ARCHIVED: Current context: The Management of the National Antiviral Stockpile: Options Report

Current Context

The Antiviral Stockpile Management Task Group (AVSMTG) considered key factors that could impact future purchasing decisions. It operated under the assumption that there was a general commitment in principle to maintaining the stockpile.  However, at the time of the establishment of the National Antiviral Stockpile (NAS) it was not stipulated whether or not the initial stockpile would be replenished once it had met its stated shelf-life or how this replenishment would be funded. 

International Comparisons

The AVSMTG examined stockpiling practices of other countries to determine how they were addressing the issue of expiring antivirals in their stockpiles. Some countries, such as the United States and Japan have unilaterally extended the shelf-life of their stockpiles, which served as a precedent for discussion regarding options for Canada’s stockpiles.  Other countries were replacing their stockpiles (see Appendix 4: Comparison of International Stockpiling Trends). 

Regulatory Considerations

Shelf-Life

If stored according to manufacturer recommended conditions, oseltamivir is a stable drug. In August 2008, Health Canada approved a Notifiable Change (NC) from Hoffman-La Roche (Roche) to extend the shelf-life for government pandemic stockpiles of newly-manufactured oseltamivir from 5 to 7 years from the date of manufacture³.  This has come with a minor change to the Product Monographⁱⁱⁱ that notes stricter storage requirements, specifically, more rigid temperature control.  

Regulatory authorities at Health Canada have noted that there is not enough evidence to consider oseltamivir safe and potent for longer than two additional years beyond its original 5 year shelf-life.  Stability testing, conducted at various times during a drug’s extended lifespan will confirm the safety and potency of expired drug. 

Zanamivir (Relenza®) may also have the potential for a longer shelf-life.  GlaxoSmithKline (GSK) has offered under recent contract awards⁴ 7 years of shelf-life from date of manufacture.  Although GSK currently has regulatory approval for 5 years of shelf-life on zanamivir, they are considering submitting a Notifiable Change for approval of a longer shelf-life that would be applicable for future purchases.  Under these contracts, and in the absence of Health Canada approval, they will honour the 7 year shelf-life by replacing new purchases as they expire to achieve a further 2 years of shelf-life.  Although expiring zanamivir will be a future stockpile management consideration, the focus of this report is on the immediate options surrounding the impending oseltamivir expiries.  

Extension of shelf-life:  Re-labeling current Oseltamivir stock

The AVSMTG extensively discussed the possibility of governments re-labeling current oseltamivir stock with a new expiry date supported by stability testing and confirmation of continued viability as one way of extending the shelf-life of the expiring stock.  The AVSMTG came to the conclusion that re-labeling was not a viable option for Canadian governments for the following reason.   Pursuant to the Food and Drugs Act only the manufacturer of oseltamivir can apply for a change to the expiry date on the label of a drug.  Governments would only be able to apply for a change to the expiry date if the manufacturer gave its permission to governments to do so.  The manufacturer is not willing to apply for a change nor is it willing to give its permission to governments to change the expiry dates.  As such, the AVSMTG determined that re-labeling current oseltamivir stock was not an option for extending the stock’s shelf-life.

New Drugs Submission

The AVSMTG explored the possibility that governments could extend shelf-life by assuming all of the responsibilities of a manufacturer.  This would involve creating a new brand name for the oseltamivir in the stockpile.  PHAC and each P/T would submit a second New Drugs Submission (NDS⁵) to Health Canada for approval.  Further consideration of this option identified that this would be compiled and time-consuming and would also require the support of the manufacturer.  After careful consideration, this option was not thought to be practical, and was not included in the Options and Analysis section of this report. 

Generic Antivirals

With the expiry of Tamiflu®’s patent in 2016 several generic submissions are expected to be available at a lower price than currently available.  Although this does not impact the impending replacement of oseltamivir in the stockpile, it may be a consideration with subsequent replacements since the new product will have a guarantee of 6 years, taking this stock to 2015 or 2016 (depending on purchase date) before it would need to be replaced.  At that time, generics may be purchased at presumably a lower cost.  Strategic planning with the generic industry could also result in a tablet formulation of oseltamivir that could have a longer shelf life and less restrictive storage requirements.

Population Data

Initial estimates for the quantity of antivirals needed in the NAS were based on CPIP assumptions using 2005 population census data.  An examination of the 2008 census data^iv revealed that there has been overall population growth in Canada over the past three years, the exception being the paediatric (age 1 to <12) population, where the data showed slightly fewer children in 2008⁶.  It was agreed by PHNC at its February 13, 2009 meeting that the 2008 census data would be used for total population estimates, but a conservative approach for children should be used, therefore maintaining the higher 2005 estimates in calculating the antiviral requirements for children (see Appendix 5 - Calculations for National Antiviral Stockpile Targets).  As a result of population growth, an increase from 55.7 million doses to 58 million doses is required for the NAS to maintain the national goal of treating 17.5% of the total population. 

Increasing Resistance to Oseltamivir

When the NAS was expanded in 2006, its composition was a 90%:10% split between oseltamivir and zanamivir respectively.  Since the initial purchase, there have been reports of increasing resistance of H5N1 influenza strains to oseltamivir, and a significant increase of resistance to seasonal H1N1 influenza strains in some countries, including Canada^v .  These findings prompted the AVWG to recommend increasing the proportion of zanamivir in the NAS as a hedge against future resistant strains. 

Expert Recommendations on the Composition of the Stockpile

The AVSMTG was tasked to incorporate the technical recommendations provided by the AVWG into its stockpile management recommendations.  In November 2008, the PHNC approved changes to the composition of the NAS, as follows:

1. That the NAS be further diversified to 20% zanamivir and 80% oseltamivir;

• To address the issue of increasing resistance and to align with international stockpiling trends

2. That the composition of the NAS be adjusted to include more paediatric oseltamivir capsules to meet national paediatric targets;

• Initially there were 2 million capsules ordered, but it was determined that additional capsules were needed for this population. 

In February 2008, the Council approved the recommendation:

3. That a separate quantity of amantadine be purchased in an amount equal to 10% of the total NAS for use in combination therapy to treat cases of severe illness; (this recommendation was made to Council in February 2008)

Roche Exchange Program

In the midst of AVSMTG deliberations, the manufacturer of oseltamivir (Roche) approached Canadian governments with a time-limited proposal to facilitate the replacement of expiring government stockpiles.  The manufacturer is planning to pilot test a method of “reprocessing” nearly-expired antiviral product into new (refreshed) product.  As per the company, the process involves extracting the active ingredient of oseltamivir from nearly expired capsules through micro-filtration.  New active ingredient would then be added to the reprocessed ingredient, and then placed within a new gel capsule⁷.

The manufacturer asserts that reprocessed capsules would be sold at reduced price and would have a projected shelf-life of 7 years⁸ for government pandemic stockpiles.  This reprocessed product would be sold only in countries where it has received regulatory approval.  This reprocessing manufacturing practices has not received regulatory authorization in any country.  At this time, there is no guarantee of its approval or expected shelf-life on the reprocessed product.

The offer by Roche to receive nearly expired stock for new stock for use in their reprocessing pilot project is hereafter referred to as the “Exchange Program”.  It is described in more detail in the Options and Analysis section of this Report.

Other Stockpile Management Considerations

Storage Conditions

In 2008, a survey of provinces and territories was conducted by the AVSMTG to assess storage conditions.  This was indicated because new oseltamivir stock with 7 year shelf-life will have a more rigid storage requirement^vi .  Ten of the P/Ts plus DND and FNIHB responded to the survey, representing 17 antiviral stockpile locations or depots.  It was reported that 15 of the 17 locations already store their stock according to the more rigid storage conditions of 25°C.  The two other locations indicated they did not monitor temperature control, and thus would not currently meet the tighter temperature control requirements but could easily upgrade.  Three of the seventeen locations reported that they may face constraints in anticipated storage space needs with the planned expansion of the stockpile.

Inventory Management

Ongoing assessment of antiviral quantities, expiry dates, and use of NAS antivirals by P/Ts is an important aspect of inventory management.  Inventory management includes the ability to assess at any point in time what the location and quantity of the current stockpile is, and to ensure NAS stock is well identified to avoid inadvertent mixing with antivirals used for seasonal influenza.

It should be noted that it is not possible to simply rotate older oseltamivir stock out of the NAS for newer stock during the interpandemic period (i.e. for use in treatment of seasonal influenza, or rotate older stock into the health care system and replace it with new stock) as a means to gradually extend the shelf-life of the stockpile. To do so would contravene existing contractual agreements that stipulate that oseltamivir purchased for F/P/T pandemic stockpiles must be used only for the purpose of emergency preparedness and response.  Also, from a practical point of view, seasonal use of oseltamivir in Canada is too low to be able to sustain a sufficient stock rotation.  There are no stipulations on product use in the contracts for zanamivir or amantadine, however, there is also very little seasonal use of these two antivirals in Canada. 

Sustainability

Efficient ongoing management of antiviral stockpiles, including replenishment of expiring stock is an important consideration for F/P/T governments.  

³ With the longer shelf-life for new antiviral purchases, subsequent government stockpiling purchase contracts require expiry dates on new oseltamivir to be 6 years or better from the date of delivery. 

⁴ As of December 2008

⁵ NDS – a sponsor (manufacturer or licensed representative) seeking to receive authorization to market a new product in Canada must complete a NDS pursuant to Division 8 of the Food and Drug Regulations (Located at: Food and Drug Regulations)

⁶During PHN-C discussions, it was noted that due to unique demographics (higher birth rate to life expectancy) in the northern jurisdictions of Canada, it would be necessary to estimate the paediatric targets using actual population data rather than per capita estimates.  These calculations were provided to Nunavut, Northwest Territories, and Yukon for their planning purposes.  This resulted in a slightly higher quantity (app. 14K doses) of paediatric capsules required than originally estimated for these jurisdictions.  There were no subsequent adjustments (reductions) to adult targets. (see Appendix 7b).

⁷The gel capsules turn brittle over time and contributes to the shorter lifespan of oseltamivir.

⁸Reprocessed stock purchased will come with the proviso that an equal amount of Tamiflu must be returned to the manufacturer.

ⁱⁱⁱHoffmann-La Roche Ltd.  (rev. April 20 2009). Product Monograph: TAMIFLU.  Located at: http://www.rochecanada.com/portal/eipf/ca/portal/roche/consumer_information

^ivStatistics Canada, Demography Division, Demographic Estimates Section, Annual Population Estimates by age and sex for July, 1971 to 2008, 2008 Preliminary PostCensal Estimates

^vPublic Health Agency of Canada (2006).  Canadian Pandemic Influenza Plan for the Health Sector, Annex E (revised May 2009).  Located at: http://www.phac-aspc.gc.ca/cpip-pclcpi/

^viHoffmann-La Roche Ltd.  (rev. April 20 2009). Product Monograph: TAMIFLU.  Located at: http://www.rochecanada.com/portal/eipf/ca/portal/roche/consumer_information