Ethical Deliberations on Using Placebos in Clinical Trials

Clinical Researcher—December 2018 (Volume 32, Issue 10)

PEER REVIEWED

Pranali M. Wandile, MS, CCRP

 

A placebo-controlled, double-blind, randomized clinical trial is the historical gold standard for clinical research, and is fundamental to the development of evidence-based medicine. Apcalisz.com research has shown that placebos produce strong, genuine psychobiological effects in both laboratory and clinical settings. Although the approach is scientifically sound, ethical concerns still arise in some cases which outweigh the benefits of this trial design.

According to the critics of placebo-controlled trials (PCTs), if a proven, effective therapy exists, a placebo should not be used. They further stress clause 33 of the Declaration of Helsinki, which states that, “The benefits, risks, burdens and effectiveness of a new intervention must be tested against those of the best proven intervention(s).”{1} It goes on to stress that, “In any medical study, every patient should be assured of the best proven diagnostic and therapeutic methods and no patient should suffer from unnecessary pain.”

However, the proponents of placebo-controlled trials argue that such trials are sometimes essential to prove efficacy and safety of the study intervention. In the absence of PCTs, every adverse event (AE) will be causally linked to the study drug; meanwhile, PCTs are expected to provide a clearer picture of the safety, efficacy, and AEs associated with the investigational drug. In the absence of such trials, ineffective drugs may come in the market, while effective drugs are kept out.

In today’s rapidly developing research and global drug development industry, it’s crucial for regulatory agencies to standardize their recommendations and guidelines for the use of placebos in clinical trials. Implementation of these guidelines will benefit almost all the stakeholders of clinical research, including human subjects, investigators, members of institutional review boards (IRBs), and sponsors.

Background

Research has shown that placebos produce a strong psychobiological effect in both laboratory and clinical settings.{2} In the 19th century, placebos were prescribed along with remedies which had little therapeutic value, but following World War II, the use of placebos has been seen mainly in clinical research. Psychological factors have been shown to play a major role in the development and progress of such disorders such as psychiatric illness, peptic ulcers, hypertension, cardiac diseases, diabetes, and asthma.{3–6}

In 1962, after the advent of the Kefauver-Harris amendments, there was a paradigm shift in the new drug approval process. For the first time, companies were not only required to prove the efficacy, but also the safety of new drugs for approval by the U.S. Food and Drug Administration (FDA). Thus, the requirement of controlled clinical trials for the approval of investigational products began.{7}

The first rules published by FDA in 1970 identified five types of controls that could be utilized for adherence to the standard of “adequate and well-controlled” trials.{7} While FDA recognized the inconsistencies in assumptions which result in clinical trial interpretations while utilizing different controls such as placebo, dose-comparison, active, historical, and no treatment, it also acknowledged the placebo control as the indispensable tool.{8}

However, some examples of PCTs have triggered serious concerns about their use. For example, in 1996, a patient was enrolled in a clinical trial for Parkinson’s disease which involved injection of embryonic cells into the brain. Prior to study participation, the subject was aware of the possibility of being allotted to the control group. A year after the study’s termination, the subject found that he had not received any beneficial treatment for his disease. During his neurosurgery, there were no embryonic cells injected into his brain since he was randomized to the control group. In this trial, out of 40 study participants only 20 patients received actual treatment.{9}

In the above example, it is clear that those 20 unfortunate Parkinson’s disease patients in the control group would have hoped and expected to receive some kind of treatment. This situation raises several questions: In general, under which medical conditions and circumstances are the use of placebos acceptable in clinical trials, and what are the physicians’ responsibilities in this regard? Further, in a new interventional treatment trial of critical illnesses or irreversible diseases, should a placebo arm be considered as a part of treatment?{9}

The remainder of this article addresses various situations in which the use of placebos in clinical trials is acceptable versus cases in which it could be unethical. Also discussed are FDA and other regulatory guidelines and views of various research experts.

FDA Guidelines for Ethical Use of Placebo

In 1979, the Belmont Report identified the principles of autonomy, beneficence, and justice as the essential principles of biomedical ethics (for more details about this report, see the article on “Revisiting Ethics and Human Subject Safety in Clinical Research” which can also be found in the December 2018 issue of Clinical Researcher).{10}

In 2008, the U.S. Office for Human Research Protections (OHRP) guidelines also stated that, in controlled clinical trials, the subjects must be informed about the risks of participating in a placebo group. The use of placebos must be justified by a positive risk-benefit analysis. Once the evidence of efficacy of the trial therapy is available, it is unethical to continue placebo treatment.{11}

Though the FDA declared in 2008 that foreign clinical trials for New Drug Applications should follow the International Council for Harmonization’s tenets of Good Clinical Practice (GCP) rather than the Declaration of Helsinki, the agency hesitated in binding U.S. clinical trials regulations to these guidelines. As what are generally considered GCPs can change without FDA approval, FDA can set its own agenda about placebo controls based on public opinion.{12}

As an example, FDA insisted on placebo controls for antidepressants and proton-pump inhibitors, because it is difficult to read the results of different equivalency trials for such products due to extensive variations in the responses of study subjects to the active drugs or to placebos.{12}

A Closer Look, Part I: Situations in Which Placebo Use Can be Ethical

According to medical ethics, a physician is legally obligated to act in the best interest of the patient. Hence it’s important to know what kind of situation can allow a physician to prescribe a placebo.{13}

The Council of International Organizations of Medical Sciences (CIOMS) created “International Ethical Guidelines for Biomedical Research Involving Human Subjects” which mention that the use of placebo in clinical trial is acceptable in the following situations{14}:

When there is no proven, effective intervention available for the condition under study, or when an established treatment is added with placebo and investigational treatment in two different arms. This includes trials of the treatments shown to be efficacious in some populations, but where the data cannot be extrapolated to the population of interest. The use of placebo in this case is typically not ethically controversial.{14}

When withholding an established, effective intervention would expose subjects to, at the most, temporary discomfort or delay in relief of symptoms. Or, we can say, when there are negligible negative consequences of being untreated or receiving no treatment. For example, clinical trials for allergic rhinitis or common headache.{15}

[Placebo usage is not acceptable in a clinical trial where there is a possibility of serious or irreversible harm{14}; for example, in a trial of medications for a serious condition. In trials of new interventions for conditions such as congestive heart failure, if reasonable effective therapy is available, then researchers should compare the new intervention with the available, effective therapy. It could be harmful to use placebo in this situation.

There are some conditions (hypertension, diabetes, etc.) not considered immediately life threatening, but which could eventually be fatal if not treated with effective medications in a timely manner. It is ethical to use placebo for these conditions for a short duration—a matter of months, rather than years.{11}]

When placebo use has compelling methodological reasons which do not expose study participants to risk of excessive harm. For example, compelling methodological reasons may exist for the use of placebo when research participants are not deprived of interventions they would otherwise receive, with the intention to develop interventions that will benefit the host population. In the U.S., Zidovudine reduced HIV transmission rate by two-thirds, however it doesn’t produce the same effect in developing countries due to economic factors. PCTs are needed in such cases.{16}

The use of placebo controls is warranted in trials of new treatments for medical conditions when responses to both established treatments and placebo treatments are erratic. For example, depression trials have fluctuating and high placebo response rates. It is common to have inconsistent effects whereby approved antidepressants show superiority to placebos in some trials, but not in others.{17,18} In reference to this phenomenon, please see the sidebar about assay sensitivity.{19}

The Vioxx Gastrointestinal Outcomes Research (VIGOR) trial showed a five times greater incidence of myocardial infarction in the rofecoxib (Vioxx) group as compared to the naproxen group.{20} Naproxen inhibits platelet function, and therefore could have a myocardial protective effect. Due to the lack of a placebo group in this trial, it was unclear if the increased risk of myocardial infarction was due to rofecoxib or due to the naproxen-related, decreased risk of myocardial infarction. Later, based on a unpublished results of a PCT of rofecoxib (“Adenomatous Polyp Prevention on Vioxx (APPROVe)”), Merck decided to withdraw the drug because of an increased cardiovascular risk.{20–23}

If one stuck to the belief that an existing effective therapy is always ethical and preferable, the APPROVe trial might not have been conducted and Vioxx would have caused much more significant damage in later days.

In India, investigators of an acute mania PCT of risperidone were condemned for unreasonably exposing participants to the risks of non-treatment. The investigators defended their work on the basis that the placebo group was required, as patients with mania generally show a high and variable placebo responses, making it difficult to identify their responses to an active medication.{24–26}


Assay  Sensitivity

Assay sensitivity is a property of a clinical trial which is defined as the ability of a trial to distinguish an effective treatment from a less effective or ineffective intervention. Without assay sensitivity, a trial is not internally valid and is not capable of comparing the efficacy of two interventions.

Research has shown that many classes of drug have problems with assay sensitivity, including analgesics, antiemetics, anxiolytics, antihypertensives, hypnotics, antianginal agents, angiotensin converting enzyme inhibitors for heart failure, beta-blockers given after myocardial infarction, antihistamines, nonsteroidal asthma prophylaxis, and motility-modifying drugs for gastroesophageal reflux disease.

If equivalence or noninferiority designs are utilized in the clinical trials of drugs which have assay sensitivity problem, it is possible that ineffective drugs will be approved, and it would be unethical to make such drugs available to needy patients based on the flawed science.


Issues

The World Medical Association (WMA) has stated that the non-availability of drugs should not be used as an ethical reason for PCTs, as this may exploit patients and poor countries may become research laboratories for developed countries.{13}

The use of placebos has also involved a risk due to the investigator self-reporting system of continuing review reports to IRBs. A U.S. Department of Health and Human Services’ Office of Inspector General report stated that, in investigator self-reporting system, IRB members are not conducting thorough reviews of previously approved research studies, they generally do not visit or audit research sites, and they rarely oversee the informed consent process.{10}

One of the purposes of continuing review reports is to make sure that a patient’s further participation in a study does not increase his/her health risk. This is very important, especially when the patient is randomized to a placebo-controlled arm lacking investigational or standard therapy. Such insufficient continuing review can mask unnoticed cases of improper, unethical conduct in clinical trials, which can ultimately jeopardize subjects’ health.{10}

In developing countries, access to emergency medical services often is not as prompt as it is in the United States or in other developed countries. Thus, it could be challenging for trial participants in developing countries to get immediate medical treatment in the event of a serious AE, especially if those patients were randomized to a non-treatment or placebo arm.

Points of View

When the available treatment is moderately and inconstantly effective, and the new treatment is not expected to be more effective than the available treatment, the scientific motivation for performing a PCT should be strongest.{27}

When the available treatment is moderately and inconstantly effective, and the new treatment is expected to be even more effective than the available therapy, a PCT is not required. In other words, we are trying to make sure that the patients will at least receive treatment which could act on their disease rather than something which is completely inert.

When the available treatment is highly and consistently effective, a PCT is not required in order to establish effectiveness of the new drug.{27}

PCTs may not be considered as a good option for cancer clinical trials under the standards of some professionals. However, the emergence of novel, molecularly targeted anticancer agents makes some cancer researchers believe that PCTs are feasible now.{28}

Dr. Schilsky and his coauthors stated that a PCT is ethically acceptable in cancer only when there is no effective therapy available for that condition. In this case, patients assigned to a placebo group should receive best supportive care for pain and for other symptoms, but won’t receive anticancer treatment. This method led to the approval of molecularly targeted anticancer  agents sorafenib for advanced kidney cancer and sunitinib for gastrointestinal stromal tumors.

Dr. Delon Human, Secretary General of the WMA, stated that a good example of the ethical use of placebo is as part of an “add-on” design for a cancer trial. In this design, all patients receive standard cancer therapy, with study drug intervention and placebo added in other arms of the trial.{13} An add-on trial design led to FDA approval of  erlotinib for advanced pancreatic cancer and for advanced non-small cell lung cancer.{28}

Meanwhile, proponents argue that PCTs are cheaper, easier to enroll for, easier to interpret, and more definitive in their results than active-controlled trials. Some would say that subjects are not harmed by not receiving effective therapy in short-term PCTs. Active-controlled trials, although valuable, informative, and appropriate in many circumstances, often do not provide reliable evidence of the effectiveness of a new therapy.{10,29}

A PCT requires fewer study participants than an active-controlled trial. In disease areas where there are limited patient populations (such as in orphan diseases) and subject enrollment becomes a challenging task, PCTs may be a good option.{30,31}

A Closer Look, Part II: Situations in Which Placebo Use is Unethical

The randomized, placebo-controlled, double-blind study is widely considered to be the foremost operational revolution in clinical research which produces the best evidence for the new treatment.{2} However, situations may arise in which PCTs lack both scientific and clinical merit, and violate the principle of “clinical equipoise.” Their use may be viewed as not only against the principles of beneficence and human autonomy in general, but also as questionable in vulnerable groups such as children, psychiatric patients, and patients suffering from serious conditions.{32–34}

Though the FDA requires PCTs for new indications, there is an issue in randomized PCTs when a control group is needed in order to establish evidence of efficacy and safety for the new treatment. Confusion may occur if the response of a placebo arm is not caused by genuine psychosocial effect, but is a reflection of the natural course of the disease; or a fluctuation in symptoms; or a regression of improvement; or indicative of other concurrent treatments; or the result of a patient’s inconsistent responses while reporting his/her subjective symptoms.{35,36}

Issues

Proponents of PCTs argue that they are essential to prove efficacy and safety of the study intervention. In the absence of a PCT, every AE will be causally linked to the study drug, but a PCT can give a truer picture of the safety, efficacy, and AEs associated with the investigational drug.

PCTs are still important due to the psychological nature of many diseases (psychiatric conditions, peptic ulcers, etc.), and are required in situations when it is difficult to read the results of different equivalency trials due to extensive variations in the responses of study subjects to the active drug. Further, concerns about a drug’s potential to harm, as opposed to its efficacy, may be difficult to validate in the absence of a placebo group.{21}

Conclusion

To summarize, PCTs may be dangerous if used in trials involving serious medical conditions, as they could deprive patients of available, effective therapy due to the principle of beneficence not being followed. Investigators need to be careful on a case-by-case basis, otherwise they could expose patients to unacceptable risks.

PCTs may be ethically acceptable in some situations when a proven therapy is available and there are compelling, scientifically sound methodological reasons which necessitate PCT usage to determine the efficacy or safety of a prophylactic, diagnostic, or therapeutic method. It may be impossible to interpret a drug’s potential for harm and to get a true picture of the AEs associated with an investigational drug in the absence of a PCT.

References

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Pranali M. Wandile, MS, CCRP, is Site Director for Central Valley Research, LLC in Fresno, Calif.