Declaration of Helsinki and Active Control Trials

1
Declaration of Helsinki and Active Control Trials

• Robert J. Temple, M.D.
• Associate Director for Medical Policy
• Center for Drug Evaluation and Research
• U.S. Food and Drug Administration

April 24, 2002
2
Placebo Controls/Active Controls

• Arguments about use of placebos are sometimes
  presented as one of conflict between science and
  ethics, a case where one sometimes weighs the two
  on a common scale
• That is incorrect. There are two issues, but
  they are distinct one ethical, one inferential
• 1. Ethical - when is it O.K. to deny patients
  known effective therapy by randomizing some to a
  placebo
• 2. Inferential - when can an active control
  equivalence study (the alternative to a placebo)
  demonstrate effectiveness

3
Active Control Trials

• Active control trials (comparing new and standard
  therapy and showing no difference between them)
  are usually proposed as a way to demonstrate
  effectiveness because a placebo-controlled trial
  is considered unethical or undesirable. It seems
  a simple and logical alternative but in fact the
  design and interpretation of such trials is often
  very difficult. In many cases the needed
  conditions for utilizing such a trial as evidence
  of effectiveness cannot be met and only a
  placebo-controlled trial will be interpretable
  (but may not be possible on ethical grounds)
• In what follows I will discuss the ethics of
  placebo-controlled trials and the necessary
  conditions for use of active control trials

4
The Ethical Issue Need to Use Effective
Available Therapy

• If there is known effective therapy for a
  condition, when, if ever, is it ethical to deny
  this treatment to some patients in a clinical
  trial?
• Doesnt it depend on what condition is being
  treated and the consequences of delayed or
  omitted treatment?

5
Declaration of Helsinki, 1975

• In any medical study, every patient - including
  those of a control, if any - should be assured of
  the best proven diagnostic and therapeutic method
• What did the 1975 Declaration mean?

6
Ethical Issue

• Some (e.g., Rothman, NEJM, BMJ) have contended
  that the 1975 Declaration must be read literally,
  and that the 2000 revision strengthens their
  view, and therefore the condition being treated
  is irrelevant. Thus
• No placebo-controlled trials in baldness
  (Rogaine)
• No placebo-controlled trials in seasonal
  allergic rhinitis
• No placebo-controlled trials in headache
• No placebo-controlled trials of any duration
  in insomnia, anxiety, outpatient depression,
  OCD
• Read literally, however, Declaration bars any
  trial (even active comparison) if there is
  existing therapy (people receiving the test drug
  dont receive best proven treatment

7
What Did Declaration (1975) Mean?

• In presenting the 1975 change, the WMA did not
  say a word about placebo controlled trials. It
  said the change was intended to reinforce the
  idea that the physician-patient relationship
  must be respected just as it would be in a
  purely therapeutic situation not involving
  research objectives

8
How the 1975 Declaration Affected
Placebo-Controlled Trials

• It had little or no effect. Despite Rothman and
  Michels (and a few others), placebo-controlled
  RCTs were performed, despite existing therapy, by
  the 1000s, were published in journals that would
  not publish an unethical trial. The people
  performing and publishing the trials considered
  them ethical and compatible with the Declaration
• Then the Declaration was changed

9
Declaration of Helsinki, 2000

• The benefits, risks, burdens, and effectiveness
  of a new method should be tested against those of
  the best current prophylactic, diagnostic, and
  therapeutic methods. This does not exclude the
  use of placebo or no treatment, in studies where
  no proven prophylactic, diagnostic, or
  therapeutic method exist.

10
Declaration of Helsinki, 2000

• The first sentence could be read as a scientific
  statement (know how new Rx compared with old),
  perhaps supporting 3-arm (test drug, control,
  placebo) studies. The second sentence makes it
  clear that was not the intent

11
What is Ethical Impediment to Placebo-Controlled
Trials in Symptomatic Conditions?

• There never has been a coherent explanation by
  Rothman, the WMA, or others of why an informed
  patient cannot volunteer to defer treatment of a
  symptomatic condition or allow a brief deferral
  of treatment of elevated blood sugar, blood
  pressure, or cholesterol (but can, in contrast,
  take a new, untested drug instead of established
  therapy)
• No impact on health
• Easily explained consequences understandable
• Context of trials not misleading (doesnt look
  like it is treatment) i.e., should be no
  therapeutic misconception
• Easy escape if treatment unsatisfactory
• Contrast with clear Declaration of Helsinki
  statement that healthy volunteers may participate
  in research

12

• Similar to choices people make every day to
  treat, or not to treat, symptoms
• Pain treatment (headache, dental, arthritis)
• Many psychiatric conditions (anxiety, OCD,
  depression)
• Seasonal allergies
• Erectile dysfunction
• Baldness
• BPH symptoms
• Insomnia
• Heartburn, dyspepsia
• Angina
• Similarly, laboratory and clinical abnormalities
  are often untreated for brief periods (e.g., 2-4
  weeks)
• Mild hypertension
• Elevated cholesterol
• Elevated blood sugar

13
Its the Consequences of Not Receiving Standard
Therapy

• The recently published FDA guidance, Choice of
  Control Group and Related Issues, a guidance
  developed by ICH (ICH E-10) takes a very
  different position
• It clearly distinguishes between current
  treatments that prevent serious harm and those
  that treat symptoms. Whether a
  placebo-controlled trial is ethical depends on
  the consequences of non-treatment

14
ICH E-10 Guidance

• The principal issue in use of placebos is the
  ethical one. There is no issue when no effective
  therapy exists. The question is when is it
  acceptable not to give existing therapy and
  randomize to drug or placebo.
• In cases where an available treatment is known
  to prevent serious harm, such as death or
  irreversible morbidity in the study population,
  it is generally inappropriate to use a placebo
  control. (Generally, because if treatment is so
  toxic that people refuse it, a placebo may still
  be possible.)

15
ICH E-10 Guidance (contd)

• In other situations, where there is no serious
  harm, it is generally considered ethical to ask
  patients to participate in a placebo-controlled
  trial, even if they may experience discomfort as
  a result, provided the setting is non-coercive
  and patients are fully informed about available
  therapies and the consequences of delaying
  treatment Whether a particular
  placebo-controlled trial of a new agent will be
  acceptable to subjects and investigators when
  there is known effective therapy is a matter of
  investigator, patient, and IRB judgement, and
  acceptability may differ among ICH regions.
  Acceptability could depend on the specific trial
  design and population chosen.

16
There Are Many Situations in Which Placebo is
Unacceptable

• All agree that a placebo-controlled trial is
  unacceptable when there is adequate evidence that
  available treatment can increase survival or
  prevent irreversible morbidity in the intended
  study population over the course of the proposed
  study. Examples
• 1. Post-infarction trials of thrombolytics, beta
  blockers, aspirin, ACEIs (in patients with
  ventricular dysfunction)
• 2. Antibiotic prophylaxis in dirty surgery
• 3. Initial treatment of childhood ALL or
  testicular cancer
• 4. Long-term trial of moderate to severe
  hypertension
• 5. CHF of virtually any severity
• NB Active control equivalence study in these
  cases may not be interpretable

17
There May Be Close Cases

• In some cases there can be debates about whether
  the risks of non-treatment of acceptable. For
  example
• Trials involving withdrawing people from
  antipsychotics to enter the study (rarely done
  usually new patients)
• Anti-emetics in severely emetogenic chemotherapy
• Duration of non-treatment of BS, BP, cholesterol

18
Metaanalysis of 17 Placebo-Controlled
TrialsBeasley et al. BMJ (1991) 303685-92

• Prozac Tricyclics Placebo
• n 1765 731 569
• Suicidal Acts 6 (0.3) 3 (0.4) 1 (0.2)
• New Substantial 14 (1.2) 15 (3.6) 10 (2.6)
• Suicidal Ideation
• Worsening Suicidal 262 (15.3) 117 (16.3) 100
  (17.9)
• Ideation
• All studies had placebo lead-in 3 suicidal
  acts 1 fatal

19
Recent Activity, U.S. and Other

• Guidance, March 2001 on interpreting reference to
  Declaration of Helsinki in 21 CFR 312.120
  (conforms to ethical principles contained in the
  Declaration of Helsinki)
• It is the 1989 version of Declaration of
  Helsinki that is referred to

20
Recent Activity, U.S. and Other

• EMEA/CPMP position paper of June 28, 2001
• notes need for placebo in many situations to
  obtain reliable evidence
• acceptable if no added risk of irreversible harm
• WMA press release 8 Oct 2001.
• Clarification placebo controls can be
  acceptable, even if proven therapy exists, if
• there are compelling methodological reasons
• in minor conditions where patients receiving
  placebo would not be subject to any additional
  risk of serious or irreversible harm

21
Why Placebo Controls May Be Needed, Even If There
is Existing Treatment

• The alternative to a placebo-controlled trial (or
  other trial showing a difference between
  treatments, such as a dose-response study or a
  study showing superiority to an active control)
  is an active control equivalence trial, showing
  that the new drug is similar to a drug with known
  effectiveness
• But equivalence trials, in many situations, are
  uninformative or misleading

22
Problems with Equivalence Trials

• Studies that are designed to show equivalence
  or non-inferiority have three principal
  problems.
• 1. There is a critical assumption that the
  trial had assay sensitivity
• 2. There is no standardized test for
  statistically significant similarity, so that
  it is critical to choose a difference between
  treatments that, if ruled out by the study, will
  demonstrate effectiveness. Choosing this
  difference is difficult
• 3. Lack of incentives to study excellence

23
Assay Sensitivity

• There is an inherent, usually unstated,
  assumption in all such trials, namely that the
  active control was effective in the particular
  study in question, i.e., that the trial was
  capable of distinguishing effective from
  ineffective drugs
• The assumption
• is not necessarily true for all effective
  drugs
• is not directly testable in the data collected
• in essence, causes an active control study
  to have elements of a historically
  controlled study

24
Evidence of Efficacy

• Two distinct approaches
• 1. Difference-showing
• Superiority of test drug to control (placebo,
  active, lower dose) demonstrates drug effect (and
  assay sensitivity)
• 2. Equivalence or non-inferiority in an active
  control study
• Showing similarity to a known effective therapy
  (active control) and attributing the efficacy of
  the active control drug to the new drug, thereby
  demonstrating drug effect
• Non-inferiority trials show that the new drug is
  not worse than the control by a defined amount,
  that amount being no larger than the effect the
  active control would be expected to have in the
  study (the non-inferiority margin, M)

25
The Logic Is Not The Problem

• Showing equivalence to a known active drug would
  be a sensible way to demonstrate effectiveness
• But you cant really show equivalence (except by
  being superior), so we seek Non-Inferiority,
• a misnomer
• Really it is showing inferiority of no more than
  a specified margin M, or delta
• C-TltM
• So its really a not-too-much-inferiority trial
• Old, naïve way (but still seen in current
  publications) was to compare C and T, find no
  significant difference and declare victory.
  Here, at least, were past that

26
Non-Inferiority Trials

• Specify as a null hypothesis that the difference
  between active control (C) and new drug (T) is
  greater than some amount M (the margin), M being
  no greater than the effect of C in that study if
  the null hypothesis is not rejected, T has no
  effect at all. That is
• Ho C-T gt M
• Ha C-T lt M
• Usually, in analogy with placebo controlled
  trials, the 97 1/2 CI (one-sided) for C-T must
  be lt M, demonstrating a statistically
  significant effect of T.

27
Assay Sensitivity

• Interpretation of the study depends completely on
  M, the effect of C that is presumed for the new
  study. But M is not measured it must be deduced
  from historical experience (generally
  placebo-controlled trials with C)
• Equivalence or non-inferiority trials always
  raise a question
• Did the active control drug have an effect of the
  size expected in the trial carried out? If it
  did not, equivalence or non-inferiority by the
  expected effect is meaningless. The equivalent
  or non-inferior drug could have no effect at all.

28
Fundamental Logic of Trials

• Superiority Efficacy
• (if control gt placebo)
• Non-inferiority ? Efficacy
• (unless assay
  sensitivity is present)

29
Determining Assay Sensitivity

• To conclude a trial had assay sensitivity, you
  need a combination of historical information and
  information about the new trial.
• Historical evidence of sensitivity to drug
  effects
• A historically based conclusion that
  appropriately designed, sized, and conducted
  trials in a particular disease, with a specific
  active drug (or group of related drugs) reliably
  show an effect of at least some defined size on a
  particular endpoint. Usually established by
  showing that appropriately sized (powered) and
  well-conducted trials in a specified population
  regularly distinguish the active drug(s) from
  placebo for particular endpoints
• Sensitivity to drug effects is an abstract
  conclusion about well-designed trials of a drug
  in a particular disease. Assay Sensitivity is a
  conclusion about a particular trial

30
Historical Evidence of Sensitivity to Drug
Effects a Precondition for Assay Sensitivity

• Examples of situations in which studies of
  current drugs lack sensitivity to drug effects
• Depression
• Anxiety
• Dementia
• Symptomatic congestive heart failure
• Seasonal allergies
• Gastroesophageal reflux disease
• Post-infarction beta blockade
• Post-infarction aspirin

31
Historical Evidence of Sensitivity to Drug Effects

• Conclusion of HESDE applies only to trials of a
  particular design (patient population, selection
  criteria, endpoints, dose, use of washout
  periods) . Changes in these can affect the
  effect size of the active control and, therefore,
  the appropriate margin, or completely undermine
  assay sensitivity

32
Assay Sensitivity and Study Quality

• If sensitivity to drug effects exists for a
  therapeutic class, assay sensitivity in a
  particular study can still be undermined by a
  variety of study conduct factors that bias
  toward the null, i.e., obscure true differences
  between treatments
• These factors include

33
Assay Sensitivity and Study Quality

• Poor compliance
• Non-protocol crossovers
• Spontaneous improvement in the population
• A poorly responsive population
• Use of concomitant medication that interferes
  with test and control treatment or that reduces
  extent of potential response
• Poor diagnostic criteria (patients lack the
  disease to be studied)
• Inappropriate (insensitive) measures of drug
  effect
• Poor quality of measurements
• Mixing up the treatments

34
Assay Sensitivity and Study Quality

• These factors, in general, have only small (or
  no) effects on variance (width of CI) but can
  reduce or obliterate A-T differences, leading to
  false conclusion of non-inferiority
• Note Some analytic approaches that are
  conservative in a difference-showing trial are
  not in a non-inferiority trial for example, an
  intent-to-treat approach reduces A-T and is not
  conservative

35
The Non-Inferiority Margin

• M has two properties of interest
• 1. It must be no larger than the entire effect of
  the control drug (C) in this study. Call this M1
• 2. It cannot be larger than a clinical difference
  (degree of inferiority) you are willing to
  accept. This is M2

36
Find M1, First

• To design a non-inferiority study, find M1, the
  effect you are sure the control agent had in the
  study. Then if
• C-TltM1,
• the test drug has at least some effect
• Then decide how much of M1 you need to preserve,
  say at least 50. In that case, M2 will be the
  reference for the null (really non-inferiority)
  hypothesis and the study will need to show
• C-TltM2

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Illustrations of Lack of HESDE

• Depression and other psychiatric conditions
• Symptomatic CHF
• Post-operative nausea and vomiting

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Historical Evidence of Sensitivity to Drug
Effects a Precondition for Assay Sensitivity

• Examples of situations in which studies of
  current drugs lack sensitivity to drug effects
• Depression
• Anxiety
• Dementia
• Symptomatic congestive heart failure
• Seasonal allergies
• Gastroesophageal reflux disease
• Post-infarction beta blockade
• Post-infarction aspirin

42
Conclusions

• 1. Placebo controls are ethical, even when there
  is existing effective therapy, if subjects on
  placebo will not be harmed
• 2. Active control non-inferiority trials are
  informative only if you can be sure the trial had
  assay sensitivity and could have detected an
  effect vs. placebo (had there been a placebo) of
  M1, the presumed effect of the active control
• 3. Assay sensitivity often cannot be presumed