header-backissues

Error

[OSYouTube] Alledia framework not found

VAX-5(6)-June-2007

Vol. 05, No. 06 - June 2007

SPOTLIGHT:

Using public health campaigns to raise awareness about HIV/AIDS

SPOTLIGHT:

Elizabeth Mataka, the executive director of the Zambia National AIDS Network (ZNAN) and the vice-chair of the board for the Global Fund to Fight AIDS, Tuberculosis, and Malaria, was recently appointed to the position of Special Envoy for AIDS in Africa by Ban Ki-moon, the Secretary General of the United Nations (UN). Mataka is a native of Botswana and has been involved with HIV/AIDS prevention, treatment, and care for the past 16 years. She succeeds Stephen Lewis, who left the post after five years when previous Secretary General Kofi Annan retired at the end of 2006.

During his time as Special envoy Lewis spoke passionately about the devastation that HIV/AIDS is causing in Africa and he became one of the most outspoken and well-known advocates for the rights of women on the continent. The appointment of Mataka fulfills Lewis's request that his replacement be an African woman. She is the first African to hold the position of Special Envoy at the UN and, as she assumes the post, the situation facing African women has never been more dire. As HIV continues to spread in sub-Saharan Africa, women are increasingly becoming infected. It is estimated that 4.6% of young women in sub-Saharan Africa are currently living with HIV, compared to 1.7% of young men.

GLOBAL NEWS

The Vaccine Research Center (VRC) at the US National Institute of Allergy and Infectious Diseases in partnership with the US company GenVec recently began a Phase I clinical trial to evaluate the safety and immunogenicity of a novel adenovirus serotype 35 (Ad35)-based AIDS vaccine candidate in 15 volunteers. Adenovirus can cause some forms of the common cold and there are several serotypes circulating worldwide. Another adenovirus serotype, known as Ad5, is already being used as a vector in other AIDS vaccine candidates to deliver pieces of HIV to the immune system (see September 2004 Primer on Understanding Viral Vectors). Ad5-based vaccine candidates are now being tested in a series of Phase II trials by the VRC and in two large Phase IIb trials by the US company Merck. However one possible drawback to candidates that use Ad5 as a vector is the high prevalence of the virus in certain parts of the world. People who have been previously exposed to Ad5 may have pre-existing immunity towards the viral vector, and that could hinder their immune responses to the AIDS vaccine candidate. The potential advantage of using Ad35 is that it has a much lower prevalence globally.

This two-part trial is the first to test another serotype of adenovirus in clinical trials. The first part will evaluate the safety of an intramuscular injection of the vaccine candidate at three different doses. Once the safety data is reviewed researchers will evaluate the safety and immunogenicity of the candidate when administered in combination with the VRC's Ad5 candidate. The Ad35 vaccine candidate was developed by the VRC and GenVec.

------------
All articles written by Kristen Jill Kresge

PRIMER

How do DSMBs monitor ongoing clinical trials?

Several different groups oversee the ethical standards of clinical trials, including those testing AIDS vaccine candidates. These committees are set up for each new trial to ensure they are performed safely, the rights of the volunteers are protected, and that the basis of the study is scientifically credible. Before a trial begins, the overarching plans for the trial or protocol is reviewed by an independent ethics committee called an institutional review board (IRB). This group is primarily responsible for reviewing the study design and all the trial-related materials, such as informed-consent documents and informational brochures (see June 2005 Primer on Understanding Informed Consent). A clinical trial can not start without approval from the IRB.

Another external committee known as a data safety monitoring board (DSMB) is responsible for monitoring the safety and progress of the trial once it is underway. DSMBs were first established in the 1960s as a way to assist organizations sponsoring medical research with data analysis, but now their most important role is to continually assess risk and monitor safety for volunteers throughout the course of a trial. A DSMB is an independent committee that can advise the trial sponsors, funding agencies, and investigators. After analyzing the safety and efficacy data the DSMB determines if the trial should continue unchanged or with modification, or if it should be terminated. This group also monitors the scientific merit of the study in light of results from other trials or advances in the field.

The function of a DSMB

A DSMB is comprised of 3 to 10 members and usually includes researchers, clinicians, biostatisticians, and community members or advocates. Members are typically independent experts, either working in the same field or in a related discipline, who have no personal or professional ties to the intervention being tested and are therefore unbiased.

Not every clinical trial requires a DSMB and different regulatory agencies, like the US Food and Drug Administration or the European Agency for Evaluation of Medical Products (EMEA), have different standards. Generally they are utilized for double-blind studies where trial sponsors and investigators don't know who is receiving the active product or placebo, whenever there is a potential risk to the study participants, or when a trial is conducted at multiple clinical trial sites. A DSMB is especially important for large, multi-center trials that take place in different countries or on multiple continents because often the principal investigators only have access to data generated at their individual sites. The DSMB, however, can monitor the safety and efficacy data accumulated from all sites to make a decision regarding the continuation of the trial.

DSMBs have several important duties. First they periodically review the safety data from the trial and analyze the risk/benefit profile of the intervention being tested and any adverse events that occur. They also regularly examine the efficacy data that is accumulated throughout the course of the trial. For example, if the trial is testing a microbicide or an AIDS vaccine candidate that is designed to prevent HIV infection, a DSMB would review the number of volunteers who become incidentally infected with HIV through risk behaviors during the course of the study to see if more of these infections are occurring in the placebo group than in the group receiving the experimental intervention, or vice versa. This can help the DSMB determine if the experimental intervention is beneficial or possibly causing harm.

The DSMB also closely watches the progress and conduct of the trial and evaluates whether or not the study protocol is being followed. This includes reviewing the number of volunteers recruited and retained, the type of volunteers (for example women versus men), the performance of the trial sites, and the integrity of the data being reported by the sites. The progress of the trial, as well as the safety and efficacy data, are reviewed by DSMB members at pre-defined intervals and their findings are reported back to the IRB.

Altering a trial

There are several possible scenarios where a DSMB might suggest modifications to a trial protocol. For example, if the DSMB determines that there are not enough volunteers being recruited to properly determine the efficacy of the product, they might recommend that the target enrollment be increased.

In many cases the DSMB might also suggest that a trial be closed. The cost and time required to run a clinical trial are significant and it is a serious decision when one is stopped midway. However, protecting the personal safety of the volunteers and ensuring the ethical conduct of the trial are the DSMB's principal concerns. A DSMB may recommend terminating a trial when the intervention being tested appears to possibly be harmful. Recently an HIV prevention trial testing the ability of the microbicide candidate cellulose sulfate to prevent HIV infection in women was stopped early by the DSMB because more new HIV infections occurred in the volunteers using the microbicide gel than in those who received an inactive placebo gel. Evaluation is now underway to determine if the microbicide candidate was actually responsible for this increase in infection.

A DSMB may also stop a study that is in progress if the intervention offers a clear benefit and is so effective that it would be unethical to continue with a placebo group. This happened recently in two randomized, controlled trials of male circumcision. The DSMB members observed such a strikingly positive effect of male circumcision on the risk of HIV infection in men that they stopped the trial and also offered the surgical procedure to the uncircumcised men.

Another reason a DSMB may stop a trial is if it is unlikely to provide conclusive results. This is known as stopping a trial for futility and it can happen when the number of incidental HIV infections in a trial is too low to actually determine if the AIDS vaccine or microbicide candidate is effectively stopping infection.