Special situation reports- PharmacoVigilance

Why PharmacoVigilance required

COVID-19 impact on PharmacoVigilance activities

COVID-19 impact on PharmacoVigilance activities

Most of the companies must have been undergoing rough phase during this COVID-19 pandemic situation. This situation shall be overcome by adapting new technologies and also by continuously testing the functionalities of these new technologies. Majority of the companies have been increasingly following Business continuous activities by implementing robust Business continuous plans (BCP).


In general, Pharma companies use multiple storage devices like electronic storage devices, Share drive devices in their daily routines of PharmacoVigilance (PV) activities.


It is evident that robust BCP and Disaster recovery (DR) testing shall surely support companies during any kind of natural calamities including COVID-19 situation.


I would like to summarise that below supporting functionalities of Pharmacovigilance activities shall be considered and tested frequently for facing any kind of situation like this.
1. Business Continuous Plan (BCP) testing
2. Disaster Recovery (DR) testing
3. Back-up and Recovery testing
4. Periodic testing of Storage platforms like Share drives and any electronic storage
5. Electronic Archival systems testing

During the current pandemic the reporting of adverse events related to the widespread use of medicinal products for the treatment or prevention of the pathogen causing the pandemic may increase. At the same time, there is a risk that during a pandemic work forces in industry may be reduced due to high employee absenteeism.

Companies can implement certain Change management practices that are deviating from the routine way of working inview of COVID-19 situation. Companies can adapt few work around practices for continuing their PV activities and document through change control and change management processes.

ICSR expedited reporting: MAHs may have understandable difficulties complying with the relevant deadlines. Hence those MAHs which are for justified reasons relating to the pandemic unable to continue standard reporting operations, they should temporarily – until the pandemic is resolved – prioritise the reporting obligations as follows:

• Submission of serious ICSRs associated with medicinal products used for the treatment or prevention of the pathogen causing the pandemic;
• Submission of other serious ICSRs;
• Submission of non-serious ICSRs associated with medicinal products used for the treatment or prevention of the pathogen causing the pandemic;
• Submission of other non-serious ICSRs.

Pharmacovigilance System Master File (PSMF): This pandemic crisis may force companies to  prioritise activities. MAHs who are impacted due to Covid-19 pandemic  and make use of prioritisation, they shall put a note in the pharmacovigilance system master file recording such practice.

Clinical trials: safety reporting shall be continued by contacting patients through phone; monitoring shall be managed virtually with remote monitoring. Refer Guidance on the Management of Clinical Trials during the COVID-19 (Coronavirus) pandemic

Follow-up (FU) management: It can be continued as usual while doing follow-up management with patients; May be it is of difficult for HCPs currently due to COVID-19 situation either to contact patients or they themselves giving relevant follow-up detauls to any PV units. Note: Certain National competent authorities (NCAs) announced these workarounds to companies performing FU management.

MedDRA coding: MSSO adding new COVID-19 terms to MedDRA and updated MedDRA version 23.0 that is initially released on 1st March 2020. These recommended practices described the validity and coding of ICSRs. These recommendations are relevant to the processing and submission of Individual Case Safety Reports (ICSRs) associated with medicinal products used for the treatment or prevention of COVID-19 infection. During this transition until it is implemented on 4th May 2020, MSSO recommended few practices on coding of Covid-19 MedDRA terms (Reaction or event term, Indication and Lab tests).

Current guidance: GVP Module VI Chapter VI.C.6.2.3.4., the indication for which the suspected medicinal product was administered should not be included in the ICH-E2B section ‘Reactions/Events’ unless aggravation of the medical condition occurs.

Interim guidance until implementation of MedDRA version 23.0: If a patient experiences an aggravation or exacerbation of their condition, then, because there is no single term for aggravation of COVID-19 infection, two reactions should be entered in accordance with MedDRA term selection:
Coronavirus infection and Condition aggravated.

Lack of therapeutic efficacy with potential life threatening events: This Covid-19 situation seems to be a prime example for ICSRs in the products which has LOE for treating or preventing Covid-19 infections. Hence ICSRs reported with LOE for treating Covid-19 are required for expedited reporting. Refer "Detailed guidance on ICSRs in the context of COVID-19".

Electronic signatures: It is difficult to sign (hand written) and scan those documents during COVID-19 situation like this. It is not advisable when a lock down situation and also no such facilities are available outside too.
Authorities also started approving Marketing Authoristaions (MAs) in timely manner by approving MAs with digital electronic signatures. It might be high time for companies who have not yet implemented electronic signatures in routine PV activities. It shall be ensured to have a validated electronic signatures in place to authenticate and validated signatures similar to hand written signatures. Refer REGULATION (EU) No 910/2014 OF THE EUROPEAN PARLIAMENT AND OF THE COUNCIL of 23 July 2014 on electronic identification and trust services for electronic transactions in the internal market and repealing Directive 1999/93/EC.

Product Information updates (SmPC and Package leaflet): Due to this Covid-19 pandemic crisis, it may be difficult for MAHs to provide and update different national language texts. Hence the CMDh has agreed to apply the labelling and packaging flexibilities to certain crucial medicines for use in COVID-19 patients only. It is possible for MAHs to notify the relevant national competent authorities in advance and should also provide a link to a website where the product information in the relevant official language may be obtained. Refer "QUESTIONS AND ANSWERS ON REGULATORY EXPECTATIONS FOR MEDICINAL PRODUCTS FOR HUMAN USE DURING THE COVID-19 PANDEMIC"

To summarise all critical PV activities shall be continued without fail irrespective of any crisis. If any non-compliance is estimated or expected, it is always better to raise a deviation or implement change management practices to implement certain workarounds. 

Can Companies or Authorities differ with ICH guidelines during their routine Pharmacovigilance activities?

ICH Guideline Implementation status by Industries and Authorities 


A report was published to know the status of implementation of ICH guidelines by Industries or Authorities in the year 2019.

It seems to be interesting as there are several companies have differ in opinion of implementing published ICH guidelines. However, they have implemented these ICH guidelines with modifications and justifying with a rationale. Majority of Authorities have implemented these ICH guidelines with adequate compliance.

The result of this survey showed the final status by both Industries and Authorities as follows:

Refer 2019 Project report: MONITORING THE ADEQUACY OF IMPLEMENTATION AND ADHERENCE TO INTERNATIONAL COUNCIL FOR HARMONISATION OF TECHNICAL REQUIREMENTS FOR PHARMACEUTICALS FOR HUMAN USE (ICH) GUIDELINES


To summarise, I feel primarily we shall implement any kind of guidelines including ICH guidelines as it is if it is more appropriate; The same guidelines can be implemented with modifications with sufficient rationale in case of any subjective changes are necessary.

Global and Local Literature screening

Literature screening

General:

The scientific and medical literature is a significant source of information for the monitoring of the safety profile and of the risk-benefit balance of medicinal products, particularly in relation to the detection of new safety signals or emerging safety issues. Marketing authorisation holders are therefore expected to maintain awareness of possible publications through a systematic literature review of widely used reference databases (e.g. Medline, Excerpta Medica or Embase) no less frequently than once a week.

MAH should review the literature search results to identify both individual cases which may qualify for expedited reporting and also safety studies which are relevant to the safety profile of the medicinal product and need to be discussed as part of the continuous review of safety data and should also be included in the next PSUR.

Market Authorization Holders:

During implementation of new EU pharmacovigilance legislation by the EMA published on the EMA website, the monitoring of selected medical literature for certain active substances suppose to start in July 2012. Further information on the start of this activity supposed to be communicated in 2013. The stakeholders were consulted in due time on guidance for the conduct of the literature monitoring activities. Until further notice MAHs should continue to report cases they have identified from the literature.

1. The process, including but not limited to how the search is done, the database(s) used, and the periodicity of those searches describing the search in the literature should be written in a procedure.

2. Searches, on the marketed drug and active pharmaceutical ingredients, in published literature should be performed on a regular basis.

3. ADRs found during literature searches should be classified according to their seriousness and expectedness. These assessments should be retained and be well documented.

4. ADR reports from the scientific and medical literature must be reported to relevant Competent authorities as per the interim arrangements and GVP module 6.

5. Results of the literature searches should be documented.

Process Model of Literature Search for Drug Safety:

1. Identify the drug.

2. Check for alternate names of the drug. Using Micromedex, type in the drug name. From the Integrated Index, click on Summary Documents and under Drug Information, click on links that might say “List of Drugdex Tradename Products” or “List of Martindale Tradename Products”. Martindale is especially good for foreign drug names.

3. Define the research setting and population in which the drug will be used.

4. Consult reference or tertiary sources as a starting point. Tertiary sources are usually summaries of available information in an understandable format (reference sourcebooks, textbooks).

5. Consult secondary sources for comprehensiveness and quality assurance. Secondary sources are databases that index or abstract the primary literature (bibliographies, reviews, indexing and abstracting services). Primary sources are patents, conference papers, case reports, journal articles, correspondence, and theses.

6. Choose the most appropriate sources of evidence of safety/adverse effects.

7. Create bibliography.

Specific requirement from Netherlands MEB:

The MEB and the Health Care Inspectorate do not define or list what publications should be covered by local literature searches since this depends on the type of product and its indication(s) for use (as well as on the geographic area). It is not possible to produce one list of local literature that covers all scenarios and products. A significant percentage of relevant articles that appear in medical and scientific publications would be included in standard global literature search databases e.g. Medline and Embase. In addition, there are relevant local publications that are not included in Medline or Embase. ‘Standard’ local medical publications (for the Netherlands these include for example Pharmaceutisch Weekblad, NtvG, Geneesmiddelenbulletin, Medisch Contact) should always be included in your literature search strategy. Depending on the product (e.g. herbal) and/or indication (e.g cardiovascular), other local publications might be relevant as well. You are therefore advised to document your rationale for ensuring that relevant local literature is included in your literature surveillance strategy

Below list of countries are few exceptions of reporting ICSRs:

UK MHRA--- updates a spread sheet with list of literature reports that received. Every MAH should review the spread sheet prior to submitting any ICSR to MHRA.

Italy---- Do not require to receive non-serious ICSRs published in literature