Clinical Trials on Vaccines

Clinical Trials on Vaccines

INTRODUCTION

Vaccines have a long history of excellent safety and a highly positive benefit/risk profile. The European Medicines Agency’s (EMA’s) Committee for Medicinal Products for Human Use (CHMP) has assembled a Guideline on Strategies to Identify and Mitigate Risks for First-in-Human Clinical Trials with Investigational Medicinal Products. EMA guidance specific to nonclinical and clinical evaluation of vaccines is available but also includes only limited guidance specific to first-in-human studies

Stages of Vaccine Development and Testing

Vaccine growth and testing in the US follows a testing -standard set of steps, the first stages are exploratory. As the vaccine makes its way through the process, control and monitoring are increasing.

Steps-1: Animal Research and Laboratory

Exploratory Stage:

This stage includes fundamental research in the laboratory and often lasts for 2-4 years. Academic and governmental scientists sponsored by the federal government discover natural or synthetic antigens that could help prevent or treat a disease.

Pre-Clinical Stage

Pre-clinical experiments use tissue-culture or cell-culture systems and animal tests to determine the safety and immunogenicity of the candidate vaccine or its ability to cause an immune response. Animals can include mice and monkeys. These studies give researchers an idea of the cellular responses in human that they could predict. They can also recommend healthy starting dose as well as a safe method of vaccine administering for the next step of study. The pre-clinical stages typically last for 1-2 years and generally includes private sector researcher.

IND Application

A sponsor, usually a private corporation, submits an application to the U.S. Food and Drug Administration for an Investigational New Drug (IND). The sponsor explains the process of manufacturing and research, the laboratory reports, and describes the analysis proposed. The clinical procedure must be accepted by the IRB representing an institution where the clinical trial will be performed. To accept the submission, the FDA has 30 days. The vaccine is subject to three phases of testing once the IND application has been approved.

Steps-2: Clinical Studies with Human Subjects

Phase I Vaccine Trails

A small group of adults, usually about 20-80 subjects, are involved in this first attempt to test the candidate vaccine in humans. If the vaccine is intended for infants, researchers will first monitor adults and then gradually decrease the age of the subjects studied until their goal is met.

 objectives

 Phase 1 test are to evaluate the safety of the candidate vaccine and to assess the form and degree of immune response triggered by the vaccine. Researchers may use the challenge model in a minority of Phase 1 vaccine trials, trying to infect participants with the pathogen after vaccination by the experimental community.

 

The Phase II Vaccines Trials

Phase II screening requires a wider group of several hundred people. Any people may be members of groups at risk of contracting the disease. These trials involve a placebo group and are randomized and well controlled.

 Objectives

 Phase II research are to study the efficacy, immunogenicity, proposed doses, immunization schedule, and delivery the method of the candidate vaccine.

 

Phase III Vaccine Trials

Effective candidate vaccines for Phase II go on to large trials, involving thousands to ten thousand of individuals. These Phase III experiments are randomized and double-blind and include evaluating the experimental vaccine being tested against a placebo.

Phase III aim is to test the safety of vaccines in a wide number of people.

Example, assume that in 1 out of every 10,000 individuals, an adverse effect related to a candidate vaccine may occur. The study would have to involve 60,000 participants.

The effectiveness of vaccines is still being evaluated. It may include

1) Does the candidate vaccine prevent illnesses?

 2) Does it prevent the pathogen from infection?

3) Does it contribute to the development of antibodies or other forms of pathogen-related immune responses?

 

Step-3: Approval and Licensure

 

License Application to the FDA will be submitted by the vaccine developer after a satisfactory Phase III trial. The FDA will then inspect the factory where the vaccine will be manufactured and approve the vaccine's labelling.

The FDA will continue to track the production of the vaccine, including the inspection facilities and the manufacturers testing of lots of vaccines for efficacy, protection and purity after licensing the vaccines. The FDA has the right to run its own vaccine tests for manufacturers.

 

Post-Licensure Monitoring of Vaccines

After they have been licensed, a number of systems track vaccines. They include Phase IV trials, the Monitoring Method for Vaccine Adverse Effects, and the Safety Datalink for Vaccines.

 

Phase IV Trials:

Phase IV trials are voluntary tests that can be performed by drug makers after the introduction of a vaccine. The vaccine may continue to be tested by the manufacturer for protection, effectiveness, and other potential uses.

 

 

VAERS

In 1990, The Vaccine Adverse Event Reporting System (VAERS) was developed by the CDC and FDA. According to the CDC, the purpose of VAERS is “to identify potential signals of vaccine related adverse events effects.” Around 30,000 events are reported to VAERS each year. About 10% and 15% of these studies document major medical events leading to hospitalization, life-threatening illness, disability or death.

VAERS is a scheme for voluntary reporting. Anyone who suspects an association between a vaccination and an adverse event, such as a parent, a health care provider, or a friend of the patient, may report the event and information about it to VAERS. The CDC then investigated the case and attempts to figure out if the vaccine actually triggered the adverse event.

The CDC states that to track VAERS data, they monitor

·       Detect adverse effects with recent, unusual, or uncommon vaccines.

·       Increases in reported adverse events track

·       Identify vaccine batches with elevated number or types of adverse effects recorded.

·       Assess the safety of vaccines that are newly approved

 

Several rare vaccination-related adverse effects have been successfully reported by VAERS. There are amongst them

·       An intestinal problem since the launch of the first rotavirus in 1990

·       Neurological and gastrointestinal diseases associated with the vaccine for yellow fever.

 

 

 

 

REFERNCES:

 

 

1.     Paul Offit; Vaccine Development, Testing and Regulation: The College of Physicians of Philadelphia.

2.     K Singh and S Mehta; Malaria Vaccine Developments Program (MVDP), International Centre for Genetic Engineering and Biotechnology (ICGEB)

3.     Safety monitoring in the Vaccine Adverse Event Reporting System (VAERS) by TT Shimabukuro, M Nguyen, D Martin, F DeStefano. Vaccine. 2015 Aug 26;33(36):4398-405.

4.     The Vaccine Safety Datalink: successes and challenges monitoring vaccine safety. MM McNeil, J Gee, ES Weintraub, EA Belongia, GM Lee, JM Glanz, JD Nordin, NP Klein, R Baxter, AL Naleway, LA Jackson, SB Omer, SJ Jacobsen, F DeStefano. Vaccine. 2014 Sep 22;32(42):5390-8.

 

 

                                                                                           By;

                                                                                                                D. Maneesha

                                                                                                                                             Pharm.D                                                                                                                           

                                                                                                              P. Pravallika                                                                                                                     Pharm.D