, excursions and gifts^23a.  Of course such events may be educational occasions as well, but usually the presentations are restricted to the promoted drug.

Are the randomized control clinical trials ethical ?

They are meant to be and usually they are.  It is unfortunate, however, that the effort to achieve scientific precision, if not restricted by ethical principles, may eventuate in criminal actions (Nazi –doctors, Tuskegee study).

Guidelines derived from declarations of human rights concerning human experimentation (Nuremberg, Helsinki and its modifications), are intended to define the precise conditions and limits of clinical trials.  However, in practice, these codes are not followed or respected ²⁴.

Recently the ethics of human experimentation are being widely discussed, because clinical trials on AIDS are being conducted in Africa, without honoring the codes observed in the developed countries.  The March 30, 2000 issue of New England Journal of Medicine reported of such a trial ²⁵and in an accompanying editorial Marcia Angel ²⁶commented: “ it is important  to be clear about what this study meant for the participants. It meant that for up to 30 months, several hundred people with HIV infection were observed but not treated”!
The usual excuse offered is that, in those countries, HIV patients cannot afford and hence do not receive treatment anyway. The fact is though that, for research workers in developing countries, it is cheaper and easier to recruit large numbers of “drug-naïve” patients.  The problem has created the proper reactions and decisions have been taken very recently for the regulation of the trials in developing countries^{27, 28}.

As has been emphasized, “clinical trials in developing countries should meet all  ethical and scientific standards of trials performed in developed countries.” and “ an experimental intervention should normally be compared with an established, effective treatment, whether or not that treatment is available in the host country”. Therefore, the presumption is that a placebo control, or any other control that is less effective than an established, effective treatment, is not ethically acceptable”^{26 , 27}

The scientific community accepts the compassionate use of an investigational drug and such use has been undertaken in AIDS patients with the approval of FDA. On the other hand severe infections are appearing that are caused by micro-organisms resistant to existing drugs, and lives can be saved by a new active antibiotic. On such occasions it would be unethical to stick to the existing protocol and not provide a potentially lifesaving drug. Most clinicians involved in an early-phase drug trials would feel the need to use an experimental drug out of the protocol to fight a resistant infection. Eventually such observations may prove valuable even though the study was aborted.

On the other side an ethical practitioner should inform a desperate cancer patient, that there is a new promising drug that might help him or her and the patient may accept the rules of the protocol and give his really informed consent.

It is interesting that now the scientific community is reconsidering and re-evaluating the value of the observational studies, which are considered to be subject to personal bias and therefore less significant.

Under the title: “ Randomized Trials or Observational Tribulations” the NEJM in an editorial²⁹on two papers ^{30, 31}in the same issue (June, 2000), asserts that the results obtained with control trials and random observations are quite comparable.

Is the use of a placebo group unethical  ?

This question is asked more and more lately. The most articulate criticism has been mounted by Rothman and Michels³²of Boston University based on the Declaration of Helsinki concerning the ethics of human experimentation, which was adopted by the World Medical Association in 1964. The declaration was revised in 1975, and again in 2000 (Edinburgh, Scotland, www.wma.net ), amid sharp debate. An international conference on the implementation of the new provisions of the declaration was held in Pretoria, South Africa in March 2001,^33,34The Declaration demands that “in any clinical study, every patient, including those of a control group, if any- should be assured of the best diagnostic and therapeutic methods” and in the Edinburgh new version “The benefits, risks, burdens and effectiveness of the new methods should be tested against those of the best current prophylactic, diagnostic and therapeutic methods”.         

The literal interpretation of that requirement precludes the use of a placebo if an active treatment is available.  The new provisions are stricter and are considered “too rigid” by many. Several groups, including FDA, do not want to accept those restrictions. The placebo is too powerful!

The Sept. 19, 2000 issue of the Annals of Internal Medicine has two articles by two FDA members who discuss the subject extensively^{35, 36}; an editorial by R. Simon³⁷of the National Cancer Institute, and a report on “ The Ethics of Placebo-Control Trials”³⁸.

The inclusion and exclusion criteria usually determine which patients should be accepted in, or excluded from a clinical trial e.g. life-threatening conditions, severe septic cases, or analogous situations are not allowed in a randomized control clinical trial, especially in a trial that has a placebo arm.

The scientific community seems to have reached a consensus that the placebo control use is always unethical in severe illnesses for which there is a treatment that improves survival, or ameliorates morbidity.

Active-control equivalence trials ( ACET). These trials compare a new treatment with an existing active treatment. The new should prove superior, or at least equivalent to the existing and accepted one.  It seems to be conceded that this frequently used method plays an essential role.  Such a search for new drugs except for the purely commercial purpose (the “me too” principle), aims at efficacy, pharmaco-kinetic improvements or a reduction in toxicity, which do not necessitate the use of a placebo (control) arm . A good example of ACET are the many and successful hypolipidemic drugs, which have been introduced to the market in the last few years. Although the differences between them are not big, the market and the need for them are great and hence the offer of better substances is welcome and profitable.   In trying a new drug, the use of a placebo is proposed when there is already an effective drug, but with an uncertain and moderate efficacy and if the new treatment is not expected to be much superior. If the existing treatment is clearly effective and well established, the comparison should be with that agent (ACET). Here there is no justifiable reason for a placebo (control) arm ^30,31. 

The equipoise principle.  A fundamental ethical and scientific principle of human experimentation states that the patient should be enrolled in a randomised, controlled trial only if there is substantial uncertainty about which of the trial treatments would benefit a patient most ^39,40

A non-treatment-non placebo arm is introduced to isolate and control the placebo effect. Because of a growing criticism of the placebo effect, many have suggested that a third arm be included in the randomized clinical trial (RCT), i.e. a group that does not receive neither the substance under trial, nor a placebo ^{41 .}  Such a method does prove that no placebo effect exists.  Our confidence in the “powerful placebo” is being shaken and we are being forced to discuss the possible existence of regression to the mean, natural history, or concurrent interventions.

In the last issue of New England Journal of Medicine (September 20,2001 ), the problem of ethics in withholding existing treatment in placebo control trials, especially as it arose after the stricter criteria of the revised Declaration of Elsinki, is discussed in an editorial⁴²and a Sounding board article⁴³.

It is argued that where there is an active drug already a middle ground to establish placebo-control can be found.  As Emmanuel and Miller of the National Institutes of Health propose in the sounding board article “placebo-controlled trials are permissible when proven therapies exist, but only if certain ethical and methodologic criteria are met”.  I cannot enter into details, but their arguments are not convincing, as they favor placebo use, even  when there is an  active substance to compare with.         

Informed Consent is the cornerstone of the code of Nuremberg. It is essential to obtain a truly informed consent from the participant in any human experimentation. This does not always happen.  Often participants are not explicitly informed as to the consequences, benefits, or risks of the trial.  As one critic has noted: “Obtaining a signature on a paper does not ensure that a participant understands the proposed research” ^{23 .}       

As it has been mentioned already customarily during the recruitment of participants, CROs do not make explicit information available to the patient. On the other hand, in developing countries, many participants cannot write, or, for that matter, understand what the study is all about. In a critical analysis of the concept of informed consent as it applies to the clinical trial, Truog and coworkers ask whether it is always necessary to obtain such consent in RCT⁴⁴. They argue that a physician, when choosing a form of therapy always conducts an experiment. During everyday practice e.g. in a acutely ill patient in an ICU the physician might decide to apply a new method that he has read about recently. He may do so if the patient or his agent has given a general consent. He does not need approval by the Institutional Review Board (IRB).  However, if he/she wants to determine which of two commonly used antibiotics works better in acute bronchitis, he/she must prepare a protocol, obtain approval from IRB, and seek written consent from the participants. Studies have shown that patients rarely demonstrate an adequate understanding of consent forms. Although this reasoning looks valid in such instances, we cannot waive the protection offered by informed consent which safeguards patients from scientific exploitation.

The National Bioethics Advisory Commission has proposed new safeguards for clinical research with adults who are unable to consent. This issue arises when an important research project concerns people who cannot consent or dissent. Wendler and Prasad in a publication in the October 2, 2001 issue of the Annals of Internal Medicine, discuss the guidelines proposed by six groups for such patients and they endorse six core safeguards, 1) institutional risk-benefit assessment, 2) consent assessment, 3) necessity requirement, 4) proxy decision maker and sufficient evidence of patients’ remaining preferences and interests, 5) respect for patient assent and dissent and 6) independent monitors. They conclude that “In the absence of specific safeguards, research with adults who are unable to consent presents an increased potential for subject abuse. However, inappropriately stringent safeguards could halt important research and block improvement in medical care for the very groups the safeguards are designed to protect”.^44a

Informing vs counselling the patient comes up often when discussing a randomized clinical trial.

The expert advice of the personal physician, especially if he is a specialist (e.g. oncologist ) usually prevails over the proposal to conduct an RCT. It is not possible that in this circumstance the physician informs but does not counsel his patient. On the other hand the line between informing and persuading is a thin one. 

Protection of Research Subjects

The participans in RCTs are not always informed explicitly about the risk of the experimental treatment. Of course, often even the investigator may not know what this risk is.  The tragic death of an 18-year-old boy, during gene therapy, greatly moved the authorities and all the scientific community. In a Sounding Board article in NEJM⁴⁵, the then Secretary of Health and Human Services (USA) Donna Shalala discussed at length the safety of patients in clinical research. “This young man’s death led to the discovery by National Institutes of Health of many hundreds of unreported adverse events among volunteers enrolled in gene-transfer experiments”

Participation of the patients.

“ HIV-AIDS changed forever the expectations of consumers in clinical research. Instead of participating in clinical trials as “subjects”, consumers became equal partners with their physicians”⁴⁶.  Activist HIV-AIDS patients succeeded in having their terms accepted and somehow have opposed paternalistic behavior in medical research, in part because the nature of the infection, which was acutely fatal did not allow for the bureaucratic delays of the past. They have pressed for more active research and for quicker drug authorization by FDA.  They also obtained compassionate release of not-yet-thoroughly-studied drugs.

This participation of the patient-activists has had both positive and negative results. A positive effect is the shortening of the time of drug authorization by FDA. In 1986, on average, 34.1 months were required for such authorization; however, by 1999 that time came down to 12.6 months.

Recently in Pretoria, South Africa activists have helped to win a “moral victory” as Lancet characterizes it⁴⁷when the Government took action in the courts against 29 international pharmaceutical companies over the price of the antiretroviral drugs.  Breast cancer has been another arena of strong patient activism.  Here “The contributions of US consumers come at all levels, in the clinical trial process-study design, steering committees, institutional review boards etc.” Unfortunately modern medicine (even Lancet⁴⁸) speaks about consumers and subjects. Also the term “client”, is freely used instead of “patient”.  The method, RCT and specifically that with a placebo arm, which is the ultimate in clinical trials, may become an end in itself ⁴¹. A recent example of a trial of surgical vs medical intervention in the treatment of epilepsy⁴⁹is relevant. As has been documented in many published reports the surgical treatment of epileptic seizures is safe and effective. Nevertheless it has not been used widely because there has never been a randomized controlled trial.

“In this regard, surgery for epilepsy has been the victim of its own success” ⁵⁰.

The principle of equipoise i.e. honest doubt about the outcome, is required for the construction of an ethical randomized controlled trial. Most epilepsy centers report rates of freedom from seizures in 70 to 90% of those operated on.”Given the fact that uncontrolled epileptic seizures may increase the risk of death by a factor of almost five, how can a patient with drug resistant epilepsy who is referred for surgical treatment be randomly assigned to continued pharmacotherapy?”⁵⁰                   

The authors devised a way out of this impass. The waiting list for surgery in their institution exceeded one year. Consequently, they believed it was ethical to assign 40 patients with temporal-lobe epilepsy to a medical treatment protocol during the one year of expected delay without introducing additional risk and assign another 40 to immediate surgery. The editorialist’s title: “Finally, a randomized CT…”^50, reminds us of the fear that RCTs  may become an end in itself , not a means to an  end ⁴¹.

EPILOGUE

I would like to conclude by letting a participant in three clinical trials for breast cancer speak about her experience. In the literary column of the Annals of Internal Medicine “On being a patient”, a 50 year old registered nurse makes important relevant points ⁵¹. “I underwent a left mastectomy, a portacath  insertion and dozens of tests and began an aggressive regiment of experimental chemotherapy - all within 6 weeks. At my first visit to the oncologist, I was filled with fear. My oncologist…. was kind, gentle, knowledgeable, and informative ….. He explained all the risks and answered all my questions, except the most important one: “Will this work?” Of course, I knew he couldn’t answer that question… But this was my doctor giving me his best advice. So I said yes and enrolled in the study…. I achieved remission and stayed there for a couple of years.” After a second successful trial for lung and lymphatic metastases, a window of treatment freedom was interrupted by brain metastases discovered on a routine CT scan.

“He presented me with treatment options, suggested I participate in a clinical trial, explained the details and the risks ….. once again, I was experiencing overwhelming fear and anxiety, hearing uncomfortable things, and being forced to make life-altering decisions on the basis of opinions of unfamiliar people. Yet, this was my doctor giving me his best assessment of my options. Once again, I said yes. It didn’t take long to determine why this was not a popular study ….. One of its side effects is turning skin green….I found myself unable to inform my friends and coworkers of this newest development”.

“ As a cancer patient and research participant, I am here to tell you .… that what really makes a difference is what you , my physician and clinical researcher, can do for me. You are the key to my future. I’ll fight the good fight as long as you supply the ammunition to win the battle- surgery, chemotherapy, radiation, tests, medications, and information…. I depend on you to do this in a positive, nurturing manner. Make sure you make each patient your most important patient for that moment. Make me feel special – I am not a “subject”…. Provide information…. my greatest fear is not being informed of all the options, missing the one treatment that could make a difference…. Prepare the informed consent form carefully. Make sure it is thorough and easy to read, and will remain confidential  ….. Explain every detail, including the likely costs and whether or not they will be covered by insurance.

….. Encourage a second opinion. Remember, I have just met you, and you are delivering an overwhelming message. Give me time. Allow me to disagree, even though you think your clinical trial is the best option. Many patients are afraid to say no out of fear of disappointing their physician, and they worry that if they don’t agree, their physician will not treat them as well, if at all ….. Show compassion and understanding to help dissolve my fears and anxiety”.

As in all of medicine, what makes the difference is the physician and his attitude. If s/he is highly motivated and faces the patient as a suffering fellow man, not a client, or a subject, even more if he feels him as his neighbor whom he should love as himself, then he will practice good medicine, a real humane medicine.

Then he will construct and execute an ethical randomized clinical trial, if it is really necessary to prove the uncertain, and he will handle experimental drugs with real loving care.

If he is a mere technocrat, perhaps a great scientist, capable of handling all molecular and sub-molecular knowledge, but without due respect for the suffering man, he may end up in real criminal actions.

In an older issue (Fall, 1990) of Humane Medicine⁵², G. Stephens presented the view that unless we stick to the Golden Rule, we cannot practice good medicine, that is true for the clinical trials as well.      

In his most interesting and very important article: “Compassion and Mercy in the practice of Medicine”, in the first number (2001) of the electronic edition of Humane Health Care, Professor D. Oreopoulos⁵³ emphasizes the proper way and attitude to the patient, which are no other than compassion and mercy, the real agape we owe to our fellow man. That of course, applies first and foremost to the clinical trials.

George K.Daikos, M.D.
12 Stratiotikou Syndesmou street , Athens 106 73 , Greece
Tel. 00301 3637024 , Fax. + 3628108 . e-mail: daik@otenet.gr