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Think

Assess

 Patient: Autonomy

 Practitioner: Beneficence & Nonmaleficence

 Public Policy: Justice

Conclude

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44. Research & Clinical Equipoise

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The good medical practitioner treats the disease; the great medical practitioner treats the patient who has the disease.
~ William Osler


Abstract

Clinical equipoise exists when there is no empirical evidence or theoretical basis for the superiority of one treatment arm over the others in a therapeutic randomized clinical trial. There is confusion over the threshold of evidence for superiority and whether the primary investigator should be kept unaware of the trial results. Ethicists argue that clinical equipoise is a disingenuous approach as the null hypothesis rarely exists and the threshold of empirical proof is undefined. Clinical equipoise and the null hypothesis are not part of the Belmont Report, Common Rule 45CFR46, or the IRB criteria for human subject protection. The four principles of medical ethics, as outlined in the Belmont Report, are respect for persons with the need for informed consent, beneficence with the need to promote the patient’s best interests and minimize exposing the subject to risk of harm, and justice with the need for fair subject selection. Medical practitioners must understand these principles in order to minimize risk and protect human subjects in medical research.

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Think 

[44:1] Clinical equipoise exists when no treatment arm of a therapeutic randomized clinical trial (RCT) has empirical evidence or theoretical foundation of superior therapeutic efficacy over the other therapeutic intervention(s). This equivocation is called the null hypothesis. The therapeutic randomized clinical trial (RCT) must be stopped once one of the treatment arms has passed the threshold of evidence for superiority so that the superior treatment can be given to the other patients in the inferior treatment arm(s).

[44:2] However, confusion exists as to what the threshold of evidence for superiority is.

  • 1. Is it when the primary investigator is convinced that equipoise no longer exists?
  • 2. Is it when the expert medical community is convinced that equipoise no longer exists?

[44:3] Confusion also exists whether the primary investigator should be kept ignorant about any clinical data reports during the randomized clinical trial (RCT) so that the clinical investigator can sustain the null hypothesis state of mind until:

  • 1. a predetermined threshold of evidence for superiority has been met,
  • 2. a specified period of randomized clinical trial (RCT) time has elapsed, or
  • 3. the expert medical community has come to a consensus on the treatment superiority of one treatment arm.

[44:4] Ethicists argue that clinical equipoise is at minimum a disingenuous approach because:

  • 1. the clinical null hypothesis rarely, if ever exists,
  • 2. the threshold of empirical proof is objectively undefinable,
  • 3. a unified expert medical community does not exist,
  • 4. keeping the primary investigator ignorant about clinical data throughout the trial could: a) increase subject risk to be higher than minimal, b) increase time before getting the superior therapeutic treatment, and
  • 5. equipoise is not a relevant condition for determining the permissibility or impermissibility of research on human subjects; rather, it is the purpose, benefits, and minimal risks to the subject that are the relevant conditions for therapeutic treatment.

[44:5] Clinical equipoise and the null hypothesis is not part of:

  • 1. The Belmont Report, which presents the three principles of bioethics for human subject protections,
  • 2. Common Rule 45CFR46, the federal law for human subject protections that legislates the implementation of the Belmont Report, and
  • 3. The Institutional Review Board (IRB) criteria for human subject protections that regulates and oversees all research on human subjects in the United States.

[44:6] The three Belmont principles for the protection of human subjects are:

  • 1. Respect for Persons: autonomy (informed consent) authorization from the research subject
  • 2. Beneficence: professional researcher obligations of:

        a) beneficence (do good) to the research subject 

        b) nonmaleficence (do no harm) to the research subject, and

3. Public Policy: 4) Justice (fair human subject selection)

[44:7] Clinical equipoise and the null hypothesis are not human protection criteria but rather a methodological criterion that would be accepted by the Institutional Review Board (IRB) as long as the methodology does not negatively impact:

  • 1. Patient: Autonomy (informed consent)
  • 2. Practitioner: Beneficence (do good) & Nonmaleficence (do no harm)
  • 3. Public Policy: Justice (be fair)

Assess
Patient: 1) Autonomy

[44:8] Whether or not research on the human subjects is therapeutic, research practitioners must always attain informed consent from the research patient for authorization. According to the Belmont Report and Common Rule 45CFR46, the research subject must be informed of:

  • 1. procedures to be performed,
  • 2. purpose of the research,
  • 3. risks and benefits of the procedures,
  • 4. alternatives including no treatment, 
  • 5. opportunity to ask questions and to withdraw from the research at any time.

[44:9] The therapeutic research practitioner has the professional obligation to provide only treatment options that will maximize the research patient’s best interests, which is usually health and recovery, and it is from those positive treatment options that the research patient has the legal right to autonomously provide an informed consent decision for authorizing the practitioner to provide therapeutic treatment.

Practitioner: 2) Beneficence & 3) Nonmaleficence

[44:10] Researchers have the professional responsibility not to expose human research subjects to any more than minimal risk, nonmaleficence (do no harm). Minimal Risks is defined by Common Rule: 45CFR46.102(i)

Minimal risk means that the probability and magnitude of harm or discomfort anticipated in the research are not greater in and of themselves than those ordinarily encountered in daily life or during the performance of routine physical or psychological examinations or tests.

This requirement might be impossible to attain when treating clinical patients with greater than minimal risk options.

[44:11] Greater than minimal risk research requires ongoing monitoring by the principal investigator, the Institutional Review Board (IRB), and may require monitoring by an independent Data and Safety Monitory Board (DSMB).

[44:12] The therapeutic research practitioner has a professional obligation to promote and honor the patient-centered patient-practitioner relationship by maximizing the patient’s best interests as determined by the patient’s reasonable goals, values, and priorities.

Public Policy: 4) Justice

[44:13] Justice (be fair) mandates that all research subject selection must be made equitably, with extra legal protections for vulnerable populations.

Conclude

[44:14] Medical practitioners must have the basic knowledge of the four principles of medical ethics that reflect the Belmont Report’s mandate to protect human subjects. Clinical equipoise is a good discussion topic for evaluating critical thinking skills and recognizing that the practitioner’s professional obligation is to minimize risk and maximize their patient’s best interests.

[44:15] In summary, while clinical equipoise serves as an interesting topic for evaluating critical thinking skills in medical research, it is essential for practitioners to prioritize the ethical principles outlined in the Belmont Report. By focusing on protecting human subjects and adhering to these principles, medical practitioners can work to minimize risk and maximize the best interests of their patients in both research and therapeutic settings.

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44. Review Questions

1. Clinical equipoise exists when the treatment arms of a therapeutic randomized clinical trial (RCT) have no empirical evidence or theoretical foundation for establishing superior therapeutic merit for the principal investigator or the expert medical community.

2. Clinical equipoise equivocation between treatment arms is called the null hypothesis.

3. The randomized clinical trial (RCT) must be stopped once one of the treatment arms has passed the threshold of evidence for patient treatment superiority.

4. Ethicists argue that clinical equipoise is disingenuous because:

5. Clinical equipoise and the null hypothesis:

6. The three Belmont principles for the protection of human subjects are mandated:

7. Clinical equipoise and the null hypothesis are human protection criteria.

8. Greater than minimal risk research requires ongoing monitoring by the principal investigator, the Institutional Review Board (IRB), and may require monitoring by an independent Data and Safety Monitory Board (DSMB).

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44. Clinical Vignettes

1. Mr. John Williams, a 65-year-old retired electrician, presents to his primary care practitioner with a one-month history of left-sided weakness and difficulty with speech. A CT scan and MRI reveal an acute ischemic stroke in the right middle cerebral artery distribution. The patient is evaluated by a neurologist and is a candidate for a thrombectomy. The patient is randomized to one of two treatment arms: the standard treatment of thrombectomy alone or a thrombectomy with a novel adjunctive agent that may improve outcomes. The patient is informed of both treatment options and is asked to decide which treatment arm to undergo. What ethical question is raised in this scenario?

2. Mr. David Mitchell is a 60-year-old retired factory worker who presents to the clinic with symptoms of chronic back pain. He has been experiencing pain for several months and has tried over-the-counter pain medications with little relief. A physical examination and imaging studies reveal degenerative disc disease. The clinical differential diagnosis includes physical therapy, spinal injections, and surgery. The ethical question is when can the primary investigator decide to stop the trial and provide the superior treatment to the other patients in the inferior treatment arm(s) in a randomized clinical trial.

3. Mr. Mark Brown is a 55-year-old retired firefighter who presents to the emergency department with complaints of chest pain, shortness of breath, and fatigue. His past medical history is significant for hypertension and hyperlipidemia. On physical exam, his blood pressure is 150/90 mmHg, heart rate is 90 beats per minute, and oxygen saturation is 92% on room air. EKG shows ST-segment depression in leads V4-V6. His clinical differential diagnosis includes acute coronary syndrome, aortic dissection, and pulmonary embolism. The attending practitioner proposes enrolling Mr. Brown in a therapeutic randomized clinical trial comparing two anticoagulant agents for the treatment of pulmonary embolism.

4. Mrs. Hillary Hernandez, a 78-year-old retired teacher, has been diagnosed with advanced stage ovarian cancer. The oncologist suggests two treatment options: chemotherapy and surgery followed by radiation therapy. The chemotherapy has a higher success rate but could result in significant side effects, while surgery followed by radiation therapy is less successful but with a lower risk of side effects. Mrs. Hernandez's daughter, who lives out of town, wants her mother to choose chemotherapy, believing that this offers the best chance of a cure. Mrs. Hernandez's son, who lives nearby, thinks that his mother should opt for surgery followed by radiation therapy, citing concerns about the impact of the chemotherapy on her quality of life. Mrs. Hernandez is struggling to decide which option to choose. Which decision-making approach is most appropriate in this case - should Mrs. Hernandez make the decision on her own, with the guidance of her practitioner, or should she involve her adult children in the decision-making process?

5. Mr. John Smith is a 45-year-old man who has been diagnosed with stage II colon cancer. He has undergone surgery to remove the tumor and is now faced with the decision of whether or not to participate in a randomized clinical trial comparing two different chemotherapy regimens. One regimen has been used for many years and is known to be effective, while the other regimen is relatively new and has not yet been widely tested. Mr. Smith is torn between wanting to receive the best possible treatment and the uncertainty of participating in a trial where he might receive the less effective treatment. The ethical question is: Should Mr. Smith be enrolled in a randomized clinical trial if there is equipoise, even though one of the treatment arms has been shown to be effective in the past?

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44. Reflection Vignettes 

1. Dr. Amanda Jones, a 50-year-old general practitioner, sees a patient in her office complaining of symptoms associated with a chronic disease that has been difficult to control. After discussing the patient's treatment options, Dr. Jones informs the patient about an ongoing clinical trial for a new medication that may offer better symptom control. The patient agrees to participate in the clinical trial, believing that this will be the best option for their treatment. However, the practitioner provided the patient with a false hope, and patient now is under the false belief that the new medication will probably be better than the current one as it relates to risks and benefits. This is a false belief because with clinical trials the principle of equipoise requires that there be genuine uncertainty as to which treatment is best, because at the present time there is no empirical evidence to think one drug is any better than the other.

Think

Assess

  Patient: Autonomy

  Practitioner: Beneficence & Nonmaleficence

  Public Policy: Justice

Conclude

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2. The patient-practitioner relationship exists between the clinical therapeutic research practitioner and the patient, while there is no such relationship between a non-therapeutic researcher and the patient. The null hypothesis in clinical equipoise can address the added dimension of the patient-practitioner relationship with the research practitioner when conducting research on research patients by ensuring that the patient is fully informed about the potential risks and benefits of participating in the study and that the research is conducted in an ethical and unbiased manner. This helps to maintain the trust between the patient and the research practitioner and ensures that the patient's welfare is protected throughout the study. Clinical equipoise requires that there be genuine uncertainty about which treatment is better, and that the treatments being compared are roughly equal in terms of their potential risks and benefits. The null hypothesis states that there is no difference between the treatments being studied, and it is used to determine whether the research question being asked is answerable. When it comes to the patient-practitioner relationship with the clinical therapeutic research practitioner, the null hypothesis in clinical equipoise helps address the added dimension of trust and ethical responsibility that the practitioner has to the patient. In conducting research on research patients, the practitioner is not only responsible for providing high-quality clinical care but also for ensuring that the research is conducted in an ethical and responsible manner. By using the null hypothesis in clinical equipoise, the practitioner can demonstrate to the patient that they are committed to conducting research in a way that is unbiased, evidence-based, and ethical. This helps build trust between the patient and the practitioner, which is essential in clinical research. In addition, by adhering to the principles of clinical equipoise, the practitioner can ensure that the research being conducted is consistent with the ethical principles of patient autonomy, beneficence, nonmaleficence, and justice thereby protecting the welfare of research patients.

Think

Assess

  Patient: Autonomy

  Practitioner: Beneficence & Nonmaleficence

  Public Policy: Justice

Conclude

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