Roadmap to Implementing the EU Directive

This article describes AstraZeneca's (AZ) experience in implementing the EU Clinical Trial Directive 2001/20/EC, which came into force on 1 May 2004. In particular, it is based on Articles 2, 16, 17, and 18 and Revision 1 of the associated guidance document, ENTR/CT3, "Detailed guidance on the collection, verification and presentation of adverse reaction reports arising from clinical trials on medicinal products for human use."

Directive 2001/20/EC establishes specific provisions regarding the conduct of clinical trials, including multicenter trials on human subjects involving medicinal products as defined in Article 1 of Directive 65/65/EEC, in particular relating to the implementation of good clinical practice.

Directive 2001/20/EC does not apply to noninterventional trials (i.e., studies where the medicinal product(s) is/are prescribed in accordance with the terms of the marketing authorization).

In this discussion of the directive, AZ comments are noted where there have been changes in practice and standard operating procedures (SOPs) in the Articles and Revision 1 of the associated guidance. If there is an explanation of the directive with no comment it is considered good current practice at AZ and there is no impact on SOPs.

ENTR/CT3 Revision 1 April 2004

This guidance applies to all clinical trials on medicinal products for human use conducted within the European Community. It applies to all investigational medicinal products (IMPs) for human use, independent of their marketing authorization status in any Member State whether or not IMPs are used under the conditions of the authorization. It sets out detailed guidance on the collection, verification, and presentation of adverse event/reaction reports arising from such trials. In addition, it sets out the responsibilities of the concerned parties (see sidebar "Setting Out Investigator and Sponsors Responsibilities").

Setting Out Investigator and Sponsor Responsibilities

Sponsor's responsibilities

The sponsor has to keep detailed records of all adverse events (AEs) reported by the investigator(s) and perform an evaluation with respect to seriousness, causality, and expectedness.

On request of a Competent Authority (CA) in whose territory the clinical trial is being conducted, the sponsor should submit detailed records of all AEs that have been reported by the relevant investigator. Each individual AE should be evaluated by the investigator and by the sponsor, including seriousness and causality.

The sponsor shall determine the expectedness of an adverse reaction according to the reference document, as defined in the protocol (e.g., the investigator's brochure (IB) for a nonapproved IMP or summary of product characteristics (SmPC) for an authorized IMP in the EU).

Glossary of Trial Terminology

Assessment of causality

All AEs judged by either the investigator or the sponsor as having a reasonable suspected causal relationship to an IMP qualify as adverse reactions. The expression "reasonable causal relationship" means in general that there is evidence or argument to support a causal relationship.

The causality assessment given by the investigator should not be downgraded by the sponsor. If the sponsor disagrees with the investigator's causality assessment, then both the opinion of the investigator and sponsor should be presented.

AstraZeneca´s Read on ASRs

SUSARs

All SUSARs (suspected unexpected serious adverse reactions) related to the IMP (i.e., the tested IMP and comparators) that occur in the concerned trial(s) are subject to expedited reporting. This includes:

• SUSARs that occur in another trial conducted by the same sponsor either in the European Community or in non-European Community countries

• SUSARS identified from spontaneous reports or from a publication(s)

• SUSARs transmitted to the sponsor by another regulatory authority

The minimum criteria for the expedited reporting of SUSARs are:

• a suspected IMP

• an identifiable subject

• an AE assessed as serious and unexpected, and for which there is a reasonable suspected causal relationship

• an identifiable reporting source.

And when available and applicable:

• a unique clinical trial identification (EUDRACT number or in the case of non-European Community trials the sponsor's trial protocol code number)

• a unique case identification (i.e., the sponsor's case identification number).

As a general rule treatment codes should be broken by the sponsor before reporting a SUSAR to the CA and ECs of the concerned Member States.

Format of SUSAR reports

Electronic reporting should be the expected method for the expedited reporting of SUSARs to the CAs. The CIOMS-1 form is a widely acceptable standard for adverse drug reaction (ADR) reporting. However, no matter what form or format is used, it is important that the basic information/data elements described in Annex 3 of ENTR/CT3 are included in any expedited report. The latest version of MedDRA should be applied.

AZ comment: Electronic reporting is new for AZ and implementation of electronic reporting had a major impact on our systems and processes. Despite reference to the CIOMS-1 form, most EU Member States require transmission via E2B.

Other safety issues

Other important safety issues may also qualify for expedited reporting when they might materially alter the current benefit–risk assessment of an IMP or when they would be sufficient to consider changes in the IMP administration or in the overall conduct of the trial, for example:

• single case reports of an expected serious adverse reaction with an unexpected outcome such as a fatality

• an increase in the rate of occurrence of an expected serious adverse reaction, which is judged to be clinically important

• poststudy SUSARs that occur after the patient has completed a clinical trial and are reported by the investigator to the sponsor

• a new event relating to the conduct of the trial or the development of the IMP likely to affect the safety of subjects, such as:

– an SAE associated with trial procedures that could modify the conduct of the trial

– a significant hazard to the subject population such as lack of efficacy of an IMP used for the treatment of a life-threatening disease

– a major safety finding from newly completed animal studies (such as carcinogenicity).

AZ comment: Expedited reporting of expected serious adverse reactions with an unexpected outcome (e.g., a fatal outcome) is new for AZ, and this change had a significant impact on our SOPs/processes as the safety database and listed table had to be amended to facilitate this change.

Reporting timelines

For fatal/life-threatening SUSARs, the CAs and ECs in concerned Member States should be notified as soon as possible, but no later than seven calendar days after the sponsor has first knowledge of the minimum criteria for expedited reporting (IMP, SUSAR, identifiable reporter, and subject).

Follow-up information should be sought and communicated to CAs and ECs in concerned Member States as soon as possible but no later than an additional eight calendar days.

AZ comment: Expedited reporting of SUSARs to ECs is new for AZ. This had a major impact on our SOPs, processes, and personnel. Compliance with submitting follow-up information within an additional eight calendar days was a challenge, and our SOPs/processes were amended to accommodate this new requirement.

All other SUSARs must be reported to the CAs and ECs in concerned Member States as soon as possible, but no later than 15 calendar days after the sponsor has first knowledge of the minimum criteria for expedited reporting. Further relevant follow-up information should be given as soon as possible.

Individual SUSAR recipients

Expedited reporting of SUSARs to the CAs is unchanged. In accordance with national legislation, ECs may only receive expedited individual SUSAR reports for subjects who have been recruited at that Member State, provided that:

a) All SUSARs from Member States and, where applicable, from third countries are reported at least quarterly, as a line listing accompanied by a brief report by the sponsor highlighting the main points for concern. In that case, a copy should be sent to the CA(s) concerned.

b) Any changes increasing the risk to subjects and any new issues that may affect adversely the safety of the subjects or the conduct of the trial should also be provided as soon as possible, but no later than 15 days.

The sponsor shall inform all investigators concerned on findings that could adversely affect the safety of study subjects. If appropriate, the information can be aggregated in a line listing of SUSARs in periods as warranted by the nature of the clinical development project and the volume of SUSARs generated. This line listing should be accompanied by a concise summary of the evolving safety profile of the IMP.

As the Directive states, ECs may receive expedited individual domestic SUSAR reports provided that all SUSARs are reported at least quarterly (section 6.3.1.6.5) and that investigators may be informed via a line listing of SUSARs in periods as warranted by the nature of the clinical development project and the volume of SUSARs generated (section 6.4); thus, AZ decided to submit quarterly line listings of all SUSARs to both ECs and investigators.

AZ quarterly line listings (QLLs) contain:

• All SUSAR cases reported for the IMP during specified time frame, regardless of where they occurred in the world.

• SUSARs on all treatment arms, including comparators. (study procedure, surgery, radiotherapy, and placebo).

• For the IMP, study procedure, surgery, radiotherapy, and placebo, expectedness is assessed against the AZ IMP.

• For comparators, expectedness is assessed against the comparator SmPC.

• The QLLs also include SUSARs on the IMP from sources other than AZ-sponsored studies, such as unsponsored studies, postmarketing surveillance studies, compassionate use, and spontaneously reported events.

• The QLLs also include SUSARs from other projects where the AZ IMP is used as a comparator.

The QLLs are produced automatically according to a defined schedule. A blinded QLL is produced for investigators and an unblinded QLL is produced for the ECs. A short safety summary is written and attached to the QLLs. This summary is written to maintain the study blind for investigators and AZ personnel. The QLLs and safety summary are then submitted to a Web site where they are retrieved by the Marketing Companies. They are printed and posted to the relevant ECs and investigators along with a cover letter.

Annual safety reports (ASRs)

In addition to the expedited reporting, sponsors shall submit once a year throughout the trial, or on request, a safety report to the CAs and ECs of the concerned Member States, taking into account all new available safety information received during the reporting period. Facts about ASRs include:

• ASRs must be produced for AZ products administered to subjects during ongoing AZ-sponsored Phase I–IV studies.

• ASRs should be submitted within 60 days of data lock point (based on first authorization of the trial by a CA).

• AZ's ASR schedule is based on Periodic Safety Update Report (PSUR), IND or EU first approval (existing products).

• for short-term trials, ASRs may be submitted within 90 days of the trial's end (AZ does not intend to routinely do this since the requirement is covered by QLLs).

• ASRs have elements similar to a PSUR and QLL.

When the sponsor conducts several clinical trials with the same tested IMP, a single ASR referring to several trials could be acceptable. In this case, the ASR must contain:

• a concise global analysis of the safety profile of the tested IMP taking into account all new findings related to the safety of the tested IMP in the concerned clinical trials and an analysis of the implications of the findings for the population included in each clinical trial covered by the report

• a detailed rationale on "whether or not it is necessary to amend the protocol or change/update the consent form, patient information leaflet, and the IB"

• line listing of all suspected serious adverse reactions (SARs), including SUSARs, by trial

• a summary tabulation of suspected SARs by trial, which

– should specify the number of reports for each body system, each ADR term, and each treatment arm, if applicable (IMP, comparator/placebo, blinded treatment)

– clearly identify the unexpected ADR terms.

Summary

The implementation of the EU CTD had a major impact on our systems, processes, and personnel. It has been extremely time consuming and resourceful. One extra headcount was recruited at each of the EU Marketing Companies to accommodate the increased workload.

AZ is complying with the escalated safety reporting requirements and is now sending expedited SUSARs and QLLs to many ECs and investigators throughout the EU. During one year, AZ produced approximately 200 QLLs, which were then distributed to numerous ECs and investigators. AZ has submitted 25 ASRs to ECs and CAs throughout the EU. Most countries accept AZ's implementation of the EU Clinical Trial Directive 2001/20/EC, however, some Member States have not yet implemented the EU Directive fully.

ENTR/CT3 Revision 2

In April 2006 Revision 2 of the CTD ADR reporting guideline was released. It is AZ's understanding that the revised guideline comes into immediate effect. Although this is unreasonable given that it will necessitate changes to companies' systems and processes, nevertheless, AZ is doing its best to fully comply as soon as it's reasonably possible.

The revised guideline is very welcome and contains some major changes regarding the reporting of SUSARs to ECs and investigators and the reporting of ASRs to ECs and CAs.

Revised changes to ASRs

For AZ, there are two major changes to the ASRs:

1. Section 5.2.1 states that the line listings should contain a trial specific line listing of all suspected SARs that were reported during the trial, from all sites within the period covered by the report.

2. Section 5.2.1 also states that expectedness is to be assessed with the reference document in force at the beginning of the period covered by the ASR.

AZ comment: AZ is pleased that the line listings will contain periodic data and will no longer contain cumulative data. AZ is currently amending the ASR to assess expectedness against the reference document in force at the beginning of the period covered by the ASR.

Revised changes to SUSAR reporting

For AZ, there are three major changes to the periodic reporting of SUSARs to ECs and investigators:

1. expectedness is to be assessed with the reference document in force at the beginning of the period covered by the periodic line listings.

2. Section 5.1.6.5 states that SUSARs should be periodically reported to ECs at least every six months.

3. a copy of the periodic SUSAR line listing should be sent to the concerned CA.

AZ comment: AZ is currently assessing these changes. All periodic reports covering a period of up to one year will be amended so that the expectedness is assessed with the reference document in force at the beginning of the period. AZ is considering continuing reporting SUSARs to ECs and investigators quarterly, rather than at six months as stated in Revision 2. The company is currently reviewing the unblinding issue and whether it is taking unnecessary precautions to prevent unblinding of AZ personnel and investigators.

Mary O'Hare, BSc, PhD, is drug safety expert, clinical drug safety, with AstraZeneca, Alderley Park, Macclesfield, Cheshire SK10 4TG, United Kingdom, +44(0) 1625 517778, email: Mary.O'Hare@astrazeneca.com.