Randomized Clinical Trials Randomized Clinical Trials (RTCs)(RTCs)

In the US, in order for a drug to be In the US, in order for a drug to be approved for distribution to the approved for distribution to the public (either by Rx or over-the-public (either by Rx or over-the-counter), it must go through counter), it must go through extensive tests to establish extensive tests to establish safetysafety and and efficacyefficacy..

Rules came about because of Rules came about because of Europe’s experience with Europe’s experience with Thalidomide.Thalidomide.

On July 15, 1962, On July 15, 1962, The Washington The Washington PostPost reported that Thalidomide was reported that Thalidomide was suspected in causing limb suspected in causing limb deformities in human babies. The deformities in human babies. The drug was widely used in Europe for drug was widely used in Europe for “morning sickness.”“morning sickness.”

Merrell Pharmaceuticals Merrell Pharmaceuticals seeking to market the drug in the USseeking to market the drug in the US

Up to this point Thalidomide had Up to this point Thalidomide had been kept off the market because of been kept off the market because of the efforts of an FDA administrator, the efforts of an FDA administrator, Dr. Frances Kelsey.Dr. Frances Kelsey.

Her campaign was joined by Dr. Her campaign was joined by Dr. Helen Tausig, from Johns Hopkins Helen Tausig, from Johns Hopkins University School of Medicine. They University School of Medicine. They gathered enough evidence to gathered enough evidence to convince the FDA not to approve.convince the FDA not to approve.

As a result of this incident (a near As a result of this incident (a near failure), the FDA adopted more failure), the FDA adopted more stringent guidelines before they stringent guidelines before they would approve of the distribution of a would approve of the distribution of a drug to the public.drug to the public.

Testing drugs (and other medical Testing drugs (and other medical interventions) typically must go interventions) typically must go through three phases.through three phases.

1. Phase I1. Phase I: designed to determine if : designed to determine if the drug is the drug is safesafe for humans (or to for humans (or to determine what constitutes a safe determine what constitutes a safe dosage).dosage).

Subjects are sometimes hard to Subjects are sometimes hard to recruit.recruit.

Controversies with some phase I Controversies with some phase I studies companies using studies companies using homeless persons; death of a healthy homeless persons; death of a healthy subject.subject.

Some are eager to volunteer for Some are eager to volunteer for certain phase I studies if they have certain phase I studies if they have an illness for which there is no an illness for which there is no treatment. treatment.

.

2. Phase II2. Phase II: trying to determine if the : trying to determine if the drug is promising (if it looks like it drug is promising (if it looks like it will help) by examining its effects on will help) by examining its effects on a small number of subjects.a small number of subjects.

3. Phase III3. Phase III: seeking definitive : seeking definitive evidence of efficacy by comparing evidence of efficacy by comparing the experimental drug/intervention the experimental drug/intervention with a placebo or with current with a placebo or with current therapies.therapies.

Phase I and II studies typically Phase I and II studies typically involve small numbers of subjects. involve small numbers of subjects. Phase III studies use large numbers Phase III studies use large numbers of subjects.of subjects.

Purpose of phase I: determine safetyPurpose of phase I: determine safety Purpose of II and III: determine Purpose of II and III: determine

efficacy.efficacy.

A RCT is typically done in Phase III A RCT is typically done in Phase III studies.studies.

RCTs involve at least two groups of RCTs involve at least two groups of subjects: subjects: the the experimentalexperimental group group (receives the new drug or treatment) (receives the new drug or treatment) and and the the controlcontrol group (receives a group (receives a placebo or the standard treatment).placebo or the standard treatment).

GoalGoal of a RCT: to determine whether of a RCT: to determine whether the experimental drug/treatment is the experimental drug/treatment is more effective than a placebo or the more effective than a placebo or the currently used therapy.currently used therapy.

Whether a subject is assigned to the Whether a subject is assigned to the experimental group or control group experimental group or control group is determined by a is determined by a randomizingrandomizing device.device.

The point of RCTs is to ensure that The point of RCTs is to ensure that any any differencedifference inin outcomeoutcome is because is because of differences in the treatments and of differences in the treatments and not some other factor (such as age, not some other factor (such as age, gender, diet, environment, etc.). gender, diet, environment, etc.). This is why a large number of This is why a large number of subjects is needed.subjects is needed.

Even when Even when nono standard Tx is standard Tx is available, a control group is needed available, a control group is needed because of (i) the placebo effect, and because of (i) the placebo effect, and (ii) an illness may have run its (ii) an illness may have run its course.course.

Some RCTs are Some RCTs are double-blinddouble-blind (neither (neither researchers nor subjects know who researchers nor subjects know who has been assigned to which group). has been assigned to which group). This is to guard against “biases” of This is to guard against “biases” of both subjects and researchers.both subjects and researchers.

Some RCTs are Some RCTs are single-blindsingle-blind (only the (only the researchers know the assignments).researchers know the assignments).

Some RCTs, by their very nature, Some RCTs, by their very nature, cannot be blinded. A well-known cannot be blinded. A well-known example is a study that compared example is a study that compared the value of “(1) lumpectomy, (2) the value of “(1) lumpectomy, (2) lumpectomy + radiation, and (3) lumpectomy + radiation, and (3) mastectomy” for certain types of mastectomy” for certain types of breast cancer.breast cancer.

It was difficult to recruit subjects for It was difficult to recruit subjects for this study.this study.

One issue: When is it morally One issue: When is it morally justifiable to justifiable to recruitrecruit subjects to subjects to participate in a RCT?participate in a RCT?

We should focus on: Will the We should focus on: Will the subjects’ autonomy be subjects’ autonomy be compromised? Will the subjects’ well-compromised? Will the subjects’ well-being be compromised?being be compromised?

Here we shall assume that Here we shall assume that freelyfreely givengiven, , adequatelyadequately informedinformed consent consent to participate in a RCT is possible.to participate in a RCT is possible.

Our focus: Does participation in the Our focus: Does participation in the RCT being conducted threaten the RCT being conducted threaten the well-beingwell-being of the subjects? The key is of the subjects? The key is the control group. [Those in the the control group. [Those in the experimental group receive the thing experimental group receive the thing we believe will help.]we believe will help.]

FourFour possibilities to consider: possibilities to consider:

1. If there is 1. If there is nono treatment available for treatment available for the medical problem in question and if the medical problem in question and if subjects in the control group are not subjects in the control group are not made worse off by their participation, made worse off by their participation, then it seems then it seems morallymorally permissiblepermissible to to initiate the RCT in question.initiate the RCT in question.

2. If there 2. If there isis a standard treatment for a standard treatment for the medical problem in question and if the medical problem in question and if those in the control group are those in the control group are receiving this treatment, then initiating receiving this treatment, then initiating such a RCT seems such a RCT seems morallymorally permissiblepermissible..If 1 and 2, no one is If 1 and 2, no one is knowlinglyknowlingly made made worse off by participating in the RCT.worse off by participating in the RCT.

3. If there 3. If there isis a standard treatment for a standard treatment for the problem in question but subjects in the problem in question but subjects in the control group receive a mere the control group receive a mere placebo, then such RCTs are placebo, then such RCTs are morallymorally questionablequestionable (because those who end (because those who end up in the control are worse off than if up in the control are worse off than if they did not participate at all).they did not participate at all).

4. If there is 4. If there is nono standard treatment standard treatment available for the problem in question available for the problem in question but the placebo given to those in the but the placebo given to those in the control group make them worse off control group make them worse off (e.g., because it causes discomfort), (e.g., because it causes discomfort), then initiating such a RCT is at least then initiating such a RCT is at least morallymorally questionablequestionable..

Perhaps particular RCTs falling under Perhaps particular RCTs falling under (3) or (4) are justifiable. But the (3) or (4) are justifiable. But the burden of proof should be on the burden of proof should be on the researchers because risk, harm, or researchers because risk, harm, or discomfort is knowingly inflicted on discomfort is knowingly inflicted on those in the control group in each those in the control group in each case. No such risk is known to be case. No such risk is known to be involved in (1) or (2).involved in (1) or (2).

Suppose the initial results of a Phase Suppose the initial results of a Phase III RCT look promising. Should the III RCT look promising. Should the trial be stopped early and the trial be stopped early and the experimental agent be made experimental agent be made available to all who have the available to all who have the problem, or should the RCT be problem, or should the RCT be carried out in its entirety so that carried out in its entirety so that statistical significance is achieved?statistical significance is achieved?

The case for The case for stoppingstopping a RCT early a RCT early when the results look promising: At when the results look promising: At least in the case of life-threatening least in the case of life-threatening maladies (ALS, AIDS, etc.), these pts maladies (ALS, AIDS, etc.), these pts may have no other chance to live.may have no other chance to live.

Thus stopping the trials early and Thus stopping the trials early and making the “treatment” available is making the “treatment” available is based on based on beneficencebeneficence..

Reasons for Reasons for notnot stoppingstopping RCTs early, RCTs early, and instead carrying them out to and instead carrying them out to statistical significance are:statistical significance are:

1. HCPs have an obligation not to 1. HCPs have an obligation not to present as routine treatment that present as routine treatment that which has not been adequately tested.which has not been adequately tested.

[Of course, pts could be informed that [Of course, pts could be informed that adequate testing had not been done.]adequate testing had not been done.]

2. Unless RCTs are carried out until 2. Unless RCTs are carried out until statistical significance is achieved, the statistical significance is achieved, the well-being of future pts is threatened:well-being of future pts is threatened:harmful side effects of the drug may harmful side effects of the drug may not be detected;not be detected;this will slow progress (because it will this will slow progress (because it will take longer to determine why take longer to determine why interventions do not work perfectly). interventions do not work perfectly).

3. We have benefited from previous 3. We have benefited from previous RCTs, so we owe it to future RCTs, so we owe it to future generations to carry out such trials to generations to carry out such trials to statistical significance. The issue here statistical significance. The issue here is is justicejustice (the fair distribution of (the fair distribution of burdens and benefits among all burdens and benefits among all affected people).affected people).

This issue of whether to stop RCTs This issue of whether to stop RCTs early involves a conflict between the early involves a conflict between the goodgood ofof thethe individualindividual (pts who are (pts who are sick) and the sick) and the goodgood ofof societysociety (long- (long-term effects on future pts).term effects on future pts).

This is a This is a conflictconflict between one’s between one’s therapeutictherapeutic obligationobligation and one’s and one’s obligationobligation asas aa researcherresearcher..

Another issue: In Another issue: In somesome cases, there cases, there are more people who want to be are more people who want to be subjects in a RCT than there are slots subjects in a RCT than there are slots available. This occurs when the available. This occurs when the medical problem for which the medical problem for which the intervention is being tested is intervention is being tested is seriousserious and there is and there is nono standard treatment standard treatment available.available.

When this occurs and when early results When this occurs and when early results look promising, the options arelook promising, the options are

1.1.Stop the RCTs early and make the Stop the RCTs early and make the treatment available to all.treatment available to all.

2.2.Run the RCTs to their completion, but Run the RCTs to their completion, but make “compassionate use exceptions.”make “compassionate use exceptions.”

3.3.Run the RCTs to completion and make Run the RCTs to completion and make no exceptions.no exceptions.

Another issue: sometimes there is a Another issue: sometimes there is a shortageshortage of subjects for RCTs of subjects for RCTs (especially when there is a standard (especially when there is a standard treatment. treatment. StrategiesStrategies researchers researchers have used: (a) give have used: (a) give incentivesincentives to to doctors to recruit subjects; and (b) doctors to recruit subjects; and (b) doing research in developing doing research in developing countries.countries.