Do Manufacturers need Pharmacovigilance (PV) Agreements with Wholesalers?

This is a question answered in a recent blog by the U.K. Medicines and Healthcare products Regulatory Agency (MHRA). One would think that wholesalers don't receive adverse event information routinely in Europe (it might be more common in other countries outside the EU). This kind of information might be received mainly by those involved in parallel importation. However a wholesale distributor could potentially receive safety-related information. And it seems that many are not aware of their responsibilities with this pharmacovigilance (PV) data. Here, a contract might help, especially if a wholesale distributor is providing PV service to the marketing authorisation holder (MAH).

According to the MHRA, a contract or agreement is needed, "in order for the MAH to ensure that activities performed and services provided by these third parties are in accordance with applicable legislation and guidelines, and in order to ensure that all parties understand and formally agree to the tasks that have been contracted".

What guidelines need to be considered? Like in the areas of Good Manufacturing Practice (GMP) and Good Distribution Practice (GDP), within Good Pharmacovigilance Practices (GVP) applicable Guidance is available. This is summarised in EudraLex - Volume 9 - Pharmacovigilance guidelines.

GVP Module VI.2.2 states that "each marketing authorisation holder shall have in place a system for the collection and recording of all reports of suspected adverse reactions which are brought to its attention". Because wholesale distributors may be a potential source of safety information, the MAH "will need to have a mechanism to collect reports of adverse reactions received by wholesaler distributors", the MHRA states.

GVP Module VI.B.7 gives basic guidance for agreements between the MAH and wholesale distributors: "Where the marketing authorisation holder has set up contractual arrangements with a person or an organisation, explicit procedures and detailed agreements should exist between the marketing authorisation holder and the person/organisation to ensure that the marketing authorisation holder can comply with the reporting obligations. These procedures should in particular specify the processes for exchange of safety information, including timelines and regulatory reporting responsibilities and should avoid duplicate reporting to the competent authorities".

And not to forget the GDP Guidelines: section 6.3 of the European Commission Guidelines on Good Distribution Practice of medicinal products for human use (2013/C 343/01) states "In the event of a complaint about the quality of a medicinal product and a potential product defect, the manufacturer and/or marketing authorisation holder should be informed without delay". It can happen that complaints received by wholesale distributors might contain a suspected adverse drug reaction. And they need to make sure to forward this information to the MAH without any delay. Here, "the implementation of an agreement between the parties may help facilitate this activity".

Are agreements needed for each and every wholesale distributor?

In the Blog, the MHRA lists factors which should be considered in the decision making process:

  • if the name and/or contact details of the wholesale distributor appears on product packaging, the patient information leaflet (PIL) or the MAH's website,
  • if the MAH does not have a contactable presence in the market where the product is being distributed, which may increase the likelihood of the wholesale distributor becoming a point of contact by a member of the public or health care professionals (HCPs),
  • if the wholesale distributor is providing services which may increase their interaction with HCPs and the likelihood of receiving safety information, such as actively promoting products via a sales team,
  • if the wholesale distributor is performing pharmacovigilance services on behalf of the MAH, for example, undertaking follow-up of adverse events in their territory on behalf of the MAH, undertaking local literature searching activities or distributing risk minimisation materials.

Additionally, the MHRA outlines provisions "which the MAH may wish to consider in agreements" in the blog entitled Do wholesale distributors require pharmacovigilance agreements?

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