The Best of BOTH worlds

Ethics in Clinical Trials and Drug Development

Ethical considerations have a multiplicity of roles during the conduct of clinical trials—from matters related to the design of a study, to the conduct and even to the reporting of results.

Introduction

• Ethical considerations have been part of the conduct of studies with humans for several decades. However, it is only since WW II and several abusive trial situations coming to attention that ethical considerations have become a prominent and critical part of the conduct of clinical trials both for safety and well-being of the subjects or volunteers enrolled in these studies.

Elements of Ethical considerations• One of the elements that should be noted is that ethical

considerations are never black & white but exist in multiple shades of grey. The nature of ethics is such that there is never one single answer to any question, but a series of dilemmas for debate and consensus building within the context of the sometimes widely-divergent opinions. Ethics is anything but exact science and one must understand that the resolution of any one ethical question will, by necessity, remain highly personal. It is clear, however, that the consensus building process noted above can shed light and allow for progression on any particular issue that is being debated.

Role of ethics in clinical trials

Ethical considerations have a multiplicity of roles during the conduct of clinical trials. These roles span a broad range—from matters related to the design of a study, to the conduct and even to the reporting of the results obtained. Each of these needs to be carefully considered and explained in the context of international and national principles and guidelines. It is also very important, in those jurisdictions where well established governance of ethics committees is in place, to conform to, and follow the principles, laws, guidance and processes that have been prescribed.

Preparing to conduct a clinical trial

• While preparing to conduct a clinical trial, it is useful to review the main elements noted above in order to ensure that the framework that will govern the ethics of the proposed trial is appropriately applied.

Design and conduct The design of a study is critical in the ethical

consideration of the trial. It has generally been recognized that, if the design of a trial is not sound so that the probability of a meaningful outcome (whether positive or negative) cannot be achieved and as a result the hypothesis being tested can not be proven or disproven, it is generally considered unethical. It is because the human beings enrolled in a trial will have been subjected to potential or real risks for no benefit to either themselves or even to society. All the comments on the other elements of a clinical trial flow from this one.

Inclusion criteria and selection of patients

• One of the critical elements which ensures the success of a study is the inclusion criteria that is considered for the proposed study. Without this consideration, there is a very low probability that all of those to be treated and those who can potentially benefit from a newly developed treatment will derive maximum benefit from the treatment they will undergo. This is also important to ensure that the entire treatable population will not be exposed to undue risks either during the study or once the therapy is marketed, because health professionals will be able to provide patients with adequate directions for use tailored to their needs, which include age and sex considerations.

Patient follow-up

• The implications of patient follow-up during the conduct of clinical trials apply to their medical/healthcare, the close monitoring to discover adverse events and reactions, the clear delineation of roles and responsibilities between the treating health professional and the one who is the investigator. The intent of this approach is to ensure that some of the most controllable conflicts of interest are prevented and that the data reported reflects actual outcomes of those trials, thus lending confidence on the part of regulators and others in the integrity of the data generated.

Informed consent When recruiting and enrolling subjects into clinical trials,

adequate information needs to be imparted to these subjects. It is neither acceptable nor ethical to represent the situation into which these subjects enter in an unfair and unbalanced manner. Exposing subjects to risks that have not been disclosed is not only counterproductive but also increases the risks of research procedures. Subjects who are not aware of the potential risks they may run into, cannot report untoward effects in a timely manner and, in some instances, will not even report illness that they might consider directly related to the study or the product administered. Enrolling subjects into trials without full and fair disclosure has been considered to be unethical in most jurisdictions. Further, in such instances, the integrity of the data generated cannot be assured.

Ensuring ethics are followed

Depending upon the country or jurisdiction, different levels of ethical reviews take place. These reviews can range form a single layer ethics review conducted under a national authority, to fully decentralized processes, to multilayer review, with a centralized ethics committee and multiple local committees that bring local sensitivities to bear on the decision on whether to approve and if so how, in respect of every single study proposed. This approach is a part and parcel of good clinical practices followed by many.

Need for ethical review

A large number and a significant variety of issues come to the fore when preparing to conduct a clinical trial. Many of them are easier to pinpoint and deal with by means of precise rules. These include the issues of conflicts of interest such as the one already noted above on the potential conflict of the role of the clinician as an investigator. Others are more subtle such as the vested interest of the investigator to publish, to gain prestige, to yield to commercial pressures and interest.

Public demands for openness and disclosure

In general, mistrust exists amongst the public, health professionals and others on the accuracy and veracity of the outcomes for clinical trials. Consequently, moves around the world to generate registries where clinical trials are registered and their results posted. There are several already in existence, but the current endeavours are intended to ensure that these become of universal scope. WHO has established a series of standards that can be used as a primary register with individual countries cross-referencing to these as secondary registers.

Issues of governance

In many jurisdictions, while ethics review is required and mandated by regulations, ethics committees themselves are largely self-governing and subject only to ethical guidelines without any regulatory oversight. In other jurisdictions, ethics committees in charge of the weighty decisions regarding the subjects who volunteer for clinical trials are subject to direct regulatory oversight. This oversight is in the form of direct regulation of these boards and/or indirect regulation via the ICH Good Clinical Practices. At the very least, there are national ethical guidelines which draw much wisdom from the international ones, there is a notation in regulations of the need for ethics review as part of good clinical practices as a generic mandate, and clinical trials are inspected to provide assurance that all provisions, including the ethical ones found in the guidelines have been respected.

Informed consent in Oncology/Cancer research

The Ethics of Cancer Research

• Historical content• Is there such a thing as informed consent?• Advantages and disadvantages of randomized

clinical trials.• The concept of equipoise.• Mechanisms of Phase I, II, and III clinical trials. • Ethical considerations in each of Trial types.

History and Human Subjects Research

• Human subject experimentation– Nazis, Japan’s Unit 731– Tuskegee Syphilis Study– Willowbrook Hepatitis Experiments– Henry Beecher– U.S. government-sponsored radiation

experiments– Nuremberg Code, Helsinki Conventions

Informed Consent

• Acknowledges the rights of patients to participate voluntarily in health care.

• Based on ethical, legal and psychological principles.

• Requires adequate disclosure of information to patients regarding a proposed intervention.

• Assures that patients understand the information.

• Assures voluntary consent to the procedure.

Informed Consent and Clinical Research

• Informed consent must be more stringent because the research subject is vulnerable.

• Does the extreme vulnerability of a patient with a life-threatening disease make informed consent an impossibility?

• Does the complex nature of the randomized clinical trial and the treatments involved make true informed consent an impossibility?

• Daugherty, et al. in DeVita, ed. Principles and Practices of Cancer Treatment .

Studies of Informed Consent in Oncology

Written informed consent in patients with breast cancer

• 100 breast cancer patients interviewed after beginning chemotherapy

• 25% unable to name any of their drugs• Most recognized side effects of nausea

and hair loss• <50% aware of potentially life threatening

side effects of infection and bleeding

• Muss, et al: Written informed consent in patients with breast cancer. Cancer 1979; 43:1549-1556.

Studies of Informed Consent in OncologyAre consent forms readable by most patients & their families?

• Review of all consent forms for oncology research protocols at one research institution found only 1-6% of consent forms were at 8th grade reading level.

• The mean scores were at a reading level equivalent to at least two years of college education.

• Grossman, et al: Are informed consent forms that describe clinical oncology research protocols readable by most patients and their families? J Clin Oncol 1994: 12:2211-2215.

Studies of Informed Consent in OncologyThe adequacy of consent forms for informing

patients • Consent forms signed by 100 patients

before beginning trials.• Only 40 patients believed the purpose of

the form was to explain treatment.• Only 52 patients could name all of their

drugs and only 4 could recall all the side effects of the drugs.

• Olver et al. The adequacy of consent forms for informing patients entering oncological clinical trials. Ann Oncol 1995; 6:867-870.

Informed Consent and Clinical Research: CONFLICT OF INTEREST

The clinical investigator is seen as having an intrinsic conflict of interest or dual allegiance with regard to his/her role as physician for an individual patient and his/her role as scientific investigator.

CONFLICT OF INTEREST:Clinician vs. Scientist

Clinician vs. Scientist

• The clinician is concerned with acting in the best interests of the individual patient medically.

• The clinical scientist is concerned with answering questions and testing hypotheses, and such scientific information will benefit humanity in general.

Equipoise

• A state of general uncertainty on the part of the clinical investigator regarding the therapeutic merits of each arm in a trial.

• An ethically necessary condition in all cases of clinical research.

• If equipoise is disturbed during the course of the trial, the trial may need to be terminated, and all subjects previously enrolled offered the superior treatment.

• Freedman, B: Equipoise and the ethics of clinical research. NEJM 1987; 317:141-5.

Can Equipoise Ever Be Achieved?The case for clinical equipoise

• The clinical community is split regarding preferred treatment. Some clinicians favor A and others favor B.

• Each side recognizes that the opposing side, which is recognized as responsible and competent, has evidence to support its position.

• There exists an honest, professional disagreement among expert clinicians about the preferred treatment.

• A clinical trial is instituted with the aim of resolving this dispute.

Randomized Clinical TrialsAdvantages

• Most likely to yield reliable and reproducible clinical knowledge quickly and efficiently.

• Least susceptible to methodological error; avoid observer bias.

• Study designs using either historic controls or nonrandomized study groups may be plagued by bias which can lead to inaccurate results.

Randomized Clinical TrialsDisadvantages

• Do not allow the clinician to participate by offering his or her opinion based on what he or she thinks, suspects, has seen, believes, or has a hunch about.

• Do not allow the clinician to use information accrued prior to or during the trial, as that information is not "statistically correct."

The Ethics of Randomized Clinical Trials

• Reflect the classic conflict between rights-based moral theory and utilitarianism.

• Rights-based theory would suggest that human beings are bearers of dignity, and should never be used as objects, or means to an end, but rather ends in themselves.

• Adapted from Hellman, S: Of mice and men: problems of the randomized controlled clinical trial. NEJM 1991; 324:1585-1589.

The Ethics of Randomized Clinical Trials

• Utilitarian theory defines what is right as that which produces the greatest good for the greatest number--social utility.

• The morally correct act is that which produces the greatest pleasure and the least pain overall, but the distribution of that pleasure and pain is of no moral consequence.

The Ethics of Randomized Clinical Trials

• Utilitarian theory denies the ethical obligation of the physician to see the interests of the individual patient as primary and compelling.

• The randomized clinical trial is utilitarian in that it asks physicians to sacrifice the interests of their particular patients for the sake of the study, and ultimately for the benefit of society.

Randomized Clinical Trials

• Phase I: measure toxicity• Phase II: measure efficacy• Phase III: measure efficacy vs. standard

therapy

Randomized Clinical Trials: Phase I

Researchers test a new drug or treatment in a small group of people (20-80) for the first time to:

• evaluate its safety• determine a safe dosage range• identify side effects.

Phase I Clinical Trial:The Case of Ms. D. and Dr. P.

• Ms. D. is a 39 year old married florist and mother of three school age children.

• She has recently been diagnosed with gallbladder cancer which has spread to the liver and surrounding lymph nodes.

Case Study

The Case of Ms. D. and Dr. P.

• The cancer is too extensive to be cured by surgery.

• There is no evidence that radiation or standard chemotherapy will be of benefit.

• She is referred by her primary care doctor to Dr. P., an oncologist at a large medical center in a nearby city.

•Dr. P. has been working with a company called Cancertech, developing a new immuno-chemotherapy in mice that looks promising as a treatment for cancer.

•He feels that if this works, it will be the beginning of a breakthrough in cancer treatment.

The Case of Ms. D. and Dr. P.

The Case of Ms. D. and Dr. P.

• He tells Ms. D that it could be tried on her cancer as part of a new study he is doing to test it in humans.

• He is very anxious to help her and to try the new treatment.

• He tells her that since there is no effective treatment for the cancer she has, it is the only thing left to offer.

•He tells her that he does not know what all the toxicities are, but that there has been some evidence of liver function abnormalities in rats and in the previous two patients who have tried the treatment.

•He does not tell her that part of his salary is supported by Cancertech, and that he is paid a lump sum for each patient he puts on one of the study drugs.

The Case of Ms. D. and Dr. P.

Phase I Trials: Ethical Considerations

• Problem of administering investigational agents to initial cohorts of patients at potentially low dose levels so that although they do not have toxicity, there is little benefit.

• Chance of response is low: in multiple reviews of Phase I anticancer trials, with 200 trials and 6500-8000 patients in each review, response rates of 4-6%.

• Daugherty, et al. in DeVita, ed. Principles and Practices of Cancer Treatment

Phase I Trials

Benefit

Toxicity

Randomized Clinical Trials: Phase II

The study drug or treatment is given to a larger group of people (100-300) to:

• See if it is effective• Further evaluate its safety

Phase II Trials: Ethical Considerations

• Although toxicity is known, it may be significant.

• Overall low probability of benefit with regard to tumor response.

• As patients accrue, and little response is seen, but not enough patients to be statistically significant, how should the information be handled?

Randomized Clinical Trials: Phase III

The study drug or treatment is given to large groups of people (1,000-3,000) to:

• confirm its effectiveness• monitor side effects• compare it to commonly used treatments• collect information that will allow the drug or

treatment to be used safely.

Phase III Trials: Ethical Considerations• Investigational therapy vs. standard of care

presents huge conflicts• Demands a state of equipoise to be an ethical

study.• Taylor, et al: 82% of physicians reluctant to

relinquish individualized decision making control in favor of randomization and adherence to protocol requirements.

• Taylor et al. Fundamental dilemmas of the randomized clinical trial process: Results of a survey of 1737 ECOG investigators. JCO 1994; 1796-1805.

Summary

• Must recognize the inherent conflict of interest in conducting clinical trials.

• Human subjects protection is always of most primary concern.

• Informed consent is more a process than a document, and must be rigorous for the study to be ethical.

• Equipoise difficult to achieve, but a significant component of clinical trials.

• Phase I trials are to measure toxicity, NOT response.