ICH-E2A: Safety Reporting in Clinical Trials in Australia

by

Dr. Ananda Kondepati, M.D. and

Dr. Shalini Pasumarthi, M.D.

Research Program Director:

Pr. Peivand Pirouzi

• The TGA is a division of the Australian Government Department of Health and Ageing, and is responsible for regulating medicines and medical devices.

• The TGA relies on the public, healthcare professionals and industry to report problems with medicines or medical devices. The TGA investigates reports received by it to determine any necessary regulatory action.

TGA : Therapeutic Goods Administration

• The TGA administers the Therapeutic Goods Act 1989 (the Act), applying a risk management approach designed to ensure therapeutic goods supplied in Australia meet acceptable standards of quality, safety and efficacy (performance), when necessary.

Therapeutic Goods Administration (TGA).

• Through the efforts of the International Conference on Harmonisation (ICH), standards of conduct for clinical trials have been determined that are now essentially uniform for all the major regulatory agencies world-wide, including Australia’s Therapeutic Goods Administration (TGA).

• These comprise the so-called principles of “Good Clinical Practice” or GCP.

• . All these principles have their origin in the World Medical Association’s Declaration of Helsinki.

• WORLD MEDICAL ASSOCIATION DECLARATION OF HELSINKI: Ethical Principles for Medical Research Involving Human Subjects <http://www.wma.net/e/policy/b3.htm> (as at 19.12.2005)

Therapeutic Goods Administration (TGA).

• The Therapeutic Goods Administration (TGA) has adopted the European Union version of these ICH GCP guidelines in Australia .

• There are two schemes under which clinical trials involving therapeutic goods may be conducted, the CTX Scheme and the CTN Scheme.

• It is the decision of the Sponsor and HREC as to which scheme is used.

• As a general rule, phase III, IV and bioavailability/ bioequivalence studies of medicines are most suited to the CTN scheme. However, the CTN Scheme can also be an option for earlier phase (I & II) studies if there is adequate preclinical review available, especially of safety. The CTN form is used to notify the TGA of HREC and institutional approval to start a trial being conducted under the CTN Scheme at a site.

Clinical Trial Notification (CTN) (Scheme)

• As a general rule, phase III, IV and bioavailability/ bioequivalence studies of medicines are most suited to the CTN scheme.

• However, the CTN Scheme can also be an option for earlier phase (I & II) studies if there is adequate preclinical review available, especially of safety.

• The CTN form is used to notify the TGA of HREC and institutional approval to start a trial being conducted under the CTN Scheme at a site.

Clinical Trial Exemption (CTX) (Scheme)

• Clinical trials are conducted under CTX Scheme when the CTN Scheme is not suitable .

• A sponsor cannot commence a CTX trial until written advice has been received from the TGA regarding the application;

• and approval for the conduct of the trial has been obtained from an ethics committee and the institution at which the trial will be conducted.

Safety Reporting in Clinical Trials in Australia

• NHMRC - Australian health ethics committee (ahec)

• monitoring and reporting of safety for clinical trials involving therapeutic products

• Position statement – May 2009

• In the Australian context, the National Health and Medical Research Council (NHMRC) plays a major role in giving guidance and advice to Human Research Ethics Committees (HRECs), for the pivotal role they play in reviewing the scientific and ethical aspects of clinical trial proposals, and undertaking the chief role of ongoing monitoring of such research.

• The National Statement on Ethical Conduct in Human Research (National Statement) recognises that sponsors, investigators/researchers, institutions and HRECs all have relevant responsibilities.

HREC

• An HREC is responsible under GCP for reviewing as a minimum the --

• trial protocol,

• investigator’s brochure,

• informed consent forms and

• patient information documents,

• procedures for subject recruitment,

• any planned payment or compensation initiatives for the proposed trial, and

• the investigator(s) qualifications.

HREC

• An HREC must receive from any investigator(s), in an expedited manner ---

• any deviations from the trial protocol that were undertaken by investigators to prevent imminent harm to subjects;

• any change significantly affecting the risk/benefit of the trial;

• all adverse drug reactions that are serious or unexpected;

• and any new, significant safety information that comes to hand.

Adverse Event (Drug)

• Any untoward medical occurrence in a patient or clinical investigation subject administered a pharmaceutical product and which does not necessarily have a causal relationship with this treatment.

• An adverse event can therefore be any unfavourable and unintended sign, symptom, or disease temporally associated with the use of a medicinal (investigational/experimental) product, whether or not related to this product.

Adverse Drug Reaction (ADR)

• For unapproved medicines: all noxious and unintended responses to a medicinal product related to any dose should be considered ADVERSE DRUG REACTIONS.

• The phrase “responses to a medicinal product” means that a causal relationship between a medicinal product and an adverse event is at least a reasonable possibility, i.e. the relationship cannot be ruled out.

An Unexpected Adverse Drug Reaction

• An Unexpected Adverse Drug Reaction is an adverse reaction, the nature or severity of which is not consistent with the applicable scientific information (e.g. Investigator’s Brochure for an unapproved investigational product or Product Information (PI) document or similar for an approved, marketed product).

• If a previously unexpected adverse reaction is added to the Australian Investigator’s Brochure, then that particular reaction ceases to be unexpected in Australia.

Investigator/researcher responsibilities • The investigator/researcher must capture and report AEs, including SAEs, which occur at their site to the sponsor in accordance with the study protocol.

Investigator/researcher responsibilities

• The investigator/researcher must report all SAEs to the sponsor immediately (within 24 hours) in accordance with the study protocol and GCP guidelines as adopted by the TGA.

For each trial, investigator/researcher must also provide:

2.1

in accordance with individual institutional requirements NB: institutions should seek to keep individual requirements to minimum or utilise such requirements in a highly targeted manner if these are particular safety concerns

to institution (or HREC as specified by institution – AEs and SAEs occurring at their sites

2.2 In a prompt manner

To HREC responsible for trial •information which materially impacts the continued ethical –acceptability of the trial or information that requires, or indicates the need for, a change to –the trial protocol, including changed safety monitoring in the view of the investigator or sponsor

For each trial, investigator/researcher must also provide:

2.3 At least six-monthly

To HREC responsible for trial listing of all susars, Australian and International, occurring with – a compound including sponsor and investigator comment as to whether action – is planned for the trial on the basis of the reports -EU format is acceptable

2.4

At least annually

To HREC-an updated investigator Brochure, or –an EU ASR(or similar format report), or –current, approved product information (pi), if appropriate (eg in a study for a product approved in Australia or where an investigator Brochure is no longer maintained) -other reports consistent with section 5.5.5 of the National Statement and Good Clinical Practice (GCP) as adopted by the Therapeutic Goods Administration (TGA

Regarding annual reports

For each, include sponsor and investigator comment as to whether action is planned for the trial on the basis of the reports

• for trials that are investigator or collaborative group sponsored in which an IB, EU ASR or PI are not available, then a trial update may be submitted that provides appropriate review of safety information in the previous 12 months

• when sponsors need to provide some or all of this information to the investigator, sponsors need to include clear advice as to whether the information requires or indicates the need for a change in the trial protocol including changed safety monitoring

Regarding annual reports • to enable investigators to fulfill their responsibilities to institutions, sponsors

need to respond to requests from investigators for clarification of such advice or information .

• when investigators report this information to the institution they should provide their own opinion in regard to potential impact on ethical acceptability and need for action .

• the timing of ASR production by sponsors and the progress report to the ethics committee by an investigator may be asynchronous.

Institutional responsibilities

• Institutions in Australia have a wide variety of models of fulfilling research governance and ethical review responsibilities.

• Institutions and HRECs should work together to establish that an adequate mechanism is in place to monitor the conduct of clinical trials at sites for which they have responsibility.

Urgent Safety Related issues • Where it is necessary to eliminate an immediate hazard to research

participants, modifications or changes to the research project will be implemented without prior HREC review and site authorisation

• The CI/Site PI will notify the approving HREC and RGO of amendments arising from urgent safety-related events immediately and in writing (email is acceptable).

• The CI will submit the implemented modification or change, the reasons for it, and, if appropriate, the proposed protocol amendment(s) to the HREC for review within 5 working days and the Principal Investigator will advise the Research Governance Officer of developments.

HREC responsibilities

• HRECs have an obligation to ensure that any changes in the benefit/risk balance of a study are compatible with continued ethical approval.

• Must be aware of the proposed monitoring arrangements as part of the approval process, and

• should be satisfied, that through the collaboration of the institution, sponsor and investigators that those processes are commensurate with the risk, size and complexity of the proposed research.

HREC responsibilities

• This may lead to the following mechanisms during the conduct of the study:

• A. Use the monitoring arrangements described in the trial protocol by the sponsor.

• These could include one or more of the following:

• - a pharmacovigilance group in a company-sponsored clinical trial

• –a trial management committee

• –a data safety monitoring board

• –a simpler but separate review process for investigator or collaborative sponsored trials.

• B. Conduct review of safety information within the HREC if the HREC has sufficient resources and expertise.

Sponsor responsibilities

• In a prompt manner, sponsors must communicate to investigators information which could adversely affect the safety of subjects, materially impact the continued ethical acceptability of the trial or that requires (or indicates the need for) a change to the trial protocol, including changed safety monitoring.

• ONLY IF the investigator, HREC or sponsor consider it to be necessary because of the risk, size or complexity of the proposed research, is the sponsor required routinely to send individual SUSARs from Australian or international sites to investigators.

Sponsor responsibilities

• Sponsors should:

• establish safety monitoring processes that are commensurate with the risk, size and complexity of the proposed research

• be in regular communication with the investigators

• keep investigators up to-date with safety issues in a trial in a manner that is consistent with the risk, size and complexity of the proposed research

• provide to investigators the periodic information listed under section 2 to facilitate investigator submission to the relevant HREC

Reporting to the TGA

• Sponsors are responsible for reporting individual case safety reports (ICSR) to the TGA in accordance with expedited reporting guidelines.

• In Australia, the TGA requires:

• • Rapid reporting of individual SUSARs and SUADEs within 7 calendar days for:

• - Fatal and unexpected events occurring within Australia;

• - Life-threatening and unexpected events occurring within Australia.

• This can be an initial report with a full report following within 8 days

Reporting to the TGA

• Reporting within 15 calendar days for:

• - All other individual SUSARs and SUADEs that are not fatal or life-threatening occurring within Australia.

• The minimum criteria that must be provided in expedited safety reports to regulatory authorities are:

• • An identifiable patient;

• • A suspect medicinal product/device;

• • An identifiable reporting source;

• • An event or outcome that can be identified as serious and unexpected, and for which there is a reasonable suspected causal relationship

Questions to be answered

• 1.What is the primary outcome variable? Is the data equivocal?

• 2. Rely on surrogate end points?

• 3. Are these outcomes specified by guidance documents as the preferred measures for the outcome of interest?

• 4. Have you considered ongoing treatment of trial subjects should they respond to unapproved medical product under investigation? E.g. Cancer and CCF pts.

• 5. Fully informed consents--- updated? Know the full description of trial participation? Lay language? Can the subject make an informed consent?

References

• 1. http:www.tga.gov.au

• 2. www.health.gov.au

• 3. ICH.org

• 4. Prof. Pivand Pirouzi’s Lecture notes, AAPS

Thank you

Thank you