Understanding Test-of-Concept Trials

Why are Phase IIb trials an important step in evaluating AIDS vaccine candidates?

AIDS vaccine candidates are evaluated in a stepwise manner in a series of clinical trials known as Phase I, II, and III. Phase I and II trials generally involve a small number of volunteers and provide researchers with critical information about the safety and immunogenicity of the vaccine. It isn't until Phase III trials that the efficacy of the vaccine is assessed. These trials test the ability of the candidate to prevent infection and/or slow progression of disease. These trials require large numbers of volunteers, are extremely expensive (can cost more than a hundred million dollars), and take a long time to set up and complete. Phase III efficacy trials are the final step before a vaccine can get approval for licensure from a regulatory body like the Food and Drug Administration in the US or the Agency for the Evaluation of Medicinal Products in Europe. To learn more about these trials see Primer on Understanding Vaccine Trials  from August 2003.

What is a test of concept trial?

As the name implies, a test of concept trial is about finding out if the vaccine concept or the type of vaccine being tested will be effective. A test of concept trial is not designed to establish the efficacy of a particular candidate but rather to help researchers decide if this candidate is worth testing in larger Phase III trials. These intermediate studies are also referred to as "proof of concept" or Phase IIb trials.

The number of volunteers required for such trials is smaller, only around 2-5,000 volunteers as compared to over 10,000 for Phase III trials. Phase IIb trials are therefore much easier to design and manage, and are less costly. Since fewer doses of vaccine are required, these trials are also much faster to implement because the manufacturing process is limited. Very importantly, they may also provide researchers with the immune correlates of protection, or the immune response generated by the vaccine that cause it to be effective. This can often be difficult to do in large Phase III trials.

However because Phase IIb trials are run in smaller populations, the precision of the trial is less. Therefore a vaccine can not be licensed based on the results of Phase IIb testing. If the results of a Phase IIb trial indicate that this approach is promising, a Phase III efficacy trial will be required before licensing and use of the vaccine. This means that the decision to run a Phase IIb trial will extend the total amount of time it takes to complete the clinical trials process. Phase IIb trials are an important screening step for different vaccine candidates and help organizations determine which ones to move forward into Phase III trials, without expending more time and money.

The idea of using Phase IIb studies is more than a decade old but the first one involving an AIDS vaccine candidate began just last year. Test of concept trials have already been done for other vaccines as well as for other preventive technologies. US-based Merck and GlaxoSmithKline Biologicals in Europe tested their respective vaccine candidates for human papilloma virus in Phase IIb trials. These candidates are now both being tested in Phase III efficacy trials. The HIV Prevention Trials Network is also testing a microbicide candidate known as Buffergel PRO2000 in an ongoing Phase IIb trial to see if this agent can block transmission of HIV.

Why are test of concept trials especially useful for AIDS vaccines?

Because the challenge of developing an effective AIDS vaccine has proven so difficult and the need remains so great, researchers must evaluate several candidates as quickly as possible. This requires testing several candidates at the same time.

Researchers are also using new approaches to try to find an effective AIDS vaccine. Test of concept studies are one way to find out quickly if these new candidates can be successful. An example of this is the first Phase IIb trial of an AIDS vaccine candidate, which is being conducted by Merck and the HIV Vaccine Trials Network. This ongoing study is testing the company's lead vaccine candidate known as MRKAd5 in approximately 3,000 volunteers. The MRKAd5 candidate primarily generates a cellular immune response, but scientists are unsure if this type of vaccine will be sufficient to protect people from HIV infection. Merck decided to test this type of vaccine in a Phase IIb trial to find out if this strategy will be able to prevent HIV infection or to slow the progression of disease in people who do become infected through exposure in their community. The results of this trial will influence the company's decision to go ahead with a Phase III trial and will provide the entire AIDS vaccine field with critical information about the importance of cell-mediated immune responses in vaccine efficacy.

Another advantage of a Phase IIb trial is that it allows researchers to evaluate a candidate in a more confined study population. The MRKAd5 candidate is based on a particular strain of a human virus that naturally causes the common cold (adenovirus serotype 5). This candidate may not work as well in people who have already developed immunity to this strain of natural adenovirus, due to what is called pre-existing immunity (see February Primer onUnderstanding Pre-existing Immunity). Initially Merck's Phase IIb trial was designed to include only people who had low levels of pre-existing immunity, so that they could find out if the vaccine concept was even feasible under optimal conditions. The trial has since been amended to include a more diverse population of volunteers.

The use of test of concept studies to evaluate AIDS vaccine candidates is also being considered by other organizations and more may be conducted in the future. For trial volunteers, communities, and health policy makers it is important to understand that a vaccine will not be approved based on the results of these studies even if the investigators are able to draw preliminary conclusions about its efficacy.