Regulatory Framework for Drug-Device Combination Products in the United States, Europe, and Korea.

Combination products (CPs) combine two or more product types such as drugs, devices, and/or biological products for increased safety and clinical effectiveness. The emergence of innovative CPs poses new challenges for regulatory agencies in assigning jurisdiction for premarket review and oversight. In US, the 1990 Safe Medical Devices Act defines and provides classification criteria for CPs, and the US government has developed a regulatory process through multiple acts, including the 21st Century Cures Act of 2016. Meanwhile, regulators in the European Union (EU) and the Republic of Korea have recently recognized the importance of premarket pathways for CPs. The European Medicines Agency (EMA) has issued guidelines and explanations on compliance issues related to drug-device CPs under MDR. EMA doesn't have the definitions of CPs, but uses the term drug-device combination products (drug-device CPs). CPs are categorized as drugs or medical devices, which follow their relevant regulatory framework. The Ministry of Food and Drug Safety (MFDS) in Korea has legal definitions of CPs under the Notice of the MFDS. CPs are designated as drugs or medical devices according to their primary mode of actions (PMOA) and follow regulatory processes through the framework of drugs or medical devices. This study aims to comprehensively summarize the regulatory oversight of CPs by analyzing the regulatory policies and legal frameworks in the US, the EU, and Korea. The regulatory challenges encountered when developing CPs are also discussed. With specific emphasis on the combination of drugs and devices, this study provides in-depth insights into the regulatory landscape, shedding light on the unique challenges associated with the development of CPs for this particular intersection of drugs and devices.

Folate, alcohol, ADH1B and ALDH2 and colorectal cancer risk.

OBJECTIVE: There is limited evidence on the interaction by alcohol dehydrogenase 2 (ADH1B) (rs1229984) and aldehyde dehydrogenase 2 (ALDH2) (rs671) regarding the associations of alcohol and a methyl diet (low folate and high alcohol intake) with cancer risk, partly because of rare polymorphisms in Western populations. DESIGN: In a case-control study, we estimated the ORs and 95 % CIs to evaluate the associations of ADH1B and ALDH2 genotypes with colorectal cancer (CRC) and the joint association between methyl diets and ADH1B and ALDH2 polymorphisms with CRC risk using logistic regression models. SETTING: A hospital-based case-control study. PARTICIPANTS: In total, 1001 CRC cases and 899 cancer-free controls admitted to two university hospitals. RESULTS: We found that alcohol intake increased the risk of CRC; OR (95 % CI) was 2·02 (1·41, 2·87) for ≥60 g/d drinkers compared with non-drinkers (Ptrend < 0·001). The associations for two polymorphisms with CRC were not statistically significant. However, we found a potential interaction of ALDH2 with methyl diets and CRC. We observed a 9·08-fold (95 % CI 1·93, 42·60) higher risk of CRC for low-methyl diets compared with high-methyl diets among individuals with an A allele of ALDH2, but the association was not apparent among those with ALDH2 GG (Pinteraction = 0·02). CONCLUSIONS: Our data support the evidence that gene-methyl diet interactions may be involved in CRC risk in East Asian populations, showing that a low-methyl diet increased the risk of CRC among individuals with an A allele of ALDH2.

Red meat intake, CYP2E1 and PPARγ polymorphisms, and colorectal cancer risk.

The association between red meat intake and colorectal cancer (CRC) may be modulated by genetic polymorphisms of cytochrome P450 2E1 (CYP2E1), a key enzyme in the metabolism of nitrosamines, and peroxisome proliferator-activated receptor gamma (PPARγ), a transcription factor involved in adipogenesis and lipid and glucose metabolism. We conducted a case-control study of 971 patients with CRC and 658 controls who were admitted to two university hospitals between 1995 and 2004 in Seoul, Korea. Participants were asked about red meat intake by using a validated food frequency questionnaire. Polymorphisms of CYP2E1 (rs3813867) and PPARγ (rs1801282 or rs3856806) were identified using the TaqMan assay. We calculated odds ratios (ORs) and 95% confidence intervals (CIs) using multivariable logistic regression models. We found that the association between red meat and CRC varied by CYP2E1 polymorphisms; ORs (95% CIs) for at least five or more vs. less than one time/week of red meat intake were 2.77 (1.23-6.25) among individuals with C alleles of CYP2E1 and 0.89 (0.51-1.54) among individuals with the GG allele (Pinteraction=0.05). Compared with those individuals with the CC allele, increasing risk of CRC with increasing red meat intake was more pronounced among individuals with T alleles of PPARγC161T (rs3856806), but the association was not significant. Our data provide evidence that East Asians with the variant type of CYP2E1 may have high susceptibility to development of CRC risk.

Total and Dietary Calcium Intake and Colorectal Adenoma in Korean Adults.

BACKGROUND: Colorectal cancer in Korea has become more prevalent over the few last decades, and calcium is considered a preventive factor for colorectal cancer development. We examined the associations between total and dietary calcium intake and the prevalence of colorectal adenoma in Korean adults. METHODS: This cross-sectional study included 112 colorectal adenoma cases and 252 adenoma-free non-cases, aged 45 to 71 years, who underwent colonoscopies at the Daegu Catholic University Medical Center from August 2011 to September 2012. Participants were asked about their diet using a validated food frequency questionnaire and about supplement use through interviews. We calculated odds ratios (ORs) and 95% confidence intervals (CIs) to evaluate the association between total and dietary calcium intake and the prevalence of colorectal adenomas using multivariable logistic regression models. RESULTS: Increasing total calcium intake from foods and supplements was significantly associated with a decreased prevalence of colorectal adenoma in women; comparing the highest quartile with the lowest quartile, the OR (95% CI) was 0.35 (0.15-0.85; P for trend = 0.03). Likewise, high dietary calcium intake from foods was associated with a lower prevalence of colorectal adenoma in women; compared with the lowest quartile, the ORs (95% CIs) were 0.32 (0.13-0.82) for the 3rd quartile and 0.44 (0.19-1.03; P for trend = 0.13) for the 4th quartile. However, the association was not clear for either total or dietary calcium intake among men. CONCLUSIONS: A higher intake of calcium was associated with a reduction of colorectal adenoma prevalence in Korean women.