Clinical Trials – What you need to Know
Did you know the public clinical trials registry, ClinicalTrials.gov, was created in February 2000 in support of a 1997 federal law requiring public registration of clinical trials? It was designed as a web-based catalog of clinical trials to serve as a resource for the patient and research community alike. The law has since expanded to require more types of clinical trials research to be registered, and for some trials, results are also required to be posted.
Did you know there are at least 4 organizations that may require you to register your study on ClinicalTrials.gov? The FDA, National Institutes of Health (NIH), International Committee of Medical Journal Editors (ICMJE) and World Health Organization (WHO) each have rules about registering. For more details on each, please click here.
Did you know the NIH and ICMJE have expanded their definitions of a clinical trial to include behavioral trials? Click here for NIH’s definition. Click here for the ICMJE definition.
Did you know that for studies that require results to be posted per the federal law with completion dates after 1/18/17, a final version of the IRB-approved protocol document and statistical analysis plan must be uploaded to the ClinicalTrials.gov record? Limited information may be redacted. For details, click here.
Should your study be registered with ClinicalTrials.gov?
For more information, see our webpages or contact Ellen Ciesielski (eciesielski@uchc.edu, 860-679-6004) in Research Compliance Services.
Inclusion of Children in Research
When a Principal Investigator (PI) proposes a research project that will involve an intervention or interaction with children, the PI must demonstrate to the IRB that the additional protections afforded to children by regulations have been addressed. The Department of Health and Human Services (DHHS) and the Food and Drug Administration (FDA) have each established regulations governing the inclusion of children in research and the UConn Health IRB has incorporated these regulations into policy. When proposing a research study that will include children as subjects investigators should review the following material:
- IRB Policy 2011-006.0, Additional Protections for Certain Populations – General Policy,
- IRB Policy 2011-006.3, Additional Protections for Certain Populations – Children,
- Form D, Additional Protections for Children Involved as Subjects in Research
In order for the IRB to approve a research protocol that will enroll children, the IRB must assess the information provided by the PI and be able to determine that the research falls within one or more of the following permissible categories and that the plans for obtaining the assent of the child and permission of the parents are appropriate. The examples provided within each category were taken from the Collaborative Institutional Training Initiative (CITI) Program.
Category 1: Research not involving greater than minimal risk.
Minimal risk means that the probability and magnitude of harm or discomfort anticipated in the research are not greater in and of themselves than those ordinarily encountered in daily life or during the performance of routine physical or psychological examinations or tests.
To be approvable under this category, the IRB must find that the research presents no greater than “minimal risk” to children, and that adequate provisions are made for soliciting the assent of the children and the permission of their parents or guardians. The IRB may determine that permission from one parent is sufficient.
Examples of Research Projects That May Fall Within Category 1
- A study to determine the relationship between maternal age and head circumference at birth. Measurement of head circumference is part of the normal newborn examination, and is therefore minimal risk.
- A study to determine the incidence of asymptomatic proteinuria in school age children. The research involves the analysis of a voided urine collection, which is minimal risk.
Category 2: Research involving greater than minimal risk but presenting the prospect of direct benefit to the individual subjects.
This category is inclusive of research in which 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. The IRB may approve research under this category only if the IRB finds and documents 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; and
(c) Adequate provisions are made for soliciting the assent of the children and permission of their parents or guardians. The IRB may determine that permission from one parent is sufficient.
Examples of Research Projects That May Fall Within Category 2:
A pilot study of a shorter duration of antibiotic treatment for uncomplicated otitis media. The potential benefit associated with the shorter duration of treatment is increased compliance, and a reduced rate of antibiotic-related diarrhea. The risk associated with the shorter duration of therapy is a higher likelihood of treatment failure.
The risk associated with this research (e.g. treatment failure) appears to be greater than minimal but can be justified by the anticipated benefit (reduce rate of antibiotic diarrhea); and there is the prospect of direct benefit to the child (increased compliance, shorter exposure time, and a reduced rate of antibiotic-related diarrhea). If the risk-benefit relationship is as favorable as the one seen with standard care (e.g. use of the antibiotic for standard time frame), this research would be approvable under this category.
Use of a placebo, or routine monitoring for safety, is not considered to provide direct benefit to subjects.
Category 3: Research involving greater than minimal risk and no prospect of direct benefit to individual subjects, but likely to yield generalizable knowledge about the subjects’ disorder or condition.
This category is inclusive of research in which more than minimal risk to children is presented by an intervention or procedure that does not hold out the prospect of direct benefit for the individual subject, or by a monitoring procedure which is not likely to contribute to the well-being of the subject. To be approvable under this category, the children to be enrolled must have the disorder or condition under study (i.e. a healthy control group would not be allowable) and the IRB must find and document that:
(a) The risk represents a minor increase over minimal risk;
(b) 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;
(c) The intervention or procedure is likely to yield generalizable knowledge about the subjects’ disorder or condition which is of vital importance for the understanding or amelioration of the subjects’ disorder or condition; and
(d) Adequate provisions are made for soliciting assent of the children and permission of their parents or guardians. In most cases permission from both parents is required.
Examples of Procedures That May Involve Minor Increase Over Minimal Risk:
- Catheterized urine collection
- Skin biopsy or bone marrow biopsy
- MRI scan with sedation
Example of Research That May Fall Within Category 3:
A study to determine the clinical relevance of a new technique to quantitate minimal residual disease (MRD) during therapy for acute lymphoblastic leukemia in children. The study requires one additional bone marrow aspirate be performed during the course of treatment. Therapy for the subject will not be altered based on the results of the assay. However, if it can be shown that the presence of MRD predicts poor outcome, in the future, patients with MRD can receive more intensive treatment and increase their chance of cure.
It can be argued that the risk of a bone marrow aspirate in a child is only a minor increase over minimal risk. Further, the risk appears commensurate with risks inherent in the subject’s actual medical situation, and the research may yield knowledge of vital importance about the child’s disease (leukemia).
Category 4: Research not otherwise approvable which presents an opportunity to understand, prevent, or alleviate a serious problem affecting the health or welfare of children
For research not otherwise approvable that presents an opportunity to understand, prevent, or alleviate a serious problem affecting the health or welfare of children the IRB must find and document:
- 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) For studies funded or supported by DHHS, the Secretary, or for studies subject to FDA oversight the Commissioner, 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 one of the aforementioned categories, as applicable, or
(2) (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.
General Requirements for Assent and Permission:
Assent means an affirmative agreement to participate in research used with those who are not competent or not of legal age to provide informed consent. Failure to object may not be construed as assent.
For children to participate in research, the IRB must determine that adequate provisions are made for soliciting the assent of the children when in the judgment of the IRB the children are capable of providing assent. The IRB will take into account the ages, maturity, and psychological state of the children involved. The judgment may be made for all children to be involved in research under a particular protocol, or for each child. When the IRB determines that assent is required, it shall also determine whether and how assent must be documented.
The IRB may determine that assent is not a necessary condition for proceeding with the research if the capability of some or all of the children is so limited that they cannot reasonably be consulted or that the intervention or procedure involved in the research holds out a prospect of direct benefit that is important to the health or well-being of the children and is available only in the context of the research.
Permission is the agreement of parent(s) or guardian to the participation of their child in research. Permission is generally documented by have the parent(s)/guardian sign an informed consent document.
For research studies not involving greater than minimal risk (Category 1 ) and research involving greater than minimal risk but presenting the prospect of direct benefit to the individual subjects (Category 2) the IRB may find that the permission of one parent or guardian is sufficient. For research studies involving greater than minimal risk and no prospect of direct benefit to individual subjects, but likely to yield generalizable knowledge about the subjects’ disorder or condition (Category 3), and for research studies not otherwise approvable which presents an opportunity to understand, prevent, or alleviate a serious problem affecting the health or welfare of children (Category 4), both parents/guardians must give their permission unless one is deceased, unknown, incompetent or not reasonably available, or unless only one parent has legal responsibility for the care and custody of the child.
If the IRB determines that a research protocol is designed for conditions or for a subject population for which parental or guardian permission is not a reasonable requirement to protect the subject (e.g., neglected or abused children) it may waive the consent requirements provided an appropriate mechanism for protecting the children who will participate as subjects in the research is substituted, and provided further that the waiver is not inconsistent with Federal, state or local law.
The choice of an appropriate mechanism would depend upon the nature and purpose of the activities described in the protocol, the risk and anticipated benefit to the research subjects, and their age, maturity status and condition.
Inclusion or Wards in Research
Children who are wards of the state or any other agency, institution, or entity can be included in research involving greater than minimal risk and no prospect of direct benefit to the individual subjects, but likely to yield generalizable knowledge about the subject’s disorder or condition (Category 3) or research that is not approvable under a defined regulatory category but that presents an opportunity to understand, prevent, or alleviate a serious problem affecting the health or welfare of children (Category 4) only if the research is related to their status as wards, or is conducted in schools, camps, hospitals, organizations, or similar settings in which the majority of children involved as subjects are not wards.
Each child must have an advocate appointed who has the background and experience to act in, and agrees to act in, the best interests of the child, and who is not associated in any way with the research, researchers, or guardian organization.