Treatment and Control Groups in Clinical Trials

ICH Guidance on Investigational Treatment (Pertains to Drugs)

• Name of product, dosing, dosing schedules, route of administration, treatment duration

• Medications permitted, including rescue medication

• Procedures for monitoring compliance.

Defining the Treatment Group

• Early studies of genotypic resistance testing– Is the intervention a genotypic resistance test or

a genotypic resistance test + expert advice? AIDS 2000; 14:F83-F93.

• Trials evaluating diagnostic devices for heart failure– Is the intervention the wireless pulmonary artery

hemodynamic monitoring or the hemodynamic monitoring + reminders/consultations with given to physicians and nurses? Lancet 2011; 377:658-676.

There is confounding of the diagnostic information and advice/reminders/consultations.

Broader Issues – What is the Question?

• Explanatory or pragmatic (practical) trial

• Comparison of treatment strategies or policies– Lifestyle interventions (e.g., MRFIT)– Timing of use of treatment (e.g., ART, dialysis)– Immediate versus deferred treatment (e.g.,

home care following MI and hospital care if needed, aggressive versus less aggressive treatment for glaucoma)

Control Group: Definition

• The reference group or standard treatment against which a new treatment is compared

• The basis for comparison in a clinical trial

• Anchor for comparison

Trial reports should have many phrases like “as compared to…”, “versus”, “different than”, “similar to” – all with reference to the control group.

Types of Controls

• Concurrent

– Randomized• Placebo (in lieu of treatment or on top of standard of care)• No treatment• Deferral of active treatment• Take away an active treatment• Active

– Single treatment (could be a different dose of same drug)– Investigator/patient’s choice of treatment– Optimized management or standard of care– Dynamic treatment regime– Usual care

• In some situations multiple control groups are of interest (e.g., multiple active arms or an active arm and a placebo arm)

– Non-Randomized

• Historical (e.g., patient registry)

• Combination of randomized and non-randomized (concurrent or historical)

One of Muench’s Postulate

“Nothing improves the performance of

therapy like the weakness of controls in its

appraisal.”

Some Recent Examples

• Cox 2 Inhibitor Studies– VIGOR – rofecoxib (Vioxx) versus naproxen

– APPROVe – rofecoxib (Vioxx) versus placebo

– MEDAL – etoricoxib versus diclofenac (should the comparator have been naproxen?)

• Vitamin K Antagonists for Patients Atrial Fibrillation– Dabigatran was found to be superior to wafarin. Should

other new agents be compared against dabigatran

N Eng J Med, January 25, 2007 and October 27, 2011

Review of Industry Sponsored Studies

• 577 trials– 187 placebo controlled– 285 active controlled– 105 dose comparisons

• 82% with single industry sponsor

• 18 head-to-head comparison trials of active interventions owned by different companies.

Lathyris D et al, Eur J Clin Invest 2010

Placebos

Placebo (def.) - A medication prescribed more for the mental relief of the patient than for its actual effect on the disorder; something tending to soothe (Webster’s Dictionary)

Note: Definition pertains to drug studies but use of “placebos” is not confined to drug trials (e.g., acupuncture study)

A pharmacologically inactive agent to maintain blinding in a clinical trial (no specific action on the patient’s symptoms or disease)

Angina Pectorisand the Placebo Effect

(Benson, H., N Eng J Med, 1979)

Subjective improvement for five 82.4 ± 9.7%inactive treatments used prior to1960 (13 studies, 1187 patients)

Other findings:• Increased exercise tolerance• Reduced nitroglycerin usage• Improved ECG results

How Big is the Placebo Effect?

• Systematic review of trials that included a placebo and no treatment group

• 114 trials

• No significant difference between placebo and no treatment except in trials with subjective continuous outcomes and in trials for pain treatment.

N Engl J Med 2001; 344:1594-1602.

Treatment of Mild Hypertension Trial

• Selected self-reported side-effects (placebo versus active treatment)– Weakness 18% versus 16%– Headaches 34% versus 22%– Muscle pain 33% versus 26%

Arch Intern Med 1991; 151: 1413-1423.

Example

After 2nd day of treatment:

Cured/Cured Improved

Antihistamine 13.4% 68.2%

Effect of Antihistamine on Colds Under One Day Duration. Br Med J, 1950.

Second Day of Treatment:

Cured/Cured Improved

Antihistamine 13.4% 68.2%

Placebo 13.9% 64.7%

1) Suggestion (placebo effect)

2) Changes in course of disease (also regression to the mean)

Example illustrates that placebos control for:

The latter, but not the former, could be controlled for with an open-labelrandomized study with a no-treatment control.

Main Reasons for Using Placebos

• Facilitates blinding

• Controls for the placebo effect

Placebo Effect

Subjective changes as well as objective

physiological changes (beneficial and toxic)

produced by placebo (not limited to psychological

responses)

See Beecher HK, JAMA 1955.

Can the Placebo be the Cure?Science, April 9, 1999

“Merck was struck by the curse of the placebo effect…patients who had received a dummy pill had done unexpectedly well.

…it highlights a chronic problem for psychopharmacology – the placebo effect”

Example of Impact of Placebo Responders

on Results of a Trial

A Crossover Experiment of Four Treatments

Treatment Order

A B C D

B A D C

C D A B

D C B A

Period

1 2 3 4

Reference: Jellinek, Biometrics Bulletin

A = a + b + c

B = a + c

C = a + b

D = placebo

Response variable = fraction of headaches relieved

A 0.84

B 0.80

C 0.80

D 0.52

A Comparison of Response to Treatments A, B and C by the

Response to D (Placebo)

A 0.82

B 0.87

C 0.82

120/199 Subjects

Patients WhoWhile on Placebo Received

Some Relief

A 0.88

B 0.67

C 0.77

79/199 Subjects

Patients WhoWhile on Placebo Received

No Relief

Placebo Effect Summary

1. Placebos can be very effective particularly as judged by subjective response variables

2. Placebos control both for suggestion and spontaneous changes in course of disease – usually difficult to disentangle

3. The placebo effect can be short-lasting (angina studies)

4. Removal of “placebo responders” before randomization (more later on such enriched designs)

– May make it easier to detect treatment differences; and

– Impacts generalizability (sacrifice some external validity)

Considerations in Using aNo Treatment/Placebo Control

• No standard therapy with established efficacy

• Cost/availability of standard therapy

• Size/clarity of results

• Toxicity of test treatment

• Risk to patients

• Informed consent

Considerations for Use of Placebo Controls

Is there effective treatment?Placebo control acceptableYes No

Is active control equivalencestudy informative? Active control acceptableNo Yes

Does treatment affect survivalor irreversible morbidity in population to be studied? Placebo control acceptableYes No

Can add-on study provideinformation? Add-on studyNo Yes

Can short-term study that isethically acceptable provideneeded evidence?

Short-term placebo-controlled studyNo Yes

Is effective treatment accepteduniformly as standard treatment? Placebo-controlled trial

where doubts existYes No

Might new treatment provesuperior to active control? Active control (superiority) studyYes

From: Ellenberg and Temple, Annals Int Med, 2000;133:464-70.

International Conference on Harmonisation of Technical Requirements for Registration

of Pharmaceuticals for Human Use

Advantages of placebo-controlled trials

• Ability to demonstrate efficacy credibly

• Measures “absolute” effectiveness and safety

• Efficiency

• Minimizes effect of subject and investigator expectations

EID: Choice of control group in clinical trials

http://www.itpma.org/ich1.html

Controversial Issues Concerning Use of Placebos

• Use of placebo in short-term studies for conditions where there are established treatments with known long-term benefits, e.g., what is short-term? how much risk is tolerable?

• Withdrawal of active treatment and random assignment to new drug or placebo, e.g., psychiatric trials

• Definition of “standard of care” varies from country to country.

Perinatal Transmission of HIV

• PACTG 076 established that efficacy of zidovudine (AZT) in preventing transmission from mother to child (67.5% relative reduction)

• AZT – antepartum (oral), intrapartum (IV), plus AZT for newborn

• Are placebo controlled trials of simpler, less costly regimens in other countries ethical?

In many active controlled trials, placebos are used to facilitate

blinding.

Patients receive exactly the same treatment that they would receive if they are not in the

trial, e.g., standard of care, optimized background treatment, usual care.

Treatment of Mild Hypertension Study (TOMHS)

Weight Loss + Na Reduction +

Alcohol Reduction

and

(1) (2) (3)

Placebo Acebutolol Amlodipine

(400 mg) (5 mg)

(4) (5) (6)

Chlorthalidone Doxazosin Enalapril

(15 mg) (2 mg) (5 mg)

“Add On” or “Augmentation” Study

AZT AZT

+ +

3TC vs. 3TC

+ +

Indinavir Placebo

Hammer et al., NEJM 1997; 337:725-33.

There are a large number of trials like this –new treatment added to “optimal” background or standard of care.

CONVINCE Clinical TrialHypertension Trial with Active Control that was

Patient/Clinician Choice

Verapamil+

Placebo for control (eitherhydrochlorothiazide or atenolol)

Hydrochlorothiazide/Atenolol

(Clinician’s choice;pre-specified)

+Placebo forVerapamil

Randomization

Once Daily versus Twice Daily Treatment

A = slow release A = conventional tablet (200 mg) (100 mg)

B = placebo B = conventional tablet (100 mg)

Once Daily

Treatment

Twice Daily

Treatment

“Take Away” or Withdrawal Studies

Withdraw OI vs. ContinueProphylaxis Prophylaxis (Placebo)

e.g., Azithromycin vs. Placebo for M. Avium Complex (see N Engl J

Med 2000; 342:1085-1092)

Patients infected with HIV taking prophylaxis forM. Avium with high CD4+ counts – Randomize:

Focus of Comparison:Treatment vs Regimen vs Strategy

• Treatment – comparison of a specific treatment at a specific dose for a specific duration (e.g., many pivotal trials done for approval)

• Regimen – comparison of one or more treatments as part of a regimen where dose can be varied and/or components of the regimen varied

• Strategy – includes plans for “second-line” and auxiliary treatments

2010 National Research Council report:The Prevention and Treatment of Missing Data in Clinical Trials

Immediate Versus Deferred Treatment: Concorde Study

AZT Placebo

Open-labelAZT

Open-labelAZT

Randomization

If AIDS/ARC or CD4+ declines to

<500 cells/mm3

Lancet 1994; 343:871-881.

Dynamic Treatment Regimes

• New treatments are added/subtracted based on the history of response to past treatments

• Examples:– ddI versus ddC “switchover”– Invasive versus conservative (deferred

catheterization, angiography and revascularization) rmanagement of MI (VANQUISH)

– STAR*D for the management of depression (multiple randomizations with ability to opt out) (see N Engl J Med 2006;354:1211-1242.Lavori P, Cont Clin Trials 2004; 1:9-20

Multiple Risk Factor Intervention Trial(MRFIT): Usual Care Control

Special Intervention (SI) aimed atlowering blood cholesterol

and blood pressure and smoking cessation

Usual Care (UC)

Randomization

What is usual care (considering variationsin clinical practice, temporal trends,…?

JAMA 1982; 248:1465-1477

In MRFIT “Usual Care” Was Pretty Good!

∆ DBP (mm Hg) -10.5 -7.4

∆ cholesterol (mg/dl) -12.3 -6.4

% quitting smoking 46 29

SI

Risk Factor ChangesAfter 6 Years

UC

MRFIT Illustrates Challenges Defining“Usual Care”

• Tension between control over experimental conditions versus relevance to clinical care – how strictly should control treatment be specified? (explanatory versus pragmatic approach)

• Best practices may be under-utilized in the “real-world”

• Evidence base to guide usual care may not be optimal and may change over a long-term study.

See also Dawson L et al, PloS Med 2009;6:e1000111

Low vs. Intermediate vs. High Dose vs. Placebo

Low Dose vs. Placebo

Int. Dose (If “Poor” response to Low Dose)

Hi Dose (If “Poor” response to Int. Dose)

Dose Comparison/Escalation

or

Cannot compare dose levels from a trial

designed to compare two forms of

management.

If dose is determined by response of

patient, then responses of patients at

different dose levels cannot be compared.

Circular Motion

(Bradford Hill)

N Engl J Med 1953; 247:113-119.

Often Cited Reasonsfor Uncontrolled Studies

1. Unnecessary for large effects

2. Controlled studies are more difficult to implement

3. Availability of patients

4. Ethical reasons– no control treatment available– untreated patients at high risk of death or

serious illness

5. Historical data for comparison is available

Historical Controls Could Result in An Effective Treatment Being Abandoned:

REMATCH Trial in Advanced HF

Design assumptions 75% 50%

Results of trial 92% 77%

NEJM 2001 15:1435-1443.

Control Medical Treatment

Treated LVAD

2-Year DeathRate (%)

2- Year DeathRate (%)

Summary

Considerations in Choice of Experimental and Control Treatments

• Acceptability by patients and clinicians

• Indifference/doubt concerning relative efficacy/safety

• Some basis for thinking that there could be a difference of clinical/public health importance

Meinert gives the following requirements for experimental and control treatments:

• Must be distinguishable

• Medically justifiable

• Ethically OK

• Both must be acceptable to patients and investigators

• Reasonable doubt concerning efficacy

• Should be reason to believe benefits outweigh risks

• Method of administration should be as similar as possible to real-world use

Ref. Clinical Trials: Design, Conduct and Analysis