Published: 31 August 2015
In April 2015 Medsafe published a draft guideline for medicines, the Guideline on the Regulation of Therapeutic Products in New Zealand. Part 8: Pharmacovigilance and sought feedback on the proposed guideline by 15 May 2015. Medsafe would like to thank those who took the time to prepare a submission and provided helpful comments and suggestions
Medsafe received 11 submissions in response to the consultation. All the submissions have been reviewed by Medsafe. The submissions are published below.
Note: Submissions have had personal information removed (where requested).
Submitters were generally supportive of the expanded detail contained in the draft guideline. There were some requests for clarity or additional detail on some matters. Several submitters suggested wording, format and layout changes for improved clarity. Where appropriate, these have been incorporated into the final document. The following section summarises the feedback received according to the themes which emerged from the submissions and Medsafe’s response.
The submissions raised the following issues for consideration by Medsafe and amendments have been made to the text of the guideline where these were considered to be appropriate.
A few submitters suggested defining the terms ‘should’ and ‘must’ to mean good practice or mandatory compliance, respectively.
Medsafe acknowledges that there is merit in this suggestion. However, in view of the age of the legislation and the potential impacts on other parts of the Guidelines on the Regulation of Therapeutic Products in New Zealand, the proposals in the suggestion should first be reviewed for impact and applicability at an organisation-wide level. This suggestion will not be included in this edition of the guideline, but may be adopted in a future edition.
A few submitters suggested including the EMA, ICH pharmacovigilance references, or association Code of Practice in Section 1 of the guideline.
Medsafe agrees that there is merit in including these references but believes these would be better placed in a new section. Medsafe has amended the guideline to include a section called “Best Practice Guidelines”.
One submitter commented that guidance on what sponsors could include in their sub-contracting arrangements should be removed from the guideline.
Medsafe is aware that most established sponsors will know of their responsibilities regarding sub-contracting for pharmacovigilance activities. However, the guideline is also intended for new sponsors and so this guidance will be retained.
One submitter suggested listing the responsibilities of a sponsor and adding contact details for a nominated person to use.
Medsafe has amended Sections 2.5.1 and 2.5.2 of the guideline to list the responsibilities expected of sponsors and Medsafe’s contact details for a nominated person.
One submitter commented that the guideline did not include advice on the sponsor’s responsibilities for reporting suspected adverse reactions in post-authorisation studies where the study has been initiated by an independent investigator.
Sponsors’ reporting responsibilities in this situation are unchanged. They should monitor and conduct timely reviews of relevant medical and scientific literature and media, and follow-up on any adverse reaction reports related to their products. Sponsors are not required to actively obtain case reports from the investigator. Therefore, such advice is unnecessary in this guideline.
Submitters commented that it should be made clear that when the sponsor agrees with the reporter that the adverse event is unrelated to the medicine, there is no need to report to CARM.
The guideline already states "all spontaneous reports notified by healthcare professionals or consumers to the sponsor are considered to be suspected adverse reactions, unless the reporter specifically states that the events are unrelated or that a causal relationship can be excluded."
Therefore, where the reporter states that the events are unrelated or that there is no causal relationship, the report is not of a suspected adverse reaction and reporting to CARM is unnecessary. No change to the guideline is required.
One submitter sought clarification on whether adverse reporting occurs only after all medicines in the case have been unblinded.
The guideline has been amended to clarify that reporting should only occur after all the blinded medicines have been identified and the identity of the suspected medicine has been determined.
One submitter suggested that there is no need to separate the type of adverse reactions as they should be treated in the same manner.
Medsafe agrees and has amended the guideline accordingly.
One submitter suggested that this point should be removed as it might discourage reporting where termination of supply was because of patient death.
A patient death that occurs in association with the use of a medicine would qualify as a serious adverse event (see Section 3.2.2) that would be required to be reported. Other instances of termination of supply do not need to be reported unless the termination was due to an adverse reaction. The guideline has been amended to make this clear.
Two submitters sought clarity on who is required to report and distinctions on the reporting requirements for different product types.
The section summary of Section 3 states clearly that this section outlines sponsor responsibilities. The title of the guideline states that Part 8 is about pharmacovigilance and the requirements apply to all medicines. There is no difference in the requirements for vitamins, biologicals, OTC or other medicines providing they are approved medicines. Devices are not included in Part 8 of the Guidelines on the Regulation of Therapeutic Products in New Zealand as they are not medicines. Information on adverse event reporting for medical devices is available on the Medsafe website under Devices.
One submitter commented that a clarification be included in the guideline to the effect that the parameters listed in Section 3.3.2 describe a valid report from the sponsors’ perspective. A different submitter advised that CARM’s validation criteria for CIOMS reports differed from the ICH criteria used in this guideline.
The listed parameters describe what a valid report should consist of, from the perspective of all parties, including regulators, sponsors and CARM.
Medsafe has discussed with CARM the issue regarding different validation criteria. Medsafe is satisfied that the ICH criteria adopted in this guideline will be used by CARM.
One submitter suggested that the example where ‘death/sudden death’ is the only detail in the report should be moved to a different section as it appeared to be an example of reaction terms.
This example has been removed from the guideline.
One submitter requested clarification and examples of what would be considered 'significant additional information'.
Medsafe has reviewed this section and concluded that additional information does not have to be significant for it to be forwarded to CARM. CARM will make a determination on the significance of the information. Medsafe has amended the guideline to make this clear.
Several submitters commented on this delay, which makes it difficult to provide additional information and identify the CARM reference number if no acknowledgement had been received.
Medsafe has discussed this issue with CARM. CARM has advised that companies may use their company pharmacovigiliance report number as a reference when submitting additional information if they have not received a CARM reference number within a week. CARM has advised Medsafe that if reports are submitted online they will receive an acknowledgement immediately, together with a web-generated number that can be used as a reference number for subsequent additional information reports.
Medsafe has changed the guidance in Section 3.3.3 of the guideline to reflect this advice from CARM.
Several submitters commented that the wording ‘shortly after 15 calendar days’ was open to interpretation and subjective. A few submitters stated this was unnecessary.
Medsafe has removed this proposed flexibility from the guideline.
One submitter commented that it would aid clarity if this section of the guideline included a reference to serious adverse reactions.
Medsafe believes this is unnecessary since only serious adverse reactions routinely need to be reported, as described in the preceding part of this section of the guideline. No change to the guideline is required.
One submitter queried why there is special reference to consumer reports in the guideline, submitting that it is questionable that consumers would report explicit causal relationship, and that these would be followed up where possible with the healthcare professional. Another submitter commented that there was potential for the same case to be reported multiple times if each healthcare professional, consumer and sponsor reported the same case. A different submitter commented that there was potential to interpret that the guideline applies to consumers and healthcare professionals as well as companies. The same submitter also asked if inclusion in the CIOMS form, of information regarding consent to follow-up being declined, was mandatory.
Sponsors have sought advice on this issue in the past. The guideline is intended to provide guidance to all sponsors, including sponsors who may be unsure (such as new sponsors) what they should do if they receive reports from consumers.
Medsafe agrees that there is always a possibility that a report may be received multiple times (duplicate reporting). For example the same report may be submitted from different sources, or the same report submitted more than once by the same source. This possibility will always exist.
Concerned parties should use appropriate procedures and checks to ensure that duplicates can be identified and the information collated into one report.
In relation to the potential for the guideline to be interpreted to apply to consumers and healthcare professionals, Medsafe points out that the section summary at the beginning of the section states clearly that the section outlines sponsor responsibilities. Medsafe has also amended the various sections of the guideline to make it clear that the sections apply to sponsors only.
Medsafe confirms that if permission to follow-up with the consumer’s healthcare professional has been declined by the consumer, inclusion of this information in the CIOMS form is optional. Medsafe has amended the guideline to make this clear.
One submitter advised replacing the word ‘severity’ with ‘seriousness’ as these are different concepts. The submitter also commented that this subsection appeared misplaced in the guideline.
Medsafe agrees, and has amended both the wording and the placement of this subsection in the guideline.
Two submitters pointed out that AEFI are routinely included in PBRERs and therefore were unclear of the threshold for notification.
If the AEFIs are serious reactions, then these should be reported to CARM as serious adverse reaction reports within the standard timeframe. This should be the case even if they are later included in PBRERs.
Several submitters requested clarity on whether a lack of efficacy had to be reported for all medicines, or for only those types listed in the guideline. One submitter suggested aligning the wording with the TGA’s guideline on pharmacovigilance on this issue. Another submitter requested information on the reporting timeframe.
Medsafe has revised this subsection of the guideline to make it clear that reports of a lack of efficacy are required only for the medicine types listed, which has been expanded to include antibiotics, medicines used for off-label purposes and sole-supply generic medicines. A lack of efficacy should be reported to CARM as described.
The revised wording mentions that the standard reporting timeframe of 15 days applies. Medsafe has also aligned the wording with the TGA guideline, as suggested.
Submitters requested clarity on whether all such cases require reporting or only serious adverse reactions.
The wording in these subsections of the guideline has been amended to make it clear that only reports of serious suspected adverse reactions associated with misuse should be reported to CARM.
Several submitters asked if reporting was mandatory. One submitter asked if this applied to specific product types and also asked for more information on the Medication Error Reporting Programme (MERP).
The wording in the guidance points out that reports of serious adverse reactions associated with medication errors, overdose or occupational overuse should be reported to CARM and other reports are encouraged to be reported to MERP.
Reporting of medication errors is voluntary. Medsafe encourages reporting but is unable to provide details on the programme. MERP is not operated by Medsafe but by the New Zealand Pharmacovigilance Centre (NZPhvC). Sponsors seeking more information on MERP should contact NZPhvC. This advice in the guideline is unchanged.
Submitters sought clarification as to which specific situations this would apply and for how long reporting should occur. One submitter asked what the regulatory basis would be for requiring ongoing reporting if there was no longer marketing authorisation.
Medsafe has reworded this section of the guidance to explain that medicines may still be in use for a time after suspension, withdrawal of consent to distribute or company-initiated withdrawal (such as discontinuation). Although the medicine may no longer be available, market reintroduction may occur later and monitoring may still be warranted. Reports should be submitted for a period up to the expiry date of the last batch that was distributed.
Submitters commented that monitoring of the many sites on the internet would create a significant burden and follow-up could be difficult, with few perceived benefits. Submitters suggested that sites that were under their responsibility or control could be monitored and that when sponsors became aware of reports elsewhere, these could be assessed whether they qualify for reporting.
Medsafe agrees with the submitters, and has revised the guidance to reflect this situation.
One submitter commented that the proposed guidance to commence review from the time of distribution of the medicine differed from that in the EU Pharmacovigilance Module VI (Appendix 2), which advised companies to commence review from the time of submission of the application for marketing authorisation. Other submitters commented on the reference to funded medicines.
It is appropriate to review the scientific and medical literature only from the time of distribution of the medicine in New Zealand as there would not be approved products being used in New Zealand prior to that time. Subsections 3.5.6 (clinical trials) and 3.5.10 (exemptions) of the guideline cover the situations where the medicine is used in New Zealand prior to grant of consent to distribute. Medsafe agrees that reference to medicines that are funded is unnecessary and this has been removed from the guideline.
Medsafe has also revised this subsection to make it clear that review and assessment are to be of reports of suspected adverse reactions occurring in New Zealand.
Submitters sought clarity on what would be defined as a quality defect (such as a lack of efficacy), whether the advice applied to non-serious or serious adverse reactions, the proposed timeframe of 72 hours or 15 days, and whether a report should be submitted to Medsafe or CARM.
Medsafe has revised the wording of this subsection of the guideline to provide definitions and to clarify the guidance.
A lack of efficacy may be related to, but is not necessarily considered to be, a quality issue. There may be various reasons for a lack of efficacy not necessarily related to quality defects, such as a patient being on a concomitant medication or being prescribed a subtherapeutic dose. Reporting of cases of a lack of efficacy is described in subsection 3.5.3.
Reports of adverse reactions (whether serious or not) associated with a suspected or confirmed report of a quality defect, adulteration, contamination or falsified medicine are considered to constitute significant safety issues and should be reported directly to Medsafe, as described in Section 5. These should not be reported to CARM.
The timeframe for reporting significant safety issues to Medsafe is generally within 72 hours of receipt of the information by the sponsor so that these issues can be followed-up with minimum delay.
Submitters asked whether sponsors are expected to retrieve information from this database, and to what purpose. One submitter commented that it would be helpful to have the database include the trade names of medicines.
The SMARS database contains only a listing of adverse events reported for a medicine. Sponsors should note that the information entered into SMARS is retrieved from adverse event reports submitted to CARM. Medsafe’s webpage on SMARS contains information on how sponsors may use the information. Use of the database is voluntary.
Medsafe has discussed the inclusion of the trade names of medicines with CARM. CARM has agreed to provide trade name information (or the name of the manufacturer) to Medsafe for publication in SMARS. CARM has agreed that provision of this information will start before the implementation of the new guideline. Where no trade names (or manufacturer information) have been provided in the report, this datum obviously cannot be included.
A few submitters sought further clarification on whether the addition of indications, routine changes in labelling, or the addition or modification of warnings, precautions or adverse reactions should be regarded as significant safety issues where these did not impact clinical practice.
Medsafe has removed 'addition of indications' as a significant safety issue, and revised the wording in the guideline to reflect that changes that do not impact clinical practice are not considered significant safety issues.
Clarification was sought on the proposed timeframe for notifying Medsafe particularly in relation to the issue of when a sponsor might be considering distributing a Dear Healthcare Professional (DHCP) letter. Medsafe was also asked to clarify what regions this applied to, such as whether Medsafe is concerned about changes to labelling in Botswana or only concerned about changes to labelling in major regions.
The timeframe for advising Medsafe of a significant safety issue begins from the time the New Zealand sponsor becomes aware, or has concluded after their review of information, that a significant safety issue exists. Where a sponsor is considering issuing a Dear Healthcare Professional letter regarding that significant safety issue, Medsafe should be advised within 72 hours of the time that the sponsor acknowledged there was a significant safety issue. Medsafe does not require or expect the draft DHCP letter to be provided within the 72 hour timeframe. Although it is not mandatory, it is good practice to provide drafts of DHCP letters to Medsafe for review prior to distribution to ensure that the DHCP letter has addressed the relevant safety issues adequately and has New Zealand specific information.
In relation to whether Medsafe may be concerned about labelling changes in any particular region, Medsafe’s concern applies to all regions where a significant safety issue exists about a medicine that is also marketed in New Zealand. Since it is possible that a particular medicine may only be marketed in New Zealand and a few countries, Medsafe does not wish to introduce limits to this guideline.
One submitter was concerned that the term ‘untoward effect’ was subjective and suggested the use of a more direct statement.
The term 'untoward effect' is the phrase used in section 41 of the Medicines Act 1981. No change to the guideline is required.
Submitters requested definitions be included in the glossary for biologicals and biosimilars, and clarity on when PBRERs should be submitted and when they are no longer required.
Medsafe has included definitions for these terms in the glossary of the guideline. Medsafe has reworded this section to make it clear that PBRERs are routinely required only for certain medicines and that these are: all biological medicines, all biosimilars, all vaccines in the immunisation programme, and all medicines where a specific requirement for the submission of PBRERs has been imposed as a condition of approval. The revised section includes information on format, interval of submission and when submission is no longer required.
Submitters also requested more detail on risk management plans (RMP) and suggested that parts of Section 7 of the guideline should be included in this subsection.
Medsafe has revised subsection 6.3 to make it clear that the European format is acceptable if sponsors are requested to submit a RMP. A new subsection has been added to explain that Medsafe does not currently routinely request submission of RMPs. When a company intends to distribute Dear Healthcare Professional Letters, other safety communications and educational materials (which normally form part of the risk management tools of an RMP), these are encouraged to be submitted as described in Section 7. RMPs may be submitted too, if the sponsor wishes to do so.
Submitters requested clarification about whether it is mandatory to provide Dear Healthcare Professional (DHCP) letters to Medsafe for review before these are distributed. One submitter commented this section should state explicitly that review or approval of the DHCP letter would be required only within the context of significant safety issues.
Medsafe has revised the guideline to make it clear that submission of DHCP letters is not mandatory, but is good practice.
Submitters commented that safety communications are normally part of the risk management plan (RMP) and asked for clarification whether any communication tools that are part of a risk management plan would then be out of scope of this section. Submitters contended that review of these materials may be difficult without the context of the RMP. Submitters also requested clarification of whether the provision of these materials is mandatory. One submitter also asked about the timeline for review of the materials and the management of changes, as this could result in delay of materials being implemented.
Medsafe has noted these comments. RMPs are not currently routinely required to be submitted, so the provision of these safety messages and educational materials to Medsafe is desirable. Medsafe does not review these materials in the sense of giving approval. Instead, Medsafe tries to ensure that any safety issue is adequately covered, within the shortest possible time so that there is the least amount of disruption to sponsor’s implementation plans. RMPs may be submitted to explain the materials if the sponsor desires.
One submitter suggested that the guideline include information on direct-to-consumer-advertising (DTCA) in order to clarify the distinction between risk minimisation and safety communications and DTCA.
Medsafe has noted this suggestion. Advertising of medicines is covered under Part 7 of the Guidelines on the Regulation of Therapeutic Products in New Zealand. Advertisements that may contain safety messages or educational material are neither safety communications nor educational materials per se and remain advertisements, and therefore are inappropriate to be included in this guideline. No change to the guideline is required.
Suggestions were made to add additional terms to the glossary, including biologicals, biosimilars and solicited reports. Some submitters considered that it was unclear who the target audience for the guidelines was, that the general wording did not clearly differentiate between responsibilities that are mandatory and those that are optional. Two submitters proposed that the draft guideline would be simplified if Medsafe formally adopted the EU, RMP and PBRER guidelines. Some submitters suggested the use of hyperlinking through the document to enable ease of cross-reference, and one submitter suggested establishing a process for work sharing with another regulator.
Medsafe has amended the guideline in response to most of the comments. The Guideline on the Regulation of Therapeutic Products in New Zealand. Part 8: Pharmacovigilance has incorporated most of the elements of the EU, RMP and PBRER guidelines into the New Zealand environment, but these cannot be adopted fully, since, for example, 'marketing approval' or 'licence' for medicines do not exist, and the funding and supply environment in New Zealand is very different to those in Europe or Australia. Medsafe has noted the suggestion regarding work-sharing of RMPs and PBRERs, and will consider this in greater detail in any future discussions with regulatory partners.
The Guideline on the Regulation of Therapeutic Products in New Zealand. Part 8: Pharmacovigilance (Edition 2.0) will be effective from 1 January 2016.
Any questions relating to this consultation and the guideline should be directed via email to: email@example.com