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 Pectoris and the Placebo Effect

(Benson, H.,

N Eng J Med

, 1979) Subjective improvement for five inactive treatments used prior to 1960 (13 studies, 1187 patients) 82.4 ± 9.7% 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 Effect of Antihistamine on Colds Under One Day Duration.

Br Med J

, 1950.

After 2nd day of treatment: Antihistamine Cured 13.4% Cured/ Improved 68.2%

Second Day of Treatment:

Antihistamine Placebo Cured 13.4% 13.9% Cured/ Improved 68.2% 64.7%

Example illustrates that placebos control for: 1) Suggestion (placebo effect) 2) Changes in course of disease (also regression to the mean) The latter, but not the former, could be controlled for with an open-label randomized 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 1 A B C D 2 B Period 3 C A D C D A B 4 D C B A

Reference: Jellinek, Biometrics Bulletin A = a + b + c B = a + c C = a + b D = placebo Response variable = fraction of headaches relieved A B C D 0.84

0.80

0.80

0.52

A Comparison of Response to Treatments A, B and C by the Response to D (Placebo)

Patients Who While on Placebo Received Some Relief A 0.82

B C 0.87

0.82

120/199 Subjects

Patients Who While on Placebo Received No Relief A 0.88

B C 0.67

0.77

79/199 Subjects

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 a No 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?

Yes No Placebo control acceptable Is active control equivalence study informative?

No Does treatment affect survival or irreversible morbidity in population to be studied?

Yes Yes No Active control acceptable Placebo control acceptable Can add-on study provide information?

No Yes Add-on study Can short-term study that is ethically acceptable provide needed evidence?

Is effective treatment accepted uniformly as standard treatment?

Yes Might new treatment prove superior to active control?

No Yes Yes No Short-term placebo-controlled study Placebo-controlled trial where doubts exist Active control (superiority) study 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) Placebo (2) Acebutolol (400 mg) (3) Amlodipine (5 mg) (4) Chlorthalidone (15 mg) (5) Doxazosin (2 mg) (6) Enalapril (5 mg)

“Add On” or “Augmentation” Study

AZT + 3TC + Indinavir vs.

AZT + 3TC + 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 Trial

Hypertension Trial with Active Control that was Patient/Clinician Choice Randomization Verapamil + Placebo for control (either hydrochlorothiazide or atenolol) Hydrochlorothiazide/ Atenolol (Clinician’s choice; pre-specified) + Placebo for Verapamil

Once Daily versus Twice Daily Treatment

Once Daily Treatment A = slow release (200 mg) B = placebo Twice Daily Treatment A = conventional tablet (100 mg) B = conventional tablet (100 mg)

“Take Away” or Withdrawal Studies

Patients infected with HIV taking prophylaxis for

M. Avium

with high CD4+ counts – Randomize: Withdraw OI Prophylaxis (Placebo) vs.

Continue Prophylaxis e.g., Azithromycin vs. Placebo for

M. Avium

Complex (see N Engl J Med 2000; 342:1085-1092)

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

Randomization AZT If AIDS/ARC or CD4+ declines to <500 cells/mm 3 Open-label AZT Lancet 1994; 343:871-881. Placebo Open-label AZT

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

Randomization Special Intervention (SI) aimed at lowering blood cholesterol and blood pressure and smoking cessation Usual Care (UC) What is usual care (considering variations in clinical practice, temporal trends,…? JAMA 1982; 248:1465-1477

In MRFIT “Usual Care” Was Pretty Good!

∆ DBP (mm Hg) ∆ cholesterol (mg/dl) % quitting smoking Risk Factor Changes After 6 Years SI UC -10.5

-7.4

-12.3

46 -6.4

29

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

Dose Comparison/Escalation

Low vs. Intermediate vs. High Dose vs. Placebo or Low Dose vs.

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

Circular Motion

(Bradford Hill)

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.

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

Often Cited Reasons for 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

Control Medical Treatment 2-Year Death Rate (%) Treated LVAD 2- Year Death Rate (%) Design assumptions 75% 50% Results of trial 92% 77% NEJM 2001 15:1435-1443.

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