Cẩm nang thực hiện thử nghiệm lâm sàng

ĐỊNH NGHĨA THỬ NGHIỆM LÂM SÀNG MỤC TIÊU NGHIÊN CỨU (ESTIMAND/GOAL OF THE CLINICAL STUDY).3 TARGET POPULATION AND PATIENT SELECTION .10 ETHICAL CONSIDERATIONS 12 SELECTION OF CONTROLS .13 STRATIFICATION ISSUES 14 EFFICACY ASSESSMENT 15 SAFETY ASSESSMENT 16 SAMPLE SIZE ESTIMATION .17 INTERIM ANALYSIS AND DATA MONITORING 19 DESIGNS FOR CLINICAL TRIALS 20 INSTITUTIONAL REVIEW BOARD/INDEPENDENT ETHICS COMMITTEE (IRB/IEC) 21 ĐỊNH NGHĨA THỬ NGHIỆM LÂM SÀNG Một thử nghiệm lâm sàng (clinical trial) đánh giá tác dụng loại thuốc (hoặc thiết bị quy trình) người tình nguyện Những thử nghiệm sử dụng để đánh giá an toàn loại thuốc người tình nguyện khỏe mạnh, để đánh giá lợi ích điều trị bệnh nhân mắc bệnh cụ thể Các thử nghiệm lâm sàng so sánh loại thuốc với loại thuốc có với thuốc giả (giả dược) chúng khơng có nhánh so sánh Trong thử nghiệm lâm sàng ngẫu nhiên, bệnh nhân nhân viên thử nghiệm cố tình khơng biết bệnh nhân dùng thuốc Các thử nghiệm lâm sàng phân loại thành nghiên cứu đơn trung tâm đa trung tâm theo số lượng địa điểm liên quan Trong nghiên cứu đơn trung tâm chủ yếu sử dụng cho nghiên cứu pha I II, nghiên cứu đa trung tâm thực giai đoạn phát triển lâm sàng Nghiên cứu đa trung tâm cần thiết cho hai lý chính:  Để đánh giá loại thuốc quy trình hiệu mặt tích lũy đủ đối tượng khoảng thời gian ngắn  Để cung cấp sở tốt cho việc khái quát hóa kết thử nghiệm, tức là, hiệu việc điều trị đánh giá nhiều loại trung tâm CLINICAL TRIAL DESIGN PARALLEL GROUP DESIGNS Mỗi bệnh nhân nhận loại điều trị mà thơi Có hai loại group comparision design matched pairs parallel design  Group comparision design: nhóm thường có số mẫu Có thể có nhóm treatment nhiều nhóm control Three-goup parallel design bao gồm nhóm treatment, nhóm active control nhóm placebo control Nhóm treatment thường có số bệnh nhân nhiều nhóm placebo (gấp gấp 3) lý đạo đức, bệnh nhân hưởng điều trị nhiều nhóm placebo Thường dùng phase II phase III  matched pairs parallel group design: randomized complete block design với block size bệnh nhân bắt cặp với bệnh nhân khác có yếu tố tiên lượng (ví dụ béo phì) cho bệnh nghiên cứu Một bệnh nhân cặp phân vào nhóm treatment phân vào nhóm control Thiết kế phù hợp cho bệnh diễn tiến bệnh ung thư Trước bệnh nhân thu tuyển vào nghiên cứu người ta thường thực run-in periods (lead-in) với thuốc placebo, khơng có thuốc nghiên cứu Nghiên cứu run-in periods có mục đích:  Xác định tác dụng placebo (tác dụng wash-out )  Dùng để làm hội tập huấn cho bệnh nhân, điều tra viên, nghiên cứu viên  Phát bệnh nhân không hợp tác giai đoạn đầu để cung cấp tư vấn cần thiết cho bệnh nhân  Run-in periods thường single-blind, bệnh nhân khơng biết sử dung placebo Tuy nhiên run-in periods thường kéo dài thời gian nghiên cứu tốn nhiều chi phí CLUSTERED RANDOMIZED DESIGNS Đối với can thiệp điều trị (như can thiệp lối sống, chương trình giáo dục) việc lấy mẫu ngẫu nhiên theo cluster (gia đình, bệnh viện, đội, nhóm) (hay cịn gọi social intact unit) giúp việc chọn ngẫu nhiên thực tốt Với thiết kế clustered randomized design lấy ngẫu nhiên mức cluster khơng phải subject level Vì unit of randomization (cluster) unit of analysis (subject) hồn tồn khác nhau, nên khơng thể áp dụng phương pháp lấy mẫu phân tích thống kê chuẩn dành cho nghiên cứu loại Chúng ta dùng ICC (intraclass correlation coefficient) để đo lường giống subject cluster Nếu ICC dương nghĩa intracluster variation nhỏ intercluster variation Phương sai trung bình mẫu tăng ICC cỡ mẫu tăng lên (VIF: variance inflation factor yếu tố làm tăng phương sai) CROSSOVER DESIGNS TITRATION DESIGNS MỤC TIÊU NGHIÊN CỨU (ESTIMAND/GOAL OF THE CLINICAL STUDY) Hai mục tiêu thử nghiệm thuốc: the efficacy safety The efficacy dùng phép kiểm để kiểm tra treatment effect, cịn safety trình bày số tóm tắt kèm khoảng tin cậy  In the case of adverse event data, the rate of occurrence of each distinct adverse event on each treatment group should be reported, together with confidence intervals for the difference between the rates of occurrence on the different treatments  An alternative would be to present risk ratios or relative risks of occurrence, with confidence intervals for the relative risk Mục tiêu nghiên cứu phải xác định rõ cách đo lường efficacy safety Phải thêm vào xu hướng giả thuyết (ví dụ thuốc có hiệu tốt hơn/ngang bằng/ thấp thuốc control) Mục tiêu có composite endpoints (nghĩa nhiều cách đo lường cho hiệu độ an tồn) Mục tiêu cịn có thêm tertiary objective dành cho subgroup quần thể nghiên cứu Ví dụ: Primary Objectives This trial is a randomized, double-blind, placebo-controlled trial conducted in x centers to assess the efficacy of the test drug under investigation at dose y, frequency z for a 52-week treatment of patients with COPD in terms of: The reduction in the risk of exacerbation of COPD for patients receiving the investigational drug as compared to the placebo A superior second pulmonary (FEV1) for function patients as assessed receiving by the the forced investigational expiratory drug as volume in compared to the placebo Secondary of the incidence Objectives The secondary investigational drug at rates patients with COPD of adverse dose events objectives y, and are to z versus frequency laboratory assess the placebo parameters over by a safety and the evaluation 52-week tolerability of the treatment of Ví dụ 2: Primary Objectives This is a randomized, parallel-group study for determining whether the efficacy of the test drug is not inferior to that of the active competitor for the prevention of all stroke (fatal and nonfatal) and systemic embolic events in patients with atrial fibrillation (AF) Secondary Objectives Secondary objectives To compare the efficacy of the test the composite embolic endpoint of and nonfatal events, the include the following: drug to that of the active competitor in terms of prevention of myocardial death, infarction nonfatal in stroke, patients with nonfatal atrial systemic fibrillation (AF) To compare the safety of the test drug to that of the active competitor with major bleeding events and treatment discontinuation as the primary safety endpoints Tertiary To Objectives compare the prevention of of more or all The efficacy strokes at following of the with months a test poor post-stroke tertiary drug to outcome or a objectives that of (defined Barthel are the as score active a less of interest: competitor for Modified Rankin than at 60 the score months post-stroke) To compare prevention of the all efficacy strokes and of the test systemic drug embolic to that events of in the active patients 75 competitor for the years age or of older with AF and to compare this with patients below the age of 75 years Estimands link study objectives and the analysis methods by more precisely defining what is to be estimated and how that quantity will be interpreted This provides clarity on what data needs to be collected and how that data should be analyzed and interpreted Conceptually, an estimand is simply the true population quantity of interest (NRC 2010); this is specific to a particular parameter, time point, and population (also sometimes referred to as the intervention effect) With the diversity in medical research and the many clinical trial scenarios that exist, consensus on a universally best estimand is neither realistic nor desirable Therefore, attention has turned to how to choose estimands Importantly, the chart makes clear that in order to determine how best to analyze clinical trial data, it is important to first consider the trial objectives and the estimands needed to be estimated in order to address those objectives For example, at the most conceptual level, estimands can be divided into two general categories based on adherence to protocol-defined interventions: (1) Efficacy is the effects of the drug if taken as directed; that is, the effects if patients adhere to the protocol-defined interventions (2) Effectiveness is the effects of the drug as actually taken; that is, the effects without regard to adherence to the protocol-defined interventions Estimand 3, the de jure estimand, can be considered hypothetical (i.e., counterfactual) for groups of patients because treatment effects are assessed as if taken as directed when in any meaningfully sized group some patients will not adhere (NRC 2010) Therefore, de jure estimands assess what is possible to achieve in a group of patients, not what actually was achieved However, de jure estimands assess what to expect if patients are adherent—and in most clinical settings the majority of patients are adherent (Mallinckrodt et al 2014) In addition, patients are advised to take their medication as directed; therefore, it is important to assess what would happen if a medication were taken as directed so that optimal directions can be developed De facto estimands can be considered counterfactual for individual patients because treatment effects are assessed from a mix of adherent and nonadherent patients, but each patient is either adherent or not adherent, no patient is both On the other hand, de facto estimands can provide useful estimates of what to expect from the group as a whole Design Considerations in Choosing Estimands Missing Data Considerations Universal agreement exists that clinical trials should aim to minimize missing data, thereby maximizing the portion of the intended data that was actually collected These considerations have often been in the context of de jure estimands However, the impact of maximizing retention on de facto estimands is also important Specifically, assessment of de facto estimands often entail using adherence as part of the primary outcome Rescue Medication Considerations Whether or not data should be collected after discontinuation of initially randomized study medication or initiation or rescue medication, and whether that data should be included in an analysis are critically important considerations Use of rescue medications for patients not adequately responding to the initially randomized medications has been suggested because this provides an assessment of pragmatic effectiveness and can reduce dropout In placebo-controlled trials, if rescue therapy is beneficial and post-rescue data are included in the analysis, the treatment effect is likely to be substantially diminished compared to the effect if postrescue data are not included Another consideration is that readily available rescue medications may reduce study discontinuation, but could increase discontinuation from the initially randomized medication, which would of course be counter to the primary goal of maximizing retention on the initial medications (Mallinckrodt 2013) This issue may be particularly important in placebo-controlled trials where patients are aware that they may be randomized to an ineffective treatment but switching to rescue guarantees use of an effective treatment With estimand (de facto, treatment regimens), data after discontinuation of the initially randomized medication and/or addition of rescue medication are included in the analyses The ICH E9 guidance is often cited when justifying choice of a primary analytic approach (http://www.ich.org/fileadmin/Public_Web_Site/ICH_ Products/Guidelines/Efficacy/E9/Step4/E9_Guideline.pdf) This guidance emphasizes the ITT principle, which is defined as “the principle that asserts that the effect of a treatment policy can be best assessed by evaluating on the basis of the intention to treat a subject (i.e., the planned treatment regimen) rather than the actual treatment given It has the consequence that subjects allocated to a treatment group should be followed up, assessed and analyzed as members of that group irrespective of their compliance to the planned course of treatment The guidance is clear on the need to include all randomized patients and that all data should be included, but it does not specifically address data after initiation of rescue treatment Rescue therapy is specifically addressed in ICH E10, Section 2.1.5.2.2 (http:// www.ich.org/fileadmin/Public_Web_Site/ICH_Products/Guidelines/ Efficacy/E10/Step4/E10_Guideline.pdf) In referring to trials with rescue, E10 states: “In such cases, the need to change treatment becomes a study endpoint.” Thus, according to E10, post-rescue data need not be included in the primary analysis In this modified approach to ITT, all randomized patients are again included, thereby maintaining consistency with the first tenant of ITT The second tenant of ITT is modified to mean that all data—relevant to the estimand—are included O’Neill and Temple (2012) noted that estimand may be a more common choice for the primary estimand in outcomes trials where the presence/absence of a major health event is the endpoint and/or the intervention is intended to modify the disease process Symptomatic trials (symptom severity is the endpoint) often use a primary estimand where the inferential target is the initially randomized treatments In these scenarios the confounding from rescue medications is avoided by excluding data after discontinuation of study medication/initiation of rescue from the primary analysis 1.4Analysis Considerations Although failure to adhere can be manifest in many ways, the most common scenario is that of missing data Patients may discontinue the study and all study-related procedures prior to the planned time of the primary assessment Patients may also discontinue the randomized study medication but remain in the study for follow-up assessments For estimand 3, data after discontinuation of the initially randomized study medication are not needed That is, post-rescue/post-discontinuation data are not included, thereby avoiding the potentially confounding effects of rescue medication That is, patients with poor outcomes are more likely to be missing than patients with good outcomes Therefore, analysis of estimand requires estimates of what would have happened if all patients were adherent, but this cannot be based on only those patients who were adherent Trials are trained for and these monitored qualified individuals individuals to report on possible • individuals practices, including clinical trial participants, verify sponsor the progress will of have the procedures trial, (but not protocol, and limited accuracy with to) enrollment the including misconduct compliance clinical good clinical adherence of to appropriate and complete the research reporting of trial if a significantly the The appropriately scientific These • using sponsor learns deficient in investigator investigator’s any to that a area, it obtain participation data clinical will either compliance in the investigator or study, is work with discontinue the notify the and relevant authorities as required ENSURING OBJECTIVITY IN RESEARCH a Independent generally Review large, interventions adverse may avoid be the external welfare blinded of to of the by research should medicine, statistics, respect, clinical have varied and trial investigator to 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travel clinical to may meetings be for expenses The appropriate for are their conjunction with venue the with these meetings travel or lodging expenses for the those offered and be specifically, modest meals or company-sponsored should in not provide conjunction to who meal should during appropriate they and meeting; events to trial, lodging, companies not clinical While appropriate is required time the venues entertainment it are circumstances of investigators, or a travel, purpose be staff their and appropriate may recreational for reasonable not receptions meetings in and compensated reimbursement resorts investigators pay are with honoraria not or involved clinical in trial d Potential Conflicts of Interest a potential conflict of interest exists, in the research setting, judgment could potential financial personal considerations for services, conflict of physicians extensively provide there influenced gain, and who or may are by expertise often a a an advancement, memberships 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who: analysis conditions 1, 2, and or and of recognition the as individuals warrant programs if information medical importance, publish the and (1) of an author who authorship major a and important journal substantial study, or (2) writes intellectual to data international provides interpretation; version the Contributors of design involving approval development to editors patients marketing, significant Journal in and for addition, standards that submission Research conception conversely, not of a investigational approved in investigators with manuscript appropriate published manner the are or on trials conducted whose and authorship, into be clinical timely trials outcome to with Medical for contributions of consistent of clinical that all the investigational registration marketed to products and about our products Authorship Authors of all and/or submission commit of regardless will committee is use results products information investigational clinical we timely the of discontinued, from the We summary are marketed summary patients the that of to involving in of already commit database products involve be not the should manuscript contribute authors or content; published, when data should in this meet b • all persons authorship, of the and three journals each the all those criteria may listed designated work should the author should a group large, responsibility collection of authors, external, and will produce conjunction either be as and recognized a named their level of contribution sufficiently in for appropriate a help research analyze such or in in direct funding, the research authorship company tables, or figures, planned publication sponsors, companies interpret investigator-author appropriately author and work, of sponsoring the presentations the of statistical the accept justify support other to supervision relevant to like with be acquisition within the needed manuscripts may who not from given staff although who conducted individuals general each content has manuscript whether employ authors for to companies; participated group the or Contributors should of respect responsibility does be reports sometimes in data, by qualify the the alone, all public with listed have identify for group, • be multi-center should should qualify of When the authors number take portions • who restrict to as data, personnel Their resulting acknowledgments, and must to act contributions publications — depending on c • contributors should of be who department might of but may be listed or “participating contribution be advisors,” “collected data,” with study manuscript available, people supported preparation that it only authors and whether data if should the in published support should also be acknowledged materially to assistance article investigators” as proposal,” patients.” had assistance data analysis, assistance identity any Financial or study they and “served study authorship the authorship function for the a support the not or who general example, cared disclose provided the for or person “clinical collection, such a their reviewed “provided examples justify as and — section not such described authorship assistance, contributed heading declare design, the have “critically or should who for include provided a criteria writing investigators,” should authors help, contributions under scientific • acknowledged who whose the acknowledgments technical persons meet an be chair Groups not in purely paper listed those provided • who and was of entity or the that material d c Related Publications For a multi-site clinical trial, analyses based on single-site data frequently professionals sponsors reference usually not have provide significant meaningful or patients and such reports should the primary statistical information therefore may not presentation limitations, not precede or for be of healthcare supported and paper and should the by always entire study d Investigator Access to Data and Review of Results We seek to provide the investigators studies multi-site data, results who which they clinical trials will of will be the trial available to participated able to the entire meaningful in and conclusion with in review have sponsors the conduct at of a in a clinical research multi-site sponsor’s trial study will reports other be for mutually agreeable sponsors study investigator and or after the any figures, in participants’ of clinical facilities, from code summary addition tables, data investigators randomization make statistical the own the will to individual their investigators relevant study participate provided the access location will results provide regardless otherwise contributes summary could publication, all a be slide clinical study report (csr) investigators of whether to the the with the presentation, or full investigator publication primary a on summary is the manuscript a synopsis an of author study submitted of the the or This for sponsor’s e investigators trial to and are review participated interested data mutually inquiry who for the in in more entire location investigators who are study data be given e Research all collaborations research between sponsors summary of participants will in Participant after at a displays a conclusion of facility study-related to support as investigators able or other scientific the publication studies are investigators, to appropriate, trial be manuscripts clinical encouraged the will of participants, as clinical reasonable Communication are multi-site sponsor’s to needed results, support the authors research trial of data response investigators the conduct extensive study agreeable will the communicate to their research in and a research sponsors, this we regard f Sponsor Review sponsors have the right to review any manuscripts, presentations, utilize our means of manner, means or data before not communication and/or intellectual property) data exist, originate are or (in Where the parties appropriate to it for differences should try may respond or be or short in of opinion resolve timely appropriate to to or other a other time that or necessary a to studies publication publications cases communication our for commit veto rare from submitted sponsors suppress publication of that they communication and of abstracts delay protect interpretation them scientific through debate g Provision of Clinical Trial Protocol for Journal Review if requested by a medical publication, clinical the trial journal the when clinical protocol understanding trial and/or that such reviewing sponsor a will pre-specified documents submitted provide a manuscript synopsis plan for data are confidential of analysis and for the with should be returned to the sponsor EXPANDED ACCESS TO INVESTIGATIONAL DRUGS clinical trials are the primary route by which patients participate in the drug development process, receive access to unapproved investigational drugs, and contribute to the collection of safety and efficacy data necessary for review and regulatory approval by national health authorities Thus, to the extent possible, patients should be encouraged to participate in clinical trials, which ultimately will result in access to new, safe and effective approved medicines for the greatest number of patients For patients with a serious or life-threatening disease who are ineligible or unable to participate in a clinical trial, use of an unapproved investigational drug via an expanded access program may be an option expanded access, including treatment use in individual patients, is the use of an unapproved investigational drug outside of a clinical trial to treat a patient with a serious or immediately life-threatening disease or condition, when there are no other comparable or satisfactory alternative treatment options Patients should consult their healthcare provider for determining the best course of action depending on their individual needs Considerations for biopharmaceutical providing drug Participation companies patients outside with of a in Expanded Access these principles following access clinical to trial an using Programs unapproved guidelines that consider investigational generally the • following: The order patient for should has a expanded have serious access a or to serious or and should have therapeutic options typically used is no longer The development clinical company to investigational secured, said, companies mechanisms The patient should Geographic able in, to not eligible limitations for alone clinical be under an has for biopharmaceutical through would considered a barrier to participation in clinical trials in unable to seeking expanded drug generally investigational participation separate underinsured otherwise patient reason, appropriate and or a unapproved not help been any medicines, for, unapproved an generally trials unapproved active biopharmaceutical of provide or treatments approval uninsured ineligible clinical an be to the is to approved for participate access be access are disease, should a or available these for discontinued programs all under in patient disease the drug regulatory is for may be development drug access That should once clinical investigational treat tolerate expanded drug or expanded to development support the exhausted investigational illness appropriate, life-threatening to drug The active • able investigational life-threatening be condition • include a clinical trial generally not be The • potential potential risks seeking the patient, safety information, The successful necessary safe to and required demonstrate effective to and broadest patient to access the trials make an the potential of specific indication made trial process indication, by is interfere adequate or impact on the the expanded or that are regulatory biopharmaceutical ongoing to granting national for health an trials by which Thus, delay, clinical is available through is drug national medicine of the preliminary investigational not of is drug availability use dosing appropriate example, drug the including clinical approval the investigational new of and robust the approval should drug the proposed investigational support consider approved medicines that population For and the completion to authorities of its the sufficiently data, for regulatory program intended the to an compromise should for obtain authorities, access be request completion patient outweigh support that the the treatment should positive which To efficacy is outweigh investigational medical determine balance for itself and to benefit-risk disease in to generally the there should benefit of drug generally, preliminary • the investigational patient should risks of the potential access potential outcome to The expanded combined the benefit companies supplies planned availability of clinical of To determine possible whether treatment expanded option access healthcare access determined to approve come and access company from can the regulatory the not been authorities should drug investigational for qualified and generally before a drug to a patient Enhancing Information biopharmaceutical internet-based expanded information access The of development or industry advocacy academia that is committed and targeted establish to facilitate between innovative, requires groups, should Access a Programs telephone to diseases patient’s qualified regulatory its an authorities, help approaches ensure to and availability of innovative new medicines for patients urgent with and there accelerate for unique biopharmaceutical patients, healthcare that healthcare medicines The work about companies effective attention continuing to and represents special regulatory policymakers, safe or communication biopharmaceutical life-threatening challenge Expanded sources programs and serious about companies provider and best request have investigational provide the patient’s committees an is the drugs effective, to drug patient, investigational boards/ethics expanded biopharmaceutical investigational individual generally safe review an an because be institutional for should provider to patient practitioners, are the appropriate development MISSING DATA In a trial context, missing data are data we intended to collect, but for one reason or another did not We distinguish three broad occurrences: If a patient missed a follow-up visit but attended at least one subsequent follow-up visit, we refer to the resulting missing data as interim missing data If a patient is no longer seen after a certain follow-up visit, we say the data is missing to due withdrawal (a) In some trials, when a patient stops complying with the intervention withdrawn they and subsequent will follow-up data will be be missing (b) In others, follow-up will continue, at least for an initial period after compliance stops In the literature, the terms dropout, attrition and loss to follow-up are also used, fairly synonymously with withdrawal typically ...ĐỊNH NGHĨA THỬ NGHIỆM LÂM SÀNG Một thử nghiệm lâm sàng (clinical trial) đánh giá tác dụng loại thuốc (hoặc thiết bị quy trình) người tình nguyện Những thử nghiệm sử dụng để đánh giá... cụ thể Các thử nghiệm lâm sàng so sánh loại thuốc với loại thuốc có với thuốc giả (giả dược) chúng khơng có nhánh so sánh Trong thử nghiệm lâm sàng ngẫu nhiên, bệnh nhân nhân viên thử nghiệm cố... sàng ngẫu nhiên, bệnh nhân nhân viên thử nghiệm cố tình khơng biết bệnh nhân dùng thuốc Các thử nghiệm lâm sàng phân loại thành nghiên cứu đơn trung tâm đa trung tâm theo số lượng địa điểm liên quan