23 June 2016

EMA/CHMP/29947/2013/Rev. 4
(Previous ref. number EMA/238/1995/Rev. 3)
Committee for Medicinal Products for Human Use (CHMP)

Guideline on clinical investigation of medicinal products in

the treatment of hypertension

Draft agreed by Efficacy Working Party 07 April 2009

Adopted by CHMP for release for consultation 22 July 2009

End of consultation (deadline for comments) 22 January 2010

Adopted by CHMP 18 November 2010

Date for coming into effect 18 February 2011

Draft agreed by Cardiovascular Working Party 05 June 2013

Adopted by CHMP for release for consultation 27 June 2013

Start of public consultation 31 July 2013

End of consultation (deadline for comments) 31 January 2014

Draft agreed by Cardiovascular Working Party 11 May 2016

Adopted by CHMP 23 June 2016

Date of coming into effect 1 January 2017

This guideline replaces Guideline on clinical investigation of medicinal products in the treatment of
hypertension EMA/238/1995/Rev. 3

Keywords CHMP, EMEA, drug evaluation, drug approval guideline, hypertension,

clinical evaluation, fixed dose combination, first line therapy,
substitution therapy, efficacy criteria, safety aspects

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Guideline on clinical investigation of medicinal products in
the treatment of hypertension
Table of contents
Executive summary ..................................................................................... 4
1. Introduction (background) ...................................................................... 4
2. Scope....................................................................................................... 4
3. Legal basis and relevant guidelines ......................................................... 4
4. Assessment of efficacy criteria ................................................................ 5
4.1. Blood pressure ..................................................................................................... 5
4.2. Morbidity and mortality ......................................................................................... 5
4.3. Target organ damage ........................................................................................... 5
5. Methods to assess efficacy ...................................................................... 5
5.1. Blood pressure ..................................................................................................... 5
5.1.1. Sphygmomanometry .......................................................................................... 6
5.1.2. Intra-arterial measurements ............................................................................... 6
5.1.3. Non-invasive ambulatory blood pressure monitoring .............................................. 7
5.1.4. Automatic self (home) measurement ................................................................... 7
5.1.5. Measurement of central blood pressure ................................................................ 7
5.2. Target organ damage ........................................................................................... 8
5.3. Morbidity and mortality ......................................................................................... 8
6. Selection of patients ................................................................................ 8
7. Study design............................................................................................ 9
7.1. Pharmacodynamics ............................................................................................... 9
7.2. Pharmacokinetics ................................................................................................. 9
7.3. Interactions ......................................................................................................... 9
7.4. Therapeutic studies .............................................................................................. 9
7.4.1. Therapeutic exploratory studies ........................................................................... 9
7.4.2. Therapeutic confirmatory studies ....................................................................... 10
7.5. Studies in special populations .............................................................................. 10
7.5.1. Elderly ........................................................................................................... 10
8. Safety aspects ....................................................................................... 11
8.1. Specific effects related to mechanism of action ...................................................... 11
8.1.1. Hypotension.................................................................................................... 11
8.1.2. Rebound hypertension...................................................................................... 11
8.1.3. Effects on cardiac rhythm ................................................................................. 11
8.1.4. Pro-ischemic effects ......................................................................................... 11
8.1.5. Effects on target organ damage......................................................................... 11
8.1.6. Effects on concomitant diseases ........................................................................ 12
8.1.7. Effects on concomitant risk factors..................................................................... 12

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8.2. Cardiovascular safety .......................................................................................... 12
9. Fixed combinations (FDCs) .................................................................... 12
10. Addendum ........................................................................................... 17

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 Executive summary
This is the 4th revision of the Guideline on clinical investigation of medicinal products in the treatment
of hypertension. The main aim of the 4th revision was to uniform the section of the Guideline on the
collection of long-term safety data with the other relevant EMA guidelines of the treatment of
cardiovascular or metabolic diseases following finalisation of the Reflection paper on assessment of
cardiovascular safety profile of medicinal products (EMA/CHMP/50549/2015). In addition to some
editorial changes, also a paragraph of measurement of central blood pressure has been added as a
supplemental method to assess efficacy of antihypertensive medication.

1. Introduction (background)
Nonfatal and fatal cardiovascular diseases - including coronary heart disease, stroke and congestive
heart failure - as well as renal disease and all-cause mortality increase progressively with higher levels
of both systolic blood pressure (SBP) and diastolic blood pressure (DBP). At every level of elevated
DBP, risks increase in association with elevation of SBP. Systolic blood pressure is more important
predictor for clinical events than DBP especially after the age of 50 years. The dividing line between
‘normotension’ and ‘hypertension’ is arbitrary and might vary with age. In the otherwise healthy adult
population values below 140/90 mmHg are considered within the normal range and values of 140/90
mmHg and greater in the hypertensive range.

Hypertension may be classified according to

• aetiology: essential or primary hypertension vs. secondary hypertension;
• severity: according to WHO/ISH, JNC 7 or ESC/ESH guidelines;
• type: systolic, diastolic or both;
• effects of treatment.

2. Scope
Guidance is provided on the design of clinical studies considered to be of relevance for the evaluation
of new, non-generic antihypertensive drugs. The main aim of the current revision was to include more
comprehensive guidance on the collection of long-term safety data, in particular cardiovascular safety.

3. Legal basis and relevant guidelines

This guideline should be read in conjunction with the introduction and general principles and Annex I to
Directive 2001/83 as amended and with the following guidelines:

- Dose-Response Information to Support Drug Registration (ICH E4)

- Statistical Principles for Clinical Trials (ICH E9)

- Choice of Control Group in Clinical Trials (ICH E10)

- The Extent of Population Exposure to Assess Clinical Safety for Drugs (ICH E1A)

- Pharmacokinetic Studies in man (3CC3A)

- Note for Guidance on the Investigation of Drug Interactions (CPMP/EWP/560/95/Rev. 1)

- Reporting the Results of Population Pharmacokinetic Analyses (CHMP/EWP/185990/06)

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- Non-clinical Development of Fixed Combinations of Medicinal Products

(EMEA/CHMP/SWP/258498/2005)

- ICH topic E7 Studies in Support of Special Populations: Geriatrics Questions and Answers

(EMA/CHMP/ICH/604661/2009

- Guideline on Missing Data in Confirmatory Clinical Trials“ (EMA/CPMP/EWP/1776/99 2 July 2010, Rev
1)

- Reflection paper on the extrapolation of results from clinical studies conducted outside the EU to the
EU-population (EMEA/CHMP/EWP/692702/2008)

- Reflection paper on assessment of cardiovascular safety profile of medicinal products

(EMA/CHMP/50549/2015)

In addition, all pertinent elements outlined in current and future EU and ICH guidelines and regulations
should also be taken into account.

4. Assessment of efficacy criteria

4.1. Blood pressure

The goal of treating hypertension is to prevent morbidity and mortality associated with high BP.
Reduction in BP has usually been accepted as a valid surrogate endpoint in order to assess whether
this goal can be achieved by an antihypertensive agent.

4.2. Morbidity and mortality

The effects on mortality and cardiovascular morbidity can only be evaluated properly in large-scale and
long-term controlled clinical trials. Until the results are available, it should be specifically mentioned in
the SmPC that the effects on mortality and cardiovascular morbidity are unknown.

4.3. Target organ damage

Although the prognostic relevance of target organ damage of heart, brain, eyes, kidneys and blood
vessels has not yet been fully evaluated in valid clinical studies, target organ damage is presumably
and plausibly associated with morbidity and mortality; this holds particularly true for left ventricular
hypertrophy and proteinuria/microalbuminuria. Trials on outcomes of antihypertensive therapy,
monitoring progression and regression of organ damage may provide relevant information on the
comparative effectiveness of a new antihypertensive agent, but the prognostic value of drug effects
with regard to morbidity and mortality (all cause or CV) remains to be established. Thus, these
endpoints are considered of supportive value. Specific studies are only mandatory when specific claims
are made or when there are suspicions of a detrimental effect.

5. Methods to assess efficacy

5.1. Blood pressure

BP lowering effects of anti-hypertensive therapy should be documented as the pre-/post-treatment

reduction of BP. SBP is the preferred efficacy variable whilst DBP is a mandatory secondary end point.

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Other secondary endpoint effects on response criteria can also be assessed. Arbitrarily, response
criteria for antihypertensive therapy include the percentage of patients with a normalisation of BP
(reduction SBP <140 mmHg and DBP <90 mmHg) and/or reduction of SBP ≥20 mmHg and/or DBP
≥10 mmHg. Results obtained should be discussed in terms of statistical significance and in relation to
their clinical relevance. BP should be measured frequently with emphasis on the maximum and
minimum effects of the drug, i.e. before the next dose is given (peak-trough ratio).

The main endpoint should be BP at trough which is defined as the residual effect at the end of the dose
interval. The peak effect is the maximum BP reduction (at steady state) identified in each patient
compared to baseline following repeated BP measurements across a dose interval. All measurements
should be performed under standardised conditions and with the patient in the office, in the same
position at the same time of day when repeated measures are performed and ambient room
temperature should be as similar as possible. Assessment of trough-peak ratio has to take into account
methodological issues and a minimum effect should be pre-specified (e.g. 50% reduction in pre-dose
BP) for the recommended dose range. The following methods are available:

5.1.1. Sphygmomanometry

Measurements with a calibrated sphygmomanometer are the standard method to determine BP in the
setting of pivotal trials. If not available, another device may be used which is calibrated carefully in
proportion to a mercury sphygmomanometer. Use of aneroid manometer is not recommended.
Appropriate cuff size must be used to ensure accurate measurement. Both SBP and DBP should be
recorded. The disappearance of sound (Korotkov phase V) should be used for the diastolic reading.
Two or more readings separated by 2 minutes should be averaged. If the first two readings of SBP
differ by more than 5 mmHg, additional readings should be obtained until stabilisation has occurred
with difference between these two readings within this limit. BP should be checked simultaneously in
both arms, at least once. BP should be recorded in the arm with the higher pressure; if differences
between arms greater than 20 mmHg for SBP and 10 mmHg for DBP are present on 3 consecutive
readings, the patient should be excluded from participating the study and the reason for the observed
difference should be examined further. BP should be measured in either supine or sitting position or
both. No shift from one position to another should be made during the study. Supine or sitting posture
should be adopted for at least 5 minutes before measurement, and when standing BP is measured, the
subject should be standing for at least 1 minute before measurement. Additional measurements of
standing BP are of value for evaluating postural changes in subjects with high risk for postural
hypotension (reduction in SBP of >20 mmHg or in DBP of >10 mmHg within 3 minutes of standing). BP
should be measured under standardised conditions, as nearly as possible at the same time each day,
on the same arm, by the same personnel, with the same apparatus. BP measurement during exercise
may provide supportive evidence for efficacy.

5.1.2. Intra-arterial measurements

Intra-arterial measurement of BP has been used in phase II studies to investigate the relation between
dose, magnitude and duration of effect, to assess changes during exercise and to measure 24-hour
efficacy. However, the method is complicated and the interpretation of the results is difficult since its
prognostic value is not fully evaluated. Thus, intra-arterial measurement of BP can be regarded as a
valuable method in initial therapeutic studies. It is not considered to be widely applicable in the setting
of clinical pivotal studies.

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5.1.3. Non-invasive ambulatory blood pressure monitoring

As ambulatory blood pressure monitoring (ABPM) provides a better insight to blood pressure changes
during everyday activities, ABPM is strongly recommended for the evaluation of new antihypertensive
agents. According to the observational data ABP correlates more closely with end-organ damage and
cardiovascular events compared to office BP. However, the clinical trial data on the effects of treatment
strategies based solely on out-of-office BP measurements is still scarce. Therefore the measurement of
ABPM is not currently accepted as the sole basis for efficacy in an approval process.

The recorders used must fulfil international acknowledged validation procedures (e.g. AAM-IBHS).
Repetitive investigations should be performed on a comparable (work-) day using the same equipment
every time throughout the study.

Readings should be done with sufficient frequency. Time intervals should be short enough to get
meaningful and reliable results at day and during night-time. The measurement intervals should be
justified in the protocol. It is important that certain issues such as circadian variation, drop in night
time pressure and time for highest vs. lowest pressure are assessable.

A certain minimum of readings/24 hours have to be evaluable. The number of evaluable readings must
be sufficient to enable a proper assessment. It is suggested that in day-time 2 readings and during
night-time 1 reading hourly may provide an appropriate database. Other approaches, if properly
justified and validated, may be accepted. Readings should cover time before drug intake. At least 8
measurements should be included between 18 and 24 hours after drug intake. Analysis of the results
could be performed in several ways, but it is recommended that mean values (± SD) for the periods of
being awake and asleep should be analysed separately. Special analysis could be performed to assess
trough-to-peak ratio, early morning rise, drop in night-time pressure etc.

5.1.4. Automatic self (home) measurement

Self (home) measurement of BP with the help of automatic devices has been advocated as an
alternative approach to better characterise a patient's BP level and to estimate the effect of
antihypertensive treatment, also in case of treatment cessation. However, as stated for ABPM, there
are insufficient data to accept self (home) measurement of BP as the sole basis for the evaluation of
efficacy in clinical studies.

Validation of the device used is necessary. The information of the validated devices and of the
validation protocols can be obtained from the dedicated websites (e.g. British Hypertension Society,
dabl Educational trust).

5.1.5. Measurement of central blood pressure

The measurement of central blood pressure and augmentation index (defined as the difference
between the second and and first systolic peaks, expressed as percentage of the pulse pressure,
preferably adjusted for heart rate) by non-invasive methods has recently raised increased interest in
the treatment of hypertensive patients. According to the cumulative data, especially augmentation
index may act as an independent (beyond brachial BP) predictor of future cardiovascular events.
However, as stated in the current hypertension guidelines, more clinical trial data of the effects of
modification of these variables on clinical endpoints is needed to establish their use in routine clinical
use. Therefore, the data based only on these measurements can currently not be accepted as a sole
basis for evaluation of efficacy in clinical studies.

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5.2. Target organ damage

Compared to ECG and chest radiography, echocardiography combines a higher sensitivity for left
ventricular hypertrophy (LVH) with a more precise assessment of the degree of LVH (i.e. as a
continuous variable reflected by magnitude of LV mass). Tissue Doppler myocardial imaging and echo
tracking events can be used to study left ventricular (LV) diastolic function and arterial compliance.
Changes in renal function can be assessed in terms of serum creatinine concentrations, 24-hour
creatinine clearance and urinary protein excretion. Renal function could also be assessed by estimated
glomerular filtration rate (eGFR) calculated by means of properly evaluated equations. The most
objective method to assess renal blood flow and/or glomerular filtration rate is by using radio-isotopes,
but this method is limited, among other reasons, by exposure to radioactivity. Clearance of para
aminohippurate (PAH clearance) and inulin can be used as alternatives. Fundoscopy can provide
evidence about retinal arteries, retina, and papilla. Ultrasound of the large vessels and/or angiography
can provide evidence of arteriosclerotic plaques or increased vascular mass or increased intimal-medial
thickness. Measurements of pulse wave velocity and ankle-brachial index are also useful tools in
detecting aortic stiffness and peripheral artery disease, respectively.

5.3. Morbidity and mortality

The evaluation of cardiovascular morbidity should especially take into account sequelae of severe
organ damage (e.g. myocardial infarction, heart failure, stroke, renal insufficiency).

The inclusion of other events, such as transient ischemic attack, silent MI, unstable angina pectoris or
therapeutic interventions (need for PCI) is used in some trials to increase statistical efficiency. The
inclusion of such softer endpoints, which are less objectively defined can complicate interpretation of
the results, and is accordingly not encouraged. If included, clinically relevant justifications should be
provided. The use of standard definitions as proposed in the appropriate clinical guidelines or
regulatory guidance documents are encouraged.

When planning an all-cause mortality study, further distinction should be made with regard to
cardiovascular mortality and sudden death. Blinded, centralised, adjudication regarding causes of
death and morbidity will be necessary.

6. Selection of patients
Generally, the study population will depend on aetiology and the type of hypertension for which the
drug is intended. Studies for the evaluation of efficacy or safety of a new antihypertensive drug are
mainly performed in patients with primary or essential hypertension of mild to moderate severity with
elevated SBP and/or DBP. In general, it is of utmost importance that the study population reflects the
intended clinical practice. Patients of both genders should be included in studies in a balanced way.
Patients with more severe stages of hypertension also need to be evaluated in studies. Attention
should be placed on ethnic peculiarities, concomitant illnesses (e.g. diabetes mellitus, renal disease).
Salt intake and other non-pharmacological measures possibly impacting BP levels should be identified,
recorded and (ideally) kept constant during the trial duration for all trials.

Patients with disorders causing secondary hypertension (e.g. phaeochromocytoma, adrenal adenoma,
renal artery stenosis) and isolated systolic hypertension should be studied separately, if such an
indication is specifically claimed. This also refers to the treatment of hypertension in pregnancy which
should also take into account the obstetrical and paediatric aspects of the problem.

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 7. Study design
Studies involving the first administration of medicinal products for hypertension to man do not differ
essentially from those dealing with other cardioactive medicinal products. Patients currently receiving
antihypertensive therapy who are to be included should be withdrawn from current existing treatment
during a wash-out. The time needed for wash-out will depend on the half-life of the agent(s) used and
time taken for the BP to return to pre-treatment levels. This will be variable but may take weeks to
months. Patients with markedly elevated BP readings may require a continuous underlying
antihypertensive drug therapy, thus making an add-on design appropriate.

Allocation of an individual patient to a study drug should only be performed if the baseline BP is stable.
Initial elevated readings should be confirmed on at least two subsequent visits during one to several
weeks. A run-in period of at least 2, sometimes as long as 4 weeks is essential before commencing a
clinical trial of a new antihypertensive agent. A prolonged run-in period may be necessary to avoid bias
due to the regression-toward-the-mean phenomenon.

7.1. Pharmacodynamics

These pharmacodynamics (PD) studies should include evaluations of tolerability, duration of action,
haemodynamic parameters (e.g. stroke volume, pulmonary capillary wedge pressure, systemic
vascular resistance), heart rate (e.g. assessed via Holter monitoring), neurohumoral parameters (e.g.
RAA-system, sympathetic nervous system) and renal function. Further studies - depending on the
mechanism of action of the drug - may include evaluations of orthostatic reactions, (intra)cardiac
contractility, impulse formation and conduction, especially repolarisation (i.e. QT/QTc intervals),
diastolic LV function, myocardial oxygen consumption, and coronary and regional blood flow. Which
tests ought to be performed depend on the drug and its characteristics and the chosen tests should be
justified by the Applicant.

7.2. Pharmacokinetics

Special pharmacokinetic (PK) studies should be performed in the elderly and, depending on the route
of elimination, in patients with varying degrees of renal dysfunction and/or hepatic dysfunction.

7.3. Interactions

Interaction studies can provide information which may help to define the position of the new drug in
the therapeutic schemes (i.e. treatment algorithms) used in antihypertensive patients. Special
attention should be devoted to potentially useful or unwanted interactions with other drugs which
might be used alongside the investigational drug for combined treatment of hypertension. These will be
other antihypertensive agents of each of the major classes, but also other drugs which are likely to be
used especially in the elderly patients. Special formal PK and PD interaction studies should be
performed if results of clinical trials or the PK and PD properties of the drug give reason to
assume/suspect specific interactions. ).

7.4. Therapeutic studies

7.4.1. Therapeutic exploratory studies

Dose-response studies should be randomised, placebo-controlled and double-blinded using at least 3

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dosages to establish the clinically useful dose-range as well as the optimal dose. The dose schedule
selected for pivotal studies must be justified on the basis of the results of the dose-finding studies in
the target population. The results of the dose-response studies of a new antihypertensive agent should
provide robust evidence of its efficacy as compared to placebo for each recommended dose. It is also
essential to demonstrate the added contribution of each dose chosen.

The dose-response studies should preferably be designed as parallel group studies. Following a run-in
period of 2, preferably 4 weeks, the comparative studies with reference agents should be double-blind
and randomised. The dose should be increased according to the dosing rules expressed in the protocol,
and at each dose level the duration of treatment should be long enough to estimate the effect of the
respective dose. The parallel group design using fixed doses should be applied in some studies, instead
of escalating doses. The investigational drug may either be given as mono-therapy or combined with
underlying therapy.

7.4.2. Therapeutic confirmatory studies

Controlled trials with reference therapy should be performed aiming at demonstration of (at least) a
similar benefit/risk of the drug under investigation in comparison to an acknowledged standard
antihypertensive agent of the same and of other therapeutic classes. Placebo-controlled withdrawal
phases can be introduced at the end of the study. A combination study with at least one other
standard antihypertensive agent is mandatory.

Special attention should be paid to reduction of the antihypertensive effect by time (tachyphylaxis).

Careful consideration should be given to the results in those patients who fail to complete the study
per protocol (e.g. drop-outs due to adverse events or lack of efficacy).

Drug therapy in the main dose-response studies should last at least 3, preferably 6 months in order to
demonstrate efficacy in terms of the antihypertensive effect and each tested dose should be
maintained over at least 4 weeks when more than one dose is used. Controlled studies with reference
agents should last even longer up to 6 months, in order to allow a comparison with respect to adverse
drug reactions as well.

7.5. Studies in special populations

The efficacy studies should include patients reflecting the target population. Generally these will mainly
include patients with mild to moderate essential hypertension, but a certain proportion of patients with
(very) severe hypertension should be enrolled as appropriate. The sample size depends, among others,
on the target variable and its variance. Subgroup analyses for gender, race, age, etc. are desirable in
order to demonstrate consistency across groups. However, these are unlikely to lead to indications in
specific subgroups when no effect is demonstrated overall. Dose schedules should be clearly defined
for elderly patients and those with various risk factors.

7.5.1. Elderly

There is a special need for data in elderly patients. Target BP targets might differ with age, particularly
for age over 80. A reasonable number of elderly patients (>65 years, >75 and > 85 years, respectively)
should be included in the therapeutic confirmatory studies. The number of subjects 75 years and older
included in (pivotal) trials should be sufficient to assess both efficacy and safety in this group.

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 8. Safety aspects
Efforts should be made to comprehensively assess any potential adverse reactions that are
characteristic of the class of drug being investigated.

All adverse events occurring during the course of clinical trials should be fully documented with
separate analysis of adverse drug events/reactions, dropouts, deaths while on therapy and clinical
laboratory results.

In the clinical studies, an overall plan for the detection and evaluation of potential adverse events,
including justification of the size and duration of the studies with respect to the possibility of detecting
safety signals, should be prospectively designed early during the clinical development, optimally by the
time of phase II studies. This program should take into consideration key elements of the safety
pharmacology, as well as key toxicological findings from non-clinical studies.

Indications of increased risk of certain adverse events are an important concern and may trigger the
request for an additional dedicated long-term safety study before or after licensing.

8.1. Specific effects related to mechanism of action

Special efforts should be made to capture potential adverse events that are characteristic of the
mechanism of action and the PD properties of the class of products being investigated. This may
include the following effects:

8.1.1. Hypotension

This may be either symptomatic or asymptomatic. Special attention should be paid to orthostasis in
conjunction with the risk to falls and first-dose phenomenon, especially at initiation of therapy or at
increase of dosage.

8.1.2. Rebound hypertension

Withdrawal phenomena, especially rebound hypertension, should be studied specifically.

8.1.3. Effects on cardiac rhythm

This includes specifically (tachycardiac) pro-arrhythmic effects and effects on impulse conduction.
Depending on the particular pharmacodynamic properties of the drug, heart rate, ECG and Holter
monitoring should be performed at frequent intervals throughout the study.

8.1.4. Pro-ischemic effects

Coronary steal effects due to coronary vasodilation, together with potential hypotensive effects, may
lead to angina pectoris and myocardial infarction. When suspected, this needs to be studied specifically.

8.1.5. Effects on target organ damage

Data on blood chemistry, urine analysis and other general laboratory investigations should be
submitted. Effects of alterations in regional blood flow in other organ systems, especially the kidney,
heart and brain can be studied. Special emphasis should be placed on renal function, electrolyte
homeostasis, and LVH. Depending on suspicion of ophthalmological side effects, ophthalmological

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examination should be performed throughout the study. Special emphasis should be placed on
cognitive functions and central nervous system (CNS)-effects (dizziness, blurred vision, syncope and
TIA), especially in the elderly.

8.1.6. Effects on concomitant diseases

Concomitant diseases (or co-morbid conditions) of specific interest include diabetes mellitus, liver
impairment, ischemic heart disease, heart failure, cerebrovascular diseases and, more rarely,
peripheral arterial occlusive disease. When specific claims are made, studies on hypertensive patients
with concomitant diseases are required. From a safety perspective, it is expected that the new agent
does not have significant adverse events or deleterious effects on other pathologies.

8.1.7. Effects on concomitant risk factors

As concomitant risk factors are often present at the same time, effects on glucose and lipid metabolism
should be evaluated with special attention.

8.2. Cardiovascular safety

It is expected that the drug development programme, containing all relevant clinical and non-clinical
data, adequately characterizes the cardiovascular safety profile enabling an evaluation of the
cardiovascular safety in the marketing authorisation application (MAA). This refers in particular to
products with a new mechanism of action or products belonging to a drug class for which the
cardiovascular safety profile is not yet established or questioned, e.g. in case of a detrimental effect on
another cardiovascular risk factor.

Requirements for the evaluation and quantification of the cardiovascular risk at the time of licensing
are further outlined in the CHMP’s “Reflection paper on assessment of cardiovascular safety profile of
medicinal products”.

9. Fixed combinations (FDCs)

9.1 General remarks
Combination therapy in hypertension is commonly applied to improve efficacy and/or safety as
compared to the respective mono-therapies. Mono-substances for the treatment of hypertension are
generally combined in a fixed manner if:

• the combination of the individual components is plausible since complementary modes of

action exist which result in additive antihypertensive effects, or a reduction of ADRs;

• efficacy and safety of the individual components have been proven in confirmatory clinical
studies;

• the individual suitable dosage ratio evaluated in confirmatory clinical trials with the free
combination has corresponded with that of the fixed dose combination (FDC);

• the joint application of the two components has proven to be efficacious, safe and thus
clinically useful.

In order to obtain a marketing authorisation for a FDC, it is mandatory to prove that each active
component in the scheduled dosage independently contributes towards the positive evaluation of the

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combination drug. Concerning morbidity and mortality data the same requirements apply as to for the
mono-components.

9.2 The clinical development of a fixed combination

In the situation where a combination has not yet been demonstrated to be safe and efficacious, the
positive benefit/risk of the joint application of the mono-components should be demonstrated by
means of one or more studies with appropriate design and dose-response data. Initially, a factorial
design should preferably be used, allowing the simultaneous comparison of various dosage
combinations with their respective components and with placebo. Ascending dosages (e.g. in a range
of dose equal or superior to two) of the FDC could be tested in patients with insufficient response.

The results of the factorial studies should be the basis for further, confirmatory, clinical trials. It is
important that the clinical studies should be designed in accordance with the indication claimed and the
wording of the indication must state clearly whether the FDC should be given as 1) first line therapy in
patients receiving previously neither of the substances 2) second- or third-line therapy in non-
responders to the mono-components, and 3) substitution therapy in patients adequately controlled
with the individual products, given concurrently, but as separate tablets at the same dose level as in
the intended FDC.

Any FDC should not raise new safety concerns other than encountered with the mono-components.
Special attention should be paid on dose-dependent side effects, including “first dose hypotension” and
symptoms and signs of organ damage (e.g. renal dysfunction) initially (e.g. 1-2 weeks) and after each
dose step. Attention should also be paid to serum electrolyte levels. Particular caution is necessary in
patients at higher risk for orthostatic hypotension for example those with diabetes mellitus, autonomic
dysfunction, and elderly patients.

9.2.1 First line therapy

In this situation the FDC is considered for patients receiving previously neither of the substances. The
FDC may contain either subtherapeutic doses, with doses lower than when given as monotherapy, or
therapeutic doses, depending on the clinical justification for the combination.

9.2.1.1 Subtherapeutic doses

In this possible, although uncommon, situation the (fixed) combination of two antihypertensive agents
contains a dosage lower than the respective lowest approved individual dosages for antihypertensive
mono-therapy. In addition to showing at least similar efficacy to the lowest approved doses of the
monotherapy, the primary aim of developing a low-dose FDC is a reduction of adverse drug reactions
in particular dose-dependent adverse events (taking into account the anticipated increased frequency
of idiosyncratic reactions if the patient is simultaneously confronted with two antihypertensive agents
new to him). Recognising that patients with mild to moderate hypertension are normally treated with
antihypertensive mono-therapy which usually will be titrated to the individually optimised dosage, in
certain patients first-line therapy with a fixed low-dose combination could be considered.

The following minimum requirements have to be met if first-line therapy is claimed for a fixed low-dose
combination.

1) Demonstration that each substance has a documented contribution within the (fixed) combination:

It is necessary (but not sufficient) that the results of a valid clinical trial evaluating a fixed low-dose
combination document a statistically significant and clinically relevant greater BP lowering effect than

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placebo, whereas the difference to each component (same subtherapeutic low dose as in the fixed
combination) given separately has to be at least statistically significant. If these objectives are
addressed by means of a factorial design which includes groups of patients on additional doses and
combinations of doses, then the conclusions regarding the low dose FDC of interest should still be
based on the pair-wise comparisons described above.

2) Demonstration of at least similar efficacy to the lowest approved doses of each monotherapy
compound

It is necessary (but not sufficient) that the BP lowering effect of the low dose FDC is better or at least
similar, i.e. at least not inferior to the effect of the lowest approved dosage of each component. The
inclusion of a placebo arm in this study is helpful to establish external validity of the trial and underline
these claims.

3) Indication for a reduction of (dose-dependent) adverse drug reactions by the low dose fixed
combination as compared to the components in the lowest approved dosages:

There should be a trend towards better safety regarding the low-dose FDC as compared to each
component administered at the lowest approved dosage.

9.2.1.2 Therapeutic doses

In this situation the (fixed) combination of two or more antihypertensive agents contains a dosage in
accordance with approved individual dosages for antihypertensive mono-therapy. According to current
recommendations, the primary aim of initiating antihypertensive therapy with a FDC would be to
achieve the BP (BP) goal in a more timely fashion, which may be more convenient and simplify the
treatment regimen. In many hypertensive patients the treatment goals for BP cannot be achieved by
one drug alone. This has been shown in several large trials, especially in the group of patients with
higher initial BP (≥160/100 mmHg or >20/10 mmHg above goal) or with risk factors for cardiovascular
events. Therefore, recent hypertension guidelines recommend that initial therapy with two or more
drugs may be used in these patients. In addition, the use of multidrug combinations may produce
greater BP reduction at lower dosage of the component agents, resulting in fewer side effects.

On the other hand, a too rapid and/or too strong reduction in BP may lead to orthostatic hypotension,
renal dysfunction and cerebral hypoperfusion. Last but not least, the indiscriminate use of FDC as first
line option may lead to unnecessary drug use.

Patient selection

Appropriate patient selection is the key point and it is recommended that the Applicant thoroughly
justifies that the patients considered for a first line FDC have a low chance to be adequately treated
with mono-therapy or by a combination in sub-therapeutic doses. Furthermore, the Applicant should
show that the risk for CVS events among the included patients is sufficiently high to justify that
treatment is initiated with more than one drug. The inability to reach the preset goal is influenced by
many factors such as initial BP levels, target BP, concomitant diseases, target organ damage and older
age. Therefore, only patients with at least moderate or severe hypertension and/or at high risk for CVS
disease are regarded to fit into the category with a high risk for inadequate BP control on mono-
therapy. The Applicant should also take into account demographic peculiarities, like age and gender,
and concomitant illnesses, as indicated in section 4 of this document. In order to properly assess the
real value of the FDC as first line therapy, it is highly recommended that the pivotal body of evidence
comes from studies conducted in treatment-naive patients fulfilling the recommendations outlined
above.

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Demonstration of the blood-pressure effect of the substances

Requirements for therapeutic exploratory studies will vary depending on what substances are used in
the FDC. The following situations are possible:

1. All substances are well known and the joint application of the two components has proven to be
efficacious, safe and thus clinically useful.

Relevant studies should be available, either as original studies or on the basis of the literature to
document the benefit/risk of the combination and the doses used. In this case, in particular when the
FDC is already available for the second-line indication, one therapeutic confirmatory study could be
sufficient to demonstrate its benefit in terms of obtaining a more rapid and at least comparable blood
pressure lowering effect compared to the dose titrating regimen of the free combination.

When all substances are known and the value of the combination of the mono-components has been
documented sufficiently, in particular when the FDC is already available for second-line indication, long
term safety demands could be satisfied to a large extent by historical data. The completed studies
should, however, supply a large enough sample for safety assessments and a safety extension may be
necessary. This could be performed with an open label design and/or comparative studies with other
FDC.

2. One or all substances are not well known and/or the efficacy and safety of the joint application have
not been established

In this case the benefit of the combination will need to be explored further, similar to the general
requirements for a FDC, before proceeding to the therapeutic confirmatory study. This will normally
include a factorial study with comparison between the mono-components and the FDC.

Design of the therapeutic confirmatory study

The therapeutic confirmatory study should demonstrate that the use of the FDC as initial therapy is
safe and provides a more timely blood pressure control as compared to a strategy initiated with
monotherapy and subsequent addition of further substances. It should be a parallel arm study to
compare the antihypertensive effects of the standard regimen of initiating and titrating one agent
before adding and titrating the second, with the new regimen of titrating the FDC. As the FDC
(substances X and Y) will normally consist of at least two ascending dosages, the effect of the lower
dose combination will be studied during the first treatment period and compared with the full dose of X
and/or Y (the mono-components) at the end of this period. At the end of this period, in non-responders,
dose should be doubled in the FDC arm and the second drug (X or Y, one or the other) should be
added in the mono-therapy arm(s). Subsequently, all treatment arms should be studied for the second
treatment period and compared at the end of this period. Dose-titration steps may be necessary in all
arms to obtain the required dosages at the end of each treatment period that should be of sufficient
duration to allow a reliable treatment effect. Ultimately, the number of treatment periods will depend
on the number of ascending dosages of the FDC. A low number of patients reaching the target BP on
monotherapy in the add-on arm is expected in an appropriately chosen target group.

With such an approach it is expected that the mean reduction in BP and the success rate in both arms
will be similar when patients have been uptitrated to the maximal target dose. In these studies, the
key parameter for evaluation of efficacy is “time until achieving target BP”. Such an endpoint is in
accordance with the primary aim to achieve the BP goal in a more timely fashion. The clinical relevance
of the time gained remains to be demonstrated for the target group of patients. Alternative approaches,
if properly justified, may be acceptable, provided that the gain obtained with the FDC as initial strategy

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is adequately documented as stated above.

Safety in those patients that could be successfully treated with mono-therapy but receive a FDC in a
first line approach should be addressed.

9.2.2 Second- or third-line therapy

A FDC may be considered when response to one or more of the mono-components is insufficient. The
following strategies in conducting confirmatory clinical studies should be considered.

Add-on therapy

Depending on the indication claimed (see addendum) at least one or two pivotal clinical study/-ies
should be performed in a population of patients whose blood pressure cannot be normalised with one
or all of the mono-components. A statistically significant and clinically relevant additional BP reduction
of the combination should be demonstrated in patients who did not respond adequately to standard
therapeutic doses of one or more of the mono-components. Dose-titration will usually be indicated.
Current clinical practice recommendations for the treatment of high BP do not recommend forcing the
dose of a single antihypertensive before considering the combination of two or sometimes even three
drugs. Therefore, it is not necessarily expected that the dose of the single agent is up-titrated beyond
the regular maintenance dose before the second or third agent is added. In any case, the selected
upper dose-titration level of each component should be adequately justified.

Furthermore, it is necessary to show that any additional safety concerns (incidence/seriousness

/severity/outcome of adverse events/adverse drug reactions) do not outweigh the additional benefit of
the combination.

In non-responders it is usually sufficient to show a clinically relevant and statistically significant

superiority of the combination regarding the SBP and DBP, but it would be optimal, if such a trial could
show a statistically significant improvement in response rate (i.e. applying a BP threshold of <140/90
mmHg) for the FDC, as well.

Sufficient duration of time (consistent with the time-response course expected for each component of
the combination) should be taken into account to ensure that BP levels are stable before the second
drug is added to the medication. In special situations, in particular for triple combinations, an
alternative study design may be appropriate.

Parallel group comparisons

A parallel comparison of the combination with the individual components using the same therapeutic
doses with the demonstration of statistically significant superior efficacy of the combination and no
additional safety concerns outweighing the additional benefits of the FDC can be supportive for the
proof of efficacy. Comparison with another FDC may also provide supportive data in the benefit/risk
assessment.

In some cases (e.g. the FDC of two diuretics one of which is assumed to have a potassium-sparing
effect) it can be mandatory to show a statistically significant and clinically relevantly superior safety
while accepting a comparable efficacy. In such a case the studies should primarily aim at safety and
the indication should be worded accordingly.

9.2.3 Substitution therapy

In this situation the FDC of two or more antihypertensive agents is intended for patients adequately
controlled with the individual products, given concurrently, but as separate tablets at the same dose

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level as in the combination. The primary aim is to reduce the number of tablets the patient has to take,
which may potentially enhance adherence to therapy.

Requirements
Requirements will vary depending on which substances are used in the FDC.
The following situations are possible:

1. All substances are well known and the joint application of the two or more components is already in
widespread use in the proposed dosage strengths, has proven to be efficacious and safe and thus
clinically useful.

This situation includes those cases where the requirements for granting a first line indication
(therapeutic doses) or an add-on indication are fulfilled. Moreover, this approach may also be
acceptable for combinations of drugs for which a wide therapeutic experience is available (e.g. 5 years
or more), provided there is a good plausibility and that the pharmacological rationale for the use of
both drugs in combination is adequately justified. Provided that the respective data are thoroughly
and reliably documented, a well founded bibliographical data analysis may be helpful in reducing the
amount of clinical trials to be performed. In this case comparative PK data are needed, demonstrating
that the two components of the FDC do not affect each other’s PK patterns. Showing bioequivalence of
the components in free combination with the FDC is the pivotal aspect in this setting.

2. One or all substances is/are not well known and/or the efficacy and safety of the joint application
have not been established

In this case, original clinical data on efficacy and safety for the combination are required. In addition to
the bioequivalence study comparing the drugs in free combination with the fixed dose, the benefit/risk
of the combination will need to be explored further, before a substitution indication can be considered.
This will normally include clinical studies showing efficacy and safety of the FDC as well as factorial
studies for the dose-response assessments. These studies should demonstrate significant additional BP
reduction of the combination and that the mono-components contribute to the effects. An add-on study
in non-responders should be considered in when clinical use in a substitution indication may not be
clearly differentiated from a second- or third line add-on use. This may be the case when the majority
of patients is not already on long term combined treatment with the individual monocomponents, but
will be treated de novo with combinations containing at least one component that is not well known.
Long term safety data will also be needed. Specific attention should be paid to the doses, as used in
the fixed combination tablet.

10. Addendum
FIXED COMBINATION ANTIHYPERTENSIVE MEDICINAL PRODUCTS IN SECOND LINE
THERAPY

The three following relevant issues were identified regarding applications for FDC antihypertensives in
second line therapy.

1. Indication

It was concluded that, provided sufficient evidence is included in the application, the second line
indication for FDC medicinal product mentioned under section 4.1. should read as follows:

“Treatment of essential hypertension, <medicinal product Z> fixed dose combination (X mg /Y mg) is
indicated in patients whose blood pressure is not adequately controlled on X or Y alone”

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2. Posology

It was agreed that in section 4.2. Posology and method of administration" the two following
recommendations should be included: “Individual dose titration with the components can be
recommended” and “When clinically appropriate, direct change from monotherapy to the fixed
combination may be considered”.

3. Clinical trials requirements for second line indication

In the Note for Guidance on clinical investigation of medicinal products in the treatment of
hypertension’, two types of trials are discussed: trials in patients who are non-responders to the
monotherapy, and trials in general population of hypertensive patients (including potential responders).

It was agreed that different trial requirements might be needed to support the three different following
indications:

3.1 In order to support the indication "Treatment of essential hypertension, <medicinal product Z>
fixed dose combination (X mg /Y mg) is indicated in patients whose blood pressure is not adequately
controlled on X alone", at least one add-on trial to active treatment in non-responders to X should be
carried out.

3.2 In order to support the indication "Treatment of essential hypertension, <medicinal product Z>
fixed dose combination (X mg /Y mg) is indicated in patients whose blood pressure is not adequately
controlled on Y alone", at least one add-on trial to active treatment in non-responders to Y should be
carried out.

3.3 In order to support the indication "Treatment of essential hypertension, <medicinal product Z>
fixed dose combination (X mg /Y mg) is indicated in patients whose blood pressure is not adequately
controlled on X or Y alone", two add-on studies one in nonresponders to X and one with non-
responders to Y should be carried out.

In some cases where only one add-on clinical study in non-responders has been carried out, data from
appropriately designed parallel group comparative studies of the combination with the individual
components may support a broader indication in both categories of non-responders.

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