Clinical Evaluation of Digital Therapeutics: Present and Future / 대한의료정보학회지

Objectives@#Digital therapeutics (DTx) are software-based therapeutic interventions based on clinical evidence. Randomized clinical trials (RCTs) are often the source of clinical evidence, similar to conventional drugs or medical devices. However, novel approaches such as the use of real-world data or digital biomarkers are also utilized. This article aimed to review how DTx products have been clinically evaluated. @*Methods@#DTx products approved by the US Food and Drug Administration as of 2020 were reviewed and products with sufficient published information were selected. Pivotal clinical trials were analyzed according to the elements of the Consolidated Standards of Reporting Trials (CONSORT) guideline. Case reviews were presented for other clinical evaluation strategies, considering the small number of publications. @*Results@#Most approved DTx products used RCTs for clinical evaluations. Similar to conventional RCTs, parallel-group designs with statistical hypothesis testing were adopted. However, DTx trials were often not blinded due to practical issues and involved various comparator groups. In addition, DTx products could be readily evaluated in home-based settings and delivered through the internet. Other evaluation approaches included retrospective analyses using insurance claims data or usage data, which enabled long-term evaluations of effectiveness. Digital biomarkers obtained from real-time and continuous log data were also used to improve the objectiveness of endpoints. @*Conclusions@#RCTs accounted for the majority of DTx evaluations. The designs of DTx trials were comparable to those of drug or device trials, but blinding and comparator elements were often different. Furthermore, the use of real-world data and digital biomarkers are also being tried.

Lessons from a multicenter clinical trial with an approved wearable electrocardiogram: issues and practical considerations

Although wearable electrocardiograms (ECGs) are being increasingly applied in clinical settings, validation methods have not been standardized. As an exploratory evaluation, we performed a multicenter clinical trial implementing an approved wearable patch ECG. Healthy male adults were enrolled in 2 study centers. The approved ECGs were deployed for 6 hours, and pulse rates were measured independently with conventional pulse oximetry at selected time points for correlation analyses. The transmission status of the data was evaluated by heart rates and classified into valid, invalid, and missing. A total of 55 subjects (40 in center 1 and 15 in center 2) completed the study. Overall, 77.40% of heart rates were within the valid range. Invalid and missing data accounted for 1.42% and 21.23%, respectively. There were significant differences in valid and missing data between centers. The proportion of missing data in center 1 (24.77%) was more than twice center 2 (11.77%). Heart rates measured by the wearable ECG and conventional pulse oximetry showed a poor correlation (intraclass correlation coefficient = 0.0454). In conclusion, we evaluated the multicenter feasibility of implementing wearable ECGs. The results suggest that systems to mitigate multicenter discrepancies and remove artifacts should be implemented prior to performing a clinical trial.

Trends of clinical trials from 2017 to 2019 in Korea: an integrated analysis based on the Ministry of Food and Drug Safety (MFDS) and the Clinical Research Information Service (CRIS) registries

Public disclosure of approved clinical trials in a reliable registry can provide the transparency of the study. Although the registration of clinical trials has increased remarkably, the integrity of the data is not always satisfactory. In this study, we analyzed public clinical trial databases updated by the Ministry of Food and Drug Safety (MFDS) and Clinical Research Information Service (CRIS) registry to provide an overview of the trends of clinical trials approved between 2017 and 2019 in Korea. Information on clinical trials approved between January 1, 2017 and December 31, 2019 was collected from two databases. Trial information was categorized and summarized by study phase, therapeutic area, and location of the participating centers. A total of 655 to 715 clinical trials were newly approved annually by MFDS during the period from 2017 to 2019. Phase 1 clinical trials accounted for the largest proportion (31.0%), followed by phase 3 (29.5%), investigator-initiated trials (24.1%), phase 2 (14.6%), and phase 4 (0.5%). The number of clinical trials classified as an Antineoplastic and immunomodulating agent was the greatest (40.1%) regardless of the study phase. The similar result was obtained from CRIS registry where therapeutic area Neoplasms (15.9%) accounted for the largest number. The number of clinical trials performed in Seoul and Gyeonggi-do was approximately 70% of the total trials. In conclusion, our study provided a comprehensive overview of clinical trials in Korea from 2017 to 2019. The discrepancy between clinical trial registries could be resolved by introducing standardized database and guidelines.

Pharmacokinetics and pharmacodynamics of a fixed-dose combination of gemigliptin/metformin sustained release 25/500 mg compared to the loose combination in healthy male subjects

A fixed-dose combination (FDC) of gemigliptin/metformin can improve the medication adherence in patients with type 2 diabetes mellitus (T2DM). In this study, the pharmacokinetic (PK) and pharmacodynamic (PD) profiles of gemigliptin and metformin were compared between FDC and the corresponding loose combination under fasted and fed states. A two-part, randomized, open label, single-dose, two-way crossover study was conducted in healthy male subjects. Under fasted (part 1) or fed (part 2) state, 2 FDC tablets of gemigliptin/metformin sustained release (SR) 25/500 mg or loose combination with one tablet of gemigliptin 50 mg and two tablets of metformin extended release (XR) 500 mg were orally administered in each period with a 7-day washout. Serial blood samples were collected up to 48 hours to determine the drug concentration and the dipeptidyl peptidase 4 (DPP-4) activity. The concentration-time profiles of gemigliptin and metformin were similar between FDC and loose combination in both the fasted and fed states. Geometric mean ratios and 90% confidence intervals of FDC to loose combination for area under the concentration-time curve and maximum plasma concentration of gemigliptin and metformin were within the bioequivalence range (0.8–1.25) in both states. DPP-4 activity-time profiles of FDC were comparable to that of the loose combination, showing similar area under the DPP-4 inhibition-time curve and maximum DPP-4 inhibition between FDC and loose combination, regardless of the fasted or fed state. In conclusion, the PK/PD characteristics of gemigliptin and metformin were similar in FDC tablets and loose combination both in fasted and fed states.

Trends of clinical trials from 2014 to 2016 in South Korea

Mandatory registration of clinical trials in public registry can ensure the transparency of clinical trials. Public clinical trial registry of can provide current chronological and geographical distribution of clinical trial throughout the country. We used public clinical trial registry provided by Ministry of Food and Drug Safety to analyze current status of clinical trial from 2014 to 2016 in South Korea. The number of clinical trials in antineoplastic and immunomodulating agents area was the greatest, followed by cardiovascular system and antiinfectives for systemic use as a whole. From 2014 to 2016, overall number of clinical trials decreased while the number of phase I clinical trials increased. Seoul accounted for more than half number of clinical trials in Korea. Supports for clinical trials in non-metropolitan area needs to be considered.

A Case of Strongyloidiasis Associated with Intestinal obstruction in a Patient with Alcoholic Liver Disease / 감염과화학요법

Human is infected by third stage filariform larvae of Strongyloides stercoralis which is a soil-transmitted nematode. Rhabditiform larvae passed in feces can transform into infectious filariform larvae either directly or after a free living phase of development. Most infected patients may be asymptomatic or have mild cutaneous symptoms or induces non-specific complaints such as moderate abdominal pain, nausea and diarrhea. However, in immunocompromised hosts, the parasite is augmented by autoinfection, resulting in hyperinfection and can disseminate widely and can be fatal. We report a case of strongyloidiasis associated with intestinal obstruction in a patient with alcoholic liver disease.

A Case of Strongyloidiasis Associated with Intestinal obstruction in a Patient with Alcoholic Liver Disease / 감염과화학요법

Human is infected by third stage filariform larvae of Strongyloides stercoralis which is a soil-transmitted nematode. Rhabditiform larvae passed in feces can transform into infectious filariform larvae either directly or after a free living phase of development. Most infected patients may be asymptomatic or have mild cutaneous symptoms or induces non-specific complaints such as moderate abdominal pain, nausea and diarrhea. However, in immunocompromised hosts, the parasite is augmented by autoinfection, resulting in hyperinfection and can disseminate widely and can be fatal. We report a case of strongyloidiasis associated with intestinal obstruction in a patient with alcoholic liver disease.

A Study of Microscopic Interpretation of Feozen Sections in Mohs Micrographic Surgery for Basal Cell Carcinoma / 대한피부과학회지

BACKGROUND: Mohs micrographic surgery (MMS) achieves higher cure rates for cutaneous squamous cell and basal cell carcinomas than any other therapeutic modality. For a unifocal tumor, a 100% cure rate after MMS should theoretically be possible, however for primary basal cell carcinoma, 98-99% 5-year disease-free rates have been achieved. OBJECTIVE: Our purpose was to investigate the pitfalls in microscopic Interpretation of frozen sections in Mohs micrographic surgery for basal cell carcinoma which decrease the cure rate after surgery. METHODS: From March 1991 to February 1998, fifty-nine patients were diagnosed with basal cell carcinoma at our department. All the tumors were removed with Mohs micrographic surgery and frozen section specimens were stained with hematoxylin-eosin. The microscopic evaluation was done by Mohs surgeon and pathologist. RESULTS: We can summarize the matters that demand special attention during microscopic Interpretation of frozen sections in Mohs surgery as two groups. First, as false negative interpretation, there are 1) small nests of tumor scattered within areas of heavy inflammation 2) tumor present along the hair follicle, 3) tumor present along a cut edge, 4) empty space in a tissue section, 5) hair follicle-like structure of the tumor, 6) gland-like structure of the tumor, and 7) infiltrative BCC-like inflammatory cells. Second, as a false positive interpretation, there are 1) foreign body reactions or scar containing trapped pilosebaceous structures, 2) horizontal and tangential cuts through the pilosebaceous apparatus, 3) some epidermal neoplasms including solar lentigines, seborrheic keratoses, and acantholytic actinic keratoses, and 4) contamination of the tumor tissue. CONCLUSION: With careful attention to the examples which can affect the interpretation as mentioned above, it may be possible to detect complete removal of tumor mass and achieve higher cure rate. We could achieve a 100% of cure rate for primary basal cell carcinoma and 95 % of cure rate for recurrent basal cell carcinoma after Mohs Micrographic surgery in our hospital from March 1991 to February 1998.

The effect of fibrin sealant to absorbable coral in osteogenesis, vessel ingrowth and physical properties

Autogenous bone graft used for the contouring and reconstruction of craniofacial bone defect has many advantages over the alloplastic material implantations. However, there are several problems associated to the autogenous bone grafting: obtaining the donor site is the most problematic; transplanted bone may be absorbed at the recipient site; and the molding to fit to the recipient site is difficult. Therefore, research in alloplastic materials is inevitable. The current research is focused on two types of hydroxyapatite, calcium phosphate and calcium carbonate. The calcium phosphate is known to show a limited osteogenesis. However, Coral(Biocoral, Inoteb B.P., Saint Gonnery, France) composed of calcium carbonate is known to be more effective in osteogenesis. Fibrin sealant(Duplojet system, Immuno AG. Vienna, Austria), a tissue glue, is known to increase tissue affinity, proliferation of fibroblast and vessel ingrowth. It is also known to have osteoinductive effect. We believe that fibrin sealant improves the effect of coral by increasing bone graft substitution, enhancement of plasticity and stability of the granular material. Therefore, we have undertaken an experimental investigation as following; Using high speed burr, three 10 mm in diameter skull defects were made on 24 New Zealand white rabbits. The defects were treated with implantations, which are divided into three samples: A) Control in which on coral or fibrin sealant, B) Coral 50 mg with fibrin sealant 0.3 cc, C) Coral 50 mg with saline 0.3 cc. The specimens of its skull were collected at 3, 7, 14, 28, 42 and 56 days postoperatively. The operative sites were carefully examined grossly, microscopially and radiologically. The experimental results are as followings: At 56 days post operation date, control group showed a thin layer of only fibrous connective tissue and minimal immature bone filling the defect. Coral with saline given group showed a thick layer of connective tissue and granule of coral, accompanied by partial new bone formation, mostly composed of woven bone, in the middle of the defect. In the group that were given coral with fibrin sealant, a thick layer of fibrous connective tissue and granules of coral, accompanied by more increased new bone formation in the middle of the defect were observed. Another difference from the Group B is a formed new bone replaced by lamellar bone.We concluded that by using coral and fibrin sealant together, contouring and reconstruction of bone defected areas were enhanced. It was difficult to prove directly that fibrin has osteoinductive effect. However, the plasticity and stability, the fibrin sealant gives to coral enhances the osteogenesis. Our study provides evidence that coral used with fibrin sealant will significantly improve the result of the craniofacial bone surgery.