MHRA Good Distribution Practice (GDP) inspectors have received queries from wholesaler distributors asking in what instances agreements are required between the marketing authorisation holder (MAH) and wholesale distributors for the purposes of fulfilling pharmacovigilance requirements. The Good Pharmacovigilance Practice (GPvP) Inspectorate provides some clarification below.
According to Article 1(17) of Directive 2001/83/EC, wholesale distribution of medicinal products is “all activities consisting of procuring, holding, supplying or exporting medicinal products apart from supplying medicinal products to the public…”. If a wholesale distributor could potentially receive safety-related information on behalf of the MAH, or if they are providing a service relating to pharmacovigilance, then they are effectively part of the MAH’s pharmacovigilance system. In this situation, contracts or agreements between the MAH and wholesale distributor need to exist, 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. In this blog post, the terms contract and agreement are used synonymously.
Provisions in published guidelines to consider
The good pharmacovigilance practices (GVP), are a set of measures drawn up to facilitate the performance of pharmacovigilance in the European Union.
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”. As indicated earlier, wholesale distributors may be a potential source of safety information. Hence, the MAH will need to have a mechanism to collect reports of adverse reactions received by wholesaler distributors.
GVP Module VI.B.7 outlines the reason why agreements between the MAH and wholesale distributors may be required “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”.
As reports of suspected adverse reactions may be brought to the attention of wholesale distributors, agreements between the MAH and the wholesale distributor support the fulfilment of the collection and recording of these reports by the MAH.
Indeed, 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”. Complaints received by wholesale distributors may include reports of suspected adverse drug reactions and should be forwarded to the MAH, the implementation of an agreement between the parties may help facilitate this activity.
Factors influencing whether an agreement is required
The MAH needs to assess if the wholesale distributor they have engaged with are a potential source of safety information (such as reports of adverse reactions, medical enquiries or product quality complaints), and/or are providing pharmacovigilance services on behalf of the MAH, and whether an agreement is required to fulfil pharmacovigilance requirements. Some factors which are likely to result in an agreement being required include:
- 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.
The above list is not intended to be exhaustive and the MAH should consider all factors which may result in the wholesale distributor becoming part of the MAH’s pharmacovigilance system.
There may be situations when an agreement is not required, for example, if the wholesale distributor is not in a contractual relationship with the MAH and would not be regarded as a potential source of safety information and thus would not form part of the MAH’s pharmacovigilance system.
Content of agreements
If an agreement between the MAH and the wholesale distributor is required, it should contain sufficient detail to ensure that pharmacovigilance requirements are met. It is the responsibility of the MAH to decide what provisions need to be included in these agreements, particularly considering the content required in agreements may vary depending on the parties involved. Some provisions which the MAH may wish to consider in agreements are outlined below, however, this list is not intended to be exhaustive and the MAH should use their judgement when deciding what information should be included in agreements:
- the roles and responsibilities of each party
- the types of safety information which should be collected and forwarded to the MAH by the wholesale distributor (e.g. suspected adverse reactions, lack of efficacy reports, product quality complaints etc.)
- timeframes for the exchange of safety information between parties and case confirmation and/or reconciliation provisions
- contact details of where the wholesale distributor should send safety information received to
- how the transfer of outstanding safety information to the MAH will be handled should commercial arrangements be terminated
- provision for the oversight of the wholesale distributor by the MAH (e.g. in process compliance measures and the right of the MAH to audit the wholesale distributor).
The MAH should consider how to ensure all parties are complying with the terms of the agreements, such as including wholesale distribution partners on the MAH’s risk-based audit programme, or implementing routine checks of pharmacovigilance relevant wholesale distributor activity, such as periodic reconciliation of reports of adverse events between the distributor and the MAH which may identify discrepancies in information exchanged.
Conclusion
In conclusion, when deciding if an agreement between the MAH and the wholesale distributor is required, the MAH needs to consider if the wholesale distributor is a potential source of safety information and/or performing pharmacovigilance tasks on behalf of the MAH, and implement agreements as appropriate. Provided the aforementioned factors have been considered, it is anticipated that there may be instances where an agreement between the MAH and the wholesale distributor is not required. The MAH should ensure that where an agreement is required, these agreements contain sufficient detail and provisions relative to the relationship between the MAH and the partner.
Further reading
European Commission Guidelines on Good Distribution Practice of medicinal products for human use (2013/C 343/01) (available from the EUR-Lex website)
GVP Module VI, Management and reporting of adverse reactions to medicinal products (Rev 1) (available from the EMA website)
Acknowledgement
Peter Twomey, former MHRA Pharmcovigilance Inspector, contributed significantly towards this post prior to him leaving the Agency
Don’t miss the next post, sign up to be notified by email when a new post is published on the Inspectorate blog.
Access our guidance on good practice for information on the inspection process and staying compliant.
11 comments
Comment by Anne Lloyd posted on
In my experience, most wholesalers will resist putting a SDEA in place as their wholesaler license includes a clause that stipulates they must forward any PV reports they receive to the MAH. This does not seem to have been considered in the preparation of the above article.
Comment by Mark Birse posted on
Anne,
Thanks for your comments.
The newer WDA(H) doesn't have any direct clause for wholesale dealers to do this within the licence, however, it does speaks to the licence holder being obliged to comply with the EU Guidelines on GDP and EU Directives.
The post emphasis is on the MAH assessing whether or not an agreement is required with wholesalers used and hopefully this will help in the decision making process and give a steer as to the Inspectorate's thinking on this matter.
Regards,
Mark
Comment by Mark Birse posted on
Additionally, it is adequate to include appropriate PV-related clauses in the main commercial agreement. A separate SDEA is not required unless the MAH deems it necessary to implement a standalone PV agreement.
Comment by Anne Lloyd posted on
Thank you for the clarification. Much appreciated.
Comment by Concepcion posted on
Thank you, very clear
Comment by Rajeev Sharma posted on
Nice article with useful information
regards
Rajeev Sharma
Comment by M Ramcharan posted on
Very interesting information. I have previously had discussions with PV Legal groups who stated that if wholesaler buys the product from the MAH, there is no longer a relationship between the parties, and the Wholesaler now owns the product and therefore there is no requirement for there to be a safety agreement, or clause in the main agreement, to address reporting of AEs to the MAH. It would seem that the point made in the article (see below) may cover this:
"There may be situations when an agreement is not required, for example, if the wholesale distributor is not in a contractual relationship with the MAH and would not be regarded as a potential source of safety information and thus would not form part of the MAH’s pharmacovigilance system."
Would the author clarify this for me?
Many thanks.
Comment by Sara Berry posted on
Yes this is correct. Where no contractual relationship exists between the MAH and a wholesaler, section 6.2 of the GDP guide applies. This requires a wholesaler in the event of a complaint about quality / potential defect to contact the MAH / manufacturer without delay.
Kind regards
Sara
Comment by Rahul More posted on
This is very helpful, thanks!
Comment by Thierry HAMARD posted on
Very useful post indeed ! There is a lot of confusion about the word "Distributor", which covers a wide range of situations. It would be great if we could come up with clear definitions for all categories to bring more clarity.
Any I would like to thank you for this contribution, even though I wish it would include some real-life examples. I would like to share one scenario I had recently:
It’s actually related to the distribution of Medicinal Products in Africa. A MAH based in Europe has no representative there and contracted a company for the distribution of its products.
The distributor is only operating from a GDP point of view, i.e. making the products available in the territories.
There is a SDEA in place between the MAH and the distributor to ensure that any PV/PQC gets reported to the MAH.
The distributor is delivering products to local wholesalers but there is no contract/agreement in place, only orders and invoices.
The distributor and the local wholesalers have no contact with prescribers, pharmacists or patients and their contact information is not mentioned on any packaging item.
It is therefore very unlikely that they would receive any AE report, although they could potentially receive PQC information
I believe the situation above is covered by the blog statement: “There may be situations when an agreement is not required, for example, if the wholesale distributor is not in a contractual relationship with the MAH”.
However the blog suggests that in such case the wholesaler has to comply with the GDPs and I am not so sure what GDP requirements apply in Africa…
Anyway, in my opinion, the situation above is acceptable. Do you agree ?
However, one could suggest that some documentation is established to raise the awareness of the local wholesalers to the reporting of complaints (quality or medical), e.g. through the invoice or a separate document, possibly signed by the wholesaler. What do you think ?
Comment by Sara Berry posted on
Dear Thierry
The MAH needs to assess whether the wholesaler in the territory is a potential source of safety information and decide how best to document their pharmacovigilance obligations. If it is deemed unnecessary to implement a pharmacovigilance agreement with the distributor due to the very low likelihood of them receiving any safety information, and the wholesale distributor is not in a contractual relationship with the MAH, there is no obligation for the MAH to implement any further documentation. However, if they wish to add a standard statement to the invoices to raise awareness of PQC/AE reporting, this would not pose any issue for the GPvP Inspectorate.
Kind regards Sara