Research Protocol vs. Research Practice: Case Studies

A talk given at the Center for Tomorrow, April 26, 2001 at the Protection of Human Subjects Workshop

Introduction • Institutional Review Boards have as their chief, if not sole, role the protection of human subjects. • Traditionally, this function has rested on overseeing the design of research, recruitment of subjects, informed consent, investigation of incidents, and issues of compensation.

This presentation illustrates some of the more interesting ways in which research that is well designed and well vetted by IRBs can go awry. • The aim is to draw some morals that may help sharpen IRBs’ review of research protocols and monitoring of research.

Equipoise: A Key Concept • A physician who recommends to a patient that the latter enroll in a research study should be in a state of equipoise: the belief that the result of being randomized to either arm of the study poses no greater risk to the patient than undergoing standard treatment. Otherwise, to recommend entry in a study when the physician believes another treatment is in the patient’s best interest would violate a primary duty to the patient: to recommend the best available treatment.

Equipoise applies to subjects • Similarly, a subject who is enrolled in a study should believe that the state of medical knowledge is such that the known risks and benefits of being assigned to the control or to the experimental arm of the study are balanced, so that no personal risk is greater given one assignment than the other.

A First Study of AZT • AZT (zidovudine, retrovir, AZido-deoxyThimidine)was the first drug to be developed to treat HIV+ individuals. • The following study sought to evaluate AZT as a potential drug to decrease the concentration of virus particles in the blood of HIV+ individuals. • It was a 2-armed, double-blind, multi-center study that used HIV+ patients as subjects.

The following slides report events that have not been recorded in published studies. The author’s representation of them is based on journalistic reporting and discussions in a variety of IRB and educational contexts.

Early AZT Study Design IF Group #1 to receive weekly supply of AZT in opaque capsules HIV+ particles in AZT group are lower Researchers to compare levels of viral particles in blood of the subjects in both groups THEN AZT is confirmed as a useful treatment for HIV-1 related AIDS HIV+ Subjects to be randomly distributed into 2 groups AND Group #2 to receive weekly supply of placebo in identical opaque capsules HIV+ particles in placebo group are higher

AZT Study Results in 2 Centers Quantity of HIV+ particles in AZT group was lower Group #1 received weekly supply of AZT in opaque capsules Researchers compared levels of viral particles in blood of the subjects in both groups AND HIV+ Subjects were randomly distributed into 2 groups Quantity of HIV+ particles in placebo group was higher, INDICATING AZT was effective in reducing the viral load associated with development of AIDS Group #2 received weekly supply of placebo in identical opaque capsules

AZT Study Results in 3rd Center #1 received weekly supply of AZT in opaque capsules Concentration of HIV-1 particles in AZT group and in placebo group were equal to one another, indicating no effect of AZT over placebo Researchers compared levels of viral particles in blood of the subjects in both groups HIV+ Subjects were randomly distributed into two groups #2 received weekly supply of placebo in identical opaque capsules

Why was there differences in the data from the third center? • The striking differences in results raised the question, Why did the individuals in the trial at the third center show no difference between experimental and control groups? • Before you go on to the next slide, speculate on why such a difference might have arisen.

Upon Investigation Group #1 gets weekly supply of AZT in opaque capsules Subjects meet after picking up weekly dosage, mix capsules in a bowl, and each draw out a number = to weekly supply All subjects now taking sub- clinical dose of AZT; groups no longer differ Concentrations of HIV -1 particles in AZT group and in placebo group were equal to one another, indicating no effect of AZT over placebo Researchers compared levels of viral particles in blood of the subjects in both groups HIV+ Subjects randomly assigned into two groups Group #2 gets weekly supply of placebo in identical opaque capsules Lauritsen, 1987

Subjects’ Rationale • Believed AZT was only hope of survival. • Each had 50/50 chance of receiving AZT under the experimental design. • By redistributing AZT and placebo, each had 100% chance of receiving AZT, thus maximizing chance of survival.

Actual Effect • Under original design, each subject had a 50/50 chance of receiving (what was believed to be) a clinically effective dose of AZT. • Under subjects’ “redesign”, no subject would receive what was believed to be a clinically effective dose of AZT. • If subjects at other centers had done likewise, AZT might well have been declared a failure.

Moral An IRB must protect subjects from the effects of their own misunderstanding; subjects must have equipoise with respect to each arm of the experimental design.

Surfactant Study in Preemies • Children born prematurely often suffer from respiratory distress syndrome, due to the immature development of the lungs. • Their lungs lack normal concentrations of surfactant, a natural coating of mature lung tissue that facilitates the transport of O2 and CO2 into and out of hemoglobin in red blood cells.

This study was designed to see if surfactant, administered artificially to the lungs of premature neonates, would improve survival and health upon discharge from the Neonatal Intensive Care Unit (NICU). • It was a multi-center, double-blind study with two arms: preemies who received surfactant, and preemies who received placebo saline.

The following slides report events that have not been recorded in published articles. The author’s representation of them is based on personal communications and discussions in a variety of IRB and educational contexts.

Premature Infant Surfactant Study Design IF Through parental consent, infants of varying degrees of prematurity were to be recruited into a trial of lung surfactant derived from fetal lambs. Infants randomized into two groups Group #1 to receive surfactant in NICU Group #1 has a higher survival rate in NICU THEN Groups to be compared as to survival in NICU Surfactant confirmed as a beneficial aid to preemies AND Group #2 to receive saline placebo in NICU Group #2 has a lower survival rate in NICU

Premature Infant Surfactant Study Results in 2 Centers Group #1 received surfactant in NICU Group #1 had a higher survival rate in NICU Through parental consent, infants of varying degrees of prematurity were recruited into a trial of lung surfactant derived from fetal lambs. Infants randomized into two groups Looks like surfactant confirmed as a beneficial aid to preemies Researchers compared groups as to survival in NICU Group #2 received saline placebo in NICU Group #2 had a lower survival rate in NICU Kwong, et al., 1985; Enhorning et al, 1985

Premature Infant Surfactant Study Results in 3rd Center Through parental consent, infants of varying degrees of prematurity were recruited into a trial of lung surfactant derived from fetal lambs. Infants randomized into two groups Group #1 received surfactant in NICU Group #1 had no higher survival rate in NICU than did Group #2; the same percentages survived and died with saline placebo as with surfactant Researchers compared groups as to survival in NICU Surfactant not confirmed as a beneficial aid to preemies Group #2 received saline placebo in NICU Shapiro et al., 1985

Why did the results in the third center differ from the others? • Noncompliance of subjects, the reason in the first study, couldn’t be the reason here, since neonates were passive participants. • Before going on to the next slide, hypothesize possible explanations for the difference in results from the third center involved in the trial.

Upon Investigation Through parental consent, infants of varying degrees of prematurity were recruited into a trial of lung surfactant derived from fetal lambs. Infants randomized into two groups The most premature infants in Group #1 and Group #2 received surfactant; the least premature infants in Group #1 and Group #2 received saline placebo Resident in NICU found he could identify surfactant and saline placebo by shaking vials and seeing which froths up. Decided to give surfactant to sickest kids in both groups. Group #1 has no higher survival rate in NICU than did Group #2; the same percentages survived and died with saline placebo as with surfactant Surfactant not confirmed as a beneficial aid to preemies Groups compared as to survival in NICU

The Resident’s Rationale • His primary obligation was to his patients. • Surfactant offered the sickest kids a better chance of survival than did the saline. • With the design, half the sickest kids would be deprived of their best chance of survival by receiving saline placebo. • So, surfactant should be given to the sickest.

The Actual Result • Resident-as-therapist’s aims for patients at hand were realized. • Resident-as-researcher’s aims for future patients were frustrated. • If all researchers in the protocol had acted as the resident did, surfactant would have been declared ineffective.

Moral An IRB must protect subjects from the effects of researchers’ confusion of roles, and insure that researchers have equipoise with respect to each arm of the experimental design and do not abandon equipoise and move from the research role to the therapeutic role with subjects.

Breast Cancer • Strikes 100,000 women in the US annually, and several million women world-wide. • Standard treatment was the Halstead radical mastectomy, in which the entire breast, lymph nodes under the arm, and pectoral muscles underneath the breast are removed.

Standard treatment left women disfigured and with swelling of the upper arm and decreased movement. • A controversy arose among surgeons in the early 1970s over whether less radical surgical treatment might have equally good results expressed in terms of survival of the disease. • Bernard Fisher designed a multi-center protocol to answer this question.

Bernard Fisher’s Radical Mastectomy vs. Simple Mastectomy Trial RANDOM I ZAT I ON RADICAL MASTECTOMY RADICAL MASTECTOMY Patient Pool Pt gives informed consent MD asks pt to participate SIMPLE MASTECTOMY MD doesn’t ask Pt refuses Marquis, 1989

Results of Fisher’s First Study • 1765 patients were enrolled in the study. • After 10 years, there was no better disease-free survival with radical mastectomy than with simple mastectomy. • As a result, many women have been subsequently spared unnecessarily deforming surgery. Marquis, 1989

Participating surgeons had equipoise; they believed, prior to the study, that there was no good reason to prefer one treatment over another. • Surgeons could thus respect their patient’s freely-given, informed consent to participate under randomization without violating any of their moral duties to patients. • Thus, the study was conducted ethically and with truly beneficial results. Marquis, 1989

Fisher’s Study of Simple Mastectomy vs. Lumpectomy • Another question emerged in the 1970s, namely, whether equally good results could result in early cases of breast cancer from removal of only the tumor and a small surrounding margin of breast, with or without radiation therapy. • Fisher designed a second study to answer this question. Marquis, 1989

Fisher’s Second Study Lumpectomy w/ radiation Other Treatment RANDOMIZATION Lumpectomy w/o radiation MD asks pt to participate Pt w/ tumors <4 cm Pt gives informed consent Other treatment Pt refuses Simple Mastectomy MD doesn’t ask Other Treatment after Marquis, 1989

Results of Second Study • Enrollment in the study was so slow that the study could not be completed as designed, because: • Women who were faced with the consequence of either radical mastectomy or lumpectomy being decided by a randomization device would not consent.

Modification of the Study • Statistician Marvin Zelen thought the reasons for poor enrollment might involve uncertainty of subjects about what treatment would result from randomization. • He suggested randomization prior to recruitment.

Fisher’s Third Study: a Prerandomized Clinical Trial Lumpectomy w/ radiation YES Informed consent requested Lumpectomy with radiation NO Other Treatment R A N D O M I Z A T I O N MD chooses to participate Lumpectomy w/o radiation Pt w/ <4 cm. lump Lumpectomy w/o radiation Informed consent requested YES Other treatment NO Simple Mastectomy YES MD doesn’t choose to participate Informed consent requested Simple mastectomy NO Other Treatment Marquis, 1989

Results of Third Study • A sufficient number of subjects enrolled. • Study established that when both lumpectomy groups were combined, disease-free survival after mastectomy was no better than disease-free survival after lumpectomy. • Study also established that disease-free survival after lumpectomy with radiation was better than mastectomy.

Why Did the Third StudySucceed in Enrolling a Sufficiently Large Sample? • The two studies are identical in terms of known risks and benefits, so women should enroll in the third study no more frequently than in the second. • Thus, the third study ought to have had no greater enrollment unless it presented to potential participants a different characterization of the risks and benefits. Marquis, 1989

Before going on to the next slide, speculate on the possible explanations of why the third study succeeded in enrolling sufficient numbers of participants, while the second study did not succeed.

Speculations as to the answer • No woman was confronted with choosing to participate in a trial in which she would be randomized between lumpectomy and mastectomy groups. • No physician had to approach a patient with what may seem to be a gambling device.

Physicians could choose to recommend participation or non-participation based on a judgment of the patient’s best interests. • Patients would feel more comfortable in consenting to be in the study because they would know what treatment they would receive before consenting to participate. Marquis, 1989

Prerandomization mimics the purely therapeutic context; the physician can “assist” the patient’s decision by emphasizing the advantages of the treatment to which the patient has been assigned. Marquis, 1989

Ethical Problems • Physicians recommending to their patients participation in a randomized clinical trial with two or more arms should have equipoise - should not, in their best medical judgment, believe one treatment to be better for the patient than another. • This trial, however, permitted physicians to pretend that they were recommending the treatment to which their patient had been prerandomized as in the patient’s interest over other possible treatments.

Patients’ have a tendency to “therapeutic misconception” (tendency to read consent forms, sign them, and still believe the treatment they are receiving was chosen for them because their doctor thought it best was not countered in this study). • So, this trial involved patients being randomized to a therapy they would view as much less desirable (because of the differing, permanent consequences for their bodies) in the absence of their physicians’ belief that the less desirable treatment offered a therapeutic advantage. Marquis, 1989

Hence, genuine informed consent was not achieved, explaining why prerandomi-zation succeeded in this case: doctors violated their duties to their patients by not ensuring their under-standing that the treatment they were to receive was chosen for them by a random selection device, not by their physicians.

A Paradoxical Result • This study had results that were of benefit to hundreds of thousands of women who now can choose less disfiguring surgery knowing they are not reducing their chances for survival. • Based on the failure of the comparable previous study, these results could not have been gained without violating the participants’ rights.

Possible Moral #1 • An IRB must insure that the experimental design does not surreptitiously violate a patient’s right to a fully-informed, freely-given informed consent through design variations such as prerandomization, and must resist the temptation to subordinate duties to the subject to the beneficial aims of the research.

Possible Moral #2 • An IRB should be prepared, in cases where highly beneficial results of a study cannot be gained in any other way, to subordinate the research’s duties to the subject to the goals of the study by permitting such devices as prerandomization to be employed when straightforward ethical design fails to obtain sufficient participation.

What is your choice?

Research Protocol vs. Research Practice: Case Studies