2022年04月急性冠脉综合征治疗新药临床研究指导原则.(英文版)

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Send a question via our website www.ema.europa.eu/contact ? European Medicines Agency, 2016. Reproduction is authorised provided the source is acknowledged. 1 April 2016 1 EMA/CHMP/207892/2015 2 Committee for medicinal products for human use (CHMP) 3 Guideline on clinical investigation of new medicinal 4

products for the treatment of acute coronary syndrome 5

(CPMP/EWP/570/98) 6

Draft

7 Draft agreed by Cardiovascular Working Party

February 2016 Adopted by CHMP for release for consultation

1 April 2016 Start of public consultation 27 April 2016 End of consultation (deadline for comments)

31 October 2016 8 This guideline replaces 'Points to consider on the clinical investigation of new medicinal products for the 9 treatment of acute coronary syndrome (ACS) without persistent ST segment elevation' 10 (CPMP/EWP/570/98). 11

12 Comments should be provided using this template . The completed comments form should be sent to CVSWPSecretariat@ema.europa.eu .

13

Keywords Acute coronary syndrome, STE-ACS, NSTE-ACS, guideline, CHMP

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Guideline on clinical investigation of new medicinal products for the treatment of acute coronary syndrome (CPMP/EWP/570/98) EMA/CHMP/207892/2015 Page 2/17 Table of contents 16

Executive summary ..................................................................................... 4 17

1. Introduction (background) ...................................................................... 4 18

2. Scope....................................................................................................... 5 19

3. Legal basis and relevant guidelines ......................................................... 5 20

4. Choice of efficacy criteria (endpoints) ..................................................... 6 21

4.1. All-cause mortality and CV mortality ....................................................................... 6 22

4.2. New myocardial infarction ..................................................................................... 6 23

4.3. Revascularisation ................................................................................................. 6 24

4.4. Unstable angina pectoris necessitating hospitalisation ............................................... 6 25

4.5. Stent thrombosis .................................................................................................. 6 26

4.6. Stroke ................................................................................................................ 7 27

4.7. Left ventricular function and heart failure ................................................................ 7 28

4.8. Composite endpoints ............................................................................................ 7 29

4.9. Endpoints in fibrinolysis studies .............................................................................. 7 30

5. Methods to assess efficacy (how to measure the endpoints) ................... 8 31

5.1. Mortality ............................................................................................................. 8 32

5.2. New myocardial infarction ..................................................................................... 8 33

5.3. Revascularisation ................................................................................................. 8 34

5.4. Unstable angina pectoris necessitating hospitalisation ............................................... 8 35

5.5. Stent thrombosis .................................................................................................. 8 36

5.6. Ventricular function and heart failure ...................................................................... 9 37

5.7. Angiographic endpoints ......................................................................................... 9 38

6. Selection of patients ................................................................................ 9 39

6.1. Study population .................................................................................................. 9 40

6.1.1. STE-ACS (ST elevation acute coronary syndrome) ................................................. 9 41

6.1.2. NSTE-ACS (Non-ST elevation acute coronary syndrome) ........................................ 9 42

6.1.3. Unstable angina ................................................................................................ 9 43

6.2. Inclusion criteria for the therapeutic studies .......................................................... 10 44

6.3. Exclusion criteria for the therapeutic studies .......................................................... 10 45

6.4. Risk Stratification ............................................................................................... 10 46

6.5. Special populations ............................................................................................. 11 47

6.5.1. Older patients ................................................................................................. 11 48

7. Strategy and design of clinical trials ...................................................... 11 49

7.1. Clinical pharmacology ......................................................................................... 11 50

7.2. Therapeutic exploratory studies ........................................................................... 12 51

7.2.1. Objectives ...................................................................................................... 12 52

7.2.2. Design ........................................................................................................... 12 53

7.3. Confirmatory Therapeutic Studies ......................................................................... 12 54

7.3.1. Objectives ...................................................................................................... 12 55

7.3.2. Background therapy ......................................................................................... 12 56

7.3.3. Choice of comparator (13)

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Guideline on clinical investigation of new medicinal products for the treatment of acute coronary syndrome (CPMP/EWP/570/98) EMA/CHMP/207892/2015 Page 3/17 7.3.4. Duration of clinical studies ................................................................................ 13 58

7.3.5. Analyses and subgroup analysis ........................................................................ 13 59

8. Safety aspects ....................................................................................... 14 60

8.1. Bleedings .......................................................................................................... 14 61

8.2. All-cause mortality ............................................................................................. 15 62

8.3. Thrombocytopenia .............................................................................................. 15 63

8.4. Rebound effect ................................................................................................... 15 64

8.5. Effects on laboratory variables ............................................................................. 15 65

8.6. Effects on concomitant diseases ........................................................................... 15 66

References ................................................................................................ 16 67

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Guideline on clinical investigation of new medicinal products for the treatment of acute coronary syndrome (CPMP/EWP/570/98) EMA/CHMP/207892/2015 Page 4/17 Executive summary 69

Two CHMP Guidelines have been previously developed to address clinical investigations of new 70

medicinal products for the treatment of acute coronary syndrome (ACS): (I) the CHMP points to 71

consider (PtC) on the clinical investigation of new medicinal products for the treatment of acute 72

coronary syndrome without persistent ST-segment elevation (CPMP/EWP/570/98), published in 2000 73

[1], and (II) the CHMP PtC on the clinical development of fibrinolytic products in the treatment of 74

patients with ST segment elevation myocardial infarction (CPMP/EWP/967/01), published in 2003 [2]. 75

Since their finalisation, major developments have taken place in the definitions, diagnosis, 76

interventions and management of ACS, as reflected in the relevant European Society of Cardiology 77

(ESC) clinical practice guidelines (3, 4). Currently, an update of the above mentioned CHMP Guidelines 78

is considered necessary to take these new developments into consideration based on literature review 79

and experience gained with medicinal products intended for treatment during the acute phase and 80

beyond. The present update includes the following changes: 1) guidance addressing both ST-segment 81

elevation myocardial infarction (STEMI) and non-ST-segment elevation myocardial infarction 82

(NSTEMI), as well as unstable angina (UA), 2) update in their definitions, 3) risk stratification using 83

different scoring systems, 4) investigated endpoints, and 5) clinical developments of new medicinal 84

products beyond the acute stage, including agents other than antiplatelets and anticoagulants. 85

1. Introduction (background) 86

Cardiovascular diseases are currently the leading cause of death in industrialized countries and also 87

expected to become so in emerging countries by 2020 [3, 4]. Among these, coronary artery disease 88

(CAD) is the most prevalent manifestation and is associated with high mortality and morbidity. ACS 89

has evolved as a useful operational term to refer to any constellation of clinical symptoms that are 90

compatible with acute myocardial ischemia. It encompasses (STEMI), NSTEMI, and UA. 91

ACS represents a life-threatening manifestation of atherosclerosis. It is usually precipitated by acute 92

thrombosis induced by a ruptured or eroded atherosclerotic coronary plaque, with or without 93

concomitant vasoconstriction, causing a sudden and critical reduction in blood flow. In the complex 94

process of plaque disruption, inflammation was revealed as a key pathophysiological element. Non-95

atherosclerotic aetiologies are rare e.g. such as arteritis and dissection. 96

The leading symptom of ACS is typically chest pain. Patients with acute chest pain and persistent (>20 97

min) ST-segment elevation have ST-elevation ACS (STE-ACS) that generally reflect an acute total 98

coronary occlusion. Patients with acute chest pain but without persistent ST-segment elevation have 99

rather persistent or transient ST-segment depression or T-wave inversion, flat T waves, pseudo-100

normalization of T waves, or no ECG changes. At presentation, based on the measurement of 101

troponins, it is possible to further discriminate between the working diagnosis of non-ST-elevation ACS 102

(NSTE-ACS) and unstable angina. 103

NSTE-ACS is more frequent than STE-ACS [5] with an annual incidence around 3 per 1000 inhabitants, 104

but varying between countries [6]. Hospital mortality is higher in patients with STEMI than among 105

those with NSTEMI (7% vs. 3–5%, respectively), but at 6 months the mortality rates are very similar 106

in both conditions (12% and 13%, respectively) [5,7,8]. Long term follow-up shows that death rates 107

were higher among patients with NSTE-ACS than with STE-ACS, with a two-fold difference at 4 years 108

[8]. This difference in mid- and long-term evolution may be due to different patient profiles, since 109

NSTE-ACS patients tend to be older with more co-morbidities, especially diabetes and renal failure.

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Guideline on clinical investigation of new medicinal products for the treatment of acute coronary syndrome (CPMP/EWP/570/98) EMA/CHMP/207892/2015 Page 5/17 2. Scope 111

The aim of this guideline is to provide guidance when performing trials to develop medicinal products 112

in the management of ACS. The primary goals of therapy for patients with ACS are to: 113

1. Treat acute, life-threatening complications of ACS, such as serious arrhythmias, pulmonary 114

oedema, cardiogenic shock and mechanical complications of acute myocardial infarction (AMI). [9] 115

2. Reduce the amount of myocardial necrosis that occurs in patients with AMI, thus preserving 116

left ventricular (LV) function, preventing heart failure (HF), and limiting other cardiovascular 117

complications. 118

3. Prevent major adverse cardiac events like death, non-fatal myocardial infarction (MI), and 119

need for urgent revascularization. 120

The focus in this Guideline concerns mainly the medical treatment of ACS (treatment goals 2 and 3). 121

The choice of interventional procedures [percutaneous coronary intervention (PCI) or coronary artery 122

bypass graft CABG)] falls outside the scope of this guideline. 123

3. Legal basis and relevant guidelines 124

This guideline has to be read in conjunction with the introduction and general principles and parts I 125

and II of the Annex I to Directive 2001/83 as amended. 126

Pertinent elements outlined in current and future EU and ICH guidelines, should also be taken into 127

account, especially those listed below: 128

? Dose-Response Information to Support Drug Registration (ICH E4; CPMP/ICH/378/95). 129

? Statistical Principles for Clinical Trials (ICH E9; CPMP/ICH/363/96). 130

? Choice of Control Group and Related Issues in Clinical Trials (ICH E10; CPMP/ICH/364/96). 131

? Points to consider on an Application with 1) Meta-analyses 2) One pivotal study 132

(CPMP/EWP/2330/99). 133

? Points to consider on multiplicity issues in clinical trials (CPMP/EWP/908/99). 134

? Investigation of subgroups in confirmatory clinical trials (EMA/CHMP/539146/2013). 135

? The Extent of Population Exposure to Assess Clinical Safety for Drugs (ICH E1A; 136

CPMP/ICH/375/95). 137

? Pharmacokinetic Studies in Man (3CC3A). 138

? Studies in Support of Special Populations: Geriatrics (ICH E7 CHMP/ICH/379/95) and related Q&A 139

document (EMA/CHMP/ICH/604661/2009). 140

? Note for Guidance on the Investigation of Drug Interactions (CPMP/EWP/560/95). 141

? Reporting the Results of Population Pharmacokinetic Analyses (CHMP/EWP/185990/06). 142

? Reflection paper on the extrapolation of results from clinical studies conducted outside the EU to 143

the EU-population (EMEA/CHMP/EWP/692702/2008). 144

? Draft Guideline on clinical investigation of medicinal products for the treatment of chronic heart 145

failure (EMA/392958/2015 )

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(CPMP/EWP/2986/03 Rev. 1) 148

4. Choice of efficacy criteria (endpoints) 149

Definitions of clinical endpoints in confirmatory trials should be in line with the relevant clinical 150

guidelines to facilitate interpretation of the results, to allow comparisons across clinical studies and to 151

extrapolate to clinical practice. Endpoints should be centrally adjudicated by a blinded committee. The 152

following endpoints are relevant to the investigation of efficacy in patients with ACS. 153

4.1. All-cause mortality and CV mortality 154

As one of the goals of treatment of ACS is reduction of mortality, this is an important endpoint to 155

measure. There is an ongoing debate around the use of all-cause versus cardiovascular mortality in 156

cardiovascular (CV) trials. All cause mortality is the most important endpoint in clinical trials for the 157

estimation of the benefit-risk balance of a drug, in particular when investigating newer medicinal 158

products with possible safety issues. On the other hand, CV mortality is more specifically linked to the 159

mode of action of CV medicinal products/intervention and is especially relevant when the earliest part 160

of the follow up is assessed. The choice is also dependent on the objective of the study i.e. in non-161

inferiority trials, CVmortality may be preferred while in superiority trials all cause mortality is usually 162

used. In fibrinolysis studies, all cause mortality is preferred (see section 4.9). 163

As such, one of the two mortality endpoints should be included as a component of the primary 164

endpoint, with the other investigated as a key secondary endpoint. 165

4.2. New myocardial infarction 166

New onset MIis a relevant endpoint in studies of ACS and should always be investigated. The definition 167

of MI has evolved through the years; at the time of drafting of this Guideline, the third universal 168

definition of MI is applicable [10]. Criteria of MI are the same as those used to define the index event 169

(see below). 170

4.3. Revascularisation 171

Some clinical trials have included revascularization endpoints (PCI or CABG) as part of the primary 172

composite with conflicting results [11, 12]. Such endpoints are considered more relevant to 173

interventional studies, and in the scope of this Guideline, their inclusion as a primary endpoint should 174

be clearly justified and their assessment pre-defined and systematically assessed. 175

4.4. Unstable angina pectoris necessitating hospitalisation 176

Unstable angina has been investigated in ACS clinical trials. Due to the varying definitions used, the 177

associated subjectivity and the influence of local clinical practice, this endpoint is not encouraged to be 178

included in the composite primary endpoint. 179

4.5. Stent thrombosis 180

Stent thrombosis (ST) is a rare event that can have fatal consequences. ST has been captured in some 181

registration studies, but not consistently in the primary endpoint (PEP). The investigation of ST as part 182

of the primary endpoint is not encouraged due to the uncertainty of the clinical relevance of all 183

captured events, except for the "definite" subcategory. Another category identified by the timing is

184

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or non-occlusive new thrombus in or adjacent to a recently implanted stent before the PCI procedure is 186

completed. Some recent studies [13,14] show that these events may be of prognostic value. As such 187

they should also be collected and presented as secondary endpoint but not included in the analysis of 188

ST. 189

4.6. Stroke 190

Stroke should be defined by a generally accepted definition [15]. Clinical studies in ACS have used 191

non-fatal stroke in the primary endpoint , including any types of strokes. However it is preferred to 192

include only ischemic strokes in the primary endpoint, as this is the true measure of efficacy; 193

haemorrhagic stroke should be included as a safety endpoint. An ischaemic stroke with haemorrhagic 194

conversion should be considered as “primary ischaemic”. The subgroup of “undefined strokes” should 195

be as small as possible in order to be able to properly assess the effect of the study treatment. In case 196

all types of strokes are included in the primary endpoint, a sensitivity analysis including only ischemic 197

stroke should be submitted. 198

4.7. Left ventricular function and heart failure 199

Some medicinal products such as modulators of reperfusion injury or inflammation, or gene/cell 200

therapy are developed to improve myocardial function and reduce the occurrence of HF. In these 201

cases, measurement of myocardial function could be a relevant endpoint to investigate the mechanism 202

of action. In phase III studies, these endpoints can be investigated as secondary endpoints to support 203

the clinical endpoints. Occurrence of HF should be considered as a clinical endpoint in phase III studies 204

aimed at showing benefit in long-term cardiovascular outcome. All-cause mortality and long term 205

follow-up are mandatory in studies with novel interventions. 206

4.8. Composite endpoints 207

Due to the rather low incidence of cardiovascular events during the follow-up period after the acute 208

phase of the ACS, composite endpoints consisting of relevant components are acceptable, both as 209

primary and secondary endpoints. The composite of CV death, non-fatal MI and non-fatal stroke (Major 210

Adverse Cardiovascular Events, [MACE]) has commonly been used in registration studies, with non-211

fatal strokes showing limited contribution to the results. As such, it is preferred to investigate the 212

composite of death and non-fatal MI in confirmatory studies; non-fatal ischaemic stroke could be 213

included in the composite if justified. Sometimes different definitions of MACE are being used with 214

novel therapies [16], that should be justified when used in place of MACE. The inclusion of less 215

objective and clinically derived outcomes in the same composite is generally not encouraged, as they 216

may either drive the efficacy or dilute the results. In case these endpoints are included they have to be 217

stringently defined, and adjudicated. Each component of the primary composite endpoint should be 218

analysed as secondary endpoint. 219

The net clinical benefit that includes both benefit and safety issues of the studied drug may be used as 220

a secondary endpoint to be evaluated if it contributes to the discussion on the benefit-risk balance of 221

the studied drug. 222

4.9. Endpoints in fibrinolysis studies 223

In fibrinolysis studies, angiographic studies using the TIMI (Thrombolysisi in Myocardial Infarction) 224

perfusion grades as evaluation criteria are often used. However, complete recanalization cannot be 225

considered as a surrogate for survival when assessing fibrinolytic drugs, as some medicinal products

226

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benefit. For this reason, all cause mortality is the most relevant endpoint or a combined endpoint as 228

previously discussed (see 4.1). Secondary endpoints such as heart failure hospitalisations, left 229

ventricular function, ventricular arrhythmias, the need for rescue recanalization (emergent and/or 230

planned) should also be considered and justified. 231

5. Methods to assess efficacy (how to measure the 232

endpoints) 233

5.1. Mortality 234

Definition of CV death should be clearly defined, in line with acceptable standards [17]. It is mandatory 235

to report and centrally adjudicate all mortality data where survival is an endpoint of the study. 236

Assessment of cardiovascular mortality will require censoring of other “types” of mortality, which may 237

complicate its interpretation, in particular when non-CV deaths are in high proportion. 238

5.2. New myocardial infarction 239

The diagnostic of MI is based on the detection of a rise and/or fall of cardiac biomarker values 240

[preferably cardiac troponin (cTn)] with at least one value above the 99th percentile upper reference 241

limit (URL). All MIs should be collected and also classified by their different sub types (i.e, 242

spontaneous, secondary to an ischemic imbalance, related to PCI, related to ST or CABG) [10]. This is 243

particularly important considering the different prognostic values of each type of MI. For the same 244

reason and to support the clinical relevance of post procedural MIs, these events should be presented 245

with higher cut-off values (≥ 5 and ≥10x upper level of normal ULN, in case of CK -MB or ≥70x ULN of 246

cTn) [18]. These higher cut-off values can also help in diagnosing MIs in the setting of elevated 247

baseline biomarkers, which is a problematic situation. In such cases, serial measurements of the 248

biomarkers are necessary, in addition to new ECG changes or signs of worsening of cardiac function, 249

e.g. HFor hypotension [18]. 250

5.3. Revascularisation 251

The underlying cause of revascularization should be identified: restenosis, ST or disease progression. 252

In the latter case target vessel revascularization (TVR) could be included. Early target lesion events 253

after revascularization (before 30 days) are more likely to be caused by an angiographic complication 254

and should preferably be included as safety endpoint (see ST). 255

5.4. Unstable angina pectoris necessitating hospitalisation 256

When investigated, robust definitions should be employed. In order to support the seriousness of the 257

event it should also be shown that it has led to a revascularisation procedure. Since a medicinal 258

product that prevents death and/or new MI might result in more patients suffering from UA, the 259

analysis of this endpoint should take into account censoring issues as well. 260

5.5. Stent thrombosis 261

ST should be collected and classified as definite, probable and possible in line with acceptable 262

definitions [19]. In addition, the timing of ST should be documented (acute, sub-acute, late and very 263

late), as risk factors and clinical sequels differ with timing.

264

Guideline on clinical investigation of new medicinal products for the treatment of acute coronary syndrome (CPMP/EWP/570/98) EMA/CHMP/207892/2015 Page 9/17 5.6. Ventricular function and heart failure 265

Investigation of cardiac function should follow state of the art methods. This can include among others 266

measurement of ventricular function by isotopic method and/or by cardiac magnetic resonance imaging 267

and/or echocardiography. Investigation of HFshould follow the relevant CHMP guidelines. 268

5.7. Angiographic endpoints 269

Angiograms should undergo central blinded reading. In principle, the rate of TIMI 3 flow (complete 270

revascularization) of the infarct related artery at 90 minutes is considered the most relevant 271

angiographic endpoint, as it has been shown to correlate with an improved outcome in terms of 272

mortality and left ventricular function. An earlier evaluation of the patency pattern (i.e. 30 and 60 273

minutes) may provide important information on the speed of recanalization. Whatever is the time-point 274

selected as primary outcome, it must be properly justified and pre-specified in the clinical trial. 275

6. Selection of patients 276

6.1. Study population 277

The definition of the different ACS subtypes should be based on current guidelines/universal definition 278

of MI including STEMI and NSTEMI as well as UA [3, 4, 10]. 279

6.1.1. STE-ACS (ST elevation acute coronary syndrome) 280

In patients with acute chest pain and persistent (>20 min) ST-segment elevation on ECG the 281

diagnostic of STE-ACS is made [3]. This condition generally reflects an acute total coronary occlusion. 282

Most patients will ultimately develop an ST-elevation myocardial infarction (STEMI) with the criteria of 283

acute myocardial infarction described before [see 5.2]. 284

6.1.2. NSTE-ACS (Non-ST elevation acute coronary syndrome) 285

In patients with acute chest pain but no persistent ST-segment elevation the diagnostic of NSTE-ACS is 286

made [4]. ECG changes may include transient ST-segment elevation, persistent or transient ST-287

segment depression, T-wave inversion, flat T waves or pseudo-normalization of T waves or the ECG 288

may be normal. The clinical spectrum of non-ST-elevation ACS (NSTE-ACS) may range from patients 289

free of symptoms at presentation to inpiduals with ongoing ischaemia, electrical or haemodynamic 290

instability or cardiac arrest. The pathological correlate at the myocardial level is cardiomyocyte 291

necrosis (NSTEMI) or, less frequently, myocardial ischaemia without cell loss (UA). Currently, cardiac 292

troponins play a central role in establishing a diagnosis and stratifying risk, and make it possible to 293

distinguish between NSTEMI and UA[4]. 294

6.1.3. Unstable angina 295

Unstable angina (UA) is defined as myocardial ischemia at rest or minimal exertion in the absence of 296

cardiomyocytes necrosis, i.e. without troponin elevation. Among NSTE-ACS population, the higher 297

sensitivity of troponin has resulted in an increase in the detection of MI [4]; the diagnosis of UAis less 298

frequently made.

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Inclusion of both STEMI and NSTEMI and/or NSTE-ACS patients in the same clinical trial (or not) 301

should be justified based on the mechanism of action of the investigated product and the proposed 302

time of intervention. If both subgroups are investigated in the same trial, both subgroups should be 303

well represented. For interventions aimed at post-acute and longer term phases (secondary 304

prevention or plaque stabilisation) it may be justified to address both conditions in the same clinical 305

trial. Time of inclusion of the patients in relation to the index event should be set and adequately 306

discussed a priori . 307

Patients with unstable angina represent a different risk category and prognosis that necessitates 308

different interventions than NSTEMI patients. However, during the acute presentation of NSTE-ACS it 309

may be difficult to discriminate NSTEMI from UA so both groups have been included in some clinical 310

studies. In general, the investigation of interventions in these patients is encouraged, but preferably in 311

separate clinical trials. 312

If fibrinolysis is considered, inclusion criteria should be in line with the current treatment guidelines 313

concerning the inclusion for fibrinolysis [3]. 314

6.3. Exclusion criteria for the therapeutic studies 315

If the patients do not fulfil the above criteria for ACS they should be excluded from the ACS studies. 316

Other life-threatening conditions presenting with chest pain, such as dissecting aneurysm, 317

myopericarditis or pulmonary embolism may also result in elevated troponins and should always be 318

considered as differential diagnoses [4]. 319

If drugs interfering with the haemostatic system are tested, patients with a significant risk of bleeding 320

(e.g. recent stroke, recent bleeding, major trauma or surgical intervention) and/or a propensity to 321

bleed (e.g. thrombocytopenia, clotting disturbances, intracranial vascular diseases, peptic ulcers, 322

haemophilia) should be excluded from participation in the clinical studies. 323

Attention should be paid to the time elapsed between a previous application of antiplatelet or 324

anticoagulant acting agent beforehand and the administration of study drug (e.g. the pharmacokinetic 325

[PK] and even more importantly, the pharmacodynamic [PD] half-life of these previously administered 326

drugs). 327

For reasons of generalisability of the study results to the future target population it is strongly advised 328

not to define the exclusion criteria too narrow, i.e. polymorbid patients (e.g. renal and/or hepatic 329

impairment, heart failure), should not automatically be excluded from the main therapeutic clinical 330

trials. 331

When fibrinolysis is considered, exclusion criteria for fibrinolysis should be strictly respected [3]. 332

6.4. Risk Stratification 333

In clinical trials, the ability of the therapy to demonstrate a treatment effect may depend on the 334

underlying risk and expected event rates. Enrichment strategies are sometimes used in trials to obtain 335

the required number of events with a reasonable time in specific subgroups who are likely to exhibit a 336

higher event rate than the overall target population and potentially larger treatment effect. In that 337

case, it has to be shown that the results of this enriched study population can be extrapolated to the 338

general population.

339

Guideline on clinical investigation of new medicinal products for the treatment of acute coronary syndrome (CPMP/EWP/570/98) EMA/CHMP/207892/2015 Page 11/17 In addition to traditional risk factors, phase III studies may recruit a broader patient population in 340

whom risk scores are evaluated to identify signals of differential/consistent treatment (or safety) 341

responses across levels of the risk score. International guidelines recommend the use of risk scores 342

such as the Global Registry of Acute Coronary Events (GRACE) or TIMI in the clinical care of patients 343

with ACS. These scores can be used to predict the risk of major cardiovascular events (MACE), and 344

they are useful to guide treatment decisions. In addition, there are scores to characterise the bleeding 345

risk e.g. CRUSADE in NSTEMI [4]. The use of biomarkers other than troponins for risk stratification 346

necessitates further investigation [e.g. markers of ischemia and inflammation (ischemia-modified 347

albumin, heart fatty acid binding protein)](20). From a regulatory perspective, risk scores should 348

either be reported or adequate data should be provided in the study files to enable risk score 349

calculations. Risk-based analyses can contribute to the interpretation of study results, especially in 350

highly heterogeneous populations, although such analyses may not always be conclusive given the 351

recognized limitations of subgroup analyses. Analysis among different risk setting using risk scores 352

should be pre-defined and foreseen in the protocol. The assessment of subgroups formed by the 353

categories of the risk score may reveal the need for further prospective studies or post-marketing 354

surveillance priorities in specific subgroups. 355

6.5. Special populations 356

6.5.1. Older patients 357

Adequate representation of older patients (above 70 years) in the clinical trials should be ensured. The 358

overall database of the dossier should be examined for the presence of age-related differences, e.g., in 359

adverse event rates, in effectiveness, and in dose-response. If these relatively crude overview analyses 360

show important differences, further evaluation may be needed. 361

Special attention should be given to the frequently associated comorbidities in the ACS population in 362

general and older patients in particular (diabetes mellitus, COPD, renal failure, anaemia), also in 363

relation to the possible drug-drug interactions. 364

7. Strategy and design of clinical trials 365

7.1. Clinical pharmacology 366

The objectives of studies related to clinical pharmacology are the investigation of the PD and 367

PKproperties of the medicinal product in healthy volunteers, uncritically ill patients of both sexes and in 368

patients with different degrees of renal and hepatic impairment as relevant. Furthermore, interactions 369

of the new substance especially with mandatory/probable co-medications which are routinely used in 370

the management of ACS (e.g. platelet inhibitors, anticoagulants as well as other CV medications) 371

should be investigated. Comprehensive advice on interaction studies is provided in the CHMP Note for 372

Guidance on the Investigation of Drug Interactions (CPMP/EWP/560/95). 373

PD studies should include evaluations of mechanism, onset and duration of action, as well as a 374

preliminary investigation of tolerability. The PD activity of the new substance should be defined as 375

much as possible, for example with regard to effects on haemostatic and haemodynamic variables.

376

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7.2.1. Objectives 378

The purpose of this development phase is to identify those patients with ACS who may benefit from the 379

medicinal product and to establish suitable therapeutic dose ranges - usually as adjunctive therapy to 380

existing standard treatment. 381

These early clinical trials often primarily aim at measuring drug activity. However, it is encouraged to 382

investigate clinical endpoints as secondary or exploratory endpoints. As some medicinal products (e.g. 383

parenteral agents) may be intended for limited duration of administration, investigation of transition 384

from and to other oral agents should be conducted. 385

Furthermore, initial information on safety should be obtained and dose schedules should be defined for 386

older patients and those with risk factors. 387

7.2.2. Design 388

Dose ranging studies should be performed using a randomised, controlled, double-blind design. 389

Different dosages should be tested for the projected duration of the treatment period. 390

The duration of these studies is - among other criteria - dependent upon the (primary) target 391

variable(s) and the extent of clinical information they are aiming at. Mostly, it is useful to include a 392

sufficiently long-term follow-up in order to estimate the incidence of significant clinical events and 393

delayed adverse drug reactions (e. g. thrombocytopenia). 394

7.3. Confirmatory Therapeutic Studies 395

7.3.1. Objectives 396

The objectives of these studies are to provide robust evidence of efficacy establishing reduction of 397

clinically relevant cardiovascular events (e.g. death/new MI) at a predefined time justified by the 398

mechanism of action and duration of administration. These studies should also establish the safety of 399

the new substance at the posology proposed for marketing (the dose schedule selected for pivotal 400

studies should be justified on the basis of the results of the dose-finding studies in the target 401

population). Longer follow-up are required when long term treatment are given after ACS, with the 402

goal to decrease cardiovascular recurrences. 403

The majority of the main therapeutic studies will use composite endpoints as primary efficacy 404

variables. Optimally, the different components of the composite will contribute to the positive results. 405

Studies aiming at the proof of efficacy must have a confirmatory statistical approach. These studies 406

must be controlled, randomised and every effort should be made to maintain double blindness. The 407

statistical approach e.g. a demonstration of superiority, equivalence or non-inferiority, has to be pre-408

specified in the protocol. 409

In some cases (e.g. large scale, multicentre, multinational trial) a single confirmatory trial could be 410

sufficient for the proof of efficacy of a new substance if the results are statistically persuading and 411

clinically relevant as discussed in the relevant CHMP guideline (see section 3). 412

7.3.2. Background therapy 413

In general, background therapy should reflect the standard of care as recommended by current clinical 414

guidelines [3,4]. However, actual availability of guideline-recommended treatments could depend on

415

Guideline on clinical investigation of new medicinal products for the treatment of acute coronary syndrome (CPMP/EWP/570/98) EMA/CHMP/207892/2015 Page 13/17 external factors such as time delays in the uptake of new ACS therapies, differences in local clinical 416

practice, local reimbursement policies, and availability of specific therapies. Alternatively, EU Registry 417

data can be helpful to determine the standard of practice and can inform the design of pivotal studies. 418

Background therapy is also relevant in the context of the used revascularisation strategy. The degree 419

to which background therapy should be specifically standardized in terms of interventions, timing, 420

drugs, and dosing will depend on the study drug’s mechanism of action or the specific question being 421

addressed by the randomized controlled trial. This may eventually have to be reflected in the labelling. 422

7.3.3. Choice of comparator 423

Depending on the class of drug tested and its mechanism of action, placebo and/or active controlled 424

trials may be adequate for the late development phases. Whenever plausible and adequate (i.e. 425

different mechanism of action than that of standard therapy) the investigational drug or placebo should 426

be given in addition to standard therapy. The choice of the active comparator can be challenging as it 427

faces the same issues as standardisation of the background therapy i.e. possible disparity between 428

guideline recommendations and regional standards of care. The appropriate comparator should be 429

clinically relevant and correspond to current medical practice with an adequate evidence base. 430

7.3.4. Duration of clinical studies 431

For medicinal products intended for short-term administration (e.g. hours to 7 days), the primary 432

endpoint should preferably be measured at 30 days following initiation of therapy in the confirmatory 433

studies. Depending on the mechanism of action of the investigated drug - shorter time spans when 434

measuring the primary endpoint may be acceptable if the follow-up data prove durability of efficacy. In 435

any case, further measurements should be performed after longer (e.g. 180 days) but also after 436

shorter duration (e.g. at time of termination of study drugs) as secondary measures of efficacy. 437

In case of longer duration of administration, an appropriately chosen duration of follow-up should be 438

pre-specified in the protocol in order to estimate longer-term efficacy and safety. The maintenance of 439

an adequate benefit risk balance should be demonstrated. Long term results should preferably also be 440

adjudicated by a blinded clinical event committee. 441

Claims of chronic administration (following ACS) necessitate support from sufficiently long studies to 442

demonstrate that a positive benefit risk balance is maintained throughout the administration period 443

and according to the pre-defined hypothesis or to the number of events calculated (in case of events 444

driven design). 445

7.3.5. Analyses and subgroup analysis 446

The database for the primary analysis, either investigator or - preferably - event adjudication 447

committee adjudicated endpoints - has to be pre-specified in the protocol. A primary analysis based on 448

the data produced by the event adjudication committee is especially important if side effects of the test 449

drug or the comparator may eventually unblind some of the patients. 450

Regarding the primary analysis, the total event rates at the pre-specified time points or time-to-event 451

within this period can be chosen. However, in any case survival curves over this period - and also over 452

the-follow-up period - should be provided for the combined endpoint and all its components in order to 453

evaluate and whether or not differences occur. 454

The components of a composite efficacy endpoint should be analysed inpidually in order to evaluate 455

their contribution to the overall results. Optimally, the results of all components of the composite 456

endpoint should point in the right direction. In a hierarchical view, the component "all cause mortality"

457

Guideline on clinical investigation of new medicinal products for the treatment of acute coronary syndrome (CPMP/EWP/570/98) EMA/CHMP/207892/2015 Page 14/17 will be considered as being the most relevant (e.g. an over-mortality cannot be compensated by a 458

decreased rate in angina pectoris). 459

At least, randomisation should be stratified for region (if applicable) and the qualifying condition 460

(STEMI, NSTEMI and UA). Other risk factors (gender, age) may be considered for stratification of the 461

randomisation, in addition. Subgroup analyses for these factors should be presented. Subgroup 462

analyses for gender, age, risk score (section 6.4) as well as for revascularisations (e.g. CABG, PCI, 463

fibrinolysis) should be foreseen in the protocol in order to demonstrate consistency of the results. 464

In addition, subgroup analyses regarding patients with different cut-offs of elevated troponin I/T 465

concentration at enrolment, as well as those regarding differences in duration between symptom onset 466

and initiation of study drugs (e.g. < 6 hours, > 6 or 12 hours) are of increasing interest. 467

8. Safety aspects 468

During the course of the clinical trials all adverse events should be carefully documented. For large 469

scale outcome trials, a hierarchy of safety reporting can be considered, the most important being 470

bleeding and all-cause death. Careful consideration should be given to those patients who died - 471

especially while on therapy - or who failed to complete the study per protocol (in particular drop-outs 472

due to adverse events/drug reactions or lack of efficacy). 473

Safety in high-risk groups (e.g. patients with organ dysfunction, older age, extremes of body weight) 474

requires special consideration. Furthermore, any information available concerning clinical features and 475

therapeutic measures in accidental overdose should be provided. 476

Special efforts should be made to investigate potential adverse drug reactions that are characteristic 477

for the class of drug being tested, in particular those listed below. 478

8.1. Bleedings 479

Bleeding is the main complication of antithrombotic and antiplatelet therapy. Similar to the efficacy 480

evaluation, the adjudication of bleeding events by a central independent and blinded committee of 481

experts, using pre-specified limits and clear terms of reference is strongly encouraged. 482

In dose-finding studies, the use of a sensitive safety endpoint to assess bleeding risk, like the sum of 483

major and clinically relevant non-major bleeding, is recommended. 484

In pivotal trials, the recommended primary safety endpoint is major bleeding, but the sum of major 485

and clinically relevant non-major bleeding should be analysed as well (secondary endpoint). 486

The description of the severity (i.e.: life-threatening versus non-life-threatening major bleed), 487

localisation (i.e.: intracranial, gastrointestinal, etc.) and temporal pattern (i.e.: time-to-event analysis) 488

is encouraged. 489

Bleedings should be categorised according to an acknowledged classification. Different bleeding 490

definitions have been used in the setting of ACS; this heterogeneity impairs the interpretation of the 491

safety profile across trials. Consensus has not been reached on a unified classification. TIMI (i.e. TIMI 492

major and minor) and GUSTO (The Global Use of Strategies to Open Occluded Arteries) criteria for 493

example, have been previously used and have been shown to be independently correlated with 494

subsequent risk of death. The Bleeding Academic Research Consortium (BARC) undertook an initiative 495

to standardize reporting, but the proposed bleeding classification needs to be validated [21]. Dual 496

reporting of bleeding events using both the TIMI and BARC definitions could be considered for future

497

Guideline on clinical investigation of new medicinal products for the treatment of acute coronary syndrome (CPMP/EWP/570/98) EMA/CHMP/207892/2015 Page 15/17 clinical trials and/or regulatory submissions to improve the comparative assessment of safety 498

endpoints across medicinal products and trials. 499

In addition, the inclusion of ISTH major bleeding may be helpful to compare major bleeding rates of 500

similar compounds across different indications (e.g., in comparison with stroke prevention in atrial 501

fibrillation and/or treatment of VTE). 502

It is advisable to use the same classification for bleedings throughout the whole clinical development 503

program. A subgroup analysis of bleedings regarding patients undergoing invasive procedures (e. g. 504

PCI, CABG surgery) - or not - is necessary. 505

Transfusions of blood, red blood cells and/or coagulation factors are further indicators of bleeding 506

severity and should thus be documented carefully (number, temporal association to application of 507

study drug and/or procedure). 508

8.2. All-cause mortality 509

All cause mortality is usually part of the efficacy evaluation, but should also be included as part of the 510

safety assessment to inform about mortality throughout the study period. 511

8.3. Thrombocytopenia 512

In particular heparins and platelet aggregation inhibitors are known to cause (acute and delayed) 513

thrombocytopenia that can be severe and the cause of serious bleedings or other complications (e.g. 514

heparin-induced thrombocytopenia in case of heparins). Consequently thrombocyte values have to be 515

monitored closely during and after therapy. In cases with thrombocytopenia, information on degree, 516

recovery time and outcome should be provided. Moreover, it has to be documented in detail (number, 517

temporal association to study drug/procedure etc.) if transfusions of thrombocytes had become 518

necessary. 519

8.4. Rebound effect 520

The studies should include the evaluation of events which are considered to be characteristic for a 521

possible rebound effect (e.g. clear increase in angina pectoris and/or new MIand/or death and/or other 522

thrombotic events) after termination of the study drug. 523

8.5. Effects on laboratory variables 524

The therapeutic clinical studies should include the investigation of effects on the white and red blood 525

cell count and should especially focus on the question whether the observed changes can be explained 526

by former bleeding. In addition, particular attention should be paid to increases in liver enzymes, 527

creatinine concentration and possible antibody formation. 528

8.6. Effects on concomitant diseases 529

The studies should include the evaluation of effects of the new drug on the function of diseased organs 530

(e.g. kidneys in case of renal impairment). 531

532

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