Health Affairs

“A child is not a small adult,” but an adolescent is not a large child.  Adult oncologists, reluctant to care for cancer patients under the age of 16, believe that adolescent and young adult (AYA) cancer patients should be within their purview.  We believe younger cancer patients are a special group needing special attention, even as the arbitrarily selected AYA age-break point is debated by clinicians, hospital administrators, attorneys, federal regulators, institutional review boards and the pharmaceutical industry.

We have two concerns about the participation of young cancer patients in clinical research.  First, as difficult as the regulatory environment has become for investigators, sponsors, and human subjects in adult oncology, it is more complex for the pediatric and adolescent populations and their physicians.  Second, the degree to which consideration must be given to the human subject protection issues surrounding informed consent in this population requires discussion, debate, and resolution.  As Morgan et al. point out, “open and frank communication is necessary to create opportunities for two-way information exchange between patient and professional”.

Promoting Research, Equalizing Regulatory Oversight

One of us (ESK) has spent the past 25 years developing MEPACT.  This is a liposome-encapsulated immunomodulator that stimulates macrophages to selectively kill metastatic osteosarcoma in the lungs of adolescents and young adults.  The addition of MEPACT to 3-drug or 4-drug chemotherapy regimens decreased the 6-year mortality rate by 30 percent.

Thomas et al. point out that “cancer is the leading disease-related cause of death in young adults” yet MEPACT stands out as one of the very few new agents developed for this patient population by academia or the pharmaceutical/biotechnology sponsors.  MEPACT’s safety profile is outstanding having greater than a 20-year follow-up for patients who received the drug with no long-term toxicities.

Compared to breast, lung, prostate and bowel cancers, AYA cancer is an orphan disease.  There is no separate NIH study section for research into pediatric or AYA cancer and Institutional Review Boards (IRBs) are often reluctant to approve the inclusion of these patients in phase 1 drug trials of the most promising targeted agents, despite the absence of data that these patients are more susceptible to adverse events than adult research subjects.  There is clear language in the Code of Federal Regulations allowing their inclusion even if the clinical investigations involve greater than minimal risk and no prospect of direct benefit to individual subjects. (See specifically 21 CFR Part 50, Subpart D, 50.53)  Indeed in most pediatric phase 1 trials using agents approved for adults, the maximum tolerated dose (MTD) is higher than that in the phase 1 adult trials.

The genesis of modern combination chemotherapy were trials in children and young adults with leukemia.  There is no reason to believe 50 years later that this age group will not contribute to new therapeutic advances if they were once again actively included in and recruited to trials. Moreover, adolescents and young adults stand to benefit from being included in research.  Recent phase 1 studies have shown that offering patients ready for a phase 1 trial access to a drug targeted to a documented molecular abnormality in their individual cancers can result in a 4- to 5-fold increase in the likelihood of antitumor response, compared to trials done without molecular testing even in patients who had received up to 4 previous drug regimens.  As specific molecular abnormalities have also been identified in some AYA cancers, adolescents with cancers having these genetic signatures should be allowed access to phase 1 trials with agents targeted to aberrant gene expression in their cancers.

We urge the formation of a separate NCI study section for the evaluation of proposed research of pediatric and AYA cancers.  We also ask the pharmaceutical industry and IRBs alike to think more inclusively about these patients when new drugs are being studied.  The paternalistic concept often held by IRBs that these younger cancer patients must be protected to a greater degree than older patients with life-threatening diseases is not reasonable.  Children and adolescents as well as adults with relapsed cancer are in desperate need of novel drugs. Given proper and detailed information, parents will make informed decisions in the best interests of the child.  As we point out below adolescents with cancer can and should participate in these crucial decisions as well.  To assume that IRBs alone are better suited to this task is questionable in our opinion, even if they are given the final legal word when conflicts arise.

Consent and Assent in Children and AYA Cancer Patients

For most IRBs, informed consent can be granted by any prospective human subject over the age of 18.  For minor patients under 7, consent is granted by the parents or guardians.  What to do with patients between the ages of 7 and 18 (or with “intellectual ages” between 7 and 18) is less clear.  While they are still minors and under the care of their parents or guardians, they are also independent human beings capable of judgments, particularly ones with which their parents or guardians may not agree. This is certainly the case when it comes to choosing their friends, making time for school work, selecting extracurricular activities, carefully operating a motor vehicle and experimenting with alcohol, drugs or sex.

At M. D. Anderson we use specific policies to guide the ethical oversight of the inclusion of adolescents in decisions surrounding their participation in clinical research. (See Note 1.)  Minors reaching the intellectual age of 7 must give affirmative assent to their participation in clinical research.  The consent of the parents or guardians is also required.  Silence or the lack of objection to participation by these patients is not equivalent to assent.  Assent is an active, formal process with specific components based on a policy that includes this: “In situations in which the (adolescent) patient will have to receive medical care despite his or her objection, the patient should be told that fact and should not be deceived.”

We expect patients from 7 to 12 to provide assent verbally and those between 13 and 18 to do so in writing.  If assent is not obtained, the reason for this must be documented in the medical record and on the assent form.

We believe this policy to be consistent with the Code of Federal Regulations, where assent is clearly part of the overall human subjects protection provisions of research involving children, even in a setting where benefit might not accrue to the adolescent subject but might provide generalizable knowledge (CFR 21, Part 50, Subpart D, 50.51, 50.52, 50.53).  The IRB’s judgment is controlling as to the absolute need for assent and as to whether the assent can be waived for all patients enrolled in a specific protocol, or even if a waiver must be obtained for each patient individually.

This is best summarized in CFR 21, Part 50, Subpart D, 50.55(c): “The assent of the children is not a necessary condition for proceeding with the clinical investigation if the IRB determines” among other things that the “prospect of direct benefit that is important to the health or well-being of the children is available only in the context of the clinical investigation”.  Also in 50.55(d)(2) it states that “even where the IRB determines that the subjects are capable of assenting, the IRB may still waive the assent requirement if it finds and documents that the waiver will not adversely affect the rights and welfare of the subject”.

The processes of consent and assent in adolescent human subjects with malignant diseases, the standard treatments for which can be both debilitating and deforming, must be handled with great sensitivity by caregivers and regulators alike.  While IRBs may have legal grounds to override a young cancer patient’s reluctance to participate in a trial or undergo potentially life-altering therapy like amputation, we firmly believe that patients and parents, above anyone else, should have the final word on trial participation if at all possible.  And when parents and their children of assenting age disagree, the full services of mental health and social work professionals should be mobilized to reach an accord for research and/or conventional treatment that truly is in the best interests of the patient without resorting to the use of regulatory mandates, even if they are legal.

Adolescents and pre-teens under 18 are likely to have legitimate opinions about their participation in a clinical trial. The development of guidelines for obtaining consent/assent from this unique group of cancer patients should be required of all IRBs and should be created in association with those caring for these patients as well as behavioral professionals, attorneys and other experts in research regulation — and, most importantly, the adolescent patients themselves and their advocates, including adult survivors of AYA cancer.

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Note 1. See the University of Texas M. D. Anderson Cancer Center Policy #CLN0547-Informed Consent Policy, December 16, 2010; the University of Texas M. D. Anderson Cancer Center IRB Policy 10.0 on Obtaining Informed Consent and Authorization for Participation in Research, January 26, 2011; and the University of Texas M. D. Anderson Cancer Center IRB Policy 10.9: IRB Guidance on Consenting Children to Research Protocols, January 26, 2011.

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This entry was posted on Friday, January 13th, 2012 at 12:16 pm and is filed under Bioethics, Biotech, Children, Pharma, Research. You can follow any responses to this entry through the RSS 2.0 feed. You can leave a response, or trackback from your own site.