The following tables outline the systematic assessment methodology outline for use of the toolkit, assessing the General Risks and the organ specific risks (Tables 1, 2, respectively). Each risk has simple binary, yes/ no decision options to indicate the necessary impacts on the protocol, allowing a simple but efficient visualization of the magnitude of necessary protocol changes.

Table 1 Assessment of general risks.Table 2 Assessment of organ-specific risks.Assessment of General Risk

The assessment of General Risks is mandatory for all products that are considered for the AYA population, however their impact on the protocol may differ, depending on the mode of action, patient population or the disease concerned.

In our resultant toolkit for General Risks, the infertility/fertility preservation topic was split into pre-pubertal and post-pubertal patients. As the infertility risk for AYA patients that have passed puberty should be no different to the risk in adult patients, we do not consider protocol changes should be required for most medications in a post-pubescent patient. However, the risk could be significantly different for pre-pubertal patients and considered relevant to update the protocol. Fertility preservation options are currently experimental in boys and more data is needed on the efficacy of the ovarian tissue cryopreservation method currently used in girls [12]. If AYA are to be included after a risk/benefit assessment per each medication, the toolkit commonly recommends the addition of Tanner stage monitoring during physical exam visits as a part of the protocol standard schedule of assessments.

The risk of impact on growth and development may be significantly different for AYA patients compared to adults and a protocol update will be needed in most cases. AYA individuals in the age range of 12–18 years old, developmentally, are still growing, with greatest increases in bone mass occurring during teenage years [13, 14]. If the decision is made to include AYA patients who are still growing in a clinical trial, changes to adult protocols include using growth charts to monitor growth at baseline and throughout study, and wrist x-ray screening to monitor growth plate fusion.

Because the risk of new primary malignancies may exist in AYA patients, recommendations for long-term follow up and cancer screening after study completion should be followed. As the AYA population would be expected to live longer than the adult population, then the overall risk may be higher for new primary malignancies. Our conclusion is that there may be no impact on the protocol, however patients should be informed if a future malignancy risk is known to exist, based on the properties of the study treatment.

Neurocognitive dysfunction in AYA patients may differ from adult patients due to the impact on neurologic function during a key phase of psychosocial growth and development [15,16,17]. AYA patients may also demonstrate a decline in cognition associated with risk factors of neuroinflammation, prior to initiation of systemic cancer therapy [17]. Age-appropriate psychosocial support is universally recommended, even in the absence of neurologic effect of medications. Cognitive impairment resulting from the effects of medications is documented for standard chemotherapy agents and should also be carefully evaluated for investigational agents. However, as a general risk, specific changes in the protocol should not be needed, unless the mode of action of the drug indicates a product specific risk that needs close neurologic monitoring.

Assessment of Organ -Specific Risks

As part of the toolkit, system-organ safety risks were also reviewed. Teams are advised to go through a checklist and indicate whether the product specific risk is different for the AYA patients and whether protocol amendment is needed. The importance of each risk and whether significant changes are required to the protocol is dependent on the specific mode of action of the investigational medicinal product. The safety toolkit also describes where it is appropriate to use different laboratory reference ranges for AYA and adults for each system organ class. Detailed discussion of the recommendations for each of the individual topics is out of the scope of this paper and will be discussed in a future publication.

Implications of the Results and Further Benefits of the Approach for Company Governance and Investment Decisions- the RAG Rating

Once product teams use the safety toolkit, they are enabled to make a detailed assessment of the benefit-risk ratio of the medicinal product for AYA patients and anticipate the feasibility of including AYA patients in the study, including allocation of site personnel resources and assessment of cost elements. This will help with the development decision of whether it is safe to lower the age of inclusion in a particular clinical trial. A key deliverable from the evaluation of the risks is the generation of a safety Red-Amber-Green (RAG) rating for each study. The RAG rating scale is intended to summarize the scope and severity of any specific treatment-related safety concerns (Fig. 2). A red rating would indicate an unacceptable benefit/risk profile for AYA with the proposed treatment plan. An amber rating signifies there may be increased safety risk compared to adults, however the benefits of an unmet medical need balance the risk. For an amber rating, protocol modifications can be made to mitigate risk. A green rating indicates no expected additional risk and/or no expected relevant protocol modifications for AYA patients to safely proceed in the study. Any protocol modifications beyond adjustments for age-appropriate normal values in laboratory or diagnostic values, is considered a relevant modification.

Figure 2

The Safety RAG rating score.

Case Example

During development of this toolkit the feasibility and application of using the toolkit for review was tested for a study investigating a medicinal product for women with locally advanced cancer. The team used the draft AYA toolkit to carefully evaluate treatment-related risks. A systematic review was conducted of each organ class and implications for mitigation of AYA-specific support was determined. (Table 4) After a thorough review of the safety data, a RAG rating of amber was assigned, and additional or modified monitoring and mitigation procedures was added to the clinical study protocol for AYA patients (Table 5).

In a worked risk evaluation case example, to understand the utility of the safety toolkit, a pharmacovigilance team reviewed an investigational agent and developed an assessment of the benefit/risk balance for inclusion of AYA for the product. (Tables 3, 4, 5) This is an example if a medication was noted to have potential adverse effect in adult patients on the cardiac system (e.g. myocardial infarction, congestive heart failure, tachycardia) and the pulmonary system (e.g. pulmonary fibrosis, pneumonitis, pulmonary artery hypertension).

Table 3 Risk evaluation of general risks.Table 4 Risk evaluation of organ specific risks.Table 5 Risk evaluation and changes to protocol.

For general risks, the protocol added physical assessments for growth and sexual maturity, based on potential risks to endocrine function. Based on pre-clinical and clinical data, there is no expected impact on fertility, however the impact is not fully understood at this time. This created missing information in terms of fertility risk. Organ specific potential risks were identified for pulmonary and cardiac systems, and additional long-term tests for cardiac and pulmonary function were recommended, using age-appropriate scales.

The overall assessment for the worked case example, was an amber rating, indicating to proceed with increased monitoring, and conveying the message that the risk/benefit balance was encouraging for inclusion of AYA in clinical trials. The rationale for generation of an amber rating was the investigational product safety profile had some missing information in terms of fertility and also potential long-term adverse effects for cardiac and pulmonary systems, which may apply to many early phase study products. There were some monitoring adjustments to the protocol to monitor for the potential adverse effects, based on the known safety profile. However, in the setting of a cancer diagnosis with unmet need, it was agreed that the possible clinical benefits outweigh the anticipated risks, therefore it was advisable to continue the development program in AYA patients.

The protocol monitoring adjustments are intended to identify and mitigate impact of treatment on organ specific organ systems to adjust for age-appropriate identification of existing organ dysfunction and to put a framework in place to predict and monitor for long-term toxicities in subjects with prolonged survival.