Pediatric Consent Errors

Consent is not just the static form; it's a dynamic process by which the subject and investigator embark on a collaborative relationship optimized via conscientious consent planning, consistent implementation, and complete verification. The ethical principles are already set in the Declaration of Helsinki and ICH-GCP, and it suffers chronic deficiencies, however informed consent remains central to the protection of human subjects. It is a process; it does not mean that the pediatric trialist just briefly explains the clinical trial and then the parents (or of-age child) signs the documents. The objective of the informed consent process is that the participants are comfortable with their choice and can comply with it. Regulatory agencies have repeatedly acknowledged that this process should be relatively constant site to site and nation to nation.

The doctrine of informed consent reminds us to respect patients by fully and accurately providing information relevant to exercising their decision-making rights. Pediatric subjects represent a vulnerable population; therefore, special considerations are needed to protect their rights and to shield them from unjustified risk. Consistently each year, informed consent related issues are among the most common deficiencies cited by monitors, auditors, and inspectors in GCP compliance. Certain errors in consent have been observed from time to time and can be categorized in three parts: content of consent form, its employment, and consent process.

Problems with content and readability

• Several consent forms do not provide any understanding about how many subjects will be exposed, as the number of study participants are not specified.

• Exact protocol title, mostly mentioned on consent forms, is complex and a number of times it is not well understood by the subject/parent.

• Inadequate discussion on compensation for injury and who will cover these costs. The wordings of terms and conditions regarding health insurance are confusing and often misleading.

• Little has been explained about length of commitment and amount of follow up required, and it is ambiguous regarding how much time the subject will be in the study.

• Risks do not match those mentioned in the investigator's brochure. Risks are downplayed. Another frequently downplayed, very important issue, is no mention of possible pain and/or other difficulties associated with study procedures.

• No statement on subject payment in benefits or cost reimbursement section. Payments for travel, daycare, and completing study visits are not listed in consent form.

• Consent forms are unclear about the percentage chance of receiving study product. This needs to be carefully explained, given the study arms and the potential for harm (i.e., going untreated and/or undiagnosed) in case of the receipt of placebo.

• Ambiguity from inconsistent references to "patients," "volunteers," "people," and "subjects."

• Sometimes alternative treatment risks and benefits are not described and it is only explained orally by an investigator during the recruitment discussion.

• Not updated with new safety information. This is a GCP requirement, but like many requirements, it is difficult to determine when it is triggered.

• IRBs usually have good reasons for requesting changes and these requests must be honored. Many times it has been found that final consent forms used for the study do not have changes made by the IRB, thus leading to non-compliance.

• Absence of a line for the time of day the consent was given. This is especially important if consent was signed on the same day as dosing or study procedures. This line helps to establish that consent was signed before study tests procedures were initiated.

Errors in employment of informed consent form

Expired. Use of an expired informed consent form (ICF) is a very common phenomenon. Confirmation of the approval and expiration date is very important. It is the investigator's responsibility to ensure that the individual signs the latest version of the consent document.

Altered. Changes made to the form itself reflecting exceptions or deviations to the approved protocol. This might happen due to lack of education and training of site staff.

Incorrect or Invalid. Awareness and understanding of the informed consent process as well as its documentation is key for good clinical practice. However, use of an incorrect and/or invalid form is a routine mistake experienced during monitoring. It occurs when related studies are being conducted simultaneously or have similar application numbers the IRB may advise for stamp and/or logo on consent form; the form may be utilized without heeding these instructions (e.g., e-mailed version wherein no stamp/logo is present).On occasion the incorrect form is distributed (e.g., e-mailed version or for another study).

Universal errors in informed consent process.

Based on the FDA inspectional observations, failure to properly obtain informed consent is one of the most commonly cited violations/deviations at research sites. Even after adequate training, errors in the consent process are the most common findings by the monitoring team and their minimization is directly related to the authenticity and integrity of data.

Signature Irregularities.

• Missing signatures—either of investigator, consent designee, subject/parent, legally authorized representative, and/or witness or subjects thumbprints was taken but there was no sign of witness.

• Signature of legally appointed representative, any relative is commonly observed on ICF even though consent demands signature of either or parent.

• Consent should be obtained and consent form should be signed by investigator or his/her approved signatories. Many times consent is obtained and/or signed by personnel not added to the study (e.g., post-docs students, research fellows, research assistants, nurses, study coordinators, administrative assistants, other clinical, or office staff).

• An impartial witness simply signs the consent document without viewing the informed consent process. Also, they should sign the consent form after the subject.

• Signatures in the wrong place (e.g., witness signed at the column for legally acceptable representative).

Irregularities in dates.

• Consent form not dated or a difference in the dates of the consent signed by investigator, subject/parent, and witness.

• Consent form dated later than the randomization date of the subject or enrollment date.

Re-consenting. In certain situations such as changes to the research plan, change in risk/benefit profile, the results of related research, etc., re-consenting is necessary. It has been noticed that failure to re-consent as per IRB/WIRB instruction is a universal event.

Errors at document organization. Data for subjects without consents may be disqualified. Thus site staff needs to be advised to maintain data in order. The following situations are very common at most of the sites: consent form lost, missing, or misfiled; missing pages of consent form; keeping only the signature page of the consent; no instruction of where forms will be stored; no verification that subject received a copy of the consent form; and documents not maintained in a secure location.

Not Following IRB Approved Procedure. The informed consent process has been visibly mentioned in various international guidelines. Along with this guidance, IRB specific procedures need to be addressed by the site. Any process for which approval is not taken/granted by the IRB should not be followed. A few errors are: sending consent home to be signed/dated; assent has not been obtained; employing an unapproved consent summary (e.g., short form) in place of the form; and utilizing an oral consent for a study requiring a written consent.

Another outright breach is the failure to get the ethics committee approval to make changes to consent documents or to give subjects sufficient time or adequate opportunity to consider participation in the trial. Sometimes the information to be imparted to potential subject/parents is complex or possibly distressful and may require some time for it to be absorbed and appreciated. In these circumstances, the researcher should present the information and discuss the issues with potential subjects/parents on more than one occasion, or allow a period of time to elapse between imparting the information and requesting a signature on the consent form.

Consent form and translation

Informed consent forms must consists of ICH-GCP (Section 4.8.10), suggested elements such as listing all of the reasonably foreseeable risks or inconveniences to the subject and, when applicable, to an embryo, fetus, or nursing infant; providing sufficient explanation of the randomization procedure and trial treatments; statement that the study involves research; participation is voluntary; and listing complete information regarding the person to contact in case of emergency.¹ At the same time the consent form and information sheet should not be unreadable, lengthy, uninformative, and should not use undecipherable language, or else it itself becomes a problem.

For countries translating the original consent forms to produce their own edition, during translation, many terms and descriptions become difficult to understand even for healthcare professionals. Content can either get omitted or be translated incorrectly. The use of software applications that translate "literally rather than for true meaning" is definitely unacceptable. Translation must be performed by unprejudiced, certified translators with informed consent documents undergoing back translation. Clinical study site professionals can enlist the help of individuals who can act as "cultural experts."

How the consent process should be

Investigations into the consent process have shown that central concepts in research such as randomization and the distinctions between phases of clinical trials are not uniformly understood by parents or older pediatric patients. Newer approaches that are being developed to help these deficits include the use of staged informed consent, the incorporation of interactive computer technologies to convey complex ideas, and variations in approaches for assent of the child based on multi-factorial assessments of competence. To assess the subject/parent's understanding, rather than asking for yes or no answers, always ask open-ended, non-directive questions. Solicit an explanation because these questions often can be answered in a variety of ways, and do not already contain the correct answer (e.g., tell me in your own words what this study is all about? Explain to me what you think we're asking you to do? Describe in your own words the purpose of the study.? What more would you like to know? What is the possible benefit to you of participating in this study? What are the possible risks? Can you describe what the alternatives to participation in this study are?). Always remember obtaining a signature on a consent form does not complete the consent process. Maintaining informed consent requires that subjects be provided with any new information that arises during the course of the study that may affect a subject's decision whether or not to continue participating in the study. When such information arises, investigators should facilitate the re-consent process by emphasizing the revisions. The adage "the end justifies the means" serves to remind the organization that obtaining the signature on a consent form can only be justified if the process itself has been adequately and ethically implemented.

Verbal assent, assent, and consent aptness

In determining whether children are capable of assenting, the IRB shall take into account the ages, maturity, and psychological state of the children involved. The purposes of assent are: information exchange between the research team and the child, enhancing the decision making process between the parents and the child, and granting the child the ability to exercise dissent.² When the IRB determines that assent is required, it shall also determine whether and how assent must be documented [45 CFR 46.408]. If assent is not obtained, the reason must be documented on the consent form wherever indicated. Parents and investigators should not exclude children and adolescents from decision making without persuasive reasons. Research relating to immunizations, performing invasive diagnostic testing, beginning of long-term therapy, removal of any growth/tumor, or the use of a medical device in management of any disease in infants and young children generally calls for informed permission of the parent(s).³

Age of assent should be determined by IRBs or should be consistent with local legal requirements. An IRB may waive the assent requirement for very young children (e.g., ages to 0–6 years) and in general whenever possible verbal assent is to be obtained from children under the age of 7. If verbal assent is to be obtained, the IRB must review a written description of the information (i.e., a script) that will be provided to the children during the assent process. If the child is 7 to 11 years old assent is favored. It may require such children to sign a separate assent written at a level appropriate to their intellectual age. For research activities involving children aged 12 and older whose capacity to understand resembles that of adults, the assent procedure should likewise include information similar to what would be provided for informed consent by adults or for parental permission. Thus, in most research studies, if children under the age of 18 are to be enrolled, the parent or guardian of the child must provide informed consent on behalf of the child.⁴

Parent(s) should realize that overruling the child may undermine their relationship with the child. Generally, the child's veto of participation is sufficient to make the child ineligible for inclusion in the study. However, the parent or guardian with physician approval, may override the veto if the intervention will benefit the child (45 CFR 46.402).⁵ If the subject is a minor at the beginning of the study and then reaches the age of maturity during the course of the clinical trial, then parents' permission would no longer constitute legally effective informed consent for research activities that takes place in the future. He/she must be re-consented as an adult and must be offered an opportunity to make the decision.

Parents' involvement

Ensure that the parent/guardian specifies their relationship to the subject. Consent of one parent is sufficient if research involves minimal risk; consent of both parents is necessary if the research involves more than minimal risk. However, if one parent is deceased, unknown, incompetent, or reasonably unavailable, or if one parent has legal responsibility or custody of the child, one parent's consent is acceptable. If parental permission is required from both parents, ensure the consent form is formatted to include two separate signature lines.⁶

Summary

Although upfront GCP training to the informed consent process helps promote compliance, deficiencies continue to be observed at investigator sites around the globe. The deficits are related to content as well as the manner and timing of consenting. In some cases, investigators delegate the consenting function to someone untrained, and/or unqualified. Poorly planned and inadequate sponsor monitoring may also result in replicated consenting mistakes. Conversely, consenting errors can be significantly reduced by ensuring monitoring begins after the first few patients are enrolled and every four to six weeks thereafter. Also, an information sheet and consent form needs to be vigilantly drafted, with an idea that someone with a fifth or sixth grade reading level should be able to read and digest the content.

Utilization of the consent process checklist is a must. The investigator or an investigator's associate must sign the consent form only after the subject/parent signs the consent form. Site staff must ensure that they document the consent process on CRF or as a source note and give the subject/parent a copy of the signed consent form. Documentation should be in detail, mentioning to who the consent was "explained to," time of consent, language in which it was signed, major questions asked by subject/parent, and answers given. Dating another person's signature is strictly forbidden and investigators are advised to generate a note-to-file explaining consent form errors, immediate response, and corrective action. Their focus should be on the corrective and preventive action taken once a problem is recognized.

Thus, informed consent is the process of providing the subject or, in the case of a minor, the custodial parent or legal guardian with relevant information regarding treatment needs so that the subject or custodial parent or legal guardian can make an educated decision regarding treatment. To reduce errors in the consent process, designing a consent form should be thoughtful. Principally in pediatric studies, the creative use of software and other technologies (e.g., audio-visual format, interactive multimedia informed consent programs, and video content) can aid during the consent process. The provision of clear and adequate information remains a key issue and ethical committees should intensify their surveillance of clinical testing.

Sameer Parekh, BHMS, MBA, is Manager Medical Affairs and Clinical Trials at Serum Institute of India Ltd., 212/2 Hadpsar, Pune -411028 India, e-mail: parekhsameer@gmail.com.

References

1. ICH Harmonized Tripartite Guidelines, "Guidelines for Good Clinical Practices," E6 (R1), June 4, 1996.

2. S. Leiken, "Minors' Assent, Consent, or Dissent to Medical Research," IRB: Ethics and Human Research, 15 (2) 1-7 (1993).

3. Committee on Bioethics, "Informed Consent, Parental Permission, and Assent in Pediatric Practice," Pediatrics, 95 (2) 314-317, (1995).

4. John Hopkins University Guidance, "Informed Consent for Minors in Research Studies," May 2005, http://www.hopkinsmedicine.org/institutional_review_board/guidelines_policies/guidelines/informed_consent_minors.

5. Code of Federal Regulations, Title 45: Department of Health and Human Services, Part 46: Protection of Human Subjects, Subpart D: Additional Protections for Children Involved as Subjects in Research, 46.402 (b) (US Government Printing Office, Washington, DC).

6. Code of Federal Regulations, Title 21, Chapter 1: U.S. Food and Drug Administration, DHHS, Part 50: Protection of Human Subjects, Sec. 50.55 Requirements for Permission by Parents or Guardians and for Assent by Children, (US Government Printing Office, Washington, DC).