requirements from regulatory agencies: endpoints, comparators, type of studies
TRANSCRIPT
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Requirements from regulatory agencies: endpoints, comparators,
type of studies
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2
Registration in Europe Post Nov 2005 : Three European Systems
Centralised Procedure(via EMA)
Mutual Recognition procedure
Decentralised Procedure
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EU Centralised Procedure • Legal Basis: Regul. (EC) No 726/2004 (also establishing “EMA”
European Medicines Agency)
• Principle: single application / evaluation single authorisation
direct access to all EU(27MSs) + Norway, Iceland and Liechtenstein
• Scope:– Compulsory for:
Biotech (recombinant DNA, gene expressed proteins, hybridoma & monoclonal antibodies) New Active Substances in Specific Therapy Areas: AIDS, Cancer,
Neuro-degenerative disorder, Diabetes, Auto-immune disease, other immune deficiencies, Viral diseases
Orphan Drugs
– Optional for: Any Other New Active Substance significant innovation (therapeutic, scientific or technical) in the interests of patients at community level Generic of Centralised reference prod. (may use CP or MRP/DCP)
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Two options
Mutual Recognition Procedure
– Art. 28 para. 2 of Dir. 2001/83/EC
– For products with an existing MA
Decentralised Procedure
– Art. 28 para. 3 of Dir. 2001/83/EC
– Only possible, if no authorisation has already been granted
– Most significant difference with MRP = consultation between MS‘s before 1st MA issued
&:
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Regulatory requirements in clinical trials
Drugs for IHD
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Assessment of Cardiovascular Dugs for the treatment of ischemic heart disease
• Acute coronary syndromes: STEMI - NSTEMI
• Chronic stable angina: 1. risk factors, 2. anti-anginals
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Assessment of Drug Efficacy in ACS
• Mortality
• Cardiovascular MortalityDischarge30 days3 months1 year
• Reinfarction
• Sudden death
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Assessment of Cardiovascular Dugs for the treatment of chronic ischemic heart disease
• Chronic stable angina: 1. risk factors, 2. anti-anginals
Risk factors: events, surrogate end points
Anti-anginals: inducible ischemia parameters, GTN consumption
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Cardiovascular Risk factorsLipids
• Approval based on effect on lipid profile
– Short term efficacy
– Long term safety
• Approval based on MACE
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Cardiovascular Risk factorsBlood pressure
• Approval based on effect on blood pressure reduction
– Short term 12 weeks vs placebo
– Short term 12 weeks vs comparator
– Long term 52 weeks safety study
– Adequate patient groups
• Approval based on MACE
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Assessment of efficacy in CSA
• Drugs: secondary prevention – anti-ischemic
• Mortality ?
• Morbidity?
• Degree of ischemia
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Assessment of inducible myocardial ischemia
• Exercise ECG
• Holter monitoring
• Myocardial perfusion scintigraphy
• Stress echo
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Assessment of efficacy for anti-anginals
• Exercise time during ETT
• Time to 1 mm ST segment depression
• HRQoL
• Number of episodes of angina
• No of GTN tablets used
• RRP to 1 mm ST
• RPP at peak exercise
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Assessment of efficacy of antianginals
Study designs
• Rx vs Placebo
• Rx vs Beta blockers
• Rx+ beta-blockers vs other antianginals + beta-blockers
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Assessment of anti-anginal drugs
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Assessment of anti-anginal drugs
Criteria of efficacy
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Assessment of anti-anginal drugs
Methods of assessment
Exercise testingReproducibility
Anginal painHRQolMorbidity and mortality
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Assessment of anti-anginal drugs
Strategy of assessment
Initial therapeutic studies
•Withdrawal of antianginals•Short acting nitrates allowed•Dose-ranging studies•Studies compared to placebo
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Assessment of anti-anginal drugs
Strategy of assessment
Main therapeutic studies
•Randomized, double-blind, placebo-controlled, parallel groups•Active control studies vs an adequate comparator adequately dosed•Comparable efficacy and safety to an appropriate standard therapy•At least 12 weeks•Monotherapy and add-on
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Example of a development plan of a drug approved for the treatment of chronic stable angina
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Placebo bidIvabradine 10 mg bid
Open label
Placebo bid
Ivabradine10 mg bid
Exercise tolerance test
2 weeks2 weeks1 week1 week 3 months3 months 1 week1 week
ETTETTETTETT ETT
2 to 7 d2 to 7 d
ETT:
Ivabradine 10 mg bid
Ivabradine 2.5 mg bid
Ivabradine 5 mg bid
Placebo bid
Ivabradine and exercise-induced myocardial ischemia
Borer JS, et al. Circulation. 2003;107:817-823.
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Increase in time to1-mm ST-segmentdepression (s)
Ivabradine and exercise-inducedmyocardial ischemia
Time (days)0 2
040
60
80
100
120
80
60
40
20
0
Placebo (n=28)
Ivabradine 5 mg (n=31)
Ivabradine 10 mg (n=31)
Ivabradine 2.5 mg (n=30)
All Patients receivedIvabradine 10 mg twice / day
Dose ranging
Borer JS, et al. Circulation. 2003;107:817-823.
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M0 ETT
25 mg od
Placebo
Atenolol 50 mg od
(n=307)
Ivabradine 5 mg bid
(n=315)
Ivabradine 5 mg bid
(n=317)
Ivabradine
50 mg odAtenolol 100 mg od
Ivabradine 7.5 mg bid
Ivabradine 10 mg bid
M1 ETT M4 ETT
Washout2-7 days
Run-in7 days
Run-out14 days1 month 3 months
Preselection
Exercise tolerance testETT:
Ivabradine
Tardif JC, et al. Eur Heart J. 2003;24:A186(Abstract)
Ivabradine and exercise-inducedmyocardial ischemia
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74 76 78 80 82 84 86 88
Ivabradine 7.5 mg
Atenolol 100 mg 78.8
86.6*
*P<0.0001*P<0.0001
P for non-inferiority
n=939
P for non-inferiority
n=939
Time (s)Time (s)
Increase in total exercise duration (4 months of treatment)
Ivabradine and exercise-inducedmyocardial ischemia
Tardif JC, et al. Eur Heart J. 2003;24:A186(Abstract)
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•No benefit in overall mortality/morbidity•Increased mortality in patients with angina
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Regulatory requirements in clinical trials
Drugs for Arterial hypertension
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Assessment of anti-hypertensive drugs
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Assessment of anti-hypertensive drugs
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Assessment of anti-hypertensive drugs
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Clinical development program
• DOSE-SELECTION STUDY1 placebo-controlled study (SPP100A 2204)
• CONFIRMATORY EFFICACY STUDIES5 active-controlled studies4 in mild to moderate hypertension – not adequately responding to aliskiren or
HCTZ monotherapy (SPP100A 2331, 2332, 2333, 2309)1 in uncomplicated severe hypertension (SPP100A 2303)
• LONG TERM EFFICACY STUDY3 studies 2 double-blind, active controlled 6-month studies (2306, 2323)1 open-label 12-month study, including a one-month, randomized, double-
blind withdrawal period to confirm long-term efficacy (2302) and a 4-month extension to this study (2302E1)
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Study 2204
Placebo Aliskiren 75 mg Aliskiren 150 mg Aliskiren 300 mg
Placebo n=195 n=184 n=185 n=183
HCTZ 6,25 mg n=194 n=188 n=176 –
HCTZ 12,5 mg n=188 n=193 n=186 n=181
HCTZ 25 mg n=176 n=186 n=188 n=173
Placebo
1 week Randomization
PlaceboHCTZ monotherapy (6,25, 12,5 o 25 mg)
2 weeks
Aliskiren monotherapy (75, 150 o 300 mg) Washout
8 weeks(double blinded)
†Ipatients randomized to HCTZ 25 mg in association with aliskiren 150 or 300 mg received aliskiren/HCTZ 150/12,5 mg for one week before up titration
Association Ali-HCTZ †
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Studies for approval of therapeutic agents for the treatment of heart failure
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Selection of patients
• AHFPatients hospitalised because of HF should be randomised within a reasonable time in order to be able to adequately assess efficacy
• CHF-LVD alone will not suffice. -Patients should exhibit a wide range of severity of CHF.
Alternatively the information can be gathered by separate studies in different patient subsets-Patients should be in stable conditions, however a shorter period from the acute event and randomisation may be considered in patients with more severe forms of HF-It is advisable to exclude patients within 3 months from a MI and with a short (<3 months) duration of the disease
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Selection of patients• AHF
Patients hospitalised because of HF should be randomised within a reasonable time in order to be able to adequately assess efficacy
Patients needing optimisation of background Rx
Patients already maximal Rx
• HHF
Patients included at discharge after an unplanned hospitalisation for HF
• CHF
-LVD alone will not suffice.
-Patients should exhibit a wide range of severity of CHF. Alternatively the information can be gathered by separate studies in different patient subsets
-It is advisable to exclude patients within 3 months from a MI and with a short (<3 months) duration of the disease
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Criteria to assess efficacy• AHF
-In Hospital and 4 wks mortality
-Depending on the indications claimed, long term mortality and duration of hospitalisation
-Improvement in haemodynamic state and symptoms (categorical composite)
-Relief of other manifestations of AHF including need of inotropic support and vasodilators
• CHF-Mortality, morbidity
-Primary composite
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Cardiovascular mortality• Since no correlation exists between short term improvement in clinical
symptoms and/or exercise capacity and mortality, many drugs are likely to require a trial which includes survival amongst its primary objectives before requesting an approval regardless of the claim being sought
• If the investigational drug belongs to a new pharmacological class or when agents of the same class have been associated with detrimental effects, a prospective, RCT aimed at assessing survival is requested
• Distinction should be made between a) sudden death b) death due to acute deterioration of clinical status c) death due to chronic progression of CHF
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Composite end pointsMay be appropriate but should include selected aspect of cardiovascular morbidity along with overall mortality. They all should be clinically relevant
Hospitalisations for HF Causes of hospitalisation (co-morbidities, non adherence etc) Worsening Heart Failure without Hospitalization No. of hospitalisations/year Patient journeys Recurrent morbid events
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Secondary end points
• Exercise tolerance: 6MWT seems to correlate better than Maximal exercise test (with or without gas exchange analysis) with the clinical effect of the drug
• Haemodynamic data: are insufficient to demonstrate benefit but may be useful to elucidate the mechanism of action
• Neuroendocrine status: data may be included but they can be only be accepted as supportive
• Physical signs and renal function: can be accepted as supportive only • Symptoms: the effect on symptoms should always be coupled with data
on mortality and morbidity• QOL: supportive only
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Safety aspects
• Hypotension
• End organ consequences (Heart, CNS, kidney)
• Effect on cardiac rhythm
• Pro-ischaemic events
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Regulatory requirements in clinical trials
What constitutes meaningful change
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Meaningful change
• Any change in a primary end point that correlates with an improvement in mortality/morbidity
• A change in a primary end points that significantly improves QOL in end stage disease patients
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Dyspnoea in AHF
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Significant Improvement of VAS AUC Endpoint
Effect evident early and maintained
* P-value is based on a two-sided two sample t-test for serelaxin versus placebo comparing area under the curve (AUC, mm-hours) of change from baseline of dyspnea visual analog scale (VAS) from baseline to Day 5.
19.4% increase in 19.4% increase in AUC with serelaxin from AUC with serelaxin from baseline through day 5baseline through day 5(Mean difference of 447.7 mm-hr)(Mean difference of 447.7 mm-hr)
AUC with placebo, 2308 ± 3082AUC with serelaxin, 2756 ± 2588*P=0.0075
6h6h 12h12h
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cm
mm
4 mm
Absolute value of changes in VAS scale
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Exercise capacity
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Riociguat in pulmonary arterial hypertension
Ghofrani et al N Engl J Med 2013; 369: 4
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Macitentan on exercise capacity and on Mortality-
Morbidity end points
6-MWT + 7.4 m macitentan - 9.4 m in Placebo-(treatment effect 16.8 m; 97.5% CI, −2.7 to 36.4; P=0.01)
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Macitentan on exercise capacity and on Mortality-
Morbidity end pointsS
urv
ival
Pro
bab
ilit
y
00
0.2
0.4
0.8
1.0
0.6
12 18 24 30 366
Macitentan 10 mg
Placebo
Placebo (n=250)
Macitentan(n=242)
Number of M/M Events 116 76
Hazard ratio (HR) 0.55
97.5% CI of HR 0.392, 0.762
p-value < 0.0001
48
Pro
babi
lity
of fr
eedo
m fr
om e
vent
Months
6-MWT + 7.4 m macitentan - 9.4 m in Placebo-(treatment effect 16.8 m; 97.5% CI, −2.7 to 36.4; P=0.01)
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Pirfenidone in pulmonary fibrosis
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Pirfenidone in pulmonary fibrosis
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How to define a meaningful change
• Change in a parameter that correlates with mortality and/or morbidity or that has a clinical relevance
• No fixed value
• Has to be related to baseline function
• Attenuation of the decline in function
• Must be significantly related to the disease
• Must have a biological plausibility