FDA Panel Considers Best Approval Process for Ebola Vaccines

Troy Brown, RN

May 13, 2015

The Vaccines and Related Biological Products Advisory Committee to the US Food and Drug Administration (FDA) met yesterday to discuss licensure of Ebola virus disease (EVD) vaccines and possible ways to demonstrate their effectiveness.

The issue is particularly urgent because the disease is waning. This is good news from a public health perspective, but the relative lack of patients means that directly demonstrating the effectiveness of candidate vaccines based on EVD clinical endpoint studies will now be much more difficult.

Randomized controlled trials using disease endpoints are recognized as the most robust study design for demonstrating the effectiveness of vaccines, but because this may not be possible, the FDA is considering other approaches to demonstrating the vaccines' effectiveness.

Pathways to Vaccine Approval

The traditional approval pathway involves an analysis by the FDA of phase 1, phase 2, and phase 3 clinical trials. The FDA continues to monitor vaccines, drugs, and medical devices after they are approved.

In the United States, the FDA sometimes will approve products for serious or life-threatening illness if they provide meaningful benefit over existing treatment under the accelerated approval provisions. For the Ebola vaccine, approval by this pathway would be granted if adequate and well-controlled clinical trials show an effect of the product on a surrogate endpoint (eg, immune response) that is "reasonably likely" to predict clinical benefit. The surrogate endpoint could come from human phase 2 or phase 3 studies that are currently being conducted or are being planned, and/or from a comparison of antibody responses in protected vaccinated individuals or vaccinated individuals who contract EVD.

Researchers could also use enzyme-linked immunosorbent assay titers obtained from vaccinated nonhuman primates that correlate with immunity to predict immunogenicity in humans. This pathway requires adequate and well-controlled studies postlicensure.

The "animal rule" may be used for products for certain serious or life-threatening conditions when definitive studies in humans are not ethical or feasible and when the other efficacy standards cannot be used. This pathway allows FDA approval based on adequate and well-controlled animal studies when their results show that the vaccine is reasonably likely to clinically benefit humans, as long as safety in humans has been established. Postmarketing studies to confirm the product's clinical benefit and further establish safety in humans must be conducted when it is feasible and ethical.

"Preliminary data presented at a December 12, 2014, US government-sponsored workshop indicated that vaccinated humans may achieve immune responses comparable in magnitude to those associated with protection in [nonhuman primates], suggesting the feasibility of an immunogenicity-based approval, although the thresholds associated with protection may differ for each vaccine," the FDA stated in a briefing.

"I do think that immunity markers have to be used for the licensure pathway because there may not be other outbreaks we would hope, but that is the future," said voting member Janet Englund, MD, from the University of Washington, Seattle, and Seattle Children's Hospital, Washington.

"As a basis for licensure, I do believe we should be leaning toward using these markers because we cannot wait until there's another huge epidemic to do anything about it," Dr Englund added.

Postlicensure randomized, placebo-controlled studies would provide the most informative data, but placebo-controlled studies may be unethical because of the high case-fatality rate associated with EVD.

Three Candidate Vaccines in Advanced Clinical Development

ChAd3-EBO-Z (Ebola Zaire strain) is a recombinant-replication-deficient chimpanzee adenovirus type 3 vectored candidate vaccine that expresses the wild-type envelope glycoprotein from the Ebola Zaire strain. The Vaccine Research Center of the National Institute of Allergy and Infectious Diseases developed it using the ReiThera (formerly known as Okairos) adenovirus vaccine platform technology, which GlaxoSmithKline Biologicals acquired in May 2013.

rVSV-ZEBOV (Ebola Zaire Strain) is an Ebola virus recombinant vesicular stomatitis virus (VSV)-vectored vaccine based on a genetically modified VSV that expresses the glycoprotein from the Ebola Zaire Kikwit strain. The Public Health Agency of Canada developed the vaccine, and commercial rights were licensed to NewLink Genetics Corp of Ames, Iowa. Merck and NewLink entered into an exclusive licensing and collaboration agreement that granted Merck exclusive rights to the rVSV-ZEBOV vaccine candidate and any other follow-on products.

Adenovirus 26 (Ad26) is a replication-defective adenovirus serotype 26 that expresses the full-length glycoprotein of the Ebola Zaire Virus (Ad26.ZEBOV). Crucell Holland BV, one of the Janssen Pharmaceutical Companies of Johnson and Johnson, developed the vaccine. It is administered in a prime-boost regimen with multivalent modified vaccinia amvankara (MVA)-Bavarian Nordic vaccine, MVA-mBN226B (or MVA-Bavarian Nordic-Filo), which expresses the Sudan virus glycoprotein, the EBOV glycoprotein, the Marburg virus Musoke glycoprotein, and the Tai Forest virus nucleoprotein.

"If you don't know exactly what the path of immunity is and you choose an antigen, it's very narrow. Each one is maybe slightly different from the other, and now the vector is different; they would be foolhardy to think that an antibody or an immunologic marker would work across glycoproteins across vectors because you don't know what all the other things are inside that might make it work," said voting committee member Sarah Long, MD, from Drexel University College of Medicine and St. Christopher's Hospital for Children Philadelphia, Pennsylvania.

Current Studies Underway

All three Ebola candidate vaccines have been studied in multiple phase 1 trials in the United States, Europe, and West Africa, and preliminary data show they are immunogenic and pose no safety issues that would prevent their examination in larger phase 2 and phase 3 clinical trials.

The US government is sponsoring two large phase 3 trials to study the safety and efficacy of the vaccines in EVD outbreak areas in West Africa.

PREVAIL Study

The National Institute of Allergy and Infectious Diseases is working with the Liberia College of Physicians and Surgeons and Liberian Institute for Biomedical Research, to conduct a study called the Partnership for Research on Ebola Vaccines in Liberia (PREVAIL) study. The study began in early February 2015 and is a phase 2/3 clinical trial that plans to enroll 27,000 participants. It will evaluate the safety and efficacy of the ChAd3-EBO-Z investigational Ebola vaccine and the rVSV-ZEBOV investigational Ebola vaccine.

STRIVE Study

The Centers for Disease Control and Prevention is partnering with the Sierra Leone College of Medicine and Allied Health Sciences to conduct a phase 3 study called the Sierra Leone Trial to Introduce a Vaccine Against Ebola (STRIVE). The study began in early April 2015 and is an event-driven, unblended, randomized, phased-introduction vaccine trial to evaluate the safety and efficacy of the rVSV-ZEBOV candidate Ebola vaccine among about 6000 healthcare and other frontline workers.

Both studies will assess vaccine efficacy using clinical disease endpoints and will collect serum samples for immunogenicity analysis. In addition, the World Health Organization is sponsoring a ring vaccination trial of the rVSV-ZEBOV vaccine in Guinea.

"Because a diagnosis of Ebola then triggers contact tracing, I suspect that there will be more access to testing than under other circumstances, but it may be prudent to plan for a contingency where there are very rural [events]," voting committee member Ruth Lynfield, MD, from the Minnesota Department of Health, St. Paul, said.

One temporary voting committee member was given a waiver because the need for her services outweighs the potential for a conflict of interest created by the financial interest involved. The remaining committee members have disclosed no relevant financial relationships.

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