Post marketing surveillance

Claudio Ceconi

ALL ABOUT CLINICAL TRIALS

Rome, 29th & 30th May 2015

Clinical trial limitations

Nature Reviews: drug discovery. 2011;10:495

•Focused on efficacy

•Safety is a secondary endpoint, generally underpowered and not pre-specified

Scientific background: The clinical trial programme in the pre-authorisation phase

Clinical trial limitations: external validity

• Excluded in 283 RCT because of:1.Children in 60,1%2.Elders (>65 years) in 38,5%. 3.Females in 47,0%

4.Concurrent diseases in 81,3% (in 30,9% of trials considered unjustified)

Van Spall HGC, et al. JAMA 2007;297:1233-40

Friedman MA et al., JAMA 1999; 281:1728-1734

Clinical trial limitations: small sample size

Challenge Faced by Regulatory Authorities Challenge Faced by Regulatory Authorities

at Marketing Approval:at Marketing Approval:

How to ensure that life-saving therapies are How to ensure that life-saving therapies are available in a timely fashion available in a timely fashion

whilewhile

Still guarantee that medicines are safeStill guarantee that medicines are safe

What we do not know at time of approval

Full safety profile including adverse drug reactions which are: • Rare. • Delayed (long latency). • From chronic exposure.• Due to cumulative effects.• Medication error/off-label use. • Associated with abuse/misuse. • Associated with populations not studied in trials

(e.g. children, elderly, pregnancy, co-morbidities).

1. Pre-authorisation studies (5 RCT, lenght 52 weeks, patients: 1967 vs. 763)

inadequate for assessing the effects of the drug on micro and macrovascular complications

2. Increase in fluid retention 3. Increase of body weight and

LDL levels

Clinical trial limitations: Extensive use of surrogate endpoints

BMJ | 11 SEPTEMBER 2010 | VOLUME 341

Impact of the new EMA PhV legislation

• Biggest change to the legal framework for human medicines since 1995

• Product life-cycle impacted• Major change project that will take a few

years to fully implement

New legislation

1. Directive 2010/84/EU of the European Parliament and of the Council of 15 December 2010. Official Journal L 348, 31/12/2010, p. 74 - 99.http://ec.europa.eu/health/files/eudralex/vol-1/dir_2010_84/dir_2010_84_en.pdf 2. Regulation (EU) No 1235/2010 of the European Parliament and of the Council of 15 December 2010. Official Journal L 348, 31/12/2010 p. 1 - 16.http://ec.europa.eu/health/files/eudralex/vol-1/reg_2010_1235/reg_2010_1235_en.pdf

Tools for monitoring and assessing risk-benefit profile

FDA EMA

Publicly available PhV Database (FAERS)

Risk Evaluation and Mitigation Strategies (REMS)

Drug Safety Initiatives:- Critical Path Initiatives- Sentinel (Mini-Sentinel)

Drug Safety Consortia:- iSAEC- CSRC- HESI

Publicly available PhV Database (EudraV)

Risk Management Plans (RMP):- PASS/PAES (New PhV Legislation)

Drug Safety Initiatives: - Encepp - IMI (Innovative Medicines Initiatives)

Drug Safety Consortia:- SOS- EU-ADR- ARITMO- Safeguard

Data Sharing

(transparency)

PASSPost-authorization safety study:definition

Any study relating to an authorised medicinal product conducted with the aim of identifying, characterising or quantifying a safety hazard, confirming the safety profile of the medicinal product, or measuring the effectiveness of risk management measures.

• to quantify potential or identified risks

• to evaluate risks of a medicinal product used in patient populations for which safety information is limited or missing (i.e. pregnant women, specific age groups, patients with renal or hepatic

impairment)

• to provide evidence about the absence of a risk

• to assess patterns of drug utilisation that add knowledge on the safety of the medicinal product (i.e. indications, dosage,

co-medication, medication errors)

• to measure the effectiveness of a risk minimisation activity.

Post-authorization safety study:objectives

PASS: observational design

PASS initiated, managed or financed by a MAH

• Pursuant to an obligation imposed by a competent authority as a condition to the granting of the marketing authorisation, or after

the granting of a marketing authorisation if there are concerns about the risks of the authorised medicinal product (category 1)

as part of a marketing authorization granted under exceptional circumstances (category 2)

• Voluntarily/required studies required in the risk management plan to investigate a safety

concern or evaluate the effectiveness of risk minimisation activities (category 3)

any other PASS (category 4)

PASS: triggering factors

1. Open label study2. A-priori hypothesis for sample size calculation overestimated (Incidence

pre-specified of the primary endpoint 11% vs. 2.6% of the true incidence) therefore sample size underpowered.

3. Incidence of AMI significantly different from the epidemiological evidence

4. Around 40% of patients withdrawn the treatment with rosiglitazone5. The Rosiglitazone group reported significantly higher treatment with

lipid lowering drugs

Post-authorisation efficacy Post-authorisation efficacy studiesstudies

Delegated Regulation to determine situations Delegated Regulation to determine situations for a PAES:for a PAES:

In order to determine the situations in which post-authorisation efficacy In order to determine the situations in which post-authorisation efficacy studies may be required […] the Commission may adopt […] delegated acts" studies may be required […] the Commission may adopt […] delegated acts" (Article 22a of Directive 2001/83/EC and 10b of Regulation (EC) No 726/2004)(Article 22a of Directive 2001/83/EC and 10b of Regulation (EC) No 726/2004)

PAES – Practical aspectsPAES – Practical aspects

• Exceptional tool for 'standard' marketing authorisationsExceptional tool for 'standard' marketing authorisations

• Context: efficacy evaluationContext: efficacy evaluation

• Identified concern - burden of proof with regulatorsIdentified concern - burden of proof with regulators

• Justified on a case-by-case basisJustified on a case-by-case basis

• Goal: address well-reasoned scientific concerns with direct Goal: address well-reasoned scientific concerns with direct impact on the maintenance of the marketing authorisationimpact on the maintenance of the marketing authorisation

• Design: appropriate to answer the scientific question – focal Design: appropriate to answer the scientific question – focal point: supplementing efficacy datapoint: supplementing efficacy data

PAES: Open Issues

Guideline document by EMA

Place in therapy

as compared to the standard of care…

Superiority vs non-inferiority design

subpopulations most likely to benefit from drug

Unmet clinical needs vs drug policies (payment by results)

Cooperation (drug companies – academia – regulators)

The Sibutramine experience

1997 sibutramine approved for weight loss by FDA labelled warning re BP and heart rate increases

2002 EMA requires CV outcomes trial (SCOUT)

10,744 overweight/obese with CV disease and/or diabetes over 3.4 years

sibutraminesibutramineSCOUT (Sibutramine Cardiovascular Outcome Trial) requested by

CHMP at the time of MAA to define risk-benefit profile in overweight high-risk cardiovascular patients

age ≥55, standard WHO BMI criteria + CVE or T2DM & add CVRF

1EP composite of MI, stroke, resuscitated cardiac arrest, CV death

N=9000

sibutraminesibutramine

interim analysis found 16% interim analysis found 16% increased risk of CV events increased risk of CV events such as MI and stroke such as MI and stroke compared with placebo-compared with placebo-treated patients (HR 1.161 treated patients (HR 1.161 [95% CI 1.029–1.311]; [95% CI 1.029–1.311]; p=0.016)p=0.016)

The Sibutramine experienceThe Sibutramine experience

1997 sibutramine approved for weight loss by FDA1997 sibutramine approved for weight loss by FDAlabelled warning re BP and heart rate increaseslabelled warning re BP and heart rate increases

2002 EMA requires CV outcomes trial (SCOUT)2002 EMA requires CV outcomes trial (SCOUT)

10,744 overweight/obese with CV disease and/or diabetes 10,744 overweight/obese with CV disease and/or diabetes over 3.4 yearsover 3.4 years

sibutramine placebosibutramine placebo

non-fatal MI 4.1% 3.2% P=.02

non-fatal stroke 2.6% 1.9% P=.03

CV death 4.5% 4.7%

primary composite 11.4% 10.6% P=.02

hazard ratio 1.16 (95% CI 1.03 to 1.31)

published NEJM Sept 2, 2010drug withdrawn by FDA, EMA etc. soon after

The specific situationsThe specific situations

Delegated Regulation

Initial assessment based on surrogate endpoints

"An initial efficacy assessment that is based on surrogate endpoints, which requires verification of the impact of the intervention on clinical outcome or disease progression or confirmation of previous efficacy assumptions"

Combination with other products

"In case of medicinal products that are used in combination with other medicinal products, the need for further efficacy data to clarify uncertainties that had not been addressed when the medicinal product was authorised"

Sub-populations "Uncertainties with respect to the efficacy of a medicinal product in certain sub-populations that could not be resolved prior to marketing authorisation and require further clinical evidence"

Long term efficacy "The potential lack of efficacy in the long term that raises concerns with respect to the maintenance of a positive benefit-risk balance of the medicinal product"

CONCLUSIONS CONCLUSIONS

Often, the Benefit/Risk balance of a medicinal product cannot be fully identified until after a drug is on the market and has been used by a large, diverse group of patients over time.

Clinical trials conducted before approval may be too small, too short, based on surrogate endpoints….. to detect all possible risks(…and efficacy).

Studies based on post marketing surveillance need to be defined at the time of MAA (case by case basis)