Regulatory Requirements Present and Future

Dr Ruben E. Keane, QRM HRB-CRF-C

UCC 7 December 2016

Collaborating CRF/Cs: HRI CRSU Limerick NICRF Belfast City Hospital NCRC Our Lady’s Children’s Hospital, Crumlin

HRB Clinical Research Coordination Ireland

Scope of presentation Interventional Clinical Trials of IMP under remit of

competent authority –Health Products Regulatory Authority ( HPRA)

– Not observational studies or other interventions (e.g exercise, physiotherapy, nutrition)

– Not medical device investigations

What’s reguired from Regulatory point of view:

Start up

During

At End

Guinea Pigs?

Current Regulatory Environment IMP (Oct 2016)

– EU Directive 2001/20/EC - Clinical Trials Directive• Implemented nationally by SI 190/2004• Amended by SI 878/2004

– EU Directive 2005/28/EC – GCP directive• Implemented Nationally by SI 374 /2006

– ICH-GCP (E6) – GMP for CT materials -Annex 13 to GMP Guideline

Why so many rules??Past abuses Patient rights, safety and welfareData Integrity

- Nuremburg– WWII abuses- Tuskegee syphilis study 1932-1972- He La cells – ‘The immortal life of Henrietta Lacks’

(2010)

)

Before starting a HPRA regulated trial : You need:

1. Ethical approval from one of the 12 recognised ethics committee (EC) in Ireland

2. HPRA approval 3. Approval of institution/hospital whereYou are carrying out the trial

Can apply to REC and HPRA in parallel

REC application includes :

- Protocol– Patient Information leaflet – Informed Consent Form– Any other documents seen by the patients-

• e.g advertisments, patient ID cards, questionnaires– CV of PI – Site Specific Assessment form

REC –Patient Safely Rights and welfare

CTA – submission includes HPRA Guide to CTA Appendix 3:

CTA

Protocol

Cover Letter

XML file

EudraCT Number

IBSmPC, IMPD

QP release

Manufacturing authoriistaion

Example of Labelling

Ongoing Communication with HPRA and REC during the study incl:

• Changes to Risk/ Benefit of the study • Amendments• Any major issues with study -

– It’s not currently a requirement to report breaches of GCP to HPRA and EC but it will be under the new EU Clinical Trial regulation 536/14

– Best practice to do so now

How is risk /benefit montiored during a study?

• Noting and reporting SAEs/SARs - Individual reports

• Development Safety Update Reports- listings and tables

• PI and Sponsor -ongoing discussions re Risk/ Benefit potential changes

• if new treatment comes on market• Lack of efficacy • Review of SAEs / AEs

• Data safety monitoring board (DSMB) or Data monitoring Committee (DMC) may be in operation

Substantial amendments- HPRA and EC HPRA - ‘substantial’- likely to have a significant impact on the safety, physical or mental integrity of the participants, or the scientific value of the trial. (HPRA Guidance document on CTA)

• It is up to the sponsor to assess what is regarded as substantial.

• Need written approval of amendment before implementing it – UNLESS it’s an urgent safety measure.

• Need to reconsent patients in study if Patient information leaflet/Informed consent form (PIL/IC) is updated.

Substantial or non Substantial amendment?

• Correction of spellings on a patient information leaflet /consent form

• Change of Inclusion criterion e.g upper age limit increased from 60 to 70 years.

• Including an extra biopsy • Inclusion of an extra site • Change in no. of patients to be recruited• Change of Prinicpal investigator• Change of study nurse at site

SAE- DOCTOR REPORTS IT TO SPONSOR IMMEDIATELY

SAE

HOSPITALISATION OR

PRLONGED HOSPITALISATIO

N

DEATH

LIFE THREATENING

PERSISTENT OR SIGNIFICANT

DISABILTITY OR INCAPACITY

MEDICALLY SIGNIFICANT

(PI)

CONGENITAL ANOMALY OR

BIRTH DEFECT

SERIOUS

RELATED TO DRUG

UNLISTED

SUSAR

Notifiction of SUSARS – HPRA and REC • SPONSOR must notify REC and HPRA of SUSARs

within – 7 days – fatal and life threatening– 15 days - all other ‘serious’ categories

Reported HPRA, REC and EUDRAVIGILANCE

Development Safety Update Reports (DSUR) : HPRA and EC

Sponsor required to submit a safety report (DSUR) once per year to HPRA and EC

Present a comprehensive , thoughtful annual review and evaluation of pertinent safety information for that period.

Lists all SAEs and SUSARs

End of Trial: HPRA and EC• Notify HPRA and EC using EU declaration of end

of trial form.

• Within 90 days of end of trial OR within 15 days if trial ended earlier than planned.

• End of trial report to be submitted within one year of completion or cancellation of the trial.

(See EU note for Guidance on Strucure and Content of Clinical Study reports on EMA website.)

What does the future hold?

2 big changes in process :

ICH-GCP revision 2

EU Clinical trial Regulation 536/14

Background to ICH-GCP revision 2

Since ICH-GCP was developed (1996 ) clinical trials have changed significantly:

– Scale, complexity and cost of trials has increased– Development of Electronic systems – eCRFs and electronic

patient records– Risk based approaches

• ‘Evolutions in technology and risk management processes offer new opportunities to increase efficiency and focus on relevant activities.’

• Many things currently being done in practice but not specifically required in old version of GCP e.g Having a monitoring plan, Validation of databases

Main areas of change

Electronic systems Quality Systems Monitoring Essential DocumentsPI supervision of personnel

ICH-GCP R2

• Quality and Monitoring systems to be Risk based: During protocol development sponsor to identify processes and data that are critical to assure

– human subject protection – reliability of study results.

• Electronic systems- Specific requirements for SOPs re system setup, installation, validation and use of electronic systems and for user training

EU CT Regulation 536/2014

• CT directive currently in place (2001)

– EU Regulation Versus EU Directive

– Counties different interpretations/ requirements

– Supposed to be a harmonizing directive but ….

– Reduction in no of CTs post directive

Number of Clinical Trials Conducted Post Directive

2007 2008 2009 20103600

3800

4000

4200

4400

4600

4800

5000

52005028

46184491

4193

20%

CURRENTLY – international IMP trial:Germany

REC

CA

DenmarkREC

CA

FranceREC

CA

IrelandREC

CA

• Must prepare and submit separate CT applications for each country• Different forms and formats – paper/ electronic etc.• Each RA and REC may ask for changes in protocol, PIL/IC,• Each RA /REC may have the same or different queries

Main Characteristics

EU Regulation 536/2014

Single set of documents

Streamlined application procedure

Harmonized procedure for assessment

EU Portal and Database

EU Database and EU Portal

All submissions and communications (with the sponsor and between MSs) must be made through the EU portal + database.

– including Start of trial, FPFV, End of trial etc.

• All documents will be stored in the EU database.

• The European Medicines Agency is responsible for the development of the portal and database

CTA dossier elements defined as General or National

One Dossier

GeneralPart I

NationalPart II

Submitted via the EU portal into the EU database

Harmonised assessment procedure

Part I and Part II

Part I - scientific part, common for all Member States - coordinated review involving CA and EC Part II – national/local

part – ethical review – independent national review

Part I - scientific part, common for all Member States - coordinated review CA and EC

Examples: • Protocol• Investigator’s brochure• Risks/ benefits• Investigational Medicinal Product

Dossier

Article 6 – Aspects covered by Part I

Part I – coordinated review CA+EC• A single MS chosen to be Reporting Member state (RMS)• RMS Leads the review, prepares a report, questions back to

applicant.• HPRA estimates that it will be RS in 30 applications per year • How work is shared/divided within the member state to be

decided by the member state• Co-operation between National competent authority and

Ethics committees • The relevant national procedures need to be developed• Effective communication vital• Short timelines – tacit approval (if no response)

Article 7– Aspects covered by Part II

Examples:• Informed consent

• Recruitment arrangements• Suitability of investigators and trial

sites• Compensation arrangements• Collection, storage and future use

of biological samples of the subject.

Sponsor will not Choose EC- EC willhave applications assigned to it.

EU regulation 536/2014

Potential Benefits 1One access

point – streamlined

process

All documents in one place

Simplification of contact

Standard timelines for

reviewTacit

approval

Potential Benefits 2 Rich

source of data for

researchers

No duplication

of trials already done

Assessment – one decision

per Member

State

No national

versions of protocol

One set of questions from CA+

REC (together)

• Transparency • Timelines (faster?) • Easier to get approval to to carry

out trials in several countries

Potential Benefits to patients :

Transparency – publically available:

-CTA dossier and assessment reports

• Protocol 

• Investigator’s brochure

• Names of investigators

• Clinical trial sites

– Results + lay persons summary (within 1 year of end of trial)

– Inspection reports 

EU regulation 536/2014 • The clinical trial regulation implementation is dependent on

the functionality of the EU portal and database.

• Estimated OCT 2018

• Key decisions to be made before implementation in Ireland: – What EC will be involved? Central EC? – How will ECs work with HPRA on applications?– Brexit….

The last word from our Nobel Prize winner….