Abstract
A clinical trial is a prospective study that investigates the efficacy and safety of a new treatment in human subjects. Most industry-sponsored treatment trials are conventionally divided into four phases. Phase I trials are intended to assess the safety, tolerability and pharmacokinetics of the investigational drug. Two most notable, early Phase I trials are the single ascending dose (SAD) and the multiple ascending dose (MAD) studies. These studies are respectively designed to determine the maximum tolerated dose (MTD) that can be given as a single dose and as multiple doses before unacceptable toxicities are experienced by the study subjects. If MAD study signifies safety and tolerability of the drug, Phase II studies ensue in patients with specific disease or condition. The purpose is to explore whether the drug exhibits credible efficacy and acceptable safety in actual patients. Phase III trial is designed to statistically confirm the efficacy of a new treatment in a larger patient population across multiple trial centers. Typically, two well controlled Phase III trials, at a minimum, are required for marketing approval. Phase IV trial, also known as the post marketing surveillance study, is mandated by most regulatory authorities to track any rare or long term adverse events that failed to emerge during the Phase III trials. Harmful adverse events discovered in the Phase IV follow-up may result in product recall or voluntary withdrawal from the market. The pharmaceutical sponsor customarily provides the investigator with a clinical protocol and an Investigator's Brochure, which are included as parts of the IRB submission for study approval. Drug makers will continue to fund clinical trials to supplement their product portfolios, despite the economical downturn and the continuing merger/acquisition activities. Excited by the opportunity to gain first-hand experience with cutting-edge therapies, an increasing number of clinicians have become interested in the clinical trial. Unequivocally, the largest clinical trial market is the United States; however, pharmaceutical globalization and ICH harmonization extend the clinical trial opportunity to international investigators. Driven by economic factors such as cost, efficiency and regulatory climate, the international outsourcing is on the rise. With a knowledgeable and skillful work force, Taiwan is in a strong position to benefit from the globalized clinical trial business.
Key Words:
clinical trial, efficacy and safety, international outsourcing, Investigational Drug, Post Marketing Surveillance
Introduction
A clinical trial is a prospective study that investigates the efficacy and safety of an interventional treatment in comparison with a placebo or an active control in human subjects. The treatment may be a new chemical entity, new screening procedure, or new diagnostic agent to be indicated for a specific disease or condition. Less commonly, the treatment could be an existing drug in different dosage forms (such as sustained release formulation) which are being investigated for a different therapeutic indication. Many of today's standard therapies are based on the successful outcomes of previous clinical trials. Clinical trials include observational and interventional types of studies. In an observational study, the investigators do not actively manage the experiment but merely observe the subjects and measure their outcomes. The Chinese Medicine Legend, SHENONG has perfected observational trials thousands of years ago. In a modern interventional study, the investigators manage randomized controlled trials to yield more compelling evidence of correlations between treatment and outcome. According to the National Institute of Health (NIH), interventional studies could be prevention trials, screening trials, diagnostic trials, treatment trials, quality of life trials or compassionate use trials1. Most clinical studies sponsored by the pharmaceutical industry are treatment trials. Clinical trials involving new drugs and biologics are conventionally classified into four phases, progressing in a concerted manner.
Clinical Trial Phase I
Phase I trials are intended to assess the safety, tolerability and pharmacokinetics of the investigational drug. Two most notable, early Phase I trials are: the single ascending dose (SAD) and the multiple ascending dose (MAD) studies. The former is designed to determine the single, maximum tolerated dose (MTD) that can be given before unacceptable toxicities are experienced by study subjects, and the latter is used to project the safe dose for eventual therapeutic use. Much of the literature has discussed how to extrapolate animal dada to the starting dose in humans2. In estimating the MTD, the investigators usually start with a low dose and escalate the dose until signs of toxicity are observed. The escalation scheme must be conservative so as not to overreach MTD, buy at the same time be efficient in the number of doses and subjects studied. Typically, a small group of healthy volunteers in several cohorts is selected for the first stage testing in man. These trials often extend over several half-lives of the drug in an inpatient clinic, where the volunteer subjects are monitored around the clock. Special circumstances may justify the use of real patients who suffer a life-threatening or serious disease for which no good alternative treatment is available. This exception to the rule most often occurs in oncologic or antiviral trials. A subset of the Phase I trials maybe designated to investigate the effects of food on absorption or to counteract the gastrointestinal side effect of the investigational drug.
Clinical Trial Phase II
If MAD study confirms safety and tolerability of the drug, Phase II studies ensue with a larger group of real patients. The purpose is to explore whether the drug exhibits preliminary efficacy in real patients and whether tolerance and side effect profile are still within acceptable limit. While some regard the Phase II trial as a whole, others divide it into Phase IIA and Phase IIB. Phase IIA is designed as the dose ranging study to define an “optimal” dose which is to be adopted for Phase IIB in a randomized and controlled fashion. In order to explore efficacy with high degree of clarity, Phase II studies are typically conducted in patients with a specific disease or condition but without complications, e.g., hypertension without diabetes. Thus, Phase II trials are more restrictive in terms of inclusion/exclusion criteria. The number of patients involved will depend on the specifics of the disease state3. For psychopharmacological agents, a fairly large sample size will be needed to discern the preliminary efficacy; for cancer trial, a relatively small number of patients may be sufficient to estimate the response rate. It is inherently clear that results of the Phase II trial will depend on the quality and adequacy of the Phase I study. Likewise, results from the Phase II study are the basis for the expanded Phase III trials.
Clinical Trial Phase III
Phase III trial is designed to confirm the efficacy of a new treatment relative to a placebo or an active control, in a relatively large patient population at multiple trial centers. The number of patient required for statistical significance may be in the thousands (e. g., life of quality trials) or in the hundreds (e. g., anticancer agents). Because of the patient number and the trial duration, Phase III trials are costly to run and more difficult to manage, especially for chronic medical conditions. Phase III studies are sometimes divided into Phase IIIA and Phase IIIB; placebo is used in the former and the market comparator is used in the latter. While Phase III may remain blinded throughout the trial period, there are circumstances where open label extension is carried out to confirm the efficacy. If efficacy becomes apparent at certain point of the trial, the study may be terminated at an earlier stage through an interim utility analysis; BiDil® trial is one example4. More often than premature termination for good causes, many new chemical entities are terminated for development due to lack of efficacy through a futility analysis. This is undertaken to avoid the unnecessary suffering borne by the study subjects, besides the obvious economical consideration. Once the Phase III trials are satisfactorily concluded, patient data from the multiple centers are pooled and analyzed for submission to appropriate regulatory authorities for review, along with a large body of information from preclinical investigation and manufacturing. Typically, two well controlled Phase III trials, at a minimum, are required for marketing approval.
Clinical Trial Phase IV
After marketing approval, the clinical trial of a drug does not stop from a regulatory perspective. Phase IV trial, also known as the post marketing surveillance study, is mandated by most regulatory authorities to track any rare or long term adverse events that failed to emerge during the Phase III trials. Harmful adverse events discovered in Phase IV trials may result in product recall or voluntary withdrawal from the market. Such examples included cerivastatin (Baycol), troglitazone (Rezulin) and rofecoxib (Vioxx) in the recent past5. Some Phase IV studies are not considered critical for marketing approval at the time of regulatory review, but clarification is important to warrant a post marketing follow-up. For example, renal study for drugs that are primarily metabolized, or drug interaction studies for drugs that are primarily excreted unchanged. Pediatric study, geriatric study and gender effect studies may also fall into this category, depending on the drug in question. There are Phase IV studies that are required for labeling change such as the effects of juice, antacid or certain foods on oral medications or boxed warning against adverse events. The drug company may also undertake Phase IV study as a marketing strategy, in which head to head comparison with the competitor product is pursued. Prescription to over-the-counter (OTC) conversion is a commercial strategy undertaken by some drug makers after years of post marketing surveillance demonstrating a high degree of drug safety. It is interesting to note that many Phase IV studies are Phase I in technical nature but Phase IV in terms of time sequence of study execution.
Clinical Trial Phase 0
Pharmaceutical development is a low-success, high-risk business, despite the strategic improvement over the years. The progression from preclinical to clinical phase is still largely dependent on animal data; although the reliability of allometric scale-up is not without question and the dilemmas of animal experimentation persisted. This inadequacy has argued for the exploratory testing in human at an earliest stage possible. Phase 0 was introduced in 2006 by the FDA as an Exploratory Investigational New Drug (IND) study. The purpose is to gather pharmacokinetic information from a very small number of human subjects given a micro-dose, usually 1/100 of the putative therapeutic dose. Through PK/PD modeling and other pharmacometric analyses, it is hoped that potential drug candidates can be rank-ordered to facilitate go/no go decision. The concept of Phase 0 is undoubtedly innovative; however, its real values are not unequivocally recognized.
Clinical Protocol
A clinical protocol is a precise study plan for executing the clinical trial. It is a common reference document for multiple centers to assure that the trials are conducted consistently across the board that pooling of data is statistically legitimate. The format and content of a clinical protocol has been largely standardized and include scientific rationale, study objective, methodology and the organization that supports the clinical trial team6. The pharmaceutical sponsor typically distributes a draft protocol to all investigators for comments and inputs before it is finalized. Details of the background information are provided to the investigator in a reference document entitled “Investigator's Brochure”, which the sponsor updates on an annual basis. The individual investigator or research coordinator should pay special attention to the inclusion/exclusion criteria for patient admission. Deviation from the protocol is a violation of Good Clinical Practice (GCP), and should be avoided at all cost. One of the performance metrics measured of the clinical site by the sponsor is compliance with GCP and SOP (standard operating procedures). On the other front, the sponsor is increasingly under public pressure to disclose the ongoing clinical trials by registering the protocol with an open access registry. The public registration of protocols opens up the opportunity for clinical trial participation by the general public, and perhaps more importantly prevents selective reporting at the conclusion of the study. To encourage clinical trial registration, the International Committee of Medical Journal Editors now requires, as a condition for publication, registration in a public trials registry7.
Clinical Trial Design
Technical aspects of Phase I trial are somewhat different from those in Phase II, III and IV; however, the scientific principles that are applied to all phases remain largely the same. In Phase I clinical studies, safety is the primary endpoint while efficacy is the primary endpoint in Phases II and III. General statistical principles include randomization, blinding, stratification and hypothesis testing. Randomization assigns patients to treatment groups by chance, eliminating any systematic imbalance in characteristics between patients who receive the test vs. the control. Blinding ensures that neither the patient nor the investigator knows to which group specific patients are assigned. The purpose of blinding is to minimize the chance for patients to receive preferential treatment or subject their data to biased interpretation. If blinding is impossible, then an independent evaluator for the outcome measure should be used. Stratification is to ensure that the number of patients assigned to the test and the control groups are balanced with respect to certain important attributes, for example gender or disease stage. After randomized controlled trials are concluded, statisticians help determine whether any observed difference in outcomes between the test and the control is real or simply chance occurrences. The process is called hypothesis testing, in which a null hypothesis articulates no difference between the observed means of the test and the control populations. Statistical inferences based on the benefit/risk ratio allow the clinicians to accept, with certain level of confidence the new treatment be selected as the intervention of choice. Phase III trials are aimed at the anticipated clinical outcomes of a specific disease or condition; therefore, the most important requirement for Phase III trial endpoint is clinical relevance. Clinical trials typically stipulate only one primary endpoint, although some disease conditions may require measurement of a co-primary endpoint. A clinical trial can have and does often have multiple secondary endpoints. When multiple endpoints yield conflicting results, conclusions can be obscured.
Surrogate Endpoints
Meaningful clinical outcomes often require many study subjects to be followed for an extended period, consuming time and financial resources. Therefore, increasing efforts have been directed toward surrogate markers in order to reduce cost and duration of clinical trial, and to shorten the exposure of patient to unknown risks. Coupled with clinical observation, surrogate endpoints can be useful in Phase II trial for identifying whether a new chemical entity is biologically active to warrant an expanded large trial. Examples are: increased CD4 cell counts for HIV trial, suppression of ventricular arrhythmia in cardiology trial and tumor regression in trials of cancer therapy. The role of surrogate endpoints in Phase III trial is still controversial; changes induced by a treatment on surrogate endpoint maybe closer to biology than to the clinical outcomes, except in some well established cases. For example, epidemiologic evidence has established that for every one mm-Hg reduction in blood pressure, there is a 5% reduction in cardiovascular related mortality and a 10% reduction in stroke8. Therefore, use of blood pressure as the primary endpoint in antihypertensive trial is apprehensible and accepted by the medical communities and regulatory authorities at large.
Adverse Events and Safety
Responsibility for the safety of participating subjects in a clinical trial is largely shared between the local investigator and the sponsor. The investigator should ask the sponsor for indemnification from liability issues related explicitly to the medicine, understandably exclusive of medical malpractice. Throughout the clinical trial, the sponsor is responsible for collecting adverse event reports from all clinical sites, and for informing all investigators of the current safety status of the investigational drug. With the aid of multi-media tools, this task has become a whole lot easier to manage nowadays. Adverse event reports are disseminated via newsletter, e-mail and other multi-media channels periodically and as necessary. For multi-center trials, some sponsors delegate an independent Data Safety Monitoring Board (DSMB) to review the un-blinded data to evaluate whether the adverse events were related or unrelated to the treatment. The DSMB typically follows an internally instituted stopping rule to recommend termination of study if serious adverse events or death occur. A physician's first and foremost duty is to protect the physical or psychological wellbeing of the patient. If a clinical investigator believes that the study treatment exposes the patient to unnecessary risks, the physician can stop the study immediately. However, the investigator often has a vetted interest in retaining the study subject for financial reason, and may not act ethically. This is where the IRB or regional regulatory agency can step in to protect the right and wellbeing of the study participants.
IRB and Informed Consent
All clinical trials must be approved by an ethics committee before permission is granted to conduct the trial. Most Institutional Review Boards (IRB) are located at the local investigator's hospital or institution, but some sponsors designate a central IRB for the network investigators. The primary function of the IRB is to review safety of the drug and procedures so as to guard the wellbeing and right of the study subjects. Secondarily, it also reviews the scientific merit of the protocol since executing a scientifically unworthy protocol is considered unethical. Before initiating a clinical trial, investigators must obtain the full and informed consent of the participating subjects. The Informed Consent is a process by which subjects learn the important facts about a clinical trial to help them decide whether to participate. The information should include purpose of the study, the tests and procedures used in the study, and the possible risks and benefits. In addition to verbal explanations from the investigator, subjects receive a written consent form detailing the study. Investigators are obligated to address questions regarding short term benefits, long term benefits, short term risks, long term risks, and treatment options. Subjects are asked to sign the consent form if they agree to participate in the study. However, informed consent is not an immutable contract; subjects can terminate participation at any time. It is also important to note that the informed consent process continues throughout the study. If new benefits, risks, or side effects are discovered during the study, the investigators must inform the participants. Study subjects are then asked to sign a new consent form if they decide to continue the participation. Common mistakes committed by the investigator include failing to update patients with new safety information in a timely manner and backdating the signature on the consent form, both are serious violations of GCP.
Patient and Volunteer Subjects
From the investigator's point of view, patients are assets of the clinical site. Lack of them, the investigator may not be able to fulfill the enrolling commitment, or worse dropped by the sponsor for underperformance in an open, competitive enrollment circumstance. In Phase I trials, volunteer subjects are remunerated to participate. The financial incentive to the healthy volunteers appears to be justifiable, considering the inconvenience they bear, being exposed to unknown risks, and expectation of no benefits. The payment could be substantial depending on the procedures to be performed and the length of confinement at the clinic. Patient volunteers, on the other hand are compensated with a small stipend for study related expenses such as regular office visits during study, follow-up visits after discharge and transportation expenses. Sponsors should consider the impact of eligibility criteria on recruitment and enrollment of participants. Excessive restrictions in an attempt to obtain a homogeneous sample can lead to difficulty in patient accrual and delayed completion of project. It's not uncommon that a sponsor relaxes the entrance criteria when faced with a sluggish enrollment. This effort may not work however, because the additional patients could lower the probability of developing the primary response variable. Nonetheless, this represents an opportunity for the clinical investigator to place more study subjects into the randomized pool.
Summary
Clinical trials represent a win/win situation for all the stakeholders in the drug development venture. As more and more companies seek to investigate and develop new drugs, devices and other technologies, most of which must be tested in a patient population, there is an increasing need for clinical investigators. Academic investigators particularly appreciate clinical studies that can change the way medicine is practiced in the future. For the community practitioners, clinical trials allow them to gain first-hand experience with cutting-edge therapies, which may serve to further strengthen the physician-patient relationship. As professional fee reimbursement continues to shrink, some physicians are looking at alternative ways to generate income to replace what Medicare and commercial insurers have taken away. One option that is becoming increasingly interesting to them is participation in clinical trials. For the patients, clinical trials can provide attractive options for those who don't have good standard treatments available to them, either because there isn't one for their disease or because their treatment ceased being effective.
Despite the economical downturn and the continuing merger/acquisition activities, drug makers will continue to fund clinical trials to support their product portfolios. According to the Pharmaceutical Research and Manufacturers Association, clinical trials of drugs account for an average of 7 billion dollars over the last several years. Considering only 3-5% of medical groups participate in clinical trials, the room of growth is appealing. The largest clinical trial market is indisputably the United States. Owing to pharmaceutical globalization and ICH harmonization, the opportunity for international participation in clinical trials is expanding. India and China have become formidable forces in the CRO market, with 11% of the total CRO spending in 2007, and are poised to grow even higher. The international outsourcing trend will continue, driven by economic factors such as cost, efficiency and regulatory climate. With a high-powered and skillful work force, Taiwan is in a strong position to benefit from the globalized clinical trial business.
References:
1. Clinicaltrials.gov web site. Available at: http\\www.clinicaltrials.gov
2. Guidelines on strategy to identify and mitigate risks for first in human clinical trials with investigational medicinal products. European Medicine Agency, London, July 2007.
3. Fundamentals of Clinical Trials. Third Edition. Friedman LM, Furberg CD and DeMets DL, Birkhauser, 1998.
4. BiDil® for Heart failure in Black patients: The U.S. Food and Drug Administration Perspective. Temple R and Stockbridge NL, Ann. Int. Med., 2007, 146:57-62.
5. Recalls.gov web site. Available at: http//www.recalls.gov
6. Guidance for Industry, E6 Good Clinical Practice: Consolidated Guidance. International Committee on Harmonization.
7. Clinical Trial Registration: A statement from the International Committee of Medical Journal Editors. DeAngelis CD et al. JAMA, 2004, 292:1363-1364.
8. Blood pressure, stroke and coronary heart disease. Collins et al, Lancet, 1990:335:827-838.
摘要
臨床試驗的目的在於探討新藥在人體的有效性和安全性。製藥工業贊助的臨床試驗通常區分為四個階段，第一階段以單劑量和多次投予的方式來測試正常人對新藥的忍受度，第二階段測試新藥對數百個無併發症病人的初步療效和安全性，第三階段擴大試體數目達千人，並可包括多種病變病人，目的在統計證實新藥的有效性。在第三階段臨床試驗結束之後，業者即可將臨床試驗分析結果呈送相關機構審核，如經核准，即可取得市場行銷許可。在藥品行銷期中，臨床試驗仍持續進行，此為第四階段，目的在於對副作用的長期追蹤。如果發現不良反應，審核機構有權力宣布藥品回收，中止銷售。因為研究參與感和實質經濟效益，有意願參加臨床試驗的醫師明顯增加。美國無疑是臨床試驗最大市場，因為新藥審核規格的國際化，使其他國家的醫師也有參與臨床研究的機會。縱使世界性經濟風暴，製藥業者仍然會持續投資新藥開發。以高科技和高品質人力資源，台灣有競爭力來爭取國際臨床試驗的商機。
關鍵字：
臨床試驗、有效性和安全性、市場行銷許可、副作用長期追蹤、新藥開發、新藥審核規格國際化
作者
美國佛羅里達州西棕櫚灘，棕櫚灘大西洋大學藥學院教授 李慶三
Charles Lee, Ph. D.
Professor of Pharmaceutical Sciences
Llyod L. Gregory School of Pharmacy
Palm Beach Atlantic University
West Palm Beach, Florida
