The Translational and Regulatory Development of an Implantable Microdevice for Multiple Drug Sensitivity Measurements in Cancer Patients - PubMed (original) (raw)

. 2022 Jan;69(1):412-421.

doi: 10.1109/TBME.2021.3096126. Epub 2021 Dec 23.

Sharath Bhagavatula, Elizabeth Stover, Kyle Deans, Cecilia Larocca, Yolanda Colson, Pierpaolo Peruzzi, Adam Kibel, Nobuhiko Hata, Lillian Tsai, Yin Hung, Robert Packard, Oliver Jonas

The Translational and Regulatory Development of an Implantable Microdevice for Multiple Drug Sensitivity Measurements in Cancer Patients

Christine Dominas et al. IEEE Trans Biomed Eng. 2022 Jan.

Abstract

Objective: The purpose of this article is to report the translational process of an implantable microdevice platform with an emphasis on the technical and engineering adaptations for patient use, regulatory advances, and successful integration into clinical workflow.

Methods: We developed design adaptations for implantation and retrieval, established ongoing monitoring and testing, and facilitated regulatory advances that enabled the administration and examination of a large set of cancer therapies simultaneously in individual patients.

Results: Six applications for oncology studies have successfully proceeded to patient trials, with future applications in progress.

Conclusion: First-in-human translation required engineering design changes to enable implantation and retrieval that fit with existing clinical workflows, a regulatory strategy that enabled both delivery and response measurement of up to 20 agents in a single patient, and establishment of novel testing and quality control processes for a drug/device combination product without clear precedents.

Significance: This manuscript provides a real-world account and roadmap on how to advance from animal proof-of-concept into the clinic, confronting the question of how to use research to benefit patients.

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Figures

Fig. 1.

Fig. 1.

The IMD. The IMD is inserted into tumors where it releases microdoses of drugs at controlled time points (a). There are 20 microreservoirs, each containing a different drug or drug combination (colorcoded in the photograph to visualize each reservoir’s pore). The IMD is attached to a guidewire and is deployed via a needle (b).

Fig. 2.

Fig. 2.

Timeline of regulatory review process. After FDA IND submission, the FDA has 30 days to review the application and provide any concerns that must be addressed. The IRB submission process is similar, but typically has a longer timeline.

Fig. 3.

Fig. 3.

IMD preparatory steps for clinical trial. Preparation of the IMD for clinical trial involves a thorough material disinfection and drug formulation process, drug loading at the pharmacy, sterilization of samples, and endotoxin and sterility testing.

Fig. 4.

Fig. 4.

The patient journey. After confirming eligibility, patients undergo either an intra-operative, image-guided, or cutaneous IMD implantation. Depending on which implantation method was used, the patient then undergoes an intra-operative or cutaneous retrieval. The tissue is then analyzed and findings are presented to the involved clinicians and the FDA.

Fig. 5.

Fig. 5.

IMD implantation and retrieval. In prostate, ovarian, and breast cancer trials, IMDs are implanted using an image-guided approach, visualized in the red circle on the prostate CT-scan (a). IMDs are retrieved during surgery 48–72 hours later, with confirmation using a specimen X-ray (d). In the glioblastoma trial, IMDs are implanted at the beginning of surgery (b) and retrieved at the end (e). In the CTCL trial, devices are implanted using a cutaneous method in an outpatient setting (c) and retrieved using a punch biopsy tool (f).

Fig. 6.

Fig. 6.

Iterative design changes to the IMD. The initial IMD prototype was a basic cylinder with reservoirs. A conical tip, widened base, and guidewire were later added. For the CTCL trial, the IMD was re-designed to include a wider and flatter base and elimination of the guidewire.

Fig. 7.

Fig. 7.

Tumor drug response readouts. Drug concentration is measured by autofluorescence or mass spectrometry (a). Drug effects are visualized by immunohistochemistry (b) and TME remodeling (c). MALDI can be used to analyze changes in the local tumor metabolism (d) and spatial transcriptomics focuses on the expression of over 1800 genes (e). Ultimately, a systems-level analysis is conducted for each drug (f).

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