Vaccine Acceleration
by Adam Istas
April 2007
Innovative trial design, effective partnerships and advances in biotechnology continue to move vaccine development into the 21st century.
For biopharmaceutical companies developing vaccines to combat public health threats, perfecting the science and manufacture of the agent is only part of the equation. The logistical challenges manufacturers face when conducting large-scale clinical trials can be daunting. But over time, by establishing both the right public/private partnerships and a network of devoted investigators, manufacturers are better positioned to ensure effective and expeditious delivery of a vaccine to the population in need.
Limited Beginnings
The 2006 U.S. Food and Drug Administration (FDA) approval for RotaTeq and the development of Rotarix for the prevention of rotavirus are the results of successful global partnerships for vaccine development. When the only approved rotavirus vaccine was withdrawn from the market in 1999, it significantly limited the options for preventing gastroenteritis in children. RotaShield had only been available for about a year when the U.S. Centers for Disease Control and Prevention (CDC) recommended that administration of the vaccine be postponed due to concerns regarding a possible association between RotaShield and intussusception, a potentially fatal intestinal obstruction primarily diagnosed in infants.
Although rotavirus is a significant global health problem, most deaths due to infection are concentrated in emerging regions. In fact, a 2003 study conducted by CDC researchers estimated that rotavirus infections were responsible for the deaths of hundreds of thousands of children in emerging regions each year (Emerg Infect Dis. 2003;9:565-572). Without any other approved vaccine available to patients in these regions, the withdrawal of RotaShield was a significant blow to the global effort to control gastrointestinal illnesses in children. Furthermore, the possible connection between live rotavirus vaccines and intussusception presented manufacturers with a sizable risk. Despite this risk, as well as the associated costs of conducting large clinical trials, both Merck and GlaxoSmithKline began developing separate rotavirus vaccine products to address the problem.
Finding Resolve
The removal of the previous rotavirus vaccine created a unique development situation for drug companies, says Dr. Penny Heaton, chief medical officer at Rockville, Md., USA-based Novavax, and former senior director of vaccines clinical research at Merck. “Since we were looking for the specific side effect of intussusception, our objective was clear and we were very deliberate in what we were looking for.” Heaton co-authored the primary paper of the Rotavirus Efficacy and Safety Trial (REST), the landmark Phase III study Merck conducted from 2001-2004 to test RotaTeq (NEJM. 2006;354:23-33). Based on the positive results of this study, the FDA approved RotaTeq for distribution in February 2006. GlaxoSmithKline’s rotavirus vaccine, Rotarix, received approval from the European Commission in February 2007, but has not yet been approved by the FDA.
Participants in the REST study—more than 68,000 infants in 11 countries—received either RotaTeq or placebo. The large sample size was necessary to evaluate the uncommon side effect of intussusception. The size also made it possible to judge the efficacy of the vaccine not only by looking at prevention of rotavirus infection, but also by evaluating reductions in hospitalizations and emergency department visits due to the disease. When conducting a trial with this many subjects, pre-specifying as many trial parameters as possible leads to a more rigorous protocol and increases the chances of success, she says. In a study such as this, “you just need to start with a very clear objective of what you’re trying to achieve,” Heaton says.
A Universal Effort
In the case of the REST study, establishing key partnerships in the trial’s early stages was vital to recruiting the number of patients needed to achieve the protocol’s endpoints. “We developed collaborations with investigators and contract research organizations all over the world,” Heaton says. “To be successful when you undertake a large a trial like this, you need a large team.”
In addition to the standard team of investigators and research organizations necessary to conduct the trial, Heaton suggests including both regulators and epidemiologists in the development planning process, regardless of the size of the planned study population. An ongoing dialogue with regulators can provide feedback and guidance on study design and manufacturing processes, she says.
The input of epidemiologists also can provide vaccine manufacturers with data on where the disease burden is greatest, Heaton says. “This data helps us establish a network of investigators and guides us in choosing clinical trial sites.”
Epidemiological data also is essential after a regulatory agency approves a vaccine and it is being administered in the field. Safety monitoring is required for all vaccines, and accurate and timely reporting of adverse events is important to ensure public safety. The Vaccine Adverse Event Reporting System (VAERS)—a cooperative program of the CDC and the FDA—is a Web-based post-marketing safety surveillance program through which study participants and clinicians can report adverse events following immunization. That information is analyzed and then disseminated to the public, healthcare providers, vaccine manufacturers, state vaccine programs and other constituencies to communicate potential safety risks attributable to a specific vaccine.
The foundation of any development program, however, is rooted in a thorough understanding of the illness being addressed. Advances in biotechnology have made vaccine production more deliberate, Heaton says. “We’ve learned so much about immunology due to research in HIV/AIDS,” she says. “Now we’re building on what we’ve already done, but we’re doing it in a way that we’ve never done before. This is an exciting time. We’re really in the middle of a vaccine revolution.”
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