This section deals only with investigation and reporting of adverse drug reactions and adverse drug events. Furthermore, this section seeks to clarify the pharmacovigilance reporting responsibilities of each party involved in delivering the homecare service, with the overall aim of ensuring compliance with good pharmacovigilance practice, whilst avoiding duplication of reports11.
Note: Throughout this section 9.3 the term manufacturer should be read as the manufacturer or marketing authorisation holder (MAH) if different.
Definiton: Adverse drug reaction (ADR)
Adverse Drug Reaction is defined in DIR 2010/84/EU as a response to a medicinal product that is noxious and unintended (side effect)” which results not only from the authorised use of a medicinal product at normal doses, but also from medication errors and uses outside the terms of the marketing authorisation, including the misuse and abuse of the medicinal product and occupational exposure.
Definition: Serious adverse drug reaction
The serious adverse drug reaction is defined in DIR 2001/83/EC Art 1(12) as an adverse reaction which results in death, is life-threatening, requires in-patient hospitalisation or prolongation of existing hospitalisation, results in persistent or significant disability or incapacity, or is a congenital anomaly/birth defect or any suspected transmission via a medicinal product of an infectious agent is also considered a serious adverse reaction.
Definition: Spontaneous adverse drug reaction report
A spontaneous adverse drug reaction report is defined in GVP VI as an unsolicited communication by a healthcare professional, or consumer to a competent authority, marketing authorisation holder or other organisation (e.g. Regional Pharmacovigilance Centre , Poison Control Centre) that describes one or more suspected adverse reactions in a patient who was given one or more medicinal products and that does not derive from a study or any organised data collection systems where adverse events reporting is actively sought, as defined in VI.B.1.2.
Stimulated reporting that occurs consequent to a “Direct Healthcare Professional Communication”, publication in the press, questioning of healthcare professionals by company representatives, communication from patients’ organisations to their members, or class action lawsuits should be considered spontaneous reports.
Definition: Solicited adverse drug reaction report
GVP VI VI.B.1.2 refers to solicited ADR reports as defined in ICH-E2D. Solicited reports of suspected adverse reactions are those derived from manufacturer’s organised data collection systems, which include clinical trials, non-interventional studies, registries, post-approval named patient use programmes, other patient support and disease management programmes, surveys of patients or healthcare providers, compassionate use or name patient use, or information gathering on efficacy or patient compliance.
Solicited ADR reports to the regulator are made by the manufacturer (or marketing authorisation holder if different) and are classified as study reports.
Reports of suspected adverse reactions obtained from any of the data collection systems listed above report should not be considered spontaneous. This is with the exception of:
- suspected adverse drug reactions in relation to those adverse drug events for which the protocol of non-interventional post-authorisation studies provides differently and does not require their systematic collection (see VI.C.1.2.1.),
- suspected adverse drug reactions originating from compassionate use or named patient use conducted in European Member States where the active collection of adverse events occurring in these programmes is not required (see VI.C.1.2.2.).
Definition: Validated adverse drug reaction report
To be valid for submission to the MHRA, an adverse drug reaction report (also known as Individual Case Safety Report or Yellow Card Report) requires the following elements:
- Anonymised Patient reference e.g. initials and gender
- Reporter identifier e.g. name/staff type/homecare provider name
- Name and details of the medicine
- Details of the adverse drug reaction
The report should also confirm:
- that the medicine was taken
- that the patient was harmed
There is reasonable suspicion or knowledge that the harm was caused by the medicine taken, usually conformed by the person first identifying or reporting the adverse drug reaction. GVP VI refers to WHO guidance on assessment of causality. It is important to note that the fact that a spontaneous ADR report is submitted to the regulator is taken to imply that the reporter has reasonable suspicion or knowledge of causality. 12
Definition: Adverse drug event (ADE)
For the purposes of this guideline, the definition of an adverse drug event is
- any untoward medical occurrence in a homecare patient administered a medicinal product and which does not necessarily have a causal relationship with the medicinal product or is related to one or more omitted doses or otherwise does not meeting the definition of a validated adverse drug reaction
- overdose, abuse, off-label use, misuse, medication error or occupational exposure with no associated adverse reaction
- pregnancy related exposure where the embryo or foetus may have been exposed to medicinal products (either through maternal exposure or transmission of a medicinal product via semen following paternal exposure) or infant exposure during breastfeeding with no associated adverse reaction.
An adverse drug reaction, by definition, results in actual patient harm so must always also be treated as a patient safety incident as described in section 9.1. Adverse drug events of clinical significance should also be reported immediately to the clinical team and treated as patient safety incidents e.g. patient harm or other clinical concerns which are not caused by the medicine; patient harm arising from omitted doses due to failed medicine delivery or medicine shortage.
The reporting of adverse drug events, which do not meet the criteria of a patient safety incident, is not so clear-cut (see section 9.3.6). Where it is suspected that an adverse drug event may meet the requirements of a valid ADR it should be reported as a possible ADR that is then subject to further validation by the manufacturer.
Whilst this section is specific to medicine and drug related incidents, it is good practice to have a similar reporting process for medical devices to capture device related events which do not fulfil the criteria for Faulty Medical Device reporting (see section 9.4), especially where the medical device manufacturer funds the homecare service.
Adverse drug reaction reports arising from patient support programmes are solicited adverse drug reaction ICSRs (see definition of solicited adverse drug reaction) and classified as a study report17.
Adverse drug event report collection is a mandatory requirement of the European wide legislation governing pharmacovigilance when manufacturers provide patient support programmes. Where the manufacturer funds homecare services and/or patient support programmes due consideration must be given within contracts and technical agreements with providers to ensure regulatory reporting requirements are met (see section 9.3.4).
Patient support programmes (PSP’s) are set up by companies to help patients and/or healthcare professionals better manage disease and optimise treatment. There is currently no regulatory definition of what constitutes a patient support programme. ABPI defines a patient support programme (PSP)20 as a service for direct patient or patient carer interaction/engagement designed to help management of medication and/or disease outcomes (e.g. adherence, awareness and education), or to provide healthcare professionals (HCPs) with support for their patients.
A PSP definition will only apply if the programme includes direct contact with patients or patient carers. The intention is to support patient care provided by the manufacturer or by a third party on the manufacturer’s behalf. Patients need to provide informed consent prior to enrolling on PSPs where they will be directly contacted. The Association of the British Pharmaceutical Industry (ABPI) guidance document providing information on pharmacovigilance requirements of PSPs20 recommends that careful consideration should be given to the design and collation of data to ensure compliance with relevant pharmacovigilance legislation and reporting requirements.
Manufacturer contracts for provision of a patient support programme related to a homecare service usually require that all known adverse drug events are captured and reported to the manufacturer. The reporting clock is started when any member of staff (nurse, pharmacist, customer services or driver) who is involved in delivering the service on behalf of the manufacturer is first made aware of the potential adverse drug event irrespective of whether they are employed by the manufacturer or the homecare provider.
Where there is direct interaction with patients within a patient support programme, there is always the possibility that adverse drug events or product complaints relating to any of the manufacturer’s products may be mentioned in passing. In these instances information may need to be recorded and reported as an adverse drug event.
In relation to manufacturer led patient support programmes, regular reconciliations are required to match adverse drug events reported by the sub-contracted homecare provider with those received by the manufacturer. In recent years, there have been increasingly onerous manufacturer audits of pharmacovigilance reporting processes within homecare providers to verify that PV reports have been complete and accurately reflect the information in the original record. In particular, manufacturers increasingly request access to source data (i.e. original clinical and patient service records). However, this is resource intensive as homecare organisations can only share non-personal identifiable data with manufacturers for audit purposes due to patient confidentiality.
When designing systems for adverse drug event reporting within patient support programmes the following should be carefully considered:
- How the essential data elements required for a valid adverse drug event report will be documented in the patient’s clinical record and how that will be captured in a suitable format for reporting
- How versions will be reconciled if there is more than one version of the adverse drug event record in various manufacture, NHS and homecare systems
- How the process for asking and documenting patient consent for the medicine homecare provider to release their contact details to the manufacturer will facilitate follow-up where needed
- How information governance regulations will be applied when sharing adverse drug event data with the manufacturer. Personal identifiable data of patients, carers, healthcare practitioners and others will need to be removed unless informed consent to share this information has been obtained
- How the adverse drug event report will be processed and sent to the manufacturer within the contracted reporting time, including consideration of weekends and public holidays.
- The capacity planning processes that are required to ensure sufficient resources are available to maintain robust adverse drug event reporting systems
- The systems that are in place to document investigations and corrective and preventative actions and reporting performance
- How adverse drug event reports will be validated and routinely and regularly reconciled with the manufacturer
- How samples of source data/patient records within the PSP database (where an adverse drug event has been reported and also when no event has been reported) will be identified, validated and if required reviewed by the manufacturer
- How adverse drug events that are also patient safety incidents (and vice versa) will be identified and handled
There is currently no clear definition within the European regulations of what constitutes a patient support programme, so it is currently the responsibility of the manufacturer to justify whether a homecare service, or part of a service, which they fund is to be treated as a patient support programme for regulatory purposes or not. In any case, the decision to designate or not designate a scheme as a patient support programme should be documented and detailed in the technical agreement between the manufacturer, and any third parties involved in delivery of the homecare service. Therefore, it is strongly recommended that homecare services defined as PSPs, or PSPs provided as optional additions to an existing homecare service, are designed in collaboration with pharmacovigilance, clinical and legal colleagues.