Back in the fall of 2017 the International Coalition of Medicines Regulatory Authorities (ICMRA) published a paper containing recommendations for pharmaceutical product regulators around the world to consider for achieving future interoperability of national or market pharma track and trace systems. That is, their recommendations were aimed at enabling interoperability between and among the various current and future pharma track & trace regulated systems around the globe. For example, their recommendations could help the US FDA exchange and accept information from the European Medicines Verification System (EMVS), and vice versa. In this way, regulators in each market could learn about problems with drug products circulating within each other’s markets. Why would you want to do such a thing? Let’s take a look at their 2017 paper.
We’ll look at their specific recommendations in a minute, but for now, the goal of the ICMRA paper is to convince all regulators around the world to adopt their recommendations which they believe will lead to:
- “…rapid exchange of regulatory information among national authorities [which] is integral to the protection of the supply chain integrity and to the protection of patient safety”;
- “…the identification and management of risks associated with counterfeit or substandard health products and enables enhanced pharmacovigilance”;
- “…contribute to further mutual reliance in risk-based decision-making as it increases certainty about the health product and the industry party at stake in particular health and safety risk situations (e.g. facilitation of recalls, detecting fraud, monitoring internet sales)”.
The paper can be found here. Now, before you get too carried away with assumptions, let me point out that the ICMRA is NOT recommending any serialization, or exchanging of transaction or shipment data. In fact, their recommendations are lot/batch-based and they don’t even include quantities, so their adoption would not result in a global “track and trace” system for drug products. The recommendations are mainly to enable global-scale pharmacovigilance. The ICMRA envisions exchanging information among the global regulatory agencies only in cases where a serious threat to public health has been observed or is anticipated. This would limit the volume of data exchanged under their recommendations.
Pharmacovigilance (PV or PhV) has to do with “…the collection, detection, assessment, monitoring, and prevention of adverse effects with pharmaceutical products.” It is primarily the study of adverse drug reactions (ADRs). To accomplish the benefits listed above, interoperability of certain elements of local track and trace systems across the globe is necessary. This is the first time I’ve heard of anyone proposing a fully global level of interoperability.
What is necessary to achieve these results? The ICMRA paper lists the following recommends to regulators in countries or markets that currently have, or plan to add, pharma traceability mandates:
I can’t figure out why the ICMRA would care about the data carrier on drug packages, considering their goals. It’s a fine idea to ask every country to use the identical technology, but their goals don’t seem to gain anything from the global use of one data carrier, or lose anything if multiple carriers are in use in different markets. I also don’t see the benefit, considering the ICMRA goals, of standardizing the encoding of the data elements within the data carrier, although I definitely see the benefit toward their goals of standardizing the format of data for data exchange. But rather than dictating the data exchange data format within each “local” track and trace system, the ICMRA should just plan on dictating the format of that data when it is exchanged between those country/market systems at the global level. That’s really what they need, so maybe that’s what they mean to recommend.
The real keys to meeting the goals laid out by the ICMRA are the remaining recommendations: the standardized global product identifier (IDMP “PhPID”) and the exchange of expiry date and relevant batches. The PhPID is NOT the saleable package identifier that we know in the USA as the National Drug Code (NDC) and in Canada as the Drug Identification Number (DIN), for two examples. Under the ISO Identification of Medical Products (IDMP) standards, the NDC and DIN are known as Medicine Product Identifiers, MPIDs. The PhPID , on the other hand, identifies the combination of the pharmaceutical substance, the dosage form and strength produced by a specific manufacturer.
The ICMRA recommendations don’t mention MPIDs, only the PhPID (by description, not by name). That’s because many companies package drug dosage units with identical PhPID in many different MPIDs—for different sized packaging and for different markets. For example, the same PhPID might be contained in MPID saleable packages for 30, 60 and 90 day supply and “hospital only”, labeled with corresponding NDCs in the USA, and in 30, 60 and 90 day supply and “hospital only”, labeled with corresponding DINs in Canada. And that same PhPID might also be used in many products in every market in the world inside of many different packages having their own unique MPIDs. By monitoring for PhV issues at the PhPID-level, you will cover all of those many MPIDs that contain the PhPID as the product doses inside them. The linkage between PhPID and MPID would probably be carried in the supply chain master data exchanged within a given market at the MPID-level, but the paper doesn’t talk about that (see “Master Data, Supply Chain Master Data and Instance Data”).
There may be a problem in the way batch numbers are constructed on saleable package (MPIDs), however. If a drug manufacturer prints the batch number of the PhPID on the MPID package, then everything works fine. However, if a manufacturer constructs the batch number for the MPIDs differently than they construct them for their PhPID, then the manufacturer would have to be careful about sharing those underlying batch numbers for PhV purposes. Perhaps that’s why the ICMRA recommends “a standardized batch number”. It’s not totally clear.
Pharmacovigilance across the globe depends on the ability to identify products that contain the identical substance, form, dosage and marketing authorization/registration holder, as represented in the PhPID, plus the batch number and corresponding expiry dates, whenever there exists a serious threat to public health. Based on that, governments could more reliably exchange alerts about problems observed in one market, using the PhPID, batch and expiry, so that the other markets would be aware of those issues, in case those same PhPID-level products are also sold in their region. These alerts would likely include recalls, adverse reaction reports, stolen, substandard and falsified notices. Think how much harder it would be to sell drugs stolen in one market, for example, to customers in a different market if those alerts were shared immediately. Or a recall, or serious adverse reactions.
Here is a list of additional benefits to interoperability of track & trace data shared among national and regional track and trace systems as called out in the paper:
- “…allow traceability of products and batches throughout the global supply-chain…”
- “…minimise patients exposure to risk associated with defective health products through immediate notification of products and batch numbers related to a serious safety incident throughout the interoperable systems.”
- “…identifying the origin of quality and safety issues associated with a product, and informing health risk mitigation measures.”
- “…support investigation of a suspect quality defect, pharmacovigilance or falsified incidents…”
- “…support regulators in addressing drugs shortages, as they would be better positioned to localise in real time where similar products are.”
- “…minimise patients’ exposure to defective and counterfeited products, by facilitating the identification of falsified or substandard products through the use of standardised product codes and batch numbers along the supply chain.”
- “…regulatory authorities [would be able to] take fast actions in their jurisdiction and concerted risk mitigation actions with regard to […] products across all the markets where the product is distributed, and as appropriate at the different points of the supply chain.”
As I said above, the ICMRA recommendations are to establish interoperability between existing and future local and regional track & trace regulatory systems, and their recommendations do not include serialization. But now that mass serialization is finally a reality in many of those markets, I’m not sure how long the regulators in those markets will continue identifying all pharmaceutical threats to public health at the batch-level. If all you are trying to track are adverse drug reactions, then maybe the batch-level would be fine, but many of the problems the ICMRA appears to be trying to address will likely be identified at the serial number level. This is particularly true of stolen and falsified drugs.
For example, if ten shipping cases of a given serialized MPID are stolen in one market, it probably won’t be a good idea to recall or cast suspicion on every PhPID that has the same batch number. That could cast suspicion on several orders of magnitude more drug packages than would be necessary.
The same would be true of an instance of small quantity falsification in one market. Because the notification between regulatory agencies would be at the PhPID and batch level, the ability to take action on the notification would be greatly reduced. Why establish interoperability only at that level? It might work fine for spreading the news about substandard products and adverse drug reactions, but even recalls might not work well at this notification granularity. Many recalls in some markets have more to do with errors in the packaging at the MPID level than the actual dose at the PhPID level. Perhaps the ICMRA might consider establishing interoperability at the serialized MPID level, at least optionally.
Everything I have discussed above came from the 2017 paper by the ICMRA. But earlier in 2019, the ICMRA created a Joint ICMRA-Industry Working Group as a “next step” toward implementation of the principles contained in the recommendations made in the earlier paper (see “Call For Expression Of Interest”). The newly formed work group will work toward the following deliverables:
- “More detailed guidance on common technical features to enable interoperability of T&T systems
- “Capacity building tools for jurisdictions wishing to implement T&T systems
- “Solutions/tools for systems to become interoperable, applicable to both new systems and already existing ones.
- “Analysis of technical aspects related to interactions between alert systems and T&T systems
- “Identification of solutions to overcome barriers to exchange of information between different T&T systems (including e.g. data ownerships and confidentiality issues)”
I am told this group has already begun holding meetings. It will be interesting to see what impact the organization can have on global PhV.