ARCHIVED - Lessons Learned Review: Public Health Agency of Canada and Health Canada Response to the 2009 H1N1 Pandemic

3. Findings

3.8 Vaccine

Background

Canadians receive many vaccines throughout their lifetime, many while at an early age. As noted by one interviewee, “Aside from food, there’s probably nothing that affects the population more than vaccines. Everybody gets them: they’re given to healthy people; our kids get eight or nine vaccines before they’re one year old.”

Within Canada, there is a division of responsibility for activities regarding vaccines.

Health Canada

Canada, like many other jurisdictions worldwide, exercises tight regulatory oversight over vaccines. All vaccines intended for human use are subject to the provisions of the Food and Drugs Act and the Food and Drug Regulations. Prior to market authorization of a new vaccine, manufacturers must file a submission with scientific and clinical evidence that demonstrates that the vaccine’s health benefits outweigh its risks and that the vaccine is efficacious and of suitable quality.

The Biologics and Genetic Therapies Directorate in the Health Products and Food Branch, as administrators of Health Canada’s vaccine regulatory program, is the focal point for activities related to the review and authorization of adjuvanted and unadjuvanted pandemic vaccines.

Since a pandemic influenza vaccine is by nature untested, the efficacy, safety and quality of the vaccine has to be established in real time. For the 2009-10 H1N1 pandemic, the development of the pandemic H1N1 vaccine could not begin until the pandemic strain was identified in spring 2009. Since the vaccine was needed almost immediately after being manufactured, there was limited time for traditional clinical trials required to authorize the vaccine under the existing regulatory framework.

The Biologics and Genetic Therapies Directorate planned for an expedited review process for a pandemic vaccine, with a “rolling” submission approach, where data would be reviewed as it became available, and with a greater emphasis on post-market commitments.

The Health Products and Food Branch reviewers assessed the risks and benefits of the vaccine, in the context of the H1N1 pandemic outbreak. While the review was expedited, early planning and extensive international collaboration on data, including clinical trial results, ensured that the safety and effectiveness of the vaccine was not compromised.

In addition to regulatory activities, Health Canada also undertook surveillance and risk management of post-market safety issues related to the use of antivirals; developed global standards for vaccine authorization, in line with the International Health Regulations that support World Health Organization global licensing efforts; monitored and enforced the removal of fraudulent health claims over the Internet; and issued alerts for products with health claims regarding H1N1.

Public Health Agency of Canada

The Public Health Agency of Canada has four key activities related to pandemic vaccine:

• managing a contract with a domestic manufacturer to develop a vaccine
• arranging a contract with Public Works and Government Services Canada for the purchase of sufficient vaccine for Canadians on behalf of the provinces and territories (the Government of Canada’s contract with the vaccine manufacturer specifies priority access to pandemic vaccine produced at its Canadian plant)
• issuing guidance for vaccine use as well as guidance for vaccine safety surveillance
• monitoring adverse events following immunization with the H1N1 influenza vaccine in Canada in collaboration with Health Canada, the provinces and territories, the Canadian Paediatric Society, and a network of researchers.

Provinces and territories

The provinces and territories are responsible for the overall delivery of health care services to the population, as well as the delivery of the vaccine and immunization program through local health authorities.

First Nation communities across Canada offer immunization as a component of their mandatory communicable disease control programming. The distribution of the H1N1 vaccine demonstrated that First Nation communities have well-established processes for obtaining vaccine, storing and handling vaccine safely, and implementing immunization programs. First Nation communities in Canada implement immunization programs based on the guidance set by the provinces and territories, which develop their policies based on the expert recommendations made by the National Advisory Committee on Immunization. Health professionals in First Nation communities also report adverse events following immunization to their respective provinces, which then send them to the Public Health Agency of Canada for analysis.

What worked well?

Advance planning for the vaccine supply ensured timely access to a safe and effective vaccine

The Public Health Agency of Canada and Health Canada have focused significant attention over the past 10 years on timely access to a safe and effective vaccine in the event of a pandemic influenza outbreak.

Contract in place with a domestic supplier to ensure enough vaccine would be available to immunize all Canadians

Canada was one of the first countries in the world to contract with a manufacturer domestically to assure a state of readiness in case of an influenza pandemic and to ensure access to enough vaccine for all Canadians as early and as quickly as possible at the time of a pandemic. Over the past few years, Canada has made significant investments to increase the vaccine production capacity of the domestic vaccine manufacturer.

Canada ordered approximately 50.4 million doses of adjuvanted and unadjuvanted H1N1 vaccine for the Canadian population, enough to immunize all Canadians who needed and wanted protection against the H1N1 influenza virus. An adjuvanted vaccine is a vaccine that includes a substance that boosts an individual’s immune system and increases the response to a vaccine. An unadjuvanted vaccine has no ‘booster’ element. Adjuvanted vaccines are included in common vaccines such as tetanus and hepatitis B. The adjuvant in Canada’s H1N1 influenza vaccine is made up of natural ingredients such as water, squalene oil and vitamin E. Guidelines were established to distribute adjuvanted vaccines, deemed equally efficient and safe by international standards, to the majority of the population. Unadjuvanted vaccines were acquired for pregnant women.^{Footnote 61} As such, vaccines considered safe and effective were available to all Canadians.

Mechanisms were in place to quickly review and authorize H1N1 vaccine for sale in Canada

The regulatory challenge for a pandemic influenza vaccine is to have mechanisms in place that can be used to review and authorize a safe and efficacious vaccine for use in Canada, within the shortest time frame possible, and to verify the vaccine in use is the most effective.

Health Canada worked closely with the manufacturer in advance of the pandemic to identify safety information and data on vaccine components or a ‘mock’ vaccine. This process, initiated in 2005, paid off during the H1N1 influenza pandemic. Once the pandemic was declared, Health Canada had limited time to review and authorize the vaccine and the experience with the mock vaccine made it possible to do this quickly. As of December 13, 2009, approximately 23.7 million doses of adjuvanted and 1.3 million doses of unadjuvanted vaccine had been delivered to the provinces and territories.

The Canadian rate of immunization was one of the highest in the world

Immunization with a safe and effective pandemic vaccine is the cornerstone of the health response to pandemic influenza in Canada. The mass immunization campaign for H1N1 was the largest ever held. Although rates of vaccine uptake varied across the country, Canada had one of the highest vaccination rates in the world, estimated by the Health Portfolio at between 40 and 45 percent.^{Footnote 62} As one interviewee noted, “We were one of the few countries in the world that had a vaccine out and in people’s arms before end of December.”

There was close collaboration with the World Health Organization and international regulatory counterparts

The close collaborative relationship was emphasized by one interviewee who indicated, “As part of our regulatory responsibilities, we worked really, really closely with our international partners and, in this particular case, it was very, very closely. It was on a real-time basis with the international community.”

Both the Public Health Agency of Canada and Health Canada have well-established linkages with international organizations including the European Medicines Agency, the medical group in the European Union, and the United States Food and Drug Administration. Between 2006 and 2007, for example, three international workshops were held with the Food and Drug Administration and the World Health Organization to establish the data required to develop, test and approve a pandemic vaccine worldwide. The workshops identified many regulatory and policy challenges that fed into Canada’s pandemic vaccine planning.

Throughout the H1N1 pandemic, the international community of regulators continued to meet on a regular basis, either in-person or by conference call, sometimes daily or, at a minimum, three times weekly. A critical meeting of international heads of regulatory bodies was held in early October 2009, just prior to the approval of the vaccine later that month.

Following the H1N1 response, Canada has continued its role as a leader in international collaboration. As recently as July 2010, Health Canada organized a workshop with the United States Food and Drug Administration and the World Health Organization to identify lessons from potency testing of pandemic vaccine, and to:

• exchange knowledge and experience in vaccine release and immunization around the world throughout the 2009 influenza pandemic
• formulate plans to address gaps in our knowledge on the use of alternative approaches to assess the potency of influenza vaccines
• identify possible ways to incorporate such assays into influenza vaccine regulation.^{Footnote 63}

Science, policy and regulatory experts worked together as a team

The H1N1 vaccine experience was a good example of how science and regulation are intertwined and benefit from teamwork. Both scientific and regulatory processes had to be adjusted to address the uniqueness of the H1N1 pandemic situation without compromising product safety or effectiveness. Science, policy and regulatory expertise at the Public Health Agency of Canada and Health Canada continue to work together on the pandemic vaccine file.

Interim orders were appropriate regulatory measures to expedite access to the H1N1 vaccine, as well as to antivirals for children under one year of age

Under section 30.1(1) of the Food and Drugs Act, “The Minister may make an interim order that contains any provision that may be contained in a regulation made under this 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.”

Interim orders deal with matters that would normally be covered under regulation; in this case, the proposed Extraordinary Use New Drugs Regulations were published in the Canada Gazette Part I but are not yet law.

The Minister of Health made three interim orders during the H1N1 pandemic to:

• allow the sale of Tamiflu® for expanded use as a prophylaxis or treatment of infection caused by the novel H1N1 influenza A virus in children under one year of age
• authorize the sale of the vaccine manufacturer’s H1N1 influenza A pandemic vaccines (adjuvanted and unadjuvanted)
• authorize a small amount of unadjuvanted vaccine for early distribution from other sources prior to the authorization of the larger supply from the domestic vaccine manufacturer.

Interim orders provided the flexibility to authorize a vaccine based on limited clinical data, imposed post-market commitments and allowed for pre-positioning of the vaccine across the country before its authorization. Pre-positioning of the vaccine facilitated earlier start-up of immunization programs in some provinces and territories.

Areas for action

Overall the timelines were met and a safe vaccine was made available. However, as one interviewee explained:

What we were not prepared for was for the pandemic to occur when it did. We thought we would have more time, because we were all looking at the H5N1 epidemiology, and that’s what we were watching. So it caught us off guard in that it occurred when it did, that it started where it started in the world, that the strain was what it was. So not everything we would have liked to have had in place was in place. But we had identified some backup mechanisms, because part of preparedness was realizing you never knew when a pandemic was going to occur.

The following four areas have been identified as key points for improvement.

Implement an integrated surveillance system for immunization, including managing inventories, tracking vaccine uptake and monitoring adverse events

During the H1N1 pandemic, it was not possible to fully track vaccine uptake/immunization coverage, such as who got the vaccine, how much was used and how much was wasted. For instance, some provinces and territories experienced delays in data entry and processing, as well as in forwarding uptake data to the Public Health Agency of Canada. In some provinces and territories, vaccines administered by physicians were not captured by the jurisdiction. Both these factors are believed to have contributed to lower-than-expected reported H1N1 vaccine coverage. Consequently, data on H1N1 vaccine uptake across the country are estimates and may not accurately represent national uptake. Tracking unexpected adverse reactions in real time was also challenging in terms of timely information sharing across the Health Portfolio and with partners.

In response to lessons learned from the Severe Acute Respiratory Syndrome (SARS) outbreak, an integrated public health surveillance system was proposed.^{Footnote 64} The ability for public health professionals to work together to efficiently manage individual cases, outbreaks, notifications, immunizations and vaccine inventories across the country was identified as a particular need. Public health professionals would benefit from the ability to forecast and record immunization information including information on consent and adverse reactions.^{Footnote 65} In support, efforts continue for establishing electronic health records.^{Footnote 66}

For more details on other aspects of vaccine surveillance, see section 3.1, Surveillance, science and research.

Review the approach for federal delivery of vaccines to provinces and territories

Sole pandemic vaccine supplier

The Government of Canada’s contract with a sole pandemic vaccine supplier results from the fact that, at the time of the open tendering and awarding of the contract in 2001, there was only one manufacturer interested in establishing sufficient domestic capacity to manufacture enough vaccine to inoculate the entire population in the event of an influenza pandemic.

Priority groups (sequencing)

Several factors influenced the timing of the production of the H1N1 pandemic influenza vaccine and contributed to delays in its production and, therefore, to an initial delay in H1N1 vaccine distribution. While Canada has domestic production capacity to manufacture pandemic and seasonal influenza vaccines, vaccine manufacturing does not allow for them to be produced simultaneously. Similarly, adjuvanted and unadjuvanted vaccine cannot be produced simultaneously.

In the early stages of the H1N1 pandemic, it was unknown whether the pandemic H1N1 influenza virus would be the only strain of influenza circulating in the fall of 2009. Therefore, in accordance with the World Health Organization recommendation that vaccine manufacturers complete their seasonal influenza vaccination production before starting its H1N1 influenza vaccine production, the Government of Canada instructed its manufacturer to complete the 2009-10 seasonal influenza vaccine production. Immediately upon completion of the seasonal influenza vaccine production, the manufacturer began pandemic vaccine production. Filling adjuvanted vaccine began on September 4, 2009. However, production of the adjuvanted vaccine was briefly interrupted to fill unadjuvanted vaccine for pregnant women in early October, in keeping with the recommendation of the World Health Organization’s Strategic Advisory Group of Experts that pregnant women receive the unadjuvanted H1N1 influenza vaccine, if available.

Finite production capacity, the completion of seasonal influenza vaccine production, and the switch to production of unadjuvanted H1N1 vaccine, contributed to a limited supply of pandemic vaccine for several weeks at the beginning of the campaign. It was anticipated that Canada’s pandemic vaccine order would be made available in batches over weeks during the pandemic and would necessitate some prioritization within the population as initial doses of the vaccine became available. Pandemic vaccine prioritization was based on a framework that considered scientific evidence, ethical considerations, program issues and additional policy considerations. In keeping with the Canadian Pandemic Influenza Plan for the Health Sector goal of minimizing serious illness and overall deaths, it was determined that those who would benefit most from immunization would be the first to receive the pandemic H1N1 (2009) influenza vaccine once it became available.

There was close federal collaboration with the provinces and territories on prioritization through the Pandemic Vaccine Task Group, including specific guidance on vaccine sequencing. However, the implementation of sequencing recommendations varied across the country at the outset. This resulted in confusion among some Canadians about the different priority groups for immunization.

While there was some initial inconsistency in implementing the vaccine sequencing guidelines, some aspects of this issue were effective. For example, there have been positive comments about the priority given to remote and isolated areas with respect to H1N1 preparations and vaccine distribution. From a northern perspective, federal/provincial/territorial coordination and cooperation was considered strong. Having a shipment of vaccine sent to one locale was useful, notwithstanding the related challenge of then distributing supplies to 30 communities. This may be an indication of the significant work which was done by the Remote and Isolated Communities Task Group.

Batching/packaging of vaccine

Doses of the vaccine were delivered to provinces and territories in batches as the vaccine became available. At times, the quantity of vaccine delivered to the provinces and territories was insufficient. In British Columbia’s report on the response to the H1N1 pandemic, the Provincial Health Officer says that “going forward, we plan to work with the federal government to see if there are ways of securing larger quantities of vaccine sooner for future pandemics.” ^{Footnote 67}

Packaging was also an issue.

The vaccine was received in large boxes of 500 doses, which was much too big for most small health care providers and physicians to receive, leading to delays while they were re-packaged. And we couldn’t start repackaging until Health Canada had approved us to do so which subsequently led to a complex and time consuming process to ensure safety and quality assurance. The day–to–day uncertainties related to our vaccine supply were another example, as were recommendations related to the choice of flu vaccine to be used in pregnant women. I would put it this way, with an eye to improving things for next time: the level of collaboration was unprecedented, but the coordination and communication that characterized our national response needs work.^{Footnote 68}

Provinces and territories were allowed to stock the vaccine in their centres before it was approved for use, an unusual practice since distribution is normally not allowed until the product is approved for sale. This was done to reduce the time lag due to the repackaging necessary for shipping smaller quantities of vaccine to smaller centres. Two issues emerged due to this strategy:

• It is unlikely that the Public Health Agency of Canada or provincial and territorial officials anticipated the amount of time needed to repackage the vaccine shipment.
• Most provinces and territories do not have the establishment licences that cover the repackaging activity. The provincial centres without licences authorizing this repackaging activity were required to provide assurances that the vaccine would be handled in a controlled environment that would not affect its quality (i.e. using a refrigerated facility).

Communication about types of vaccines

There was also confusion about the types of vaccines offered. Five different types of vaccines were available during the immunization period (adjuvanted H1N1 vaccine, Canadian unadjuvanted H1N1 vaccine, Australian unadjuvanted H1N1 vaccine, and two seasonal influenza vaccines). This range of vaccine options complicated the process in terms of volume of documentation required, staff education and stockpiles.

Establish a permanent regulatory regime for future public health events

Given the need for timeliness in pandemic response, regulatory capacity must be sufficient so as not to delay delivery of safe and effective vaccine. The 2009 H1N1 influenza pandemic brought unprecedented attention to the regulatory requirements for the release and marketing authorization of pandemic influenza vaccines.

Rather than relying on interim regulatory measures, a permanent regulatory regime should be established for future public health events. Work had been under way for the past three years to identify particular regulatory challenges related to releasing vaccines during an emergency.

Two draft regulatory amendments were in development that recommended new frameworks for authorizing the sale of a vaccine without the use of an interim order:

• Proposed amendments respecting the sale of Extraordinary Use New Drugs; these proposed regulations detail the criteria that a new drug would have to meet before the manufacturer could file an Extraordinary Use New Drug submission. The regulatory framework outlines requirements for submissions, labelling, plans for post-market safety and efficacy data acquisition and annual reporting. However, the Extraordinary Use New Drugs Regulations had not been published in the Canada Gazette Part I by the onset of the 2009 H1N1 pandemic.
• Proposed amendments respecting the block release of drugs to address public health emergencies continue to be developed, and, therefore, were not law at the onset of the 2009 H1N1 pandemic.

Effectively communicate regulatory processes and mechanisms

It is important that Health Portfolio staff at all levels understand the approval process for vaccines and the role of each of the key players in terms of communicating with the manufacturer (i.e. Health Canada’s role as the regulator and the Public Health Agency of Canada’s role in negotiating the contract).

Some interviewees suggested that, “When we got into this situation of pandemic, we realized that basically there was no knowledge…this is not unique to Canada…the Australians … from the therapeutic drugs administration …said [their] biggest challenge was explaining to [their] own Minister what [they] do and that you can’t make a vaccine in a couple of hours.”