Prof. Howard Lee demanded that generic approval in Korea be tightened by not allowing the so-called 'joint-bioequivalence' or 'consigned-bioequivalence' route at a Korea National Assembly Forum, co-sponsored by Rep. Yoon Il-Kyu of the ruling Democratic Party and the Korean Doctor's Weekly. The forum was held to go over various regulatory issues associated with the recent recall of valsartan-containing anti-hypertensive agents by the Ministry of Food and Drug Safety in a haphazard way, prompted by a similar regulatory action by the European Medicines Agency, which was caused by a concern that the active ingredient manufactured by a Chinese company contained NMDA, which could be carcinogenic in humans.

According to Prof. Lee, there were at least three regulatory practices that could have prompted the valsartan debacle in Korea: too low bar for generic entry into the market, lack of a consistent quality assurance system to ensure the quality of generics and their sources (active pharmaceutical ingredients), and too generous pricing for generics. "These unique regulatory systems for generics in Korea have favored the incompetent generic maker to enter the market rather unruly", Prof. Lee emphasized. Prof. Lee added, "Many pharmaceutical companies, most which were not unsure of their quality, got generics approved through the join- or consigned-bioequivalence testing, and this system needs to be abolished."

More detailed story about the Forum can be found in the following articles in Korean or English. 

"The recent recall of valsartan API made by Zhejiang Huahai (China) following detection of a potential carcinogen has revealed the weak and scientifically unsound basis of the generic approval system in Korea", Prof. Lee spoke in a telephone interview with KBS. Prof. Lee detailed about this issue in a newspaper column. The number of recalled valsartan generics in Korea was 115, which was way greater than that in the UK (only 8) and Japan (only 1). The reason behind this difference was that Korea has maintained a relatively low bar for the approval of generics. For example, any company can sell generics if they could obtain them from anyone who has a marketing authorization of the generic. In other words, the company is not necessarily responsible for the quality of the generic, nor they have to show that they could make a qualified generic, which meets all of the regulatory requirements including the proof of bioequivalence. 

As a result, there are numerous generics for a single original product. This, in turn, has introduced an exceptionally high competition among the companies, which has implicitly encouraged unethical business practices such as kick-back and unlawful rebates. The issue also has brought some quality issues to manufacturing of generics in Korea. For example, many companies have switched their API source after approval, mostly to a low-quality Chinese company, of which Zhejiang Huahai may be one. 

Therefore, to preempt the recurrence of this quality API source issue for generics in Korea, the approval system has to be heightened, Prof. Lee summarized.    

The best model for humans is human. Drug development has long been suffering from the lack of translatability and predictability of the preclinical animal experiments to humans. Dr. Richard Klausner, former Director of the US National Cancer Institute, commented in 1998, “the history of cancer research has been a history of curing cancer in the mouse. … and it simply didn’t work in humans.” Twenty years fast forward, drug development scientists are still struggling with the same issue.

Microtracing/microdosing is an innovative technology that can revolutionize the current paradigm of clinical drug development. Typically, a very small amount of the drug, i.e., ‘microdose’, which is less than 100 micrograms (or 30 nmoles for proteins), is administered to humans. Since this is much smaller than 1/100 of the pharmacologically active dose, microtracing/microdosing technology can be employed at a very early stage of clinical drug development even when there is limited animal toxicology data. Furthermore, in order to trace minute doses, an accelerator mass spectrometer (AMS) is required and the compound should be labeled, typically with ¹⁴C. The microtracing/microdosing study allows clinical drug development scientists for generating the intravenous pharmacokinetics, mass balance, metabolite profiling, and absolute bioavailability data much easier, faster, and at a lower cost.  

Dr. Howard Lee has spearheaded the employment of microtracing/microdosing technology for drug development in Korea since 2012, supported by three government grants. Dr. Lee has successfully d a new research ecosystem for the microtracing/microdosing study, which helped him perform the first microtracing/microdosing study under a full investigational new drug (IND) application in 2014. The result of this study was published at the most reputable journal in the field. Dr. Lee has conducted two additional microtracing/microdosing studies, and has recently won a two-year grant of $1 mil, in which microtracing/microdosing technology will be applied to a new drug development study with biologics.

CCADD has done research on studying the strategic policy issues to efficiently and seamlessly integrate standalone clinical research systems in Korea such as drug- or disease-registries (public or private), government's open data, and hospital's electronic medical records (EMRs). This research was sponsored by the Korea National Enterprise for Clinical Trials (KoNECT). In this research, CCADD has first enumerated the available clinical trial resources in Korea followed by a systematic investigation of the current legal, societal, and cultural works that have prevented clinical trial systems being fully integrated. CCADD has also studied the following topics:

- Current status of integration of EMRs in Korea

- Technologies available for integration of public health data and EMRs

- Availability of a metadata model for integrated clinical research systems in other countries

- Roles and responsibilities of the centralized coordinating center for integrated clinical research systems

CCADD performed an exhaustive and systematic search for various articles and papers that described the current status and critical obstacles in integrating EMR data to be used as a source of clinical trials, including data quality and healthcare stakeholder engagement. The result of this study was written as a white paper titled "임상시험자원 통합정보시스템 구축을 위한 기획연구: 병원간의 전자의무기록 표준화 통합을 위한 구조적 접근 ". In this paper, we suggest a number of potential solutions to address current challenges. 

Many of CCADD members have attended the Spring Conference of The Korean Society of Medical Informatics (KOSMI), held at Samsung Medical Comprehensive Cancer Center on June 14-15, 2018. Reflecting the recent drastic increase in the demand and importance of data science in health sciences, the theme of the conference was 'Evolving Data for Better Health'. More than 600 researchers, practitioners, and vendors in health informatics gathered together to share their knowledge, experience, results of research, and expertise through a series of keynote speeches, symposia, oral/poster presentations, and exhibitions.

Four abstracts by CCADD were accepted for poster presentation. Yoomin Jeon proposed a new approach to transform clinical trials eligibility criteria (EC, free-text) into structured data using the OMOP-CDM(Feasibility of Using the OMOP Common Data Model to Assess Clinical Trial Feasibility). She found that >75% of the EC could be mapped by the proposed approach, and the most important data group was condition.

Serin Lee, a student intern, gave her poster presentation entitled 'Dimensionality Reduction Model for Common Eligibility Criteria to effectively use Electronic Medical Record: A Pilot Study.' She proposed a dimensionality reduction model for common eligibility features (CEFs) based on ontology and semantic features of EC to reasonably compose the concept sets.

Dr. Soohyun Kim proposed a new type of command data model for clinical trials (Clinical Trial Common Data Model, CT-CDM) to support decision-making processes in clinical trials, entitled 'CDISC-based Common Data Model for Developing an Integrated Decision-Support System in Clinical Trials'. This command data model fully complies with the standards of Clinical Data Interchange Standards Consortium(CDISC) as a global, platform-independent data standard guaranteeing system interoperability. 

Lastly, but not the least, Dr. Jeong-An Gim shared his research findings: Application of Machine Learning Technology to Classify Healthy Subjects into Different Pharmacokinetic Exposure Groups to Tacrolimus. Using the decision-tree approach employed in R, Dr. Gim aimed to identify SNPs that are associated with the exposure to tacrolimus. The rs776746 in the CYP3A5 gene was the most influential mutation.

More detailed research findings can be downloaded below.

Much to everyone's delighted surprise, Serin Lee won an external solid-state drive of 1TB at the raffle draw! Since Serin will graduate in August, the prize was certainly a nice present. 

Lee H. Equivalence Margin of the Biosimilar Product. J Korean Soc Clin Pharmacol Ther. 2012;20(1):17-33 

Prof. Howard Lee has been recently awarded a government grant from the Korea Clinical Trials Global Initiative or KCGI to develop a clinical trial resource integration system, and a grant kick-off meeting was held on March 15, 2018. The total research funding was $560,000, which is equivalent to 500 million Korean Won. The title of Prof. Lee's proposed research plan was the AI-based Clinical Trial Resource Information System or ACTRiS, which is pronounced 'Act Ris'. All of the CCADD members have contributed a lot to planning and completing the research plan for ACTRiS, and they will also actively participate in the grant one way or another. In ACTRiS, Prof. Jang Hee Hong, Choongnam University College of Medicine and Choongnam University Hospital, will be leading a subset project to develop an integrated web-based system for review activities by the Institutional Review Board, particularly for multisite clinical trials. Additionally, Prof. Jin Wook Choi, Seoul National University Hospital, and Prof. Hyun Joong Kong, Choongnam University Hospital, have joined to lead the IT development projects. Furthermore, codings and programming works will be outsourced to Mebixon, a leading life science solution development company in Korea.    

What makes ACTRiS unique is its active employment of state-of-the-art user experience technologies, which will be led by Prof. Joongseek Lee, along with his UX lab at the Graduate School of Convergence Science and Technology, Seoul National University. Not only that, several aspects and system components of ACTRiS will be fortified by applying AI technologies. For example, the accuracy and completeness of the contents in ACTRiS will be automatically checked and corrected by AI. 

"It means a lot to CCADD that we finally secured this start-up grant for the smart clinical trials initiative in Korea, which is expected to officially start next year", Prof. Lee said. "This signifies the vision that CCADD set out was right. Smart clinical trial is the future."