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Published: 8 November 2018

Consultations

Outcome of the consultation on the Update to the Guideline on the Regulation of Therapeutic Products – Part 11: Clinical Trials

About the consultation

In June 2018 Medsafe sought feedback on a proposed major revision of the regulatory guidelines dealing with the requirements for clinical trials. The revision was intended to update changes to requirements and processes that had occurred since 2015, and included a trial of the Ministry of Health's new consultation process using the Citizen Space consultation tool. Medsafe would like to thank all who took the time to prepare a submission and provided their comments and suggestions.

Submissions received

Medsafe received 20 submissions on the Citizen Space platform, and one submission by email. The submissions are published below, except for four submissions where permission to publish was withheld. Personal information that can identify the submitters has been removed where requested.

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Consultation feedback

The consultation opened on 22 June 2018 and closed on 10 August 2018. The consultation period was extended for a week by request.

More than half the submissions were made on behalf of an organisation based in New Zealand. Just over a third of submitters were on behalf of organisations based in Australia. Over 75% of submitters felt that the information presented in the updated guideline to be appropriately presented, and the content was relevant to describe the situations where approval for clinical trials is required, and the processes involved. 85% of submitters considered the revised Clinical Trial Site notification process to be an improvement. A similar percentage of submitters agreed that submitting a synopsis of the final clinical trial report was sufficient.

There were some requests for additional detail on some matters. A number of submitters raised concern over the proposal to require the Principal Investigator to maintain a Product Specification File. Several submitters also suggested wording changes for improved clarity, and minor corrections to omissions, punctuation or phrasing, and adding links to useful information. Where appropriate, these have been incorporated into the final document. The following summarises the feedback received according to the themes which emerged from the submissions and Medsafe's response.

Section 1 - Legislation

Add section 32 Treatment Injury to the reference to the Accident Compensation Act 2001.

A suggestion was received, to add section 32 to the listing for the Accident Compensation Act.

Response

Medsafe would prefer not to mention section 32 of the Accident Compensation Act, only including a reference to that Act, and to leave the applicant to determine their responsibilities under that Act. Applications should contact the Accident Compensation Corporation (the ACC) directly if they have queries. The ACC can be contacted at: https://www.acc.co.nz/contact/.

Section 2 - Overview of Regulation of Clinical Trials in New Zealand

Clinical trials and placebos

Queries were made about the likelihood of a trial involving only placebos, the definition of a placebo, and whether Medsafe would be happy that a placebo that consists of excipient, detergents and vaccine by-products are tested without review.

Response

In the context of the clinical trial, a placebo is a version of the investigational medicine without the active ingredient(s), and thus one that does not have a therapeutic effect. Medsafe has revised Section 2.4 to explain that trials involving only approved medicines and placebos do not require approval. Under the current Medicines legislation, there is no provision for requiring approvals of placebos in clinical trials, or of substances that do not have a therapeutic effect.

Consistency of definition of a unapproved medicine

A suggestion was made to keep consistency with the prior definition of an unapproved medicine (new dosage form or strength) stated in the guideline rather than use 'different formulation' which has a broader meaning.

Response

Medsafe has revised the guidance in Section 2.4 of the guideline to say "'Unapproved medicines' include new chemical or biological entities and new dosage forms and new strengths of approved medicines, and a different, unapproved formulation of an approved medicine."

Email notification of clinical trials of medical devices and clarification regarding whether medical devices trials require approval

A query asked whether it was acceptable to have only a simple notification of clinical trials of medical devices. A request asked to change the phrasing about the exclusion of the definition of medical devices from the term 'medicine'.

Response

The clinical trials guideline can only apply under current legislation (the Medicines Act 1981 and the Medicines Regulations 1984). Medsafe has changed the guidance in this bullet point in Section 2.4 to replace "Clinical trials of medical devices do not require approval" with "There is no provision under the current Medicines legislation to require approval of clinical trials involving medical devices."

The Food and Drug Administration Safety and Innovation Act (FDASIA) and encouraging clinical trials to be conducted in New Zealand

A submitter proposed that there should be a designation of breakthrough therapy to encourage home-grown innovative research and allow innovative medicines to be developed in New Zealand.

Response

There is no provision under the current Medicines Act to enable encouraging clinical trials to be conducted in New Zealand. This would require changes to the Medicines legislation, which is outside the scope of the review of the clinical trials guideline.

Publication of clinical trials and results and patients' rights to know about the results of their trials

There was a proposal that there should be regulation regarding publicising clinical trials and publishing results, and that patients should have access to both positive and negative results.

Response

There is no provision under the current Medicines Act to require publicising clinical trials or publishing study results or to inform patients of the results. This would require changes to the Medicines legislation, which is outside the scope of the review of the clinical trials guideline. Information on clinical trials being conducted can be found on the Australian New Zealand Clinical Trials Registry at http://www.anzctr.org.au/.

Greater clarity regarding all clinical trials following GCP

A suggestion was made that the guideline should say that all clinical trials should follow GCP, not just clinical trials that require approval.

Response

Medsafe has revised the introduction to Section 2 to make this clear.

ACC-equivalent compensation of injuries as a result of a clinical trial

A request was made to include in the guideline, legally binding provision for compensation of injuries arising from clinical trials.

Response

The issue of compensation for injuries suffered as a result of a clinical trial is beyond Medsafe's authority and the scope of the Medicines legislation. Applicants requesting approval of a clinical trial should consult with the Accident Compensation Corporation about their responsibilities for compensation in the case of injury suffered as a result of a clinical trial. The issue of compensation for injuries arising from a clinical trial may be a matter for Ethics Committees to consider also.

Section 3 - Application for approval of a clinical trial

SCOTT and GTAC application forms

A submitter queried whether Medsafe will be adding a GTAC option to the Online Forms system.

Response

Following discussion between Medafe and the GTAC standing committee secretariat, the GTAC has agreed to use the SCOTT Online Form. Hence, all applications should now be made using the SCOTT form on Online Forms. The guideline has been updated to reflect this change. Unfortunately, it is not possible at this time to change the form itself to mention both SCOTT and GTAC.

Medsafe's approval letter, importation of trial medicine and other items such as ediaries

There were queries about what is authorised by Medsafe's approval letter (of the clinical trial) to be imported into the country, and whether the imported products could be delivered to alternative sites.

Response

The approval letter from Medsafe will only authorise the importation of trial medicines (including rescue medications) that are the subject of the trial. These should be declared in the application. The approval letter is not intended to authorise the importation of other, restricted, non-medicine items into the country. Alternative delivery site addresses and additional investigators for the trial medicines should be declared on the application form. If this is done, they will be captured and included in the approval letter.

Abbreviated approval process for clinical trials that meet an unspecified need

A request was made for consideration of an abbreviated clinical trial approval process for NZ research centres that have innovative research, and for clinical trials for unmet needs.

Response

An abbreviated process for clinical trial approval is unnecessary. Almost all applications are reviewed (and, if appropriate, are approved) within 2 to 3 weeks of receipt.

Greater flexibility, Sub-investigators, GPs or patients' doctors participating in a trial without being part of the clinical trial site

A submitter commented that it should be possible for sub-investigators or patient's doctors to participate without being part of the clinical trial site. This would allow the patient's own doctor to monitor the patient in long-term trials.

Response

This is already possible. All this needs is for the study investigators to design the parameters of the trial accordingly to build in the necessary flexibility to allow participation (by patients and their doctors, as remarked in the comment), to seek protocol amendments, to add new sites, to inform of upcoming trials and request subjects, and to determine or screen participants for clinical trials. There is no provision in the Medicines legislation to impose these as requirements for clinical trials.

Email address for submitting changes to clinical trials, adverse reaction reports and study reports and communications about clinical trial applications

There was a query about whether there is a separate email contact for clinical trials, other than info@medsafe.govt.nz.

Response

Medsafe now has a new email address for correspondence relating to clinical trials: clinicaltrials@medsafe.govt.nz . This will be used in the updated guideline for all clinical trial related correspondence and reports.

Whether the applicant (sponsor) must be present in New Zealand

A query was made about whether the applicant must be present in New Zealand.

Response

Section 30(1) and (2) of the Medicines Act 1981 states that "…an application for the approval of the Director-General in respect of this section shall be made by the importer, manufacturer etc. in New Zealand of the medicine, and shall…"

The reference to 'in New Zealand' in section 30 of the Act clearly means that the person (or company or organisation) must be present in New Zealand.

Whether an applicant must be a person, and whether a company can be an applicant

A query was made about whether the applicant must be a person, as for the majority of the applications, it is the company or organisation that is legally responsible.

Response

Various sections (for example, section 23A, or section 30) of the Medicines Act refer to an applicant as a person, not a company, institution or organisation. However, section 51(b) of the Act allows that an applicant can be a body corporate. Thus, in the regulatory guideline, Section 5.2.1 states that it is common for a local person, company or organisation to act as the applicant. Medsafe accepts that for the majority of the time, the company is the applicant and is the entity that is legally responsible, and the person signing the application is acting on behalf of the company (ie, holds the delegated responsibility).

Section 30 providing for exemption from the requirements of section 20

A query was received about whether it is the intention to make the sponsor legally liable, as section 30 of the Act exempts the applicant from the provisions of section 20.

Response

The purpose of section 30 is to allow an unapproved medicine to be distributed, for the sole purpose of clinical trial, in order to obtain scientific and clinical information. While the penalties associated with section 20 in relation to the distribution of an unapproved medicine may not apply, section 30 provides for the Director-General of Health to require information to be provided about the trial or the trial medicine, to determine whether an exemption under section 30 should be granted (the propriety of the application), or to stop a clinical trial from proceeding by revoking approval if the trial is not being conducted according to the approved protocol.

Pre-submission meetings

A submitter asked if it is possible to have an option for pre-submission meetings with Medsafe for high risk protocols or products.

Response

This is not currently possible. The applications for scientific and clinical approval of clinical trials are reviewed and considered by SCOTT or GTAC, not by Medsafe.

Omission of Sections 3.6 and 3.7 from the guideline, and addition of links to Sections 5 and 6.

A submitter queried the omission of Sections 3.6 and 3.7 from the index, and another submitter suggested adding a link to Sections 5.21 and Section 6 to the references in Section 3.3

Response

Sections 3.6 and 3.7 were omitted accidentally from the index and this has been corrected. Links to Sections 5.21 and 6 have been added.

Section 4 - Notification of Clinical Trial sites

Clarification of site manager and the notification of sites

A submitter commented on the clarity of the wording of the guidance. A submitter queried if 'site manager' is the best title.

Response

Medsafe has clarified the guidance to say that applicants requesting approval should check the list of notified sites, and not commence a clinical trial that requires trial subjects to stay overnight (or longer) for observation, at a site unless the site has been notified. Medsafe has added an explanation that in most instances, the site manager will be a site staff member who has the responsibility for managing the site, its staff, and its procedures.

Section 5 - Good Clinical Practice requirements

A guideline for appropriate emergency equipment that should be available to hand

A suggestion was made that perhaps there should be a guideline on what emergency equipment is appropriate to have at hand in the event of an adverse reaction.

Response

Medsafe considers that it is for the Site Manager, in connection with the applicant and/or the Principal Investigator to take on the responsibility to determine what equipment and procedures they must have at hand in order to respond to an emergency (such as a Critical Incident) in trial subjects staying overnight at a clinical trial site.

Approval for protocol changes thought to be required now, and impact on timelines

Submitters queried the change in requirements, in that approval is necessary for protocol changes and amendments.

Response

This is not a new requirement. Approval has always been required for changes to trial protocol. Section 2.4 on page 7 of the current guideline states "Approval must be obtained for each study using a new medicine. Any subsequent amendment of a trial protocol must also be approved." There should be no impact on timelines, as there has been no change to the current situation.

Queries about what type of changes to trial protocol require approval

Submitters asked about what changes require approval (eg, logistical or administrative), for example administrative protocol amendment or major protocol amendment.

Response

All changes should be notified. The revision seeks only to provide a logical flow to the order of information - no changes to the requirements has occurred.

Mentioning that approval is also required by HDEC

A submitter commented that changes to trial protocol also requires HDEC approval.

Response

Medsafe has amended the guideline to mention that approval is also required through HDEC, and included a link to Section 6.6.1.

Reference made to Good Research Practice Standards

A submitter queried the reference to Good Research Practice Standards in Section 5.2.1 of the guideline

Response

This was an error. Medsafe has revised this reference to say 'Good Clinical Practice' standards instead of Good Research Practice standards.

Monitor and monitoring of clinical trials

A submitter sought clarification on the monitor (or clinical research associate), suggesting that the New Zealand sponsor may not do this if they are just the applicant.

Response

Section 5.2.1 explains that when the trial is approved, the applicant becomes the sponsor of the trial. The sponsor has responsibilities in regard to ensuring that the trial is being conducted in accordance with the approved protocol. This is usually done by monitoring the conduct and progress of the trial. The sponsor does not have to appoint a monitor (usually a clinical research associate) and may choose to do this monitoring themselves. Regardless of who does the monitoring, it remains a responsibility of the sponsor to ensure that it is done.

HDEC usage of terminology such as Principal Investigator, Lead Investigator, Coordinating Investigator

Submitters commented on the inconsistency of definition of terms used by HDEC and Medsafe for Principal Investigator, Sub-Investigator, Lead Investigator, Coordinating Investigator and Sponsor.

Response

Medsafe's usage of the terms is in line with global usage. Changes to definition of these terms as they are used in the guideline are not necessary. The role of the Coordinating Investigator is not the same as that of the Principal Investigator. The Principal Investigator is usually not the Sponsor, and they have different responsibilities.

Product specification file (PSF) and its maintenance

Submitters raised concerns regarding the purpose of a product specification file, and who should be responsible for its maintenance, noting that Principal Investigators usually have no involvement in product manufacture and that it is the role of the sponsor to check that specifications are met.

Response

Medsafe has noted the concerns. The reason for the requirement regarding a specification file (of the investigational product) is to enable Medsafe to audit manufacturers based in New Zealand which are manufacturing a trial medicine for a clinical trial. The manufacturer will be required to hold a specification file, and provide to the sponsor of the clinical trial a certificate of analysis for each batch of investigational medicine manufactured. The manufacturer of the medicine is responsible for maintaining the specification file. The sponsor will verify the investigational product meets the specifications of the Investigator's Brochure before it is released for administration to trial subjects. Medsafe has revised the guidance in this section of the guideline.

Certificate of Analysis

Submitters also queried the issuing of a Certificate of Analysis to the Principal Investigator, noting that it is the sponsor who checks that specifications are met. A submitter also asked if the Certificate of Analysis is required to be part of the SCOTT application form. A submitter asked if the Certificate of Analysis is the details of how UP vials are used in compounding the final product to be infused.

Response

Medsafe has noted the concerns. The Certificate of Analysis is a document issued by a testing laboratory (and this testing can be done by the product's manufacturer) to attest that the manufactured product meets the specifications that have been set by agreement (or by approval of the regulator). The Certificate of Analysis for the investigational medicine does not need to be part of the application for approval of the clinical trial. However, the sponsor or principal investigator must assure themselves that the investigational product meets the approved specifications (ie, is indeed the product described in the Investigator's Brochure) before it is allowed to be administered to the study participants. Medsafe has revised the guidance to reflect that a Certificate of Analysis for each batch of investigational product manufactured should be issued to the sponsor, who will check that specifications are met before releasing the batch for the trial.

Labelling of investigational product and the effect of classification change

A submitter sought clarification on whether the labels of investigational products used in trials need to include the New Zealand applicant's contact details. A query was also made about how changes in classification affects labelling, for example, a controlled drug that is B2 which might be reclassified soon.

Response

The New Zealand contact details must be used, in the event that an emergency occurs and the sponsor or Principal Investigator has to be contacted. The address and telephone number of the main contact for information on the product, clinical trial and for emergency unblinding need not appear on the label where the subject has been given a leaflet or card which provides these details and has been instructed to keep this in their possession at all times.

Medsafe considers that the provisions relating to the usual label requirements for medicines (as detailed in Regulation 15 of the Medicines Regulations 1984) as a result of changes to classification do not apply to unapproved medicines being used in clinical trials, particularly as it would not be possible to 'blind' the trial if it included a classification statement.

To aid navigation through the guideline, Medsafe has placed information relating to labelling of investigation products in a new subsection 5.3.1, and information relating to distribution and supply of investigational products in a new subsection 5.3.2.

Section 6 - Records and Reporting

Using broad, instead of specific, references to legislation to avoid having to update the guideline on a regular basis

A suggestion was made to have more broad statements such as "…ensure compliance with New Zealand privacy legislation…" instead of specifying the actual legislation, to avoid having to update the guideline on a regular basis with changes of legislation references.

Response

Medsafe aims to review the regulatory guidelines at appropriate intervals. If there have been changes to other legislation referenced in the guideline in the meantime, the appropriate changes will be incorporated at the next review.

Storage of records outside New Zealand and the Privacy Act

A submitter queried whether storage of records outside of New Zealand is within the parameters of the Privacy Act.

Response

Medsafe does not consider allowing trial records to be stored outside of New Zealand to be operating outside the scope of the Privacy Act. Medsafe has added clarification that the records may be stored overseas provided they stored in accordance with New Zealand privacy legislation and Health (Retention of Health Information) regulations, and are maintained in an accessible form until they are disposed of in accordance with New Zealand law.

Medsafe timeframe for retention of records and HDEC timeframe for keeping records of paediatric trials

Submitters pointed out the difference in timeframes for record keeping and suggested that Medsafe's requirement match that of the HDEC.

Response

The regulatory guideline says that the timeframes of records will depend on the nature and duration of the trial. No change was made to this statement. Medsafe's requirement for clinical trials is that records must be kept for a minimum of 10 years. Where it is necessary to meet the longer timeframe of another regulatory regime (for example, HDEC requirements relating to paediatric trials), this would also meet Medsafe's requirement for retention period.

Informing Medsafe of safety related events and overseas events

Submitters made suggestions to improve the wording of the guidance.

Response

Medsafe agrees with the suggestions, and has revised the guidance.

Advice regarding HDEC requirements

A suggestion was made to provide more information about HDEC requirements.

Response

Medsafe considers that it would be inappropriate to provide advice in Medsafe's regulatory guideline on which HDEC requirements have to be met. Applicants should contact the HDEC directly regarding their requirements and approvals. Medsafe has added a statement to Section 2.6: "Applicants are advised to contact the Health and Disability Ethics Committees regarding their reporting requirements."

Aligning with HDEC's definitions of what amendments need submitting and approval

A suggestion was made to align with HDEC's definitions of what amendments need submitting and approval.

Response

This is not possible since SCOTT, GTAC, and HDEC consider different issues when reviewing clinical trial applications and any subsequent changes.

Timeframes for notification of changes, and the documents that should be submitted

Requests were to specify a timeframe to notify changes or amendments to trials, and to clarify the document types that should be submitted, and whether the 6-monthly time report can be used as a timepoint for notification of documents that have changed in the prior 6 month period.

Response

Medsafe does not intend to specify a timeframe for notification of changes to trial protocols. Since changes to trial protocols must be approved before they can be implemented, Medsafe considers that applicants will notify the proposed changes in good time so that approval can be obtained.

Medsafe has added an Appendix to the Guideline, listing the essential documents that should be submitted with the application for approval, and when there have been changes to the trial protocol. Changed essential trial documents should be submitted as soon as is practicable. Approval for changes to the other documents mentioned in the CHMP GCP guideline list still need to be obtained. These other documents may be submitted at any time. The six monthly reporting period would be suitable for submission of these other changed documents.

More clarity on 6-monthly clinical trial reporting

Submitters sought more clarity on when 6-monthly reporting to Medsafe ceases.

Response

There is no need to continue providing 6-monthly reports to Medsafe after the New Zealand arm of the trial has ended, even if the trial is continuing elsewhere. However, Medsafe should be informed when the New Zealand trial or the New Zealand arm of a multinational trial is completed. Section 6.6.2 has been revised to make this clear.

At the global End of Trial, a synopsis of the final report should be sent to Medsafe when available, using a Post Approval Form (PAF) in Online Forms at https://nz.ethicsform.org .

Clinical Trial Site Notification Form

Scope of practise, trial site information, and qualifications at the notified site

A suggestion was made that the notification form should ask for the scope of practice of the notified site, the trial site information and qualifications of staff.

Response

Medsafe considers that it is unnecessary to declare the scope of practise of the site on the site notification form. Only sites where trial subjects stay overnight are required to be notified, and the site should have processes and staff in place to respond to an emergency in the event of any critical adverse reaction to the trial medication (Critical Incident). It is not intended that the site must be a site for the practice of medicine.

Clarification regarding site manager for a large hospital where trials are run through multiple departments

A submitter commented that the process is very vague in the situation where clinical trials are run through multiple departments that do not overlap.

Response

Medsafe recommends that a large hospital where clinical trials are conducted should have a clinical trials coordinator to manage the legislative regulatory aspects of all the trials, and this person should be the person to provide the notification that the hospital is equipped to deal with emergencies.

Form to list types of trials being conducted (phase, indication, research purpose, status)

A comment was made that the form could include descriptions of the types of trials being conducted and the status of the study.

Response

The only purpose of the form is to notify that the site has appropriate procedures in place to deal with an emergency arising from a clinical trial. It is not intended to be a registry of trials at the site. The Australian New Zealand Clinical Trials Registry is located at http://www.anzctr.org.au/.

Form to include contact name of person who can answer questions from potential patients

A request was made to include the name of a person who can answer questions about the trial from potential patients.

Response

The only purpose of the form is to notify that the site has appropriate procedures in place to deal with an emergency arising from a clinical trial.

The person who can answer questions from potential patients would be the Principal Investigator. Trial subjects will have this information on being contacted to investigate their suitability for participation in the trial.

Form to include name of site, address of site, and the manager of the site

A comment was made that the form could include the name of the site, the site address and the manager of the site.

Response

These details are already on the notification form.

Re-notification of clinical trial site

Clarification of the self-certification process sought as each listed site does not show the types of trials, and some sites show up several times with several different contact people

A submitter commented on the current list of self-certified sites, as it did not show the types of trials being conducted, and some sites appear on the list several times with different contact people.

Response

The self-certification process was not intended to show which sites are doing what type of trials. It was intended to show which sites (where trial subjects stay overnight) are adequately prepared to respond to an emergency (such as a Critical Incident). Medsafe has reviewed the listing, and concluded that requiring the Principal Investigator to make the declaration for the site had resulted in the same site being listed multiple times, by different Principal Investigators associated with different trials. This is the reason why Medsafe is changing to a process where the manager of the site makes the declaration.

Suggestion to add the sponsor to the list of notified clinical trial sites.

A suggestion was made to include the name of the sponsor of the trial to the list of notified sites.

Response

The list of notified sites is only to indicate that the site has been declared to have appropriate emergency procedures in place to respond to an emergency (such as a Critical Incident) affecting a trial subject staying overnight at the clinical trial site. Addition of a sponsor's name serves no utility.

Suggestions to require re-notification 6 monthly or annually, or to email the site managers each year to ensure currency of the list, to add the date of completion of the Clinical Trial Site Notification form, and a site contact email address

Submitters commented that it would be imperative for the list to be kept current. Suggestions to achieve this included 6-monthly or yearly notification.

Response

After deliberation, Medsafe has decided not to require 6-monthly or annually at this time. Medsafe will review how well the process is working at the next review of the guideline. Medsafe will consider including the date that a notified site is listed, and the email address of the site contact person.

Other comments or suggestions

Implement change to enable access to, and participation in clinical trials

A number of comments urged Medsafe to make changes so that patients could find out more about clinical trials being conducted that might be applicable to them, and have access to participation, and to the results.

Response

Medsafe has to work within the current Medicines legislation. It is not possible to make the changes suggested at this time, as this would require changes to the legislation. The scope of this review is limited to the regulatory guidance regarding applying for clinical trials, and the obligations of sponsors. There is no provision in the current legislation to require the publicising of trials or the publication of trial results. A register of clinical trials being conducted in the trans-Tasman region is available at http://www.anzctr.org.au/ .

Medsafe notes that where a patient does not meet the criteria to be included in a trial, the patient's physician is able to ask the sponsor to supply the investigational product on compassionate use. Medsafe continues to list the criteria for a fee waiver for clinical trial applications in the guideline in order to encourage trials of innovative medicines.

Suggestion to have an on-line algorithm to work out whether approval is required, such as the UK clinical trials toolkit at: http://www.ct-toolkit.ac.uk/ , or the MHRA's algorithm at: https://assets.publishing.service.gov.uk/government/uploads/system/uploads/attachment data/file/317952/Algothrim.pdf

A submitter commented that it would be useful to have an on-line algorithm similar to those used in the UK.

Response

Essentially, the criteria for whether an application for approval of a clinical trial is required are:

Is the investigational product a new medicine?

Is the trial investigating a therapeutic purpose?

If the answer to both question is 'yes', an application is required.

If the answer to either question is 'no', an application is not required.

Medsafe will investigate creating additional guidance to supplement the guideline, such as flow chart. When it is ready, it will be presented for comment prior to incorporation into the next edition (as a minor update).

Disappointment at the lack of communication about this consultation

Some submitters expressed dismay at the lack of advance notice of the consultation.

Response

Medsafe apologises to the industry about inadequate advance notice. Medsafe endeavours to inform subscribers in advance as much as possible. On this occasion this was not possible, as this was the Ministry of Health's first trial of the consultation tool (Citizen Space). The timing of the process was not wholly within Medsafe's control.

Comments regarding the consultation tool

A number of comments were received about the ease of use of the tool, and suggestions for improvement.

Response

Medsafe and the Ministry of Health thank all submitters who provided feedback on the utility of the Citizen Space consultation tool. Over 70% of the submitters found the tool to be adequate, easy, or very easy to use. Only one submitter found it more difficult to use. Five submitters did not respond about ease of use. Suggestions for improving the tool, such as being able to move back-and-forth between pages, including space for additional comments, including space for including comments about the history and background of the submitter, downloading, saving, printing and forwarding a copy of the submission to other interested people, are very important in making the process as useful and as simple as possible. The suggestions have been sent to the developer of the software.

The following are Medsafe's responses to other issues that were also raised that are not in the submissions above.

Guidance on timeframe for retention of records to mention discontinuation of clinical development of the investigational product

A suggestion was made to change the timeframe for retention or records to include from the time of discontinuation of development of the investigational product.

Response

Medsafe considers that it is unnecessary to change the guidance to "Records must be kept for a minimum of 10 years from date the study ends or the formal discontinuation of clinical development of the investigational product". If a trial commences and ends normally, records are required to be kept for 10 years from the date the study ends. If the study has commenced and formal clinical development of the investigational product is discontinued, then the study would be halted and records would be required to be kept for 10 years from the date the study is halted.

Request for Medsafe clarification of HDEC standard operating procedures regarding Urgent Safety Measures and temporary halts

Medsafe was asked to clarify what HDEC's standard operating procedures relating to Urgent Safety Measures and temporary halts refers to safety related actions only.

Response

Medsafe cannot comment on whether HDEC's standard operating procedures regarding Urgent Safety Measures and temporary halts to clinical trials refer to safety actions only. The submitter must seek clarification from HDEC. However, Medsafe has added a request to the guideline to be informed in the event that a trial that is also being conducted overseas has been temporarily halted for safety reasons.

Arrangements for halting the New Zealand arm on termination of an overseas study

A comment was made that the last point of Section 6.5 of the guideline mentioned overseas studies only, and that arrangement should also apply to halting the New Zealand arm of the study.

Response

If a clinical trial that has a New Zealand arm is being halted overseas for safety reasons (eg, serious or unexpected adverse events, then the New Zealand arm of the trial should be halted also. Medsafe must be informed of the reasons, and the arrangements for doing so. Medsafe has revised subsection 6.5 regarding actions that require reporting, irrespective of whether these occur overseas or in New Zealand.

Clarification on where to report adverse events

Clarification was asked on where adverse reports should be reported, since Section 6.2 mentioned reporting to Medsafe, and the following Section 6.3, Reporting Other Adverse Events, mention is made of reporting to CARM.

Response

Medsafe has revised the information in the Section 6.2 to include the statement "Adverse reactions to unapproved medicines used in clinical trials are to be reported to Medsafe".

Rescue medication

A request was received to clarify if a rescue medication from a different sponsor, imported from overseas can be used in a clinical trial.

Response

The rescue medicine must be the same as that approved in New Zealand. If it is a different formulation, presentation (including packaging and labelling), strength, dose form etc. it is an unapproved product, and so must be included as an investigational medicine. Medsafe has added this an explanatory point in Section 2.4 of the proposed update to the guideline.

Online Forms user manual

A suggestion was made to include a link to Online Forms user manual.

Response

A link to the Online Forms User Manual has been added to the guideline.