28 March 2001 The Revised Declaration of Helsinki
Applying Ethical Principles toApplying Ethical Principles to
Research in...
Declaration of Helsinki §8
Ethical Standards of theEthical Standards of the
Declaration of HelsinkiDeclaration of Helsinki...
Research Involving Children (1977); The Belmont Report
Respect for ChildrenRespect for Children
 Declaration of Helsinki ...
Declaration of Helsinki (2000) Paraphrased
BeneficenceBeneficence
 Well-being of the child subject takes precedence over
...
JusticeJustice
 The Belmont Report (1979)
• Fair sharing of burden and
benefit of research
 Declaration of Helsinki (200...
Specifying an Ethical FrameworkSpecifying an Ethical Framework
Minimal risk (“beneficence”)
• Establishes proper scope of...
Additional SafeguardsAdditional Safeguards
Subpart D of 45 CFR 46
• Restricts allowable risk exposure for research
that d...
Research without direct benefitResearch without direct benefit
Restrict to “minimal risk” research (§404), or
• “not grea...
Minimal RiskMinimal Risk
Definition (§46.102(i))
• probability and magnitude of harm or discomfort
anticipated in the res...
§46.405 Greater than Minimal Risk Research
Prospect of Direct BenefitProspect of Direct Benefit
For more than minimal risk...
45 CFR 46.407
National Review PanelNational Review Panel
 Process (advisory to Secretary of DHHS)
• Consultation with a p...
ControversiesControversies
 Exposing healthy children to more than minimal
risk
• Controls; single dose PK studies
 Prev...
QuestionQuestion
 Fact: A medication is approved as “safe and
effective” treatment for a condition.
 Principle: Genuine ...
§29, Adopted 52nd WMA General Assembly, October 200
Declaration of HelsinkiDeclaration of Helsinki
 “The benefits, risks,...
ProtocolProtocol
Children ages 6 to 11 years with primary
nocturnal enuresis (“bedwetting”)
Approved “best current” “pro...
AAP Committee on Drugs (1995)
Placebo/Observational ControlsPlacebo/Observational Controls
 No commonly accepted therapy;...
Tri-Council Policy Statement - Canada (August 1998)
Placebos and equipoisePlacebos and equipoise
 Substantial doubt regar...
ICH E-10 Section 2.1.3 Ethical Issues (July 2000)
ICH: Choice of Control GroupICH: Choice of Control Group
Placebo control...
Edited Transcript FDA Pediatric Advisory Subcommittee
Applicability of E-10 to ChildrenApplicability of E-10 to Children
...
45 CFR 46.406
Application of §46.405 to PlaceboApplication of §46.405 to Placebo
Controlled TrialControlled Trial
“Researc...
Limiting Placebo ExposureLimiting Placebo Exposure
Active control design
• Equivalence or superiority design
Three arm t...
E-11 Clinical Investigation of Medicinal Products in the P
Sufficient Pediatric ExpertiseSufficient Pediatric Expertise
S...
Upcoming SlideShare
Loading in …5
×

Robert M. Nelson, MD PhD: Applying Ethical Principles - IRB Forum ...

547 views

Published on

0 Comments
1 Like
Statistics
Notes
  • Be the first to comment

No Downloads
Views
Total views
547
On SlideShare
0
From Embeds
0
Number of Embeds
1
Actions
Shares
0
Downloads
7
Comments
0
Likes
1
Embeds 0
No embeds

No notes for slide
  • UN Declaration of the Rights of the Child
    Principle 7: “The child… shall be given an education which will promote his general culture and enable him, on a basis of equal opportunity, to develop his abilities, his individual judgment, and his sense of moral and social responsibility, and to become a useful member of society. The best interests of the child shall be the guiding principle of those responsible for his education and guidance; that responsibility lies in the first place with his parents.”
    The National Commission in The Belmont Report wrote about the “special provision[s]” for children that respect for persons requires, including “the opportunity to choose to the extent they are able” (i.e., assent), honoring dissent “unless the research entails providing them a therapy unavailable elsewhere” and “seeking the permission of other parties [e.g. parents] in order to protect the subjects from harm.” The Belmont Report (1979)
  • The National Commission also established “an order of preference in the selection of classes of subjects (e.g., adults before children)” as “a matter of social justice” based on the judgment that children ought not to bear the burdens of research unless absolutely necessary. The Belmont Report (1979)
    Australia: National Statement on Ethical Conduct in Research Involving Humans – June 1999 4. RESEARCH INVOLVING CHILDREN AND YOUNG PEOPLE
    4.1 Research is essential to advance knowledge about children’s and young peoples’ well-being but research involving children and young people should only be conducted where:
    (a) the research question posed is important to the health and well-being of children or young people;
    (b) the participation of children or young people is indispensable because information available from research on other individuals cannot answer the question posed in relation to children or young people;
    (c) the study method is appropriate for children or young people; and
    (d) the circumstances in which the research is conducted provide for the physical, emotional and psychological safety of the child or young person.
  • The National Commission discussed the scope of parental authority in enrolling a child in research, arguing that such decisions are morally justified either if the research may directly benefit the child (reflected in 45 CFR 46.405) or that the risks of participation in the research “are equivalent to normal risks of childhood” (i.e., the concept of minimal risk found in 45 CFR 46.404 and 406). The National Commission. Report and Recommendations: Research Involving Children (1977).
    The moral authority for parents to make decisions that are in a child’s best interest is reflected in the waiver of assent if an intervention that may benefit the child is only available within the research.
    From Australian National Statement:
    4.3 An HREC must not approve, and consent cannot be given for, research which is contrary to the child’s or young person’s best interests.
    4.4 A child’s or young person’s refusal to participate in a research project must be respected.
  • Roughly, anchoring allowable risk exposure to minimal risk assumes that parents may only permit a child to be exposed to research risks that are equivalent to the risks of that child’s everyday life. The concept of “minimal risk” serves not only as an index of allowable research risk, it also establishes the basis for a child’s assent in light of a child’s past experience. For example, in 45CFR46.406, the requirement that “the intervention or procedure presents experiences to subjects that are reasonably commensurate with those inherent in their actual or expected medical, dental, psychological, social, or educational situations” was developed, not as a further restriction on allowable risk, but as the basis for a child’s assent to the procedures involved in the research.
  • Indexing of minimal risk:
    The National Commission initially stipulated that this standard should be indexed to the lives “of healthy children” More recently, NBAC argued “that the standard for minimal risk should be an absolute standard and should be related to the risks of daily life that are familiar to all of us in the general population.” The panel interprets “daily life” to refer to the daily life of healthy children in the general population. The panel notes that the regulatory standard is quantitative rather than qualitative. A risk that is of an uncommon type may nonetheless be no greater in probability and magnitude of harm and discomfort than are the more familiar risks of daily life. For example, routine diagnostic radiographs obtained on a single occasion would not automatically be considered to be of greater than minimal risk.
    The panel notes that ambiguity in the phrase “ordinarily encountered” leads to differences of opinion about the level of risk presented by specific research procedures; these may in part relate to a tension between statistical and normative interpretations of the concept. Commonly used synonyms for “ordinarily,” such as “routinely,” “commonly,” “frequently,” “normally” and “usually” might individually lead to different interpretations about the application of the minimal risk criterion. NBAC believes the standard should not refer to the particular risks encountered by particular persons or groups. It should refer, therefore, to common risks – driving to work, crossing the street, getting a blood test, or answering questions over the telephone.
    In evaluating whether a given procedure or intervention qualifies as “minimal risk,” an IRB should consider whether the risks presented are comparable to the risks that parents may ordinarily allow their children to experience in the course of their everyday lives.
    Accepting the argument in favor of an absolute standard of minimal risk, one could still allow a relative standard of a minor increase over minimal risk provided that the research “intervention or procedure presents experiences… that are reasonably commensurate with those inherent in [the child’s] actual or expected… situations.” In effect, only those interventions or procedures which are reasonably commensurate with a particular child’s experience could be considered as only a minor increase over minimal risk. “In evaluating whether a given procedure or intervention qualifies as “minimal risk,” an IRB should consider whether the risks presented are comparable to the risks that parents may ordinarily allow their children to experience in the course of their everyday lives.”
  • For research that is greater than a “minor increase over minimal risk” to be approved, there must be “research equipoise” between two (or more) arms of a concurrently controlled trial (assuming one arm represents currently accepted practice), or between a single arm trial and the alternatives available outside of the research.
    “Research equipoise is the state in which there is “an honest, professional disagreement” among experts about whether the proposed study interventions – both experimental and control interventions (including placebos) – should be the preferred treatment or practice. In other words, neither the experimental nor control intervention is preferred; there is genuine uncertainty about which intervention is better. A judgment of research equipoise relies upon a comparison of the risks and potential benefits of the proposed study interventions with those of accepted practice.
    CANADA: Clinical equipoise means a genuine uncertainty on the part of the expert medical community about the comparative therapeutic merits of each arm of a clinical trial.The tenet of clinical equipoise provides a clear moral foundation to the requirement that the health care of subjects not be disadvantaged by research participation.
    A phase 1 pediatric oncology trial is usually considered under this category, since the standard alternatives have been exhausted and the only remaining prospect for direct benefit may be the experimental intervention. Although a parent’s decision to enroll a child in a phase 1 oncology trial is difficult, many believe the decision may be justified provided that the alternatives of no further experimental treatment and palliative care are presented.
  • §46.407 Research not otherwise approvable which presents an opportunity to understand, prevent, or alleviate a serious problem affecting the health or welfare of children.
    DHHS will conduct or fund research that the IRB does not believe meets the requirements of §46.404, §46.405, or §46.406 only if:
    (a) the IRB finds that the research presents a reasonable opportunity to further the understanding, prevention, or alleviation of a serious problem affecting the health or welfare of children; and
    (b) the Secretary, after consultation with a panel of experts in pertinent disciplines (for example: science, medicine, education, ethics, law) and following opportunity for public review and comment, has determined either:
    (1) that the research in fact satisfies the conditions of §46.404, §46.405, or §46.406, as applicable, or (2) the following:
    (i) the research presents a reasonable opportunity to further the understanding, prevention, or alleviation of a serious problem affecting the health or welfare of children;
    (ii) the research will be conducted in accordance with sound ethical principles;
    (iii) adequate provisions are made for soliciting the assent of children and the permission of their parents or guardians, as set forth in §46.408.
  • DECLARATION OF HELSINKI
    Ethical Principles for Medical Research Involving Human Subjects
    Adopted by the 52nd WMA General Assembly, Edinburgh, Scotland, October 2000
    29.       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 exists.
  • “There is a moral imperative to formally study drugs in children so that they can enjoy equal access to existing as well as new therapeutic agents.”
    Placebo/Observational Control Groups
    Placebo or untreated observational control groups can be used in pediatric studies if their use does not place children at increased risk. The conditions under which placebos may be ethically employed in drug research in children include the following:
    1. When there is no commonly accepted therapy for the condition and the agent under study is the first one that may modify the course of the disease process;
    2. When the commonly used therapy for the condition is of questionable efficacy;
    3. When the commonly used therapy for the condition carries with it a high frequency of undesirable side effects and the risks may be significantly greater than the benefits;
    4. When the placebo is used to identify incidence and severity of undesirable side effects produced by adding a new treatment to an established regimen; or
    5. When the disease process is characterized by frequent, spontaneous exacerbations and remissions and the efficacy of the therapy has not been demonstrated.
  • Article 7.4 The use of placebo controls in clinical trials is generally unacceptable when standard therapies or interventions are available for a particular patient population.
    Consistent with clinical equipoise, a placebo may be used as the control treatment in a clinical trial in the following circumstances:
    (a) There is no standard treatment;
    (b) Standard therapy has been shown to be no better than placebo;
    (c) Evidence has arisen creating substantial doubt regarding the net therapeutic advantage of standard therapy;
    (d) Effective treatment is not available to patients due to cost constraints or short supply. (This may only be applied when background conditions of justice prevail within the health care system in question; for example, a placebo-controlled trial is not permissible when effective but costly treatment is made available to the rich but remains unavailable to the poor or uninsured.)
    (e) In a population of patients who are refractory to standard treatment and for whom no standard second-line treatment exists;
    (f) Testing add-on treatment to standard therapy when all subjects in the trial receive all treatments that would normally be prescribed; or
    (g) Patients have provided an informed refusal of standard therapy for a minor condition for which patients commonly refuse treatment and when withholding such therapy will not lead to undue suffering or the possibility of irreversible harm of any magnitude.
    When a clinical trial involving a placebo control is undertaken, the researcher and the REB must ensure that patients or authorized third parties are fully informed about any therapy that will be withdrawn or withheld for purposes of (1) the research, (2) the anticipated consequences of the withdrawing or withholding of the therapy, and (3) the reasons why investigators deem a placebo-controlled trial to be necessary.
  • ICH HARMONISED TRIPARTITE GUIDELINE CHOICE OF CONTROL GROUP AND RELATED ISSUES IN CLINICAL TRIALS (Recommended for Adoption at Step 4 of the ICH Process on 20 July 2000 by the ICH Steering Committee) 2.1.3 Ethical Issues
    When a new treatment is tested for a condition for which no effective treatment is known, there is usually no ethical problem with a study comparing the new treatment to placebo. Use of a placebo control may raise problems of ethics, acceptability, and feasibility, however, when an effective treatment is available for the condition under study in a proposed trial. 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. There are occasional exceptions, however, such as cases in which standard therapy has toxicity so severe that many patients have refused to receive it.
    In other situations, when 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 noncoercive and patients are fully informed about available therapies and the consequences of delaying treatment. Such trials, however, even if ethical, may pose important practical problems. For example, deferred treatment of pain or other symptoms may be unacceptable to patients or physicians and they may not want to participate in a trial that requires this. 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 institutional review board (IRB)/independent ethics committee (IEC) judgment, and acceptability may differ among ICH regions. Acceptability could depend on the specific design of the trial and the patient population chosen, as will be discussed below (see section 2.1.5).
    Whether a particular placebo-controlled trial is ethical may, in some cases, depend on what is believed to have been clinically demonstrated and on the particular circumstances of the trial. For example, a short term placebo-controlled trial of a new antihypertensive agent in patients with mild essential hypertension and no end-organ disease might be considered generally acceptable, while a longer trial, or one that included sicker patients, probably would not be.
  • Applicability of E10 to Pediatrics:
    Dr. Robert Temple of the FDA indicated in a recent public meeting that the threshold of irreversible morbidity or death contained in ICH E10 presumed informed consent and should not be applied to children.
    Transcript DHHS FDA CDER Pediatric Subcommittee of the Anti-Infective Drugs Advisory Committee, Monday, September 11, 2000. DR. NELSON: “A question for Dr. Temple. The threshold that you offer… for a placebo to be considered is when the withholding of the effective treatment would not result in either death or irreversible morbidity. My question is whether you believe E-10 discussed that issue in the context of pediatrics, and if not, whether it would be appropriate to tackle it in E-11.” DR. TEMPLE: “I don't think E-10 really did consider it. It presumed informed consent. That was an important part of its consideration. Informed consent is clearly a different animal in children. So, I think E-11 probably does need to discuss it, but E-10, I don't believe did.”
  • §46.405 Research involving greater than minimal risk but presenting the prospect of direct benefit to the individual subjects.
    DHHS will conduct or fund research in which the IRB finds that more than minimal risk to children is presented by an intervention or procedure that holds out the prospect of direct benefit for the individual subject, or by a monitoring procedure that is likely to contribute to the subject's well-being, only if the IRB finds that: (a) the risk is justified by the anticipated benefit to the subjects; (b) the relation of the anticipated benefit to the risk is at least as favorable to the subjects as that presented by available alternative approaches.
    In effect, there must be “research equipoise” between two (or more) arms of a concurrently controlled trial (assuming one arm represents currently accepted practice), or between a single arm trial and the alternatives available outside of the research. The concept of research equipoise refers to “the state in which there is “an honest, professional disagreement” among experts about whether the proposed study interventions – both experimental and control interventions (including placebos) – should be the preferred treatment or practice. In other words, neither the experimental nor control intervention is preferred; there is genuine uncertainty about which intervention is better.” Whether or not research equipoise exists does not “does not require numeric equality of intervention risks or potential benefits. Rather, research equipoise requires approximate equality in the risk/potential benefit ratios of the study and control interventions.”
  • Placebo-Controlled Trials
     Placebo-controlled trials may be acceptable if there are no approved or adequately studied therapies for children with the condition under study. For serious or life threatening conditions, a DMC should be used with planned interim monitoring and stopping rules to permit early termination of a study that has shown clear evidence of effectiveness or unacceptable risks prior to completion of planned studies. In studies of less serious symptoms, it may be helpful to build in individual patient failure criteria (early escape) so that exposure to ineffective treatment is limited. *[Note: If there are good reasons for believing that the pediatric disease would respond similarly to the adult disease (and there are well-developed data for adults), it may be difficult to justify an outcome study in children although short-term studies with symptomatic or pharmacodynamic endpoints can be considered].
     Add on trials that do not deny any element(s) of the standard of care (SOC) are acceptable if individual patient discontinuation rules are outlined. These studies do not usually require a Data Monitoring Committee (DMC) unless the studies involve serious and life-threatening disease/condition.
     In placebo-controlled studies reflecting minor illness or discomfort symptoms, exposure to placebo can sometimes be minimized by use of a randomized withdrawal design. Such studies generally would define failure criteria (escape rules) so that the time of exposure to ineffective treatment is minimized. These studies can be used to demonstrate long-term effectiveness when a long-term placebo-controlled trial would be unacceptable. DMC's generally are not needed for studies of symptomatic conditions but would be desirable if there were important safety concerns.
  • 45 CFR 46.107 (and 21 CFR 50.107) requires that “an IRB [which] regularly reviews research that involves a vulnerable category of subjects, such as children… consideration shall be given to the inclusion of one or more individuals who are knowledgeable about and experienced in working with these subjects.” Given that an IRB should also be “sufficiently qualified through the experience and expertise of its members,” the simple addition of a pediatrician to an adult-oriented IRB does not create an IRB capable of reviewing pediatric research. The International Conference on Harmonization (ICH) draft document on pediatric research (E11) requires that “there should be IRB/IEC members or experts consulted by the IRB/IEC who are knowledgeable in pediatric ethical, clinical, and psychosocial issues.” The special protections afforded to children found in Subpart D are in addition to the general criteria for IRB approval. First, the risks to children in the protocol must be minimized. The IRB should consider the risks from the perspective of a child and not simply focus on the physical and economic risks. For example, the research area should be “child friendly” with adequate play area and space for parents to remain with the child. Study-related laboratory samples should be obtained at the time of diagnostic testing, whenever possible. With the growing number of pediatric drug studies, the IRB should be familiar with the various research design methods that minimize risk to the child. An IRB which reviews research involving children needs to possess sufficient experience and expertise, needs to be familiar with the special protections afforded pediatric research subjects by Subpart D, and needs to be capable of both ethical, scientific and regulatory analysis of research trials from a pediatric perspective. Just as it is inappropriate for an investigator to conduct research involving children without sufficient pediatric expertise, an IRB which does not have the necessary knowledge and skill to analyze a pediatric research trial according to the “sound ethical principles” embodied in Subpart D is not in compliance with existing guidance and regulation.
  • Robert M. Nelson, MD PhD: Applying Ethical Principles - IRB Forum ...

    1. 1. 28 March 2001 The Revised Declaration of Helsinki Applying Ethical Principles toApplying Ethical Principles to Research in PediatricResearch in Pediatric PopulationsPopulations Robert M. Nelson, M.D., Ph.D. Chair, Committee on Bioethics American Academy of Pediatrics Chair, Committees for the Protection of Human Subjects The Children’s Hospital of Philadelphia
    2. 2. Declaration of Helsinki §8 Ethical Standards of theEthical Standards of the Declaration of HelsinkiDeclaration of Helsinki Medical research subject to ethical standards Promote respect for all human beings Protect their health and rights Special protection for the vulnerable
    3. 3. Research Involving Children (1977); The Belmont Report Respect for ChildrenRespect for Children  Declaration of Helsinki (2000) • Obtain informed consent from parent (§24) • If child capable, obtain assent (§25)  The National Commission (1977, 1979) • Parental Permission (but within limits)  Protect child’s health and safety (i.e., beneficence) • Child Assent (not as a right, but a benefit)  Nurture child’s moral growth and developing autonomy
    4. 4. Declaration of Helsinki (2000) Paraphrased BeneficenceBeneficence  Well-being of the child subject takes precedence over interests of science and society (§5) • ICH GCP Guidelines 2.3 “The rights, safety, and well-being of the trial subjects are the most important considerations and should prevail over interests of science and society.”  The physician in medical research [must] protect life, health, privacy, and dignity of the child subject (§10)  Responsibility for the child subject always rests with medically qualified person and never with the parent, even though parent has given permission (§15)
    5. 5. JusticeJustice  The Belmont Report (1979) • Fair sharing of burden and benefit of research  Declaration of Helsinki (2000) • Medical research only justified if reasonable likelihood that population in which research carried out may benefit from results (§19) • A child… should not be included in research unless necessary to promote health of similar children and cannot be performed on adults (§24)
    6. 6. Specifying an Ethical FrameworkSpecifying an Ethical Framework Minimal risk (“beneficence”) • Establishes proper scope of parental authority in exposing child to non-beneficial research risk • Waive child assent if research beneficial (§25?) Assent (“respect”) • Research presents similar experiences to child Disorder or condition (“justice”) • Exposure to risk justified by potential direct benefit • If not, incremental risk limited to “minor increase” only if child’s experience similar to actual situation
    7. 7. Additional SafeguardsAdditional Safeguards Subpart D of 45 CFR 46 • Restricts allowable risk exposure for research that does not offer prospect of direct benefit (§46.404 or §46.406) • Restricts justification of risk exposure for research that offers prospect of direct benefit (§46.405) 21 CFR 50, 56 (FDA Regulations) • Required to adopt Subpart D by 17 April 2001
    8. 8. Research without direct benefitResearch without direct benefit Restrict to “minimal risk” research (§404), or • “not greater than ordinarily encountered in daily life” “Minor increase” over minimal risk (§406) if… • Research experience similar to child’s own situation • Knowledge of vital importance for understanding or treatment of child’s disorder or condition  ICH Good Clinical Practice Guidelines (§4.8.14) • Foreseeable risks are low (same as minimal risk?) • Negative impact on well-being minimized and low • Unless exception justified, should be conducted in patients having disease or condition for which product is intended
    9. 9. Minimal RiskMinimal Risk Definition (§46.102(i)) • probability and magnitude of harm or discomfort anticipated in the research are not greater than those ordinarily encountered in daily life or during routine physical or psychological examinations or tests Interpretation? (balance “respect” and “justice”) • Daily life of healthy child or sick child? Absolute or relative standard of minimal risk? • Statistical versus normative interpretations? A child is or should be exposed to “routine” risks?
    10. 10. §46.405 Greater than Minimal Risk Research Prospect of Direct BenefitProspect of Direct Benefit For more than minimal risk research, require…  prospect of direct benefit for individual child  risk justified by anticipated benefit to child • risk not justified by resulting knowledge  relation of anticipated benefit to risk similar to available alternatives (i.e., research equipoise)  adequate provisions for child assent and parental permission
    11. 11. 45 CFR 46.407 National Review PanelNational Review Panel  Process (advisory to Secretary of DHHS) • Consultation with a panel of experts • Opportunity for public review and comment  Required findings • reasonable opportunity to understand, prevent, or alleviate serious problem affecting children • conducted according to sound ethical principles • adequate provisions for assent and permission
    12. 12. ControversiesControversies  Exposing healthy children to more than minimal risk • Controls; single dose PK studies  Prevention trials with more than minimal risk • Disorder or condition? (obesity, schizophrenia)  Use of placebo controls • Declaration of Helsinki versus ICH Choice of Control Group • Threshold “death or irreversible morbidity”? • Alternative designs to minimize placebo exposure
    13. 13. QuestionQuestion  Fact: A medication is approved as “safe and effective” treatment for a condition.  Principle: Genuine uncertainty on the part of the expert medical community about the comparative therapeutic merits of each arm of a clinical trial is required.  Question: Can one ethically perform a placebo-controlled trial even though “safe and effective” treatment for that condition exists?
    14. 14. §29, Adopted 52nd WMA General Assembly, October 200 Declaration of HelsinkiDeclaration of Helsinki  “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 exists.”
    15. 15. ProtocolProtocol Children ages 6 to 11 years with primary nocturnal enuresis (“bedwetting”) Approved “best current” “proven” treatments • Imipramine and Desmopressin (DDAVP) • Only 25 to 50% effective, serious adverse reactions Study Medication: Ibuprofen/pseudoephedrine Study Design: randomized, placebo-controlled, six week duration (baseline, intervention, post- intervention baseline), single bedtime dose
    16. 16. AAP Committee on Drugs (1995) Placebo/Observational ControlsPlacebo/Observational Controls  No commonly accepted therapy; study agent first one that may modify course of disease  Commonly used therapy • questionable efficacy • high frequency of undesirable side effects • risks significantly greater than benefits  Identify undesirable side effects produced by adding new treatment to established regimen  Disease with frequent, spontaneous exacerbations and remissions; efficacy of therapy not demonstrated
    17. 17. Tri-Council Policy Statement - Canada (August 1998) Placebos and equipoisePlacebos and equipoise  Substantial doubt regarding net therapeutic advantage of standard therapy  Informed refusal for minor condition; no undue suffering or irreversible harm of any magnitude from withholding therapy  Effective treatment not available to patients due to cost constraints or short supply • Conditions of justice prevail in health care system
    18. 18. ICH E-10 Section 2.1.3 Ethical Issues (July 2000) ICH: Choice of Control GroupICH: Choice of Control Group Placebo controls may be used if…  No serious harm of withholding effective treatment (or) … • Serious harm: “death or irreversible morbidity”  Effective treatment has severe toxicity  Voluntary and informed consent required • Noncoercive setting and patients fully informed
    19. 19. Edited Transcript FDA Pediatric Advisory Subcommittee Applicability of E-10 to ChildrenApplicability of E-10 to Children  QUESTION: “Dr. Temple, the threshold… for a placebo to be considered is when withholding the effective treatment would not result in either death or irreversible morbidity. Do you believe E-10 discussed that issue in the context of pediatrics, and if not, would be appropriate to tackle it in E-11?”  DR. TEMPLE: “I don't think E-10 considered it. Informed consent was an important part of its consideration. Informed consent is clearly different in children. So, I think E-11 probably does need to discuss it, but E-10, I don't believe did.”
    20. 20. 45 CFR 46.406 Application of §46.405 to PlaceboApplication of §46.405 to Placebo Controlled TrialControlled Trial “Research equipoise” essential Prospect of direct benefit • Do not assume safety and efficacy of study intervention in analyzing risks and benefits Risk justified by anticipated benefit (each arm) • Equipoise between arms internal to the trial Anticipated benefit and risk as favorable as available (non-research) alternatives • Equipoise among trial arms and non-trial alternatives
    21. 21. Limiting Placebo ExposureLimiting Placebo Exposure Active control design • Equivalence or superiority design Three arm trial (decrease subjects exposed) Add on trial (in addition to standard care) Trial of non-responders to standard care Decreased duration of placebo exposure • Early escape, randomized withdrawal, short term trial with physiologic/surrogate endpoint, limited PK/PD trial if efficacy can be assumed
    22. 22. E-11 Clinical Investigation of Medicinal Products in the P Sufficient Pediatric ExpertiseSufficient Pediatric Expertise Sponsor • Appropriate protocol design to minimize risk Institutional Review/Ethics Board • Knowledge of pediatric ethical, clinical, psychosocial issues • Consider risks from child’s perspective • Familiar with research designs that minimize risk Investigator • Trained and experienced in studying children, including evaluation and management of AEs

    ×