Re: Ethics in design of clinical research

[Guest guest]

Dear friends,

Ethical Considerations in Randomized

Controlled Trials (RCTs)

Features of RCTs

Description

Questions/Considerations

Equipoise

No convincing evidence that one intervention is better, i.e.,

more effective or less toxic than the other.

How to factor in early evidence?

Is a requirement for

equipoise conflating research and therapy?

Choice of control

Appropriate choice of control is necessary for scientific

validity and generalizability.

Choice of control is not simply a scientific decision.

Placebos as controls require ethical justification.

Randomization

Random assignment decreases bias and controls for many

factors

Random assignment does not allow for autonomouspreferences.

Blinding

Either single or double blinding is often used to decrease

bias

Research participants consent to temporarily suspend knowledge

of which intervention they are receiving. A blind

may need to be broken to treat some clinical problems.

Sharing preliminary information

As evidence accumulates, information about risks and benefits may change and equipoise may be disturbed

Study monitors, independent data and safety monitoring

boards, and others carefully monitor data to help determine when the study should be stopped or

information should be shared with participants.

Regards,Dr. MangeshNagpur

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[Guest guest]

Dear members,

Randomized clinical trials (RCTs) remain

the principal method and “gold standard†for demonstrating safety and efficacy in

the development of new drugs and biologics, such as vaccines, surgical

interventions, behavioral interventions, and systems interventions. An RCT has

several characteristic features. It is controlled, randomized, and usually

blinded; also, the significance of the results is determined statistically according

to a predetermined algorithm. An RCT typically involves the comparison of two

or more interventions (e.g., Drug A versus Drug to demonstrate the equivalence

or the superiority of one intervention over the other in the treatment,

diagnosis, or prophylaxis of a specific disorder. The ethical justification to

begin an RCT is usually described as that of “an honest null hypothesis,â€

also referred to as equipoise or clinical equipoise.

In an RCT comparing intervention A and B, clinical equipoise is

satisfied if there is no convincing evidence available to the clinical

community about the relative merits of A and B (e.g., evidence that A is more

effective than or less toxic than . The goal of an RCT is by design to

disturb this state of equipoise by providing credible evidence about the

relative value of each intervention.Regards,Dr. MangeshNagpur

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[Guest guest]

Dear sir

Thanks for initiating discussion on "Ethics in design of clinical research". I do agree that ethical consideration is of utmost importance in randomized controlled trials (RCTs). Randomized controlled trials have been designed to minimize bias by distributing risks and benefits equally among the research participants but one group may either receive placebo or standard therapy.

Is it ethical to conduct placebo controlled trials?

As we know placebos are not going to help subjects in their disease condition. On the contrary, it may worsen the condition of the trial subject under study. What is your opinion?

Even in case of Blinding where subjects dont know whether they are receiving active drug or placebo (single blinding) and in other case where subject or investigator dont know about the type of treatment (double blinding), how far it is ethically acceptable?

Can you elaborate more on Blinding, types of blinding, design and their impact on clinical research?

Thanks and Regards

TARUN WADHWA

SENIOR RESEARCH FELLOW

DEPARTMENT OF PHARMACOLOGY

J N MEDICAL COLLEGE

NEHRU NAGAR, BELGAUM-590010

KARNATAKA, INDIA

PH: 09844564634

E.MAIL: pharmamanipal@...

From: mangesh bankar <drmangesh_bankar@...>Subject: Re: Ethics in design of clinical researchnetrum Date: Sunday, 27 December, 2009, 11:51 AM

Dear friends,

Ethical Considerations in Randomized Controlled Trials (RCTs)

Features of RCTs

Description

Questions/Considera tions

Equipoise

No convincing evidence that one intervention is better, i.e., more effective or less toxic than the other.

How to factor in early evidence?

Is a requirement for equipoise conflating research and therapy?

Choice of control

Appropriate choice of control is necessary for scientific validity and generalizability.

Choice of control is not simply a scientific decision. Placebos as controls require ethical justification.

Randomization

Random assignment decreases bias and controls for many factors

Random assignment does not allow for autonomous

preferences.

Blinding

Either single or double blinding is often used to decrease bias

Research participants consent to temporarily suspend knowledge of which intervention they are receiving. A blind

may need to be broken to treat some clinical problems.

Sharing preliminary information

As evidence accumulates, information about risks and benefits may change and equipoise may be disturbed

Study monitors, independent data and safety monitoring

boards, and others carefully monitor data to help determine when the study should be stopped or

information should be shared with participants.

Regards,Dr. MangeshNagpur

The INTERNET now has a personality. YOURS! See your Homepage.

The INTERNET now has a personality. YOURS! See your Homepage.

[Guest guest]

Dear Members,Random

assignment to different treatment groups is a powerful means of eliminating

bias in research. Eliminating bias is an important obligation in designing and

conducting research, since it would be inappropriate to expose participants to

research that is unlikely to yield valid information. However, the use of

randomization or any other method of assigning treatment arms can be

inappropriate if participants are unnecessarily harmed as a result, such as being

deprived of a therapy known to be effective. Accordingly, the use of

randomization needs to be justified. While different proposals work to justify

the use of randomization, one that has gained much currency involves the notion

of “clinical equipoise.â€Regards,Dr. MangeshNagpur

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[Guest guest]

Dear Members,

Clinical equipoise is the situation in

which experts are uncertain as to whether any of the proposed arms of a trial

is superior to another. For example, clinical equipoise exists if there is

uncertainty in the expert community as to whether treatment A is better than

treatment B, or whether treatment A is better than placebo. It is argued that

it is acceptable to consider the use of randomization when

clinical equipoise exists but unacceptable to

do so if it does not. Even if clinical

equipoise exists, it is important to realize that

there are lingering ethical challenges associated with

randomization in clinical research due to the usual tight relation

of research to clinical care. First, obtaining valid informed consent can be

difficult in many circumstances. Patients who are asked to participate in

research may not recognize the distinction between clinical care and research,

failing to understand that their medical care has been selected by

randomization rather than by their physicians. In fact, empirical work has

demonstrated that such a “therapeutic misconception†exists in clinical research.

Second, the obligation of clinicians to

provide personalized care is central to medical practice. Randomization may

simply interfere with personalized care. Third, individual patients may prefer

one treatment to another, even in the setting of clinical equipoise, and there

may be strong reasons to honor these choices.Regards,Dr. Mangesh,Nagpur.

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[Guest guest]

hello,

Mangesh this post is not clear . it is in some other script. Is it the problem with my computer or all have recd. the same alien script? pl. post it again.

kunda

From: mangesh bankar <drmangesh_bankar@...>Subject: Re: Ethics in design of clinical researchnetrum Date: Sunday, 27 December, 2009, 11:59 AM

Dear members,

Randomized clinical trials (RCTs) remain the principal method and “gold standard†for demonstrating safety and efficacy in the development of new drugs and biologics, such as vaccines, surgical interventions, behavioral interventions, and systems interventions. An RCT has several characteristic features. It is controlled, randomized, and usually blinded; also, the significance of the results is determined statistically according to a predetermined algorithm. An RCT typically involves the comparison of two or more interventions (e.g., Drug A versus Drug to demonstrate the equivalence or the superiority of one intervention over the other in the treatment, diagnosis, or prophylaxis of a specific disorder. The ethical justification to begin an RCT is usually described as that of “an honest null

hypothesis,†also referred to as equipoise or clinical equipoise. In an RCT comparing intervention A and B, clinical equipoise is satisfied if there is no convincing evidence available to the clinical community about the relative merits of A and B (e.g., evidence that A is more effective than or less toxic than . The goal of an RCT is by design to disturb this state of equipoise by providing credible evidence about the relative value of each intervention.

Regards,

Dr. Mangesh

Nagpur

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[Guest guest]

In the case of traditional remedies being studied for validation or in some other circumstances when relief to pateinets is more important as in the case of cancer etc. then observation studies are now gaining ground.

Nandini K. Kumar

Co-investigator NIH project

National Institute of Epidemiology

R 127, 3rd Avenue,

TNHB, Ayapakkam,

Chennai 600077

netrum From: drmangesh_bankar@...Date: Sun, 27 Dec 2009 18:06:43 +0530Subject: Re: Ethics in design of clinical research

Dear Members,Random assignment to different treatment groups is a powerful means of eliminating bias in research. Eliminating bias is an important obligation in designing and conducting research, since it would be inappropriate to expose participants to research that is unlikely to yield valid information. However, the use of randomization or any other method of assigning treatment arms can be inappropriate if participants are unnecessarily harmed as a result, such as being deprived of a therapy known to be effective. Accordingly, the use of randomization needs to be justified. While different proposals work to justify the use of randomization, one that has gained much currency involves the notion of “clinical equipoise.”Regards,Dr. MangeshNagpur

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[Guest guest]

Dear friends

Clinical equipoise, also known as the principle of equipoise, provides the ethical basis for medical research involving patients assigned to different treatment arms of a clinical trial. First created in a laboratory in the state of Israel, under the guidance of scientist Freedman. The term was first used by Freedman in 1987. Ethical concerns during a clinical trial arise in human trials when the investigator(s) begin to believe that one arm of the trial is more beneficial than another. Clinical equipoise means that there is genuine uncertainty over whether or not the treatment will be beneficial. Even if the researcher truly believes in a hypothesis, there is no actual proof that the benefit exists. Once there is sufficient evidence the research is usually stopped since clinical equipoise is not met.

Ref: http://en.wikipedia.org/wiki/Clinical_equipoise

Anupama

From: nandini kumar <nadkku@...>Subject: RE: Re: Ethics in design of clinical researchnetrum Date: Sunday, 27 December, 2009, 7:07 PM

In the case of traditional remedies being studied for validation or in some other circumstances when relief to pateinets is more important as in the case of cancer etc. then observation studies are now gaining ground.

Nandini K. Kumar

Co-investigator NIH project

National Institute of Epidemiology

R 127, 3rd Avenue,

TNHB, Ayapakkam,

Chennai 600077

netrumgroups (DOT) comFrom: drmangesh_bankar@ .co. inDate: Sun, 27 Dec 2009 18:06:43 +0530Subject: Re: Ethics in design of clinical research

Dear Members,Random assignment to different treatment groups is a powerful means of eliminating bias in research. Eliminating bias is an important obligation in designing and conducting research, since it would be inappropriate to expose participants to research that is unlikely to yield valid information. However, the use of randomization or any other method of assigning treatment arms can be inappropriate if participants are unnecessarily harmed as a result, such as being deprived of a therapy known to be effective. Accordingly, the use of randomization needs to be justified. While different proposals work to justify the use of randomization, one that has gained much currency involves the

notion of “clinical equipoise.â€Regards,Dr. MangeshNagpur

The INTERNET now has a personality. YOURS! See your Homepage.

New Windows 7: Find the right PC for you. Learn more.

The INTERNET now has a personality. YOURS! See your Homepage.

[Guest guest]

Dear Anupama,Thanks for providing historical aspects of clinical equipoise. In my opinion, definition of

clinical equipoise that defines uncertainty as a lack of

scientifically-validated information gives a physician the best chance of

acting in his patient's best interests. It enables him to give his patient the

most accurate information available, even though such accuracy entails

uncertainty. Such uncertainty not only makes it possible for both physicians

and patients to seek out the best treatment by being involved in clinical

trials, but it also may enable them to better define "best" as that which meets

the patients needs, both in terms of physiology and values. Under such

circumstances the physician-researcher is better able to manage the inherent

conflict between his responsibilities as a physician to provide the best care

for his patient, and his responsibilities as a researcher to increase

generalizable knowledge and thus enable better care of all patients.Regards,Dr. MangeshNagpur.

From: nandini kumar <nadkkuhotmail (DOT) com>Subject: RE: Re: Ethics in design of clinical researchnetrumgroups (DOT) comDate: Sunday, 27 December, 2009, 7:07 PM

In the case of traditional remedies being studied for validation or in some other circumstances when relief to pateinets is more important as in the case of cancer etc. then observation studies are now gaining ground.

Nandini K. Kumar

Co-investigator NIH project

National Institute of Epidemiology

R 127, 3rd Avenue,

TNHB, Ayapakkam,

Chennai 600077

netrumgroups (DOT) comFrom: drmangesh_bankar@ .co. inDate: Sun, 27 Dec 2009 18:06:43 +0530Subject: Re: Ethics in design of clinical research

Dear Members,Random assignment to different treatment groups is a powerful means of eliminating bias in research. Eliminating bias is an important obligation in designing and conducting research, since it would be inappropriate to expose participants to research that is unlikely to yield valid information. However, the use of randomization or any other method of assigning treatment arms can be inappropriate if participants are unnecessarily harmed as a result, such as being deprived of a therapy known to be effective. Accordingly, the use of randomization needs to be justified. While different proposals work to justify the use of randomization, one that has gained much currency involves the

notion of “clinical equipoise.â€Regards,Dr. MangeshNagpur

The INTERNET now has a personality. YOURS! See your Homepage.

New Windows 7: Find the right PC for you. Learn more.

The INTERNET now has a personality. YOURS! See your Homepage.

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[Guest guest]

Dear Members,

Institutional ethics committees (ECs) need

to demand more of study investigators who submit proposals for trials of new

drugs. If a placebo arm is included for a drug that will compete with an

established treatment, the study protocol must supply a persuasive

justification for using a placebo control. EC, in other words, must approach studies

of new drugs more skeptically and approve studies only when they have enough

information to make an independent judgment about the desirability or undesirability

of a placebo control.

In providing the information necessary to

justify a placebo control, the study’s investigators would have to explain why

adequate results could not be obtained by comparing the study drug with an

existing therapy in a well designed study with ample subjects, or why adequate

results could not be obtained by using the study drug plus existing therapy in

one arm and the existing therapy plus placebo in the other arm.

In some cases, investigators will observe that

costs are a consideration in using placebo controls, that a placebo controlled study

can often be completed with fewer subjects and in a shorter period of time.

If an IRB is to make judgments on cost

grounds, the board would need specific information about the costs of the proposed

and alternative studies. Indeed, as a general matter, common arguments in favor

of placebo controls are not adequate to justify a particular use of a placebo control.

In deciding whether study investigators have

persuasive justification for including a placebo control, EC should rely on government’s

basic requirements for medical research, a requirement that is too often overlooked.

In the language of the regulations, EC

shall not approve a study unless it is satisfied that the “risks to subjects

are minimizedâ€. In other words, it is not sufficient to demonstrate relatively

low risk; it is also necessary to demonstrate that risks have been made as low

as possible given the potential benefits at stake. Thus, if the same benefits

as the proposed study can be obtained from a different study and the different

study would pose less risk to the subjects, the IRB must reject the proposed study.

Regards,Dr. Mangesh,Nagpur.

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