한국보건정보통계학회지 제36권 제1호 Journal of The Korea Society of Health Informatics and Statistics 2011; 36(1): 1-14 What is the Clinical Trial? Young Jack Lee† LSK Global PS Abstract No drug is a drug until it is proven safe and effective (safety first-emphasis added). All drugs in these days have been approved by government authority after a series of clinical trials. Today, clinical trials have begun in Korea only recently. Nevertheless Korea is fast becoming a popular destination for multinational clinical trials. Korea Food and Drug Administration has defined that clinical trial is any investigation in human subjects to study effects of investigational products. Clinical trial is a process that must strictly abide by rules, regulations and study plans. Clinical trial of new drug candidate has very high chance of failure and thus is very difficult. Finally, clinical trial is scientific experiment within frame of ethics and respect for human rights. Technical core of this last point is statistical principles of minimizing bias and design of experiment. Final product of clinical trials is statistical inference about effects of investigational products in human body. So, answer to “What is the clinical trial?” is “a statistically valid medical inference- making process for medicine.” Keywords: Clinical trial, Statistical principles, Design of experiment, Clinical research [접수일: 2011년 5월 30일, 수정일: 2011년 6월 15일, 게재확정일: 2011년 6월 17일] Ⅰ. Introduction the clinical trial was allowed generally if the drug was being marketed elsewhere in the world, Korea has a short history of the modern day primarily the US, Western Europe and/or Japan. clinical trial. Before 2002 when Korea Food and During the era when IND was part of NDA, Drug Administration (KFDA) introduced the KFDA would give a tentative marketing appro- current Investigational New Drug (IND) system, val to a drug for its clinical evaluation. Generally new drug trials were rare in Korea. IND was 30 to 100 subjects would be treated with the part of New Drug Application (NDA) then and drug and the drug would be approved for mar- † Coresponding author: 이영작, 서울시 서초구 서초동 1579-6 평환빌딩 5, 6층, LSK Global PS E-mail: [email protected] * 본 논문은 2010년 한국보건정보통계학회 추계학술대회에서 발표한 내용이며, 관련 연구자 및 회원들의 학술활동에 매 우 유익할 것으로 생각하여 저자에게 요청하여 재작성한 것입니다. 2 Young Jack Lee keting authorization. Such a drug was generally is almost always a relative effectiveness against being marketed in the region of its origin and its a control or controls. A fair comparison between Korean trial was not rigorous, because the trial an NME and a control or controls is not a was a matter of formality for approval. simple matter and it is not an overstatement to Before 2002, thus, clinical trials of new mole- state that the phase III study is all about fair cular entities (NMEs: term NME is more inclu- comparisons. At the same time, because an sive than new chemical entity) were not possible. NME is yet to be proven effective in human sub- A new molecular product considered as a jects, rights and well-beings of trial participants candidate material to be a drug is called an become the priority matter in the clinical trial. NME. An NME is not considered a drug until it To me, the clinical trial is like an elephant to is shown safe and effective in human. three blind men. Many stakeholders are involved In 2002, the IND was separated from NDA, in clinical trials and each stakeholder insists his/ and an NME is now allowed to be administered her own definition of clinical trials. Therefore into human if there is enough evidence for safe there is no simple way to define clinical trials. human administration. This process is generally Nevertheless trial results have to satisfy all the known as the phase I study after which the dose stakeholders including the drug approval authority. or doses for subsequent studies are selected. There can be a number of ways of defining The NME is evaluated in a relatively small the clinical trial, and KFDA[1] has adopted the group of patients who may benefit from the following definition by Guideline for Good NME. It is then determined whether the NME Clinical Practice by International Conference on has a good potential to become a drug for a Harmonization (ICH)[2] defines the clinical trial/ given indication. This stage of evaluation is study as follow. generally known as the phase II study. Phase I and phase II studies are exploratory in “Any investigation in human subjects intended to nature. According to ICH guideline on statistical discover or verify the clinical, pharmacological and/or other pharmacodynamic effects of an investi- principles for clinical trials, a priori determined gational product(s), and/or to identify any adverse hypotheses are not necessarily required for phase reactions to an investigational product(s), and/or I and II studies. Medical observations from to study absorption, distribution, metabolism, and phase I and II studies and other available data excretion of an investigational product(s) with the object of ascertaining its safety and/or efficacy. provide bases for medical hypotheses about the The terms clinical trial and clinical study are NME’s efficacy in a given patient population. synonymous.” Clinical trials to test such medical hypothesis are generally called phase III studies. Because this definition is an all-purpose one, The phase III study of an NME is almost it may serve regulatory bodies well. However always a comparative study. When a drug is this definition does not fit the purpose of my said to be effective, we say, “effective compared presentation well. to ‘what.’” In other words a drug’s effectiveness In this presentation, I will define the clinical 한국보건정보통계학회지 제36권 제1호 What is the Clinical Trial? 3 trial on my own way. A reader not agreeing research regulated by laws and regulations (em- with my definition may consider my view just phasis added). Infringement and negligence may as a view. result in punishment. Patients exposed to frau- The NME in clinical development is generally dulently approved drugs may be injured. Therefore called Investigational Product (IP). A drug may emphasis is on “laws and regulations.” As a be also called an IP if the drug is part of CEO of a CRO (contract research organization), clinical studies. I may use terms “test drug” and it is very important that the clinical trial under “test treatment” in lieu of IP as opposed to my company responsibility is compliant with all control for the rest of my presentation. the applicable rules, regulations and procedures. Before proceeding to the main body of the When the trial result is submitted to KFDA presentation, I would like to recommend “Funda- for marketing authorization, we have to make mentals of Clinical Trials” by Friedman, Furberg sure that the trial has been conducted according and DeMets (FFD)[3]. This book is oriented to all the applicable rules and regulations and its toward understanding the basic principles of result passes inspection by KFDA. Recently, clinical trials. Many examples are cited in FFD KFDA has strengthened its inspection program to help understand clinical trials. It is clear from of trial sites, sponsors and CROs to make sure FFD[3] that most clinical trial methodologies that the data are honest and the trial has been have evolved from mistakes and naïveté. I want conducted as the approved plan and according to to point out that the clinical trial is extremely applicable rules and regulations. Inspections fragile in the sense that even a tiny mistake can generally take place years after the trial starts ruin the entire trial. and generally one to two years after the trial is Statistics in clinical trial is often misunderstood completed. Therefore the inspection is focused as a discipline of just calculating sample sizes on trial documents. Because honesty and inte- and analyzing data. Such an understanding is a grity of documents are inspected, documentation big misunderstanding. Clinical trials principles has to be up to date with the progress of the and methodologies are founded on statistical prin- trial. Documents based on recollection and memory ciples, particularly principles of design of experi- can be inaccurate and undocumented activities ment. I hope this paper will help readers to are activities not performed. Fabrication of study understand the role of statistics in clinical trials. documents is fraud and is punishable act. Second, to me the clinical trial is a high risk Ⅱ. What is the Clinical Trial? undertaking. In the developed part of the world, it is generally known that one out of 10,000 I will define the clinical trial in three different new molecules succeeds as a new drug. The ways. I choose these definitions for the audience process can take years and cost hundreds of of this journal. Under a different situation, I millions US dollars, if not billions. Only one in may define the clinical trial differently. ten NMEs entering the clinical development First, to me the clinical trial is a scientific process is approved as a drug according to a Journal of The Korea Society of Health Informatics and Statistics, Vol. 36, No. 1, 2011 4 Young Jack Lee recent news report. I am told that the success even if the IP is not effective at all. rate for oncology drugs is even lower. A success- The pharmaceutical industry must understand ful product, however, brings in a fortune. Some its trials can fail and learn to accept the failure. blockbuster drugs earn the company billions of If the 20% failure rate of an effective drug is US dollars a year. too high to be accepted, the pharmaceutical Success or failure of an IP is determined by sponsor should be willing to increase the sample the data from the clinical studies.