Hi Mojtaba,

This is a wonderful question.  My feeling is that it is absolutely not ethical if the human test subjects are participating in the trials because they are desperately in need of the drug treatment and they are poor and uneducated tribal people who do not understand that they may not actually receive the treatment so desperately needed (so desperate that they agree to serve as guinea pigs for experimental drugs).  The immorality is, of course, compounded when a company continues to give placebos after the drug has been proven successful.  Glaxo-Kline continued to give placebos to pregnant women in Ghana even after the AIDS drugs being tested were proven to be effective in preventing a mother from passing the HIV-AIDS virus to her fetus.

Gwen

A very interesting question indeed, from my point of view, the use of placebos is absolutly ethical as long as one does not knowingly increase the overall danger or suffering of an individual patient...

For example, if clinical studies of an expensive and secondary effected medicine do show an empirically observed chance of 75% to help the patient. But on the other hand have an 25% chance to provoke critical secondary effects, we are still in the range of 'guessing' regarding the scope of application, So to my mind, it is absolutly ethical to test a placebo to evaluate it's performance in comparison to a proprietary commercial medicine.

Furthermore, I would tend to say that it would be unethical to not evaluate the performance of a placebo compared to a full-priced medicine ...

This is an interesting and challenging question. Being from a rehabilitation background, I share a different opinion in this regard. I believe if there is an established method of intervention, that should serve as the control. In rehabilitation, we use what is known as an "Active control group" Here, the control group receives what is an established intervention rather than providing a pure placebo intervention. (Clinical Rehabilitation 2009; 23: 675–680)

I believe this also replicates the usual practice. Most patients are never on "no therapy" in clinical practice. Therefore, it is important for the clinician to be able to decide between various interventions. Thus, the utilisation of "active control groups" may in fact be more clinically relevant and also reduce ethical concerns with regard to witholding established treatements from deserving patients.

I never considered randomizing a patient to a placebo knowing that there is already a standard treatment in use. For example- knowing that a person is hypertensive and knowing that there is amlodipine, would we subject a hypertensive patient to be randomized to receive either the placebo or amlodipine- absolutely unethical. It would be best to randomized  the patients as an add on therapy and once more concrete resutls are available than it can be randomized for a head to head study without a placebo. Just my 2cents worth

As an additon to my prior post, I must point out that I do not have a medicinal background. Therefore, I might miss the correct technical terms and detailed information about the common methodology on how the effectivenss of an 'established treatment' is assessed.

But as I understand it some kind of 'ground truth' is needed? I suppose this is basically done by comparing the results of different test-groups?

Group A is treated with some pharmaceutical ingredient, Group B does not receive the ingredient. Disregarding secondary effects, the tested ingredient can be considered effective if a significantly higher percentage of Group A show positive effects compared to Group B.

As I understand it, another Group C (treated with a placebo) is needed in addtition to Group A and B, to be able to really appraise the effectiveness of a treatment. If 50% of Group A show a positive effect while at the same time 50% of group C show a positive effect, I would hardly consider the treatment as effective - or did I understand that incorrectly?

That is basically what I wanted to express with my sentence:

'I would tend to say that it would be unethical to not evaluate the performance of a placebo compared to a full-priced medicine.'

I agree with Muhammad Awais.  I doubt ant any review committee would agree to a placebo use if there is an effective treatment available.  This would be highly unethical for the patient not to receive the standard of care in a trila.  Mhuammad makes the excellent point that the proper handling of the trial would be to use non-inferiority testing where we are attempting to ascertain if the new treatment is no worse than the standard.   The trial should be of effectiveness and the question of cost comes in because we are looking for an alternative at least as effective as the more expensive drug or theraphy.  If the tial proves that both treatments are relatively the same in terems of outcome and there are fewer side effects the decison on whether to promote this treatment becomes a policy issue..

When there is no treatment available or when you are looking to test a compound siuch as say a vitamin then there is no ethical issue in using a placebo. You can imagine a trial such as beta carotine intake to prevent a condition like lung cancer. We did such a trial where we had a placebo vs a beta carotine preparation and the study population were current smokes.  Unfortunately, contraty to expectations the beta carotine actually increased the incidence of lung cancer.  But that is a much more complex story. When no effective drug theraphy is available then a placebo arms presents no issue. 

This was an important question.  In the US all trials must go through an institutionla review board.  They consider the options and ethics of the study. Basic requirements for informed consent must be adhered to to prevent recruiting people who do not understand the trial and any potential risks they would be exposed to.  Reading level and comprehension are critical so the issue of recruting poor people who do not understand is removed.  No matter how careful we are in our design of clinical studies we are often confronted with  unethical investigators such as those mentioned in some responses.  All we can do is ensure that what we do is for the good of the patient or the populace and that we do not take advantage of participants to fulfill our own ambitions.

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Placebos are often used in randomized double blind cancer "add-on" trials designed for drug approvals, where the investigational  arm gets standard of care plus the new agent, and the control arm gets standard of care plus placebo.  

Sometimes patients perceive the term "placebo' to mean "no treatment" when in fact the use of placebos does not preclude standard of care.  In cancer, at least in the US, it is not considered ethical to not treat a patient if a standard of care treatment exists.  But there are situations where "no treatment" actually is standard of care, for example, following adjuvant treatment in early breast cancer.  In this case, it would be ethical to do a trial comparing "no treatment" (i.e. standard of care) to an intervention that might lower the risk of recurrence--for example extending hormonal treatment beyond 5 years vs. placebo.  

This is an important point.  Standard of care is the other arms.  You can add to this as Musa said in his cancer trials something like platelets so that the patient would get infusions whether on the treatment or the placebo standard of care arm.  Several people have commented on the need to provide available therapies for cases where they are available. In the case that Musa mentioned where there is o treatment option, or this is the standard option then a placebo arm would be an ethical option

In my view, the presumption should always be that the control arm in a trial should be 'standard of care' rather than placebo. Now, in specific cases there might be a compelling reason why the evidenced-based standard of care is not feasible in a particular setting. In that case, with community consultation and consent, the researchers could argue their case to the relevant ethics committee, who could then determine whether it was justified in this particular instance. Usng a placebo where an evidence-based treatment could easily be  a form of exploitation, so it is very important that is exceptions are made to the rule of 'standard of care' they are carefully justified and that the decision includes community voices, not just those of the research establishment. I agree with Gwen that placebo-controlled trials in mother-to-child HIV prevention when established interventions had been proven were highly problematic.

It depends on the situation. For examples, evaluation of drugs - whether they are antiallergic agents or adrenergic receptor antagonists - needs placebos. Your question encompasses substances other than drug candidates I am assuming. Dietary intervention studies  do not  have placebos. Placebo here is meaningless, because of baseline factors. In certain studies cross over and randomization are done. In prophylactic studies, placebo is common (placebo for vitamin C). Placebo does not serve its purpose in certain evaluations. . Creating a placebo for a chocolate extract has its own problems. In the case of wine or grape seed and skin components evaluated for endothelial function the coming up with an appropriate placebo is a challenge. Propranolol is a therapeutic agent; it has been used in the treatment of several conditions.

I agree with the consensus opinion that has been expressed - that an active control would be more appropriate (ethical) than a placebo, where a treatment known to be efficacious exists.

As a medical educator who has been teaching both ethics and research methods, I also wanted to contribute my general frustration at the textbooks (in both disciplines) on this topic.    Most of the core texts, because they are largely outdated, overemphasize the role of placebos in clinical research and some give examples from the 70s and 80s.

Unfortunately this may have lead to a generation of newly qualified medics who have outdated thinking in regard to the use of placebos.   This is especially true in international medical education, where there can be even more lag in teaching new approaches to ethics and research.

A very topical question posed by Mojtaba . As an ethical requirement the generic advise would be:  no, it is not ethical (unless it is for a very mild condition in which the 'patient will not be subject to any risk of serious or irreversible harm (Helsinki Declaration).

One of my papers is on this issue. Below I  write some extracts from it regarding the ethics of placebo control trials in the light of the  principle of utility,beneficence, justice, non-maleficence and equipoise.

Placebo controls and utility

An argument in favour of conducting a placebo control trial (PCT) is based on a principle of ethics, that of utility, which is to always produce the maximal balance of “positive value” over negative value and that PCTs provide quicker and more reliable answers to scientific questions – PCTs are more efficient. However, using a utilitarian calculation to justify placebo use especially in conditions that result in morbidity, and/or mortality, violates the principle of beneficence, even if consent is obtained. It can be argued that ethical principles sometimes conflict with the scientific rigour of the trial: this argument is based on the assumption that PCTs are methodologically superior and hence beneficence and informed consent may be trumped by scientific rigour and social utility. However, the methodological superiority of PCTs has been questioned (see Michels K B, Rothman KJ. Update on unethical use of placebos in randomised trials. Bioethics.2003 Apr;17(2):188-204. Howick J. Questioning the methodologic superiority of 'placebo' over 'active' controlled trials. Am J Bioeth. 2009 Sep;9(9):34-48. Freedman B, Weijer C, Glass KC. Placebo orthodoxy in clinical research. I: Empirical and methodological myths. J Law Med Ethics. 1996 Fall:24(3):243-51. Nonetheless alternative trial designs can also be formulated such as ‘add-on’ trials.

It is also noteworthy that the phenomenon of placebo effect, wherein the placebo mimics the active drug response can contribute to the variability in outcome data. This has implications: if the placebo effect is strong then the number of patients required to overcome this effect will increase.

Placebos and justice

The principle of justice may be violated by conducting PCTs: it is plausible that if an active control trial in developing countries identified effective but less expensive and less toxic drugs, then these regimens would be implemented in the developed world. Or, if the superiority of one drug were to be established over the other when both “ran” against each other, the result could have implications, both therapeutic and economic, in developed countries. This can have major financial implications for companies that have already established a market for one drug. If the cheaper regimen turns out to be more effective than the established treatment, or if it turns out to be equally effective, then the companies could lose substantially. Take the example of the HIV/AIDS trials, the success rate in reducing mother-to-child transmission was considerably higher in developed countries where the 076 regimen was in use; but not in developing countries, where a short regimen was in use. However, the point to note here is that the knowledge generated through the use of the short regimen in developing countries was used by researchers in developed countries to create more effective treatment regimens for patients in developed countries (see Landes M. Can context justify an ethical double standard for clinical research in developing countries? Global Health. 2005 Jul 26;1(1):11.

Placebos and non-maleficence

PCTs are also beset by another consideration that is both practical and ethical: participants in a trial need to be informed that during randomization they may be assigned to the placebo arm. However, “potential participants may be more likely to consent to a trial where they are certain to receive an ‘active’ treatment than they are if they might get a ‘placebo’” (31: 43). There may be problems of noncompliance when these patients either do not take the “placebo medicine”, or withdraw, or covertly seek treatment (see Howick J. Questioning the methodologic superiority of 'placebo' over 'active' controlled trials. Am J Bioeth. 2009 Sep;9(9):34-48. In the developing countries especially, it is the provision of treatment that impels patients to enrol in trials.

Placebo and equipoise

An ethical prerequisite for starting a randomised controlled trial is clinical equipoise, a state in which the medical community, on the basis of available data, is equally poised between the two treatments being tested. “As a normative matter, it defines ethical trial design as prohibiting any compromise of a patient’s right to medical treatment by enrolling in a study…these principles allow for testing new agents…. At the same time they foreclose the use of placebos in the face of established treatment. (Freedman B, Weijer C, Glass KC. Placebo orthodoxy in clinical research. I: Empirical and methodological myths. J Law Med Ethics. 1996 Fall:24(3):243-51).

Equipoise does not exist because when one compares the test drug with ‘no treatment’ (placebo) then the advantages of the former over the latter are already established: placebos cannot treat a disease. Furthermore, randomized controlled trials are phase III trials by which time preliminary data from earlier phases provides some information about the potential benefits of the test drug that would suggest that the new therapy is better than placebo .Conducting a PCT in the light of such evidence -- where equipoise is lost -- is ethically tenuous.

Mojtaba,

So far, you have already received very nice feedback. To put it in simple terms, if you are doing a study you need "something" to compare your treatment/intervention to, right? the choice of what that "something" is has to be guided by the subject/participant best interest. Usually drugs that are approved or are in the market are acceptable and if you want your treatment to go in the market you probably want to compare it to something already established and show it is at least as good as that or even better.

Hope this helps.

Dear Mojtaba

Congratulations for raising this  question which is clear enough  and  some answers are not straight to the point.  . 

Is it ethical to use placebo in clinical trials on conditions which have current evidence based treatments?

Certainly under this specific conditions it´s not ethical. There are plenty of alternatives  for studing and or compare dtugs already available.

Can you imagine  prospective,  double blind....for

hypothireoidismo

male hypogonadismo

Female  recurrent urinary infection

TRT for those  presenting with anorchismo.

Prostate biopsy with and without profilatic antibiotics.

I wonder if each one could read  again Mofjaba  question.  

thanks

The question itself is the answer. If there is already a standard care available for the disease (lets say cancer), then what is the purpose of comparing our drug (say XYZ) with placebo. Every researcher (or pharma company) would like to prove that XYZ is more beneficial then standard of care medicine in cancer. Proving it works better than the placebo, makes no sense. On the other hand, if there is no established drug for a condition, then you can use a placebo, but still it would be unethical....Ethics committee, will want the use of best possible available care as a comparator. And that is why most trails use the 2 arm study.....standard of care + placebo compared with standard of care and XYZ

If we use patients in a placebo study knowing we do have good treatment options for the particular disease the participant is suffering from we are actually withholding treatment........the Tuskegee study comes to mind....

Placebo is a misnomer, being cared for is what makes all the difference. For all intense and purposes being given a placebo is pragmatically speaking (in absolute terms) usually as good as being given the real thing (with a few notable exceptions). The physiological effect of the placebo is the stimulation of "self-healing mechanisms" which have been described in the ever increasing psychoneuroimmunology literature, and works even if the patient knows he is "only" given the placebo [1]. The ethical question, for me at least, relates to the issue why one needs to subject large numbers of people to placebo-controlled trial just to find some miniscual absolute benefit defined by a p-value. Drugs that work, like a parachute, don't need a trial, especially not a placebo-controlled one. What are the ethics of doctors proclaiming to practice "evidence-based medicine" as a disguise for being "sales people" on behalf of drug companies?

[1] Placebos without Deception: A Randomized Controlled Trial in Irritable Bowel Syndrome. http://www.plosone.org/article/info%3Adoi%2F10.1371%2Fjournal.pone.0015591

it is unethical to allow someone to suffer if we can avoid