Stamp of Approval: H1N1 and the Flu Vaccine Licensing Process

As reports of the “new” 2009 H1N1 (swine) flu emerged last spring, its unknown implications frightened many. But, even more frightening was the fact that there was no vaccine to prevent it. And, it appeared highly likely that, considering the time required to get a vaccine to market, it would not be ready when the first wave of the 2009 H1N1 flu hit. Yet, while it was in short supply during that first wave, vaccine did become available, despite the many steps required to obtain approval by the Food and Drug Administration (FDA).

Of course, the speed needed to get the 2009 H1N1 vaccine into circulation to inoculate tens of millions of Americans raised concerns about its safety. And, when the first doses of the vaccine were distributed in the U.S. in October, a mere five months after 2009 H1N1 came on the scene, many were skeptical of the approval process. But, the scrutiny the 2009 H1N1 vaccine underwent for approval was at least equal to, if not more intensive than, the annual review of the seasonal flu vaccine. Understanding how the approval process works may help to alleviate both physicians’ and patients’ concerns.

Determining a Virus’ Strain

When the World Health Organization (WHO) declared the 2009 H1N1 flu virus a pandemic last June, an incident management system was used by staff at the FDA to look at the virus and determine the appropriate response. According to FDA Public Affairs Specialist Paul Richards, “Scientists immediately began working with WHO Essential Reference Laboratories (ERL) to make a reference strain for possible use in vaccine production and to prepare potency testing reagents to be used in the development of seed viruses needed for vaccine formulation. Additionally, a pathway to approval was developed and presented to the public on July 23, 2009, during a meeting with the Vaccines and Related Biological Products Advisory Committee (VRBPAC).

Prior to this time, experts from the FDA, WHO, the Centers for Disease Control and Prevention (CDC) and other institutions were studying virus samples and patterns collected from around the world in an effort to identify strains that were most likely to cause the most illness in the upcoming season. Based on those forecasts and on the recommendations of VRBPAC, the FDA determined the strains that manufacturers should include in their vaccines for the U.S. population. Unfortunately, by the time the 2009 H1N1 strain had been identified, it was too late to include it in the seasonal flu vaccine for this season, so it became its own vaccination.¹

As such, the 2009 H1N1 vaccine was approved as a strain change to each manufacturer’s FDA-approved seasonal influenza vaccine. And, shortly after the VRBPAC meeting, the FDA began receiving strain change supplements, with the first four approved in September.

The Process of Vaccine Production

The 2009 H1N1 vaccine was approved and evaluated by the FDA after review of supplemental applications submitted by manufacturers, using the same regulatory process by which it approves new viral strains contained in the annual seasonal influenza vaccines. And, while these strain change supplements are not required to be supported by new clinical data, immunogenicity and safety data were made available through clinical studies.

After production, the vaccine underwent testing in clinical trials by several thousand volunteers, which took place in three phases. First, there were safety studies on a limited number of people. Next, there were studies of dosage amounts conducted on hundreds of people. And, last, thousands of trials were conducted on people taking the vaccine so scientists could study its effectiveness, safety and side effects.

When all three phases were successfully underway, the manufacturers received the approval from the FDA for the request to supplement their Biologics License Application (BLA) for influenza virus vaccine to include the new influenza (H1N1) 2009 monovalent vaccine. At the same time, the FDA acknowledged the manufacturers’ commitments to submit results from ongoing clinical studies, which would be used as an efficacy supplement to the existing BLA.²

Safety First Because less than half of the expected 2009 H1N1 vaccine doses had been delivered by early December, many called the vaccine production method into question. The current method relies on egg-based technology, which requires growing cultures in hundreds of millions of eggs to create vaccines. Unfortunately, using this method, there is no way to speed up the process. (New production methods are now being tested. See the article, “Scientists Flying the Coop on Flu Vaccine Manufacturing,” on page 48 of the January 2010 issue of BioSupply Trends Quarterly.) This slow pace of 2009 H1N1 vaccine delivery prompted Health and Human Services secretary Kathleen Sebelius to call for a federal review of the handling of public health emergency preparedness.

But, safety must come before efficiency. According to Richards, “Although there were tremendous efforts to get a vaccine on the market as quickly as possible, the vaccines approved for this pandemic were approved and manufactured with the same production and testing methods used in the seasonal vaccines. These methods and tests were previously approved at the time each manufacturer was initially licensed to manufacture influenza vaccines, and are based on decades of influenza vaccine experience and a strong scientific foundation. Protecting the public health is [the] FDA’s primary mission. Emergency preparedness is an important part of that effort.”

Monitoring for Safety

Once a vaccine is on the market, many different organizations monitor it for safety. The FDA and CDC oversee its production and safety through the CDC’s Immunization Safety Office (ISO) using a number of methods, including the Vaccine Adverse Event Reporting System (VAERS), which looks for adverse events or side effects either coincidental or attributed to the vaccine that might be significant to public health. With VAERS, physicians, clinicians and even family members or the patients themselves can voluntarily report any adverse or suspected adverse effects after a patient receives a vaccine. The FDA and CDC cannot determine from this report whether there is a clinically significant link between the adverse effect and vaccine, but it can refer those cases that warrant further investigation.³ VAERS can be thought of as an “early warning detection.”

TheVaccine Safety Datalink (VSD) project is a collaboration between the FDA and eight managed care organizations that review adverse events that could be associated with new vaccines via a large linked database.⁴ Established in 1990, the VSD looks at the date of the vaccination, the type of vaccine and other metadata, and can compare results to millions of other patients to determine safety outcomes.

The Clinical Immunization Safety Assessment (CISA) Network, made up of six medical research centers with expertise in immunization safety, meets monthly to look at specific adverse event cases to determine an assessment of the situation and a plan.⁵ And, the Center for Biologics Evaluation and Research (CBER) within the FDA regulates vaccine products once they are approved and coordinates the availability of those vaccines.

Should a vaccine or vaccine batch need to be recalled, typically it is due to its effectiveness, rather than its safety. When vaccine potency is discovered to be weakened, the ensuing recall usually is voluntary on the part of the manufacturer. This was the case when Sanofi Pasteur determined that four lots, or about 800,000 doses, of its pediatric prefilled syringes of 2009 H1N1 vaccine had a drop in its potency (strength) below the required range.⁶ Similarly, MedImmune reported 13 batches of its nasal spray vaccine had lost potency.⁷ Both companies notified the FDA and CDC, and the lots were recalled.

Rare Side Effect

Some skeptics are still questioning the 2009 H1N1 vaccine safety. One reason is the potential for the rare occurrence of Guillain-Barré syndrome (GBS), which was reported in 1976 after the introduction of another swine flu vaccine. The WHO calls the relationship between GBS and the 1976 vaccine “well established” and “causal.”⁸

That vaccine was suspended when it was apparent that the risk of developing GBS slightly increased with its use. According to the CDC, GBS normally strikes one to two out of 100,000 people, while the 1976 swine flu vaccine was associated with GBS at a rate of one additional case per 100,000 people. And, while subsequent studies of seasonal flu vaccines have shown no consistent relationship between the vaccine and the incidence of GBS,⁹ two studies did find a potential link between the seasonal flu vaccine and a slight increase in GBS risk.¹⁰

According to the VAERS report for Jan. 8, 2010, 37 cases of GBS are under investigation in the U.S. 11 (In the U.S., approximately 80 to 160 GBS cases are expected each week, regardless of vaccinations.)

Monitoring = Patient Safety

States are now able to offer the 2009 H1N1 vaccine to all residents, not just high-risk groups. And, the FDA, CDC and other local, state and federal organizations continue to monitor its safety. At the same time, manufacturers are analyzing their production methods and vaccine potency. Couple this with maintaining strict FDA approval processes for vaccines — even in times of crisis — and it’s clear that many organizations are working responsibly to keep our population safe and to keep the 2009 H1N1 virus at bay.

In the 2010-2011 influenza season, manufacturers will look to re-create this mirrored process and produce new virus strains to be included in the season’s flu vaccine. And, because the H1N1 virus likely will once again pose a serious threat, it will be combined with two other strains in time for the next season’s trivalent flu vaccine.