ARCHIVED: Mandate #1: The Management of the National Antiviral Stockpile: Options Report - Management of the Expiring Stock
Mandate #1: Management of the Expiring Stock
This section addresses the primary mandate of the AVSMTG: managing oseltamivir NAS antivirals set to expire in 2009/2010. While this Report focuses only on the oseltamivir component of the NAS, many of the proposed strategies are equally applicable to the stockpile as a whole, and might be useful in future decision-making as other antivirals expire. Below is a description of the various Options, and their advantages and disadvantages. A summary can be found in Table 2 at the end of this section.
Under this option, expiring stock of oseltamivir in the NAS would be replaced with new stock. As current lots of oseltamivir within the NAS expire, new stock with a 7 year shelf-life would be purchased at full price. This approach can be used to transition the stockpile to the recommended composition by purchasing less adult oseltamivir and more zanamivir and paediatric oseltamivir.
Expired stock would be disposed of, via incineration. Roche estimates that based on their disposal processes, the cost of disposal could be approximately $29 per 1,000 courses. Each jurisdiction would be responsible for its own disposal arrangements and costs.
The purchase of new stock was the most straightforward option compared to the other 3 options. The expired stockpile would simply be replaced with the same quantity of new stock and thus, the NAS would continue to contain ‘in date’ antivirals with a possible reserve of additional expired antivirals that may still be useable (see Option 2 for discussion on the implications on the use of expired antivirals). This option allows provinces and territories to adjust stockpile composition to meet desired targets through the purchase of less adult oseltamivir for more zanamivir and paediatric oseltamivir capsules.
The administration of drug to patients that has reached its stated shelf-life - even if that stock is proven to continue to be stable, safe and potent, through regular testing – was anticipated to be a risk that is mitigated by the outright purchase of new stock. The perception from health workers and patients during an influenza pandemic was presumed to be in favour of using new stock.
It was thought that purchasing too much new oseltamivir with a 7 year shelf-life may be premature given the current state of antiviral resistance in seasonal strains of influenza. If purchased, the oseltamivir component of the stockpile would be “locked” for an additional 7 years. If resistance to oseltamivir continues to increase, the stockpile may eventually contain unusable drug without the ability (lack of supply or financial resources) to transition to different products.
The purchase of replacement antivirals at full price is the most expensive option. The cost of purchasing full-price antivirals would be in addition to the cost and logistical effort of disposing of expired stock. In addition, there may eventually be a shortage of storage space if holding expired stock in addition to new purchases.
Finally, if disposing antivirals, there is a risk that this will be perceived as wasteful given that it is very likely that the product will continue to be usable beyond its 5 year approved shelf-life.
OPTION 2: Keep existing oseltamivir stock for 2 years beyond its expiry date, stability test held stock, then purchase replacement
Under this option, the expiring stock of oseltamivir in the NAS would be replaced with new stock (as in Option 1), but instead of disposing of the expired stock, Governments would hold this expired stock (separate from new stock) for up to two years and stability test it. It should be noted, however, that the expired stock would be held for possible use only where an emergency arose before governments had acquired new stock to replace the expired stock.
If during the two year timeframe post expiry, while governments had been making efforts to acquire new stock, an influenza pandemic occurred, governments could still consider using the expired stock if; 1) there were insufficient supplies of ‘in date’ antivirals, and 2) stability testing established the ongoing safety and efficacy of the antivirals. The risks and benefits of using expired stock in these circumstances would have to be carefully weighed by each government.
It is possible that in an emergency situation such as where there are insufficient supplies of antivirals available, the use of the expired antivirals could be authorized by way of an Interim Order made by the Federal Minister of Health under the Food and Drugs Act. If the Minister believes that immediate action is required to deal with a significant risk, direct or indirect, to health, safety, or the environment, the Minister has the authority to make an Interim Order that would change the regulatory requirements that apply to the use of a drug. In this case, the Interim Order would authorize use of antivirals even after their labelled expiry date. However, there is no guarantee that the Minister of Health would agree to making an Interim Order to this effect, or perceive it to be appropriate in the circumstances.
It is important to note that this approach would only be useful for existing oseltamivir stock with a 5 year shelf-life (as opposed to future oseltamivir purchases that have a 7 year shelf-life). Governments maintaining their stock of expired drug would conduct stability testing to assess the stock’s continued safety and effectiveness, up to a maximum of two years beyond the current 5 year expiry date. As discussed earlier, oseltamivir has been found to be stable for at least two years beyond the 5 year expiry date if stored in proper conditions. The stability can be assessed and verified through regular testing of the drug, which could be done by Roche to avoid any intellectual property issues that might arise with the involvement of a third party review. Stability testing would be conducted by lot and storage site, whereby a small sample (6 packs/lot/location) would be shipped to Roche for testing in Mississauga. The estimated cost of this testing would be approximately $2200 CDN per lot. If the stock was not used within the two-year timeframe, it would then have to be disposed of (see Option 1).
This approach provides the flexibility to monitor the global situation regarding antiviral resistance over the next two years and make decisions regarding replacement accordingly. It would also allow jurisdictions to take advantage of new antiviral products that may be developed in the interim.
This is also a relatively inexpensive option in the short-term, save for the small cost of annual stability testing for up to two years. In addition, this approach effectively extends the original investment on current stock for a further two years before replacement is necessary. Postponing disposal for two years will also mitigate the potential perception of waste in the short-term.
Stock being held beyond its expiry date can no longer be exchanged through the Roche Exchange program. Hence, stock held under this approach must still be disposed of and replaced in two years, presumably at full cost. If exercised for the entire expiring stockpile, it could delay the transition of the stockpile to its new composition targets for another two years.
Should a pandemic occur while the stock is being held, the deployment of this stock (if no other new stock is available for purchase at that time) could result in a delay in being able to use a portion of the stockpile. First, an Interim Order from the federal Minister of Health would have to be expedited with an appropriate disclosure and disclaimer being produced and attached to each package – all at a time when stock must be distributed as quickly as possible.
There is also a risk that the public will resist taking expired antivirals during a pandemic, even if proven safe through stability testing.
If stock is being held beyond its stated shelf-life, it should be quarantined or separated from stock that is not. If replacement is deferred and stock is allowed to expire, the NAS may be perceived as temporarily falling short of the targets for stockpile size and composition. This could be mitigated by using the term “usable doses” but will require consideration of a common communications message so that this approach is understood by the public. Furthermore, deferring replacement of stock for another two years will potentially result in increasing fiscal pressures when another surge of antiviral expiries is expected in 2011/2012 and more antiviral purchases may be needed unless a similar ‘delay’ strategy is taken at that time.
As described earlier in this Report, Roche approached governments with a time-limited offer to replace (exchange) any amount of nearly-expired stock with new stock at a reduced price. Jurisdictions would commit by a certain deadline to replace as little or as much of their stock as they wanted, now or in the future. With further negotiations it was established that this offer could also be used to exchange expiring adult capsules for new adult or paediatric capsules.
Expiring antivirals that are certified to have been stored within the manufacturer’s specifications would be returned to the manufacturer at their facility in Basil, Switzerland at least one month prior to the expiry date. Replacement (new) stock would be provided in either adult or paediatric formulations shortly before a jurisdiction is obligated to return its nearly-expired stock. Payment for replacement stock under the Exchange Program would be required upon receipt of the new stock (i.e. in the fiscal year in which the stock to be returned to the manufacturer will expire).
A deadline for participation in the pilot program was originally set at November 30th, 2008 so that Roche could make a global corporate decision on whether to proceed with the reprocessing pilot or not. This deadline was subsequently extended to April 30th, 2009 to allow provinces and territories to budget and decide accordingly.
In January 2009, a variation of the Exchange Program offer was made available to provinces and territories. Roche proposed a jurisdiction could commit to return nearly expired stock (now or in the future), and obtain (now) an equal amount of the drug substance, or active pharmaceutical ingredient (API) used in the manufacture of oseltamivir, in bulk which would be identified as the property of that jurisdiction and held in Roche’s warehouse in Basil, Switzerland. Subject to a pre-approved schedule, the bulk API would be placed in capsules (in either adult or paediatric doses)and shipped to the participating jurisdiction just prior to the date on which they would be obligated to return the nearly expired product to the manufacturer. If delivery is required early, P/Ts could inform Roche and the capsule or suspension will be prepared and sent to the P/T with a minimum of 6 months notice. Payment (reduced pandemic price) is made upon notification by Roche that the bulk API has been set aside. The expiring product to be exchanged would also have to be returned to Roche early and an additional payment made to Roche to bring the total cost to that of the regular pandemic price. The P/T would receive new stock with a 7 year shelf life.
The negotiation of the bulk variant was conducted to provide a method by which provinces and territories could utilize available 2008/09 funds to exchange stock expiring in future years. The opportunity to participate in this offer expired on February 28, 2009.
While there are many variations, the “exchange” approach offers a means of obtaining new product with a 7 year shelf-life at a reduced price.
This option can also be used to exchange adult doses of oseltamivir for paediatric capsules and would allow all jurisdictions to immediately reach their paediatric targets in the new stockpile composition recommendations9 . The remaining expiring adult oseltamivir could be exchanged for new adult oseltamivir to maintain the adult oseltamivir NAS target. This approach will also provide new stock with 7 year shelf-life, which will not expire until approximately when Tamiflu®’s patent protection ends in 2016, when generics may become available.
This approach would demonstrate Canada’s support to Roche’s investigation of reprocessing as a viable production process. Without this support, there may be less of an incentive for Roche to develop this method (a precedent within the pharmaceutical industry) and/or seek regulatory approval in Canada. If not supported, a potential opportunity to obtain stock at a lower price in the future may be lost.
The most significant benefit of this option is that the total stockpile size is maintained with new replacement product, at a lower price. Because expiring product would be returned to Roche, disposal is not an issue under this approach, which mitigates the perception of waste.
Since the exchange will result in product with a 7 year shelf-life, there is a similar risk as expressed in Option 1 of “locking” the oseltamivir component of the stockpile for 7 years a possible inability to transition to other products due to unavailability or lack of finances at the time. If continued oseltamivir resistance to seasonal influenza occurs, the newly-exchanged stock may not be effective if similar resistance develops in a pandemic virus.
As with using expired drug, it is uncertain what the public perception of the Government of Canada supporting the investigation of using reprocessed drug would be. The task group also acknowledged that there may be some risk in storing active ingredient overseas through the bulk API offer discussed above. Although there is still uncertainty surrounding the issue of border closures during a pandemic, there is a possibility that the replacement of provincial and territorial stocks may be delayed or blocked during a pandemic. An embargo of antivirals stored overseas is a risk to be considered.
Finally, the opportunity to hold and use potent, stable, but expired drug for an additional 2 years would be lost through the use of this Option.
OPTION 4: Combination Option: Exchange some expiring oseltamivir stock through Roche Exchange program, hold some expired oseltamivir stock for 2 years beyond its expiry date and stability test
This option is a combination of Options 2 and 3 above. Under this option, governments would exchange some expiring adult oseltamivir stock for paediatric or adult capsules, while holding the other portion of the expired stock (separate from the exchanged stock) for up to two years and stability testing it. Once again, the expired stock would be held for possible use only where an emergency arose before governments had acquired new stock to replace the expired stock.
As stated in Option 2, if an influenza pandemic occurred during the two year timeframe post expiry, while governments had been making efforts to acquire new stock, governments could still consider using the expired stock if; 1) there were insufficient supplies of ‘in date’ antivirals, and 2) stability testing established the ongoing safety and efficacy of the antivirals. The risks and benefits of using expired stock in these circumstances would have to be carefully weighed by each government.
As under Option 2, it is possible that in an emergency situation the use of the expired antivirals could be authorized by way of an Interim Order made by the Federal Minister of Health under the Food and Drugs Act (see discussion above).
This combination option allows for a staggered schedule of replacement, and ensures all paediatric targets are met in a cost-effective manner, with minimal waste.
The combination approach provides a unique opportunity to leverage the advantages of Options 2 & 3 that allows governments to replace expiring stock and transition to new stockpile targets as funds become available.
This option also allows the balancing of investments over time as the staggering of purchases spreads the financial burden more evenly over the life span of the stockpile to avoid surges in expenditures. As a sustainability strategy, this also allows the opportunity to adjust stockpile compositions as new developments (i.e. increasing resistance rates, new technologies such as H5N1 vaccines) arise.
A combination approach also assumes the risks of Options 2 and 3. It also introduces additional logistical complexities to stockpile management. Combining approaches will yield a mix of new and older stock with a varied schedule of replacement, exchange and disposal over time that will require careful inventory management and monitoring over time. It will also be more difficult to publicly communicate the size and composition of the NAS in any given year given the various permutations of approaches that are possible and that may be implemented across the provinces and territories.
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