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					                              MODULE 2: SCIENCE AND RESEARCH
                     COMMUNITY PREPAREDNESS TRAINERS MANUAL




           HIV vaccine
                        MODULE                                     4
         research and
         development
Contributing authors: André Croucamp, Dr Eftyhia Vardas,
Dr Ashraf Grimwood
Useful comments and additions: Dr Carol Metcalf, Dr Keren
Middelkoop, Dr Tim Tucker, Mrs Matilda Mogale, team members
of Masikhulisane – the SAAVI Community Involvement Programme,
Community Advisory Group (CAG) and Community Outreach teams
from the following HIV vaccine trial sites: Africa Centre, Klerksdorp,
Orkney, Stilfontein and Hartebeesfontein (KOSH), Chris Hani
Baragwanath (Soweto), MRC Durban, MEDUNSA, Masiphumelele
and Nyanga.


Outcomes of this module
By the end of this module, you should be able to:
1. Explain the difference between a preventative and a therapeutic
   HIV vaccine, how an HIV vaccine works, what is meant by an
   ‘effective’ HIV vaccine, and the different test HIV vaccine designs.
2. Explain the four stages in the HIV vaccine research and
   development process.
3. Outline the four phases of an HIV vaccine clinical trial.
4. Describe which type of study design is used for
   HIV vaccine trials and why it is used.
5. Discuss what policies, guidelines and laws apply
   to HIV vaccine research and development.
6. Explain which parties are involved in approving,
   running and quality assuring HIV vaccine
   clinical trials.
7. Explain how HIV vaccine trial sites are chosen.
8. Identify where HIV vaccine clinical trials are
   happening in the world.


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                             MODULE 4: HIV VACCINE RESEARCH AND DEVELOPMENT




                             Section 1: Background information on HIV
                             vaccine research and development
                             1. WHAT IS THE DIFFERENCE BETWEEN A PREVENTATIVE
                                 AND THERAPEUTIC HIV VACCINE?
                             Most vaccines in public use today and most HIV vaccines in clinical
                             trials are preventative vaccines. Preventative HIV vaccines are those
                             vaccines that are meant to prevent HIV infection, or to stop or
                             slow disease progression if HIV infection occurs. They are tested
                             in people who are HIV negative. In this module we refer to ‘test’
                             HIV vaccines, but sometimes researchers call them ‘candidate’
                             vaccines. This means that like job candidates, they are vaccines
                             which may be able to do the job. Researchers are also interested
                             in therapeutic HIV vaccines. These are vaccines that are meant
                             to strengthen or boost the immune response of people who
KEY WORDS
                             are already infected with HIV. They help to stop or slow disease
Preventative
                             progression, and are usually tested in people who are HIV positive.
HIV vaccines:
Those tested in HIV-
negative people to see       Is there a successful HIV vaccine?
if they will prevent HIV     Currently, there is no successful preventative or therapeutic HIV
infection, or if infection   vaccine. However, there are several that are being tested in different
occurs, whether they         phases of clinical trials around the world. See page 39 of this
will halt or slow disease    module for more information on clinical trial sites around the world.
progression.
Candidate:                   How will a successful preventative HIV vaccine work?
A vaccine that may be        A successful preventative HIV vaccine, when given, will teach
able to do the job and       the body to recognise and defend itself against the HI virus that
will be tested.
                             causes AIDS, either preventing infection or slowing down disease
Therapeutic HIV              progression if infection occurs. When a person is vaccinated, the
vaccines:                    information on how to defend the body against the HI virus will
Those tested in people       become part of the person’s immune system memory. This means
already infected with HIV    that the immune system will remember how to fight back if HIV
to strengthen or improve     enters the body through sexual contact or in other ways, at a later
their immune response,       date. Remember how we explained this in Module 2.
helping to stop or slow
HIV disease progression.
                             What is an ‘effective’ HIV vaccine?
Sterilising immunity:        Graph 1 opposite, shows the normal progression of HIV infection
Complete prevention
                             when there is no antiretroviral treatment or vaccination. Now
of infection.
                             compare this graph to Graph 2. It shows what researchers consider
                             to be first prize, or what they call, a ‘primary end-point’ – an HIV
                             vaccine that will completely prevent infection in all those who are
Refer to Module 2 for
                             vaccinated. This is called sterilising immunity.
more information on the
immune system and
on ARVs.




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                                   HIV VACCINES FACILITATOR'S MANUAL




                NORMAL INFECTION                                   PRIMARY END-POINTS
                                                               Complete protection against HIV
                                                                   (sterilising immunity)




                                         The viral
  Viral                                  setpoint varies
  load                                   from person
                                         to person.


               Undetectable levels                                      Undetectable levels
                 of HIV in blood.                                         of HIV in blood.
              Detecti on threshold


   ‘Normal’ infection with variable levels of viral load                  No infection

Graph 1: Normal infection.                                 Graph 2: First prize – prevent infection.



But we are unlikely to achieve this first prize. So the next best or
                                                                                              KEY WORDS
the secondary end-points that we are aiming for, include an HIV
                                                                                              End-points:
vaccine where:
                                                                                              Outcomes.
   if a person is infected, then the vaccine will help the immune
   system to clear the infection (see Graph 3 on the next page); or                           Infectiousness:
   if a person is infected, then the vaccine will keep the virus under                        Ability to transmit
   better control because of the vaccine’s effect on the immune                               the virus.
   response. (See Graph 3 on the next page.) This could
   mean that:
   – The vaccine will help to slow down disease progression –
         the time it takes to develop AIDS, and/or
   – The vaccine will help to reduce a person’s level of
         infectiousness by helping to control the level of virus in                           Refer to Module 2 for
                                                                                              more information on
         the blood. Research has shown us that the lower the viral
                                                                                              the viral load.
         load in a person’s blood, the less chance there is of the
         person infecting others with HIV. This means that if we
         find a successful vaccine and we use it to vaccinate a
         large percentage of the population, then all those who are
         vaccinated will be less infectious and will have a smaller
         chance of infecting others with HIV. The number of new
         infections in the wider community or population would then
         come down.




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                               MODULE 4: HIV VACCINE RESEARCH AND DEVELOPMENT




                                                          SECONDARY END-POINTS
                                     Protection against disease (slowing disease progression in those
                                                         who receive the vaccine)




                                                                                              It is hoped that the
                                                                                              vaccine will keep the
                                                                                              viral setpoint and
                                                                                              viral load down.




                                           Undetectable levels          Viral       Undetectable levels
                                                                                    Undetectable levels
                                             of HIV in blood.           load          of HIV in blood.
                                                                                      of HIV in blood.

                                     Initial infection ‘controlled’              Establishment of chronic
                                                                                infection with low viral load

                               Graph 3: Keeping the viral load under control.


                               Researchers would prefer the first prize – a vaccine that prevents
                               infection in 100% of those vaccinated. However, there is no vaccine
                               in general use today that is completely 100% effective, so this is
                               unlikely with any new vaccine.

                               How will a successful therapeutic HIV vaccine work?
                               A successful therapeutic HIV vaccine will boost the body’s immune
                               response to HIV and slow down disease progression in those
                               already infected. HIV-positive individuals already have an immune
                               response to the HIV proteins that are present in their body as a
                               result of their immune response to HIV infection. Remember how we
                               looked at some of the structural proteins of HIV in Module 2. The
                               therapeutic HIV vaccine consists of artificially-made HIV proteins
                               (see HIV vaccine designs on pages 5 –9 of this module). When an
                               HIV-positive person is vaccinated with this kind of vaccine, the body
                               is presented with HIV proteins in a different way. This researchers
                               believe will further increase the person’s immune response against
                               HIV, helping to slow disease progression. Currently there is some
                               evidence that for treatment to be most effective, therapeutic HIV
                               vaccines will need to be used together with ARVs.
KEY WORD
Arm:
                               A vaccine designed for a preventative trial when tested in a person
Any one of the
                               who is HIV positive, might also delay disease progression to AIDS.
intervention or control
groups in a randomised
                               To test this hypothesis or idea, researchers may use the same
clinical trial. Participants   vaccine design in both a preventative and a therapeutic HIV vaccine
will be randomly assigned      trial. Or, researchers may do one trial that includes one arm of HIV-
to one of these arms.          negative trial participants and another arm with HIV-positive trial
                               participants to see if the vaccine prevents infection, or if it slows
                               disease progression in those who are infected.


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                         HIV VACCINES FACILITATOR'S MANUAL




                                                                             Refer to Module 2
DID YOU KNOW?                                                                for more information
In 1984, soon after HIV was isolated, photographed                           about the different HIV
and described, the US Secretary of Health and Human                          subtypes, the different
Sciences, Margaret Heckler, said that an HIV vaccine                         immune responses,
would be developed within two to three years. But the                        and the traditional
search for a vaccine has proven much more difficult.                         vaccine designs.
Here are some reasons:
• Researchers have taken a very long time to
   understand the characteristics of HIV and the exact way
   it works. This understanding is crucial to developing a
   vaccine that can effectively protect humans against HIV
   infection or can treat them if they are infected.
• Researchers are still debating whether they can produce
   one vaccine that works to fight all subtypes of HIV, or
   whether they need to produce a vaccine for each of the
   different subtypes, as well as for the different circulating
   recombinant forms of the virus. (See definitions in Module
   2, pages 23–24.)
• No humans have recovered from HIV infection, and so
   researchers are still debating which immune response they
   should design a vaccine to stimulate – a humoral response
   or a cellular immune response (see Module 2 for more
   details). Most researchers think that an effective vaccine
   should stimulate both responses.
• Researchers do not use the traditional vaccine approaches
   described in Module 2 because of the safety concerns
   involved. (See below.)
• HIV can change or mutate rapidly to avoid an effective
   immune response to it. Researchers thus need to design
   an HIV vaccine which can overcome this challenge.



DID YOU KNOW?
Although they cause the biggest immune response, currently HIV vaccine designs do
not use the traditional whole-killed or the live-attenuated approaches that we find in
many of the vaccines in public use today. This is because of concerns that use of these
designs in an HIV vaccine could result in HIV infection.

• Whole-killed/inactivated vaccine design: Here the germ causing the disease is
  disabled or killed using heat or chemicals to make it harmless. This design is not used
  for HIV vaccines because current technology may not kill all the HIV virions. This could
  result in HIV infection.
• Live-attenuated vaccines: Here the germ is changed in some way by e.g. removing
  on or more of its genes, so that it can no longer cause disease. We cannot use this
  design for an HIV vaccine because HIV is always mutating. So, even if HIV is weakened
  by removing one or more of its genes, based on our current knowledge about HIV,
  researchers believe that HIV could mutate back into a disease-causing form of the virus.


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                                   MODULE 4: HIV VACCINE RESEARCH AND DEVELOPMENT




                                   What kind of HIV vaccine designs are there?
KEY WORD
Replicate:                         The following tables on pages 6 to 8 briefly describe the different
To reproduce.                      types of designs that are used in test HIV vaccines today. None of
                                   these designs can cause HIV infection, because they do not contain
                                   any whole or live HI virus.

                                   Rather, researchers include only one or more laboratory-made
                                   proteins, or peptides or genes from HIV, which on their own cannot
                                   cause HIV infection. However, our body still recognises these parts
                                   as foreign, which should result in an immune response including
                                   antibodies and/or killer T-cells to those parts of HIV included in the
                                   vaccine. As we saw in Module 2, in preventative vaccines, once
                                   these antibodies and/or killer-T cells have done their job of fighting
                                   the mock infection, they leave behind memory B and T-cells. These
                                   cells stay on guard in the body triggering a quick immune response
                                   of antibodies and/or killer T-cells, which can prevent or reduce
                                   infection if we encounter the real germ, in this case HIV, at a later
                                   date. As a reminder about how antibodies and killer T-cells are made,
                                   see information on the Acquired or Specific immune response in
                                   Module 2.

                                   Now let's look at the different HIV vaccine designs that are being
                                   tested in human clinical trials today. As you read through the
                                   descriptions, remember that researchers have not yet found if any
                                   of these designs are effective in humans. That is why the designs
                                   are all still being developed, and tested in human clinical trials.



           Name of                           How it could work                       A diagram of what
        vaccine design                                                                  it looks like
     Recombinant           Here researchers include one or more HIV proteins
     subunit protein       that are made in the laboratory by using genetic
     vaccine               engineering – they are not taken from the actual HI
     (one of the subunit   virus. The proteins that they include are, for example,
     approaches)           ones that are found on the envelope surface of HIV                    gp120
                           e.g. gp120. When vaccinated, the body will see these
                           proteins as foreign. Researchers hope that this will
                           create a big enough immune response to HIV, allowing
                           the body to prevent of slow HIV infection.

     Peptide vaccines      These vaccines are similar to the subunit protein
     (one of the subunit   vaccine, but they include only laboratory-made
     approaches)           fragments of the HIV proteins to try to cause an anti-
                           HIV immune response.


                                                                                       fragments of HIV
                                                                                       protein




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                                     HIV VACCINES FACILITATOR'S MANUAL




      Name of                                How it could work                         A diagram of what
   vaccine design                                                                         it looks like
Vector vaccines            Researchers make a vector vaccine by placing one
                                                                                             Gag
                           or more harmless HIV genes into a live bacteria or
                           non-HIV virus, which is changed so it cannot multiply
                           or cause disease. This change is done using genetic
                           engineering. They use the bacteria or non-HIV virus
                           as a vector, or vehicle, to carry the HIV gene/s into    Vector vaccines are like
                           the body cells. The body cells produce proteins as       a car that is carrying a
                           a result of the HIV genes. These proteins are hoped      passenger.
                           to stimulate an anti-HIV immune response leading to
                           vaccine-made immunity.                                                  Vector
                                                                                                   vaccine
                                                                                                   using a
                                                                                                   bacteria that
                                                                                                   is changed

DNA vaccines               These vaccines do not rely on a vector. Rather,
                           researchers stitch one or more laboratory-made HIV
                           genes into circular loops of DNA, called plasmids.
                           Through vaccination, the plasmids enter the body
                           cells where they cause production of HIV proteins as
                           a result of the laboratory-made HIV genes that were
                           included in the plasmid. These proteins should trigger         HIV gene/s
                           an anti-HIV immune response.                                   stiched into a
                                                                                          ring of DNA
                           South Africa is designing a candidate HIV vaccine
                           based on the DNA vaccine approach. A DNA vaccine         DNA vaccine design
                           may need to be used in combination with another
                           HIV vaccine design to get the most effective immune
                           response (see page 8 for the combination approach).

Replicon vaccine           In this design, researchers use a laboratory-made
designs                    non-HIV virus whose DNA has been removed. This
(one of the subunit        is called a replicon, and consists only of the virus
                                                                                                           one or
approaches)                envelope which is used as a vector into which                                   more
                           researchers place one or more HIV genes. The non-                               but not
                           HIV virus carries the one or more HIV genes into the                            all the
                           body cells where they cause production of proteins                              HIV
                                                                                                           genes
                           which should cause an immune response. The non-
                           HIV virus is safe as it has no genes of its own, so it   Replicon vaccine design
                           cannot replicate or multiply to cause infection.



     KEY WORDS
     Vector:          Plasmid:             Replicon:
     Vehicle.         A small circular     A synthetically
                      loop of DNA that     made non-HI
                      can replicate        virus whose
                      independently        DNA has been
                      within a cell.       removed.

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                                           MODULE 4: HIV VACCINE RESEARCH AND DEVELOPMENT




       Name of                                 How it could work                           A diagram of what
    vaccine design                                                                            it looks like
 Pseudovirions or            Here researchers use some but not all HIV proteins
 virus-like particles        and put them together to look like the HI virus. These
 (VLPs)                      are called virus-like particles or pseudovirions.
                             They do not include HIV genes so they cannot
                             cause HIV infection, because they do not contain
                             the instructions that they need to replicate. When
                             vaccinated with a VLP vaccine, the body will                Virus-like
                             recognise the HIV proteins as foreign, which should         particles or VLPs
                             cause an anti-HIV immune response. Researchers do
                             not use this approach often as it is difficult to produce
                             VLPs that look close enough to HIV to cause a
                             significant immune response.

 Combination                 Here researchers give more than one type of HIV
 approach                    vaccine design to trial participants. A first vaccine,
 This is often called        using one type of design, is given to prime the
 a ‘prime boost’             immune system. This is followed by a second,
 strategy.                   different type of HIV vaccine design to boost or                                gp120
                             strengthen the immune response. One design may
                             cause an antibody response, while the other may
                             cause a cellular immune response (killer T-cells).
                             Or, the first vaccine may cause a weak but broad
                             immune response, which the boost will make
                             stronger. This approach is hoped to cause a stronger
                             anti-HIV immune response than vaccinating people
                             with only a single vaccine design.
                                                                                         A combination approach e.g.
                                                                                         a protein subunit design and
                                                                                         a DNA vaccine design



KEY WORDS
Prime:
The first test HIV vaccine
design that is given to
produce a first kind of
immune response.
Boost:
A second test HIV
vaccine design that
                                           An HIV vaccine is like a car with its engine removed. It contains
is given to increase                       some of the parts of a whole car, but it does not contain the engine
or strengthen the first                    that is needed for the car to drive i.e. it does not contain all the HIV
immune response.                           genes that are needed for the HI virus to replicate and to cause HIV
                                           infection. If we find a successful HIV vaccine and give it to a person,
                    cont'd
                                           their body should remember those one or more parts of HIV that
                                           were included in the vaccine. This should cause their memory B
                                           and/or T-cells to trigger a quick immune response to stop or slow
                                           the virus if HIV enters the body through sexual contact or in other
                                           ways, at a later date.
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                               HIV VACCINES FACILITATOR'S MANUAL




As you can see from the tables on pages 6 –8, the aim of an HIV
                                                                        KEY WORDS        cont'd
vaccine is to get the body to recognise those parts of the HIV virion
                                                                        Broad immune
or cell that researchers have included in the vaccine, e.g. one or      response:
more proteins or genes from HIV's structure or RNA. Researchers         Recognition and an
hope that the immune system will then respond to these parts            immune response to
by making B-cells (antibodies) and/or T-cells (cytotoxic T-cells) to    many HIV proteins/genes
fight infection. Therapeutic HIV vaccines would help to produce         included in the vaccine
B- and/or T cells to strengthen and improve the existing immune         design/s.
response to HIV and, in this way, slow down disease progression.
In a preventative HIV vaccine, some of the B- and/or T-cells would
become memory cells with the aim of ‘tricking’ the body into building
up an immunity to HIV. If the person is ever exposed to the virus,
then these memory cells would be triggered and cause a faster
immune response to neutralise or bring the infection under control.




All HIV vaccines are made according to strict Good
Laboratory Practice (GLP) and Good Manufacturing Practice
(GMP) standards




    REMEMBER
    An HIV vaccine cannot cause HIV infection because it does
    not include any whole or live HIV. Researchers include only
    one or more laboratory-made proteins or peptides, or genes
    from HIV, which on their own cannot cause HIV infection.




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                           MODULE 4: HIV VACCINE RESEARCH AND DEVELOPMENT




                           Take 5 minutes …
                           How would you explain the following to others:
                              What is a vaccine and how does it work?
                              What is the aim of any vaccine?
                              What are the different types of test HIV vaccine designs?
                              Currently, which designs are not used in the test HIV vaccines?

                           We do not yet know which test HIV vaccine designs are effective
                           enough to produce a strong immune response to HIV. To measure
                           the strength of this immune response, it is important for researchers
                           to test the vaccine in different ways and in different stages. We will
                           now look at the different stages in the development of an effective
                           HIV vaccine and the various ways in which it is tested.

                           2. HOW ARE HIV VACCINES DEVELOPED AND TESTED?
                           In Module 3 we discussed drug and vaccine development and
                           testing in general. We will now apply this information to HIV vaccine
                           research and development.

                           What happens in each stage of the HIV vaccine research and
                           development process?
                           The stages in HIV vaccine research and development are the same
                           as those for any other new drug or vaccine. Remember in Module 3
                           we said that there are four separate stages to developing a vaccine:

                           Stage 1: Discovery: Basic research and development
Both stages 1 and 2
                                    in the laboratory.
form part of preclinical
                           Stage 2: Exploration: Studies in non-humans/animal studies.
studies.
                           Stage 3: Clinical trials in humans:
                                        phase I (tests mainly for safety);
                                        phase II (still tests for safety, the best dose and way to
                                        give the vaccine, and to see if the vaccine triggers an
                                        immune response); and
                                        phase III (tests mainly for efficacy, and always
                                        for safety).
                           Stage 4: Public implementation: Licensure and large-scale
                                    manufacture.
                                        phase IV studies (the reason for the studies is
                                        to monitor how well the vaccine performs when
                                        distributed and administered on a large scale under
                                        real-life conditions, as opposed to the controlled
                                        conditions in earlier phases).




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                             HIV VACCINES FACILITATOR'S MANUAL




Stage 1: Discovery: Basic research and development
           in the laboratory
Researchers isolate the virus or germ, in this case HIV, that is                            Stage 1:
causing the disease, in this case AIDS, and try to understand all                           Discovery
its characteristics. They then use this knowledge and the latest
technology to develop a candidate or test HIV vaccine design in
                                                                                            Stage 2:
the laboratory. Although AIDS was first identified in 1981, the germ
                                                                                            Exploration
causing AIDS, namely HIV was only isolated in 1984. This process,
and getting a complete understanding of the different characteristics
of the virus and the exact way it works, took researchers many
years. (See page 5 of this Module.) This is one of the reasons it has                       Stage 3:
taken them so long to develop HIV vaccine designs.                                          Clinical
                                                                                            trials in
                                                                                            humans
Stage 2: Exploration: Animal studies
Researchers test the HIV vaccine design that they developed in
the laboratory, on small animals. The aim is to
measure how safe the test HIV vaccine is and
what kind of immune response it causes. If the
data is promising, then more tests are done on
larger animals.                                                              Stage 4: Licensure
                                                      Stage 1: Discovery
The information from the preclinical studies must
show that:                                                                  KEY WORD
  researchers have identified a candidate or test                           Isolate:
  HIV vaccine;                                                              To identify, separate or
  the test HIV vaccine is safe and well-tolerated                           remove a specific germ
  in animals – if any, it produces the very smallest                        from a combined mixture,
  negative effects;                                                         e.g. a blood or tissue
  it is not toxic; and,                                                     sample.
                                                     Stage 2: Exploration
  there is immunogenicity – it produces a
  promising immune response.

If the preclinical studies show promising results, then sponsors
and researchers can submit a research protocol to the country’s
regulatory body for approval to test the HIV vaccine in humans.
Remember that in South Africa the regulatory body is the Medicines
Control Council (MCC). As described in Module 3, researchers must
also get approval from all other relevant parties, e.g. the Research
Ethics Committees (RECs). If the vaccine will be tested in other
countries as well, then the Sponsor must get approval from the
relevant bodies in each country where the trial will take place. The
researchers must also apply for and obtain a clinical trial register
number from the South African National Department of Health (DOH).




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                           MODULE 4: HIV VACCINE RESEARCH AND DEVELOPMENT




KEY WORD
                                                      Stage 3: Clinical trials in humans
Adolescent:                                           Remember that there are different phases in
A teenager.                                           the clinical trials. The tables on pages 14–19
                                                      in this module, show information about the
                                                      four separate phases and how they apply to
You can read more about                               HIV vaccine trials. As you read through these
adolescents and clinical
                                                      tables, take note of the following general
trials in Module 6.
                           Stage 3: Clinical trials   points:
                           in humans


                           Who is involved? In all phases of clinical trials for therapeutic HIV
                           vaccines, only people who are infected with HIV and still have a
                           reasonably strong immune system are included. Currently in South
                           Africa, participants should be over 18 years of age and should not
                           be pregnant or breastfeeding. There may also be other criteria,
                           depending on the requirements of each trial.

                           Generally, the following applies to trials for preventative HIV
                           vaccines:
                              currently only people 18 years and over are included although
                              there is an interest in including adolescents in the trials;
                              participants may need at least 12 years of education;
                              pregnant or breastfeeding women are not included;
                              in phase I, healthy individuals who are at lower risk of HIV
                              infection are included;
                              in phase II, healthy individuals who are at high and low risk of
                              HIV infection are included;
                              in phase III, healthy individuals who are at high risk of HIV
                              infection are included; and
                              in phase IV, when researchers are measuring the vaccine’s
                              impact on the epidemic, people from the general public will
                              receive the vaccine.

                           Often researchers will choose several national and international
                           trial sites to make sure that there are enough participants. These
                           participants also represent a wider range of groups, who may react
                           differently to the vaccine. For example, groups in Europe could
                           react differently to the vaccine than groups in Africa because of
                           genetic differences, or because different HIV subtypes are found in
                           each region.

                           How long? The length of each phase will differ depending on
                           factors such as, how long it takes to recruit the different number of
                           trial participants needed in different phases of the clinical trials.

                           What order? The phases run from I–IV and in exact order.
                           Researchers cannot move from one phase to the next unless the


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                              HIV VACCINES FACILITATOR'S MANUAL




results of the previous phase show that the test HIV vaccine is safe
and promising. There may also be trials that occur between e.g.
phase II and phase III, such as a phase IIb trial. Here researchers
collect additional data to what was obtained in the previous phase,
e.g. phase II, to guide future research (see page 15).

Where are they tested? Researchers realise that some trials
will show that certain HIV vaccines are not suitable for further
development, but that others will get to phase III. So, several
different HIV vaccines are being tested around the world at the
same time – this is hoped to speed up the time taken to find a
successful HIV vaccine.

Is there peer review of the trial protocol and results? Suitably
qualified doctors and researchers from the relevant regulatory and
ethical bodies must peer review the results of each clinical trial. They
must also review and approve the protocol of any new clinical trial
before researchers can begin the next phase of clinical trials.

Researchers may also submit articles about trial data, particular
aspects of the trial and trial results, for publication in relevant peer-
reviewed academic journals. These articles are reviewed by an
editorial board consisting of peers or experts in the same field as the
author. This process is called peer review. These experts decide if
the information in the article is reliable enough for publication. Once
trial results are known, other researchers may repeat the work to
see if they get similar results.



                                                                            Remember the purpose
                                                                            that researchers
                                                                            communicate their
                                                                            results for peer review
                                                                            as discussed in Module
                                                                            2, and in Step 6 of the
                                                                            scientific method?




Step 6: Communicate results

What happens in the four phases of HIV vaccine clinical
trials?
The tables on the next few pages apply the general information that
we discussed in Module 3 about the four phases of clinical trials to
test HIV vaccines.



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                          MODULE 4: HIV VACCINE RESEARCH AND DEVELOPMENT




                          Phase I: Safety

KEY WORD                         What are               Who is involved?            How long does
Immunogenicity:                 the aims?                                              it last?
Capable of producing an
immmune response.          The aims are to test:   This phase has the lowest       It usually takes
                           • mainly for safety     number of participants.         about 12–18
                              in humans,           It usually includes 40–120      months to
                              looking at the       people.                         conduct the trial,
                              adverse events;                                      plus 3–4 months
                                                   In preventative HIV vaccine
                           • tolerance – how                                       to analyse the
                                                   trials the participants
                              acceptable the                                       data.
                                                   should be healthy, HIV-
                              vaccine is to
                                                   negative, adults (over 18),
                              humans; and
                                                   who are at low risk of
                           • to a certain
                                                   HIV infection. In addition,
                              extent
                                                   participants in South Africa
                              immunogenicity
                                                   may need at least 12 years
                              – is there
                                                   of education.
                              an immune
                              response.            In therapeutic trials,
                                                   participants will be HIV
                                                   positive and should have
                                                   an immune system that is
                                                   still reasonably strong.


                           If the results from this phase show that the test HIV vaccine is safe
                           and looks promising, then researchers can submit a protocol including
                           these results and the protocol (trial plan) for the next phase of clinical
                           trials to the relevant bodies, for approval.




                                                                                       Phase I: Mainly
                                                                                       for safety.




14
                                HIV VACCINES FACILITATOR'S MANUAL




Phase II: Safety, the best way to give the vaccine, and whether it
          causes an immune response.

       What are                            Who is involved in each trial?                           How long does
      the aims?                                                                                        it last?

 The aims are to test:     This phase usually involves 100s of participants.                     This phase usually
 • still for safety and                                                                          takes about 1–2
                           In preventative trials, it involves healthy, HIV-negative adults,
    immunogenicity;                                                                              years, plus 4–6
                           who are at low and high risk of infection.
 • the best way                                                                                  months to analyse
    of giving the          Currently in South Africa, people need at least 12 years of           the data.
    vaccine, e.g. by       education to participate.
    injection, syrup,      Participants in therapeutic trials should be HIV positive. Trials
    pill and dosage,       usually require people whose immune system is still relatively
    etc.; and              strong to see if the vaccine can delay disease progression to
 • when, how much
                           AIDS.
    and how often to
    give the vaccine.

 If the results from this phase show that the vaccine is safe and looks promising, then researchers can apply to
 the relevant bodies to do a phase III trial. They may also prefer to first do a phase IIb trial, to decide whether to
 move the test HIV vaccine into a large-scale phase III clinical trial, which is more expensive.




                                                                 Phase II: Safety, the best way to give
                                                                 the vaccine, and whether it causes an
                                                                 immune response.


   DID YOU KNOW?
   What is a phase IIb efficacy trial?
   Phase III trials are very expensive due to the large number of trial participants
   required – sometimes up to 10 000 or more. As a result, researchers, following
   promising results from a phase II trial, may rather do a phase IIb efficacy trial to help
   them to decide how or whether to do further research on a particular HIV vaccine
   candidate e.g. to decide whether it is worth spending the resources to do a phase
   III clinical trial. A phase IIb study looks to see if the vaccine is effective (whether it
   works) and that is why it is called an ‘efficacy’ study. It usually needs 2000 to 3000 trial
   participants, which is much smaller than a phase III trial. However, it still has enough trial
   participants (sample size) to indicate whether the vaccine definitely works or whether it
   definitely fails to prevent infection or to delay HIV disease progression.


                                                                                                                   15
                               MODULE 4: HIV VACCINE RESEARCH AND DEVELOPMENT




                               Phase III: Efficacy, and always safety

                                    What are               Who is involved?              How long does
                                   the aims?                                                it last?

                            Participants get the        Therapeutic trials           It usually takes 3–4
                            optimum dose of             involve 1000s of             years to recruit and
                            the vaccine, given          HIV-positive people,         vaccinate all trial
                            in the best way as          usually whose immune         participants, followed
                            established in phase II.    systems are still            by 12–18 months
                            The aim is to see if the    relatively strong.           of data analysis to
                            test vaccine is effective                                establish vaccine
KEY WORDS                   – i.e. can it prevent       Preventative trials          efficacy. But interim
Vaccine efficacy:           HIV infection, or slow      involve 1000s of             results are possible
How the vaccine works       disease progression.        healthy, HIV-negative        before the trial
                                                        people who come from         completes. If the data
under the controlled
                            In preventative trials,     communities at high          is very promising – it
conditions of a clinical
                            this is measured            risk of HIV infection.       shows the vaccine is
trial.
                            by comparing how                                         safe and effective –
Target population:          many people become          The exact number             researchers can apply
The group or community      infected with HIV           of trial participants        to register and licence
that will be targeted for   in the intervention         depends on how               the vaccine. At this
recruitment and from        group compared to           high the rate of HIV         point trial participants
                            the placebo group;          infection is in the target   are told if they got the
which trial participants
                            or if infections occur,     population, and how          placebo or the vaccine.
will be drawn.
                            whether disease             many trial participants      The placebo group may
Interim:                    progression to              researchers think will       be offered a successful
The time between one        AIDS is slower in those     stay on throughout in        vaccine.
event, process or period    who get the vaccine.        the trial.
and another.
                            In therapeutic trials,                                   In a preventative HIV
                            success may be                                           vaccine trial, it takes
                            measured by looking                                      another 3–4 years to
                            at differences in CD4                                    monitor and track the
                            count and viral load                                     impact of the vaccine
                            in those who received                                    on disease progression
                            the intervention and                                     in participants who
                            in those who got the                                     become HIV infected
                            placebo. A significantly                                 during the trial. During
                            higher CD4 count                                         this period there is
                            or lower viral load in                                   ongoing data analysis.
                            those who received the
                            intervention would be
                            indicators of success.

                            Researchers can apply for registration and licensure if the results from the
                            phase III trial show that the test HIV vaccine is safe and effective in preventing
                            HIV infection, and/or slowing disease progression.

                               Take 5 minutes …
                                  Why do you think so many people are needed for phase III trials?
                                  What do you think are the expected outcomes of phase III trials?
                                  Why must people at high risk of HIV infection be included in
                                  phase III preventative HIV vaccine trials?

16
                                   HIV VACCINES FACILITATOR'S MANUAL




Phase III: Efficacy, and always safety.

In Module 3, page 5, we discussed the importance of sample
size. Remember, we said that for researchers to ensure that their
results are not just due to chance, it is important for them and for
statisticians to calculate a high enough number of trial participants
to be included in a research study. This is the same in HIV vaccine
clinical trials.

In a phase III preventative HIV vaccine trial, researchers need to
recruit volunteers who are at high risk of HIV infection. However,
once volunteers are enrolled as trial participants, they receive
intensive HIV risk-reduction counselling. This ensures that the trial
is ethical. Because the counselling should decrease the number
of HIV infections that would otherwise occur in the group of
participants, a much larger number of participants are needed for
the trial. This is the only way that researchers will see a sufficient
number of HIV infections to determine or tell if the HIV vaccine is
working. Remember, that if the vaccine works, e.g. the number of
HIV infections in the control group (the group that gets the placebo)
should be sufficiently higher than the number of HIV infections in the
intervention group (the group that got the HIV vaccine). Before the
trial starts, statisticians can calculate what this number of infections
should be, to ensure that the clinical trial results are not due to
chance.

Even if a preventative vaccine does not work to prevent HIV
infection, but it slows down disease progression, the trial would still
be seen as successful because researchers may have discovered
the vaccine’s therapeutic effect, i.e. its potential use as part of
treatment for people who are infected with HIV.

Let’s now look at the final stage of clinical trials.




                                                                           17
                                        MODULE 4: HIV VACCINE RESEARCH AND DEVELOPMENT




              CASE EXAMPLE OF A PHASE III PREVENTATIVE HIV VACCINE TRIAL:
              AIDSVAX TRIAL
              AIDSVAX is a preventative test HIV vaccine that was used in a trial in North America
              and Thailand. It was tested in a phase III clinical trial with 5 417 trial participants from
              communities at high risk of HIV infection. Participants either received an injection of
              the vaccine or placebo, seven times over the three years of the trial. The vaccine was
              designed to trigger an antibody immune response with the hope that these antibodies
              would prevent people from becoming infected with HIV.

              What were the goals of the trial?
              The main goal was to see if AIDSVAX offered any protection from HIV infection. Other
              goals were to see if the vaccine was safe.

              What were the findings?
              Researchers followed the two groups over three years to see whether the vaccinated
              group had fewer HIV infections than the placebo group. They found that in each group
              slightly more than 5.5% of participants became infected with HIV through natural means.
              Because the number of infections in both groups was similar, this showed that the
              vaccine did not offer protection against HIV.

              Initial results showed that the vaccine was safe. The most common adverse events were
              pain in the area where the vaccine was given and headaches. Researchers followed up
              trial participants who became HIV infected by natural means to see if the vaccine would
              help to slow down the disease progression of HIV.

              Was this clinical trial a ‘failure’?
              In this case, the clinical trial showed that the vaccine did not protect people against
              HIV infection. However, researchers still learned a great deal from the trial which
              together with newer technology can contribute towards the development of better HIV
              vaccines that may work.

              (Adapted from Understanding the results of the AIDSVAX trial, the AIDS Vaccine Advocacy
              Coalition (AVAC), www.avac.org.)



                                        Stage 4: Public implementation: Licensure and
                                                   large-scale manufacture
                                        The ideal outcome at the end of a phase III clinical trial is an HIV
                                        vaccine that is safe and effective. In South Africa, if a vaccine is
                                        successful in a phase III trial, then the researchers can apply to
                                        the Medicines Control Council (MCC) for a licence to allow public
                                        distribution of the vaccine. This can take years to manufacture
                                        enough of the vaccine for public distribution.
Stage 4: Public
implementation
                                        Once an HIV vaccine has been licensed and produced on a large
                                        scale, and is ready for public use, then phase IV or field studies
                                        can begin. In this phase, researchers would monitor how well the


18
                                HIV VACCINES FACILITATOR'S MANUAL




HIV vaccine performs when distributed and administered on a large
scale and under real-life conditions, as opposed to the controlled
conditions in earlier phases of clinical trials.

Phase IV: Post-licensure or field studies


          What are                    Who is          How long does
         the aims?                  involved?            it last?

 The aims are to test:          The general public   Usually this would
 • how well the HIV             is involved.         be a long-term
    vaccine performs in the                          evaluation of the    Phase IV: Performance on a
    general public, on a                             impact of the        large scale
    large scale, and in real-                        HIV vaccine on
    life conditions, rather                          the number of
    than in the controlled                           new infections,
    environment of the                               and/or whether
                                                                           KEY WORD
    clinical trials;                                 it slows disease
                                                                           Adverse drug
 • for rare adverse                                  progression to
                                                                           reactions (ADRs):
    drug reactions;                                  AIDS.
                                                                           Any harmful and
 • how the HIV vaccine
                                                                           unintended adverse
    stands up to wide-
                                                                           events that are caused
    scale storage, transport
                                                                           by the investigational
    and distribution; and
                                                                           product, in this case the
 • the impact of the
                                                                           test HIV vaccine.
    vaccine on public and
    community health
    – does it have any
    impact on the rate of
    new HIV infections, or
    disease progression in
    the general public?


During phase IV the vaccine is on the market and is given to the
general public. The results are monitored to pick up any rare
adverse drug reactions, which may only appear because there is
now a large enough group of people who are receiving the vaccine
under real-life conditions. A test HIV vaccine that does very well in
phase III may not do as well in phase IV. This may be because of
differences in the populations receiving the vaccine, poor storage,
incorrect use, and uncertainty about how to give the vaccine.
Studies are done in different countries and the results are analysed
so that any problems can be addressed, e.g. the need for further
training of healthcare providers, or for the purchase of adequate
cooling storage facilities. Refer to page 15 of Module 3 for an
example of the rotavirus vaccine, which was suspended in the
United States because of reports of a rare adverse event associated
with the vaccine.


                                                                                                 19
                              MODULE 4: HIV VACCINE RESEARCH AND DEVELOPMENT




                              Take 5 minutes …
                                 What criteria are used for trial participants for each phase of
                                 the HIV vaccine trials?
                                 Who is not included in preventative HIV vaccine trials
                                 at present?
                                 Do you think preventative HIV vaccines should be tested on
                                 children (people below 18 years)?

                              For a successful preventative vaccine to make an impact on the
Refer to Module 6 for         HIV epidemic, it should ideally be given to people before the age
more information about        that they first start to have sex. However, children are regarded as
the legal and human           a vulnerable group, and there are specific ethical and human rights
rights issues that must
                              issues that must be considered and special measures that must
be taken into account
                              be taken if they are to be involved in HIV vaccine trials. In South
when including vulnerable
                              Africa, we are still considering whether or not to include children
groups such as children
in clinical trials.           in HIV vaccine clinical trials and if so, at what point they should be
                              included, e.g. perhaps only after promising results from a phase II
                              trial on a test HIV vaccine.
KEY WORDS
Children:                     3. WHICH RESEARCH DESIGN IS USED FOR HIV
Anyone up to 18
                                  VACCINE TRIALS?
years old.
                              Remember that in Module 3 we covered the different types of
Gold standard:                research designs used in drug and vaccine trials. HIV vaccine trials
An ideal model or a           generally make use of randomised, double-blind and placebo-
model of excellence.          controlled research designs. This is the ‘gold standard’ for clinical
Bias:                         trials and is used to ensure that:
A researcher’s or                 There is not researcher or participant bias, because the
participant’s belief              researchers and the trial participants do not know which
or viewpoint that may             trial participants are getting the test HIV vaccine and which
influence the way s/he            participants are getting the placebo. This is possible as
interprets results or             participants were randomly assigned to the groups and both the
reports their experience          researchers and the participants were ‘blinded’ to which groups
of the vaccine. For
                                  the participants were allocated. If a researcher knows which
example, if the participant
                                  group a participant is in, this might influence the way that he or
believes that the vaccine
                                  she would interpret and report findings from medical check ups.
will cause bad adverse
events (AEs) and s/he             This in turn could influence the results of the clinical trial. In a
knows they are getting            similar way, if a trial participant knows that he or she is getting
the test vaccine, then the        the test HIV vaccine, then he or she may behave differently or
participant may report            ‘experience’ certain things such as lots of headaches or nausea,
more AEs than if he or            especially if he or she is expecting to experience these adverse
she did not know they             events due to the vaccine.
got the vaccine. This             The only difference in the two groups is the intervention – the
causes bias because               test HIV vaccine and nothing else. This means that if there is
it makes it look like the         any significant change to the participants in the intervention
vaccine causes worse              group, which does not occur in the control group, then we can
adverse events than it            say that this change is because of the intervention (the vaccine)
actually does.                    and nothing else. Assuming that the sample size is correct, the


20
                              HIV VACCINES FACILITATOR'S MANUAL




   change cannot be said to be because of chance or accident as
   long as the sample size is large enough.


    DID YOU KNOW?
    The mind is very powerful. Sometimes we experience certain symptoms because that
    is what our mind tells us we should expect to experience. For example, if a person
    knows she is getting a vaccine that is expected to cause headaches and nausea in
    some participants, then her mind might subconsciously make her start experiencing
    these symptoms. In other words, the symptoms might not have anything to do with
    the actual vaccine, but more to do with the power of the mind over the body. This is
    called the ‘placebo effect’.


Take 5 minutes …
In your own words, explain the following:
   What is a randomised control design?
   What does double-blind mean?
   What does placebo-controlled mean?

For answers, we suggest you go back to pages 9–10 of Module 3.

4. WHAT ARE THE POLICIES, GUIDELINES AND LAWS
                                                                                Refer to Module 3
    THAT APPLY TO HIV VACCINE RESEARCH?
                                                                                for more details on
In Module 3, you read that for all drug or vaccine trials, researchers          the general policies,
need to submit a trial protocol for approval to the relevant regulatory         guidelines and laws that
bodies and ethics committees. This also applies to HIV vaccine                  also apply to HIV vaccine
trials to ensure that the research is scientifically and ethically sound.       research.
All clinical trials in South Africa must also be registered with the
Department of Health. See www.sanrr.org.za.

In addition to the legal, ethical and clinical policies and guidelines
discussed in Module 3, the following guidelines apply specifically
to HIV vaccine research including clinical trials: the UNAIDS
Ethical considerations in preventive HIV vaccine research, and
more recently, the MRC Guidelines for medical research: HIV
preventive vaccine research (Book 5). Copies of these documents
at the are available on the Internet at the website addresses that
are listed on page 42. Although the guidelines specifically address
preventative HIV vaccine research, many of the principles, such
as the need for informed consent, apply equally to therapeutic
HIV vaccine trials. In Modules 5 and 6 we expand on some of the
principles and details in these documents.




                                                                                                     21
     MODULE 4: HIV VACCINE RESEARCH AND DEVELOPMENT




     5. WHO IS INVOLVED IN APPROVING, RUNNING AND
        QUALITY ASSURING CLINICAL TRIALS AND WHAT
        ARE THEIR ROLES?
     Generally, the same parties discussed in Module 3 are involved in
     approving, running and quality assuring HIV vaccine clinical trials.
     However, there may be other specific parties depending on the type
     of vaccine being tested, and parties may differ from country
     to country. Let’s look at the main parties in HIV vaccine trials and
     their roles.

     Parties involved in approving HIV vaccine clinical trials
     Although each clinical trial is unique, the following parties (groups
     or individuals) are usually involved in the approval process for
     HIV vaccine clinical trials in South Africa:

                                    Regulatory                  South
                                                                      Afr
                                    authorities                    nati ican s
                                                                H      on a
                               e.g. MCC do scientific
                                                            D
                                                              O            l le ocie
                                      review.                                  v e ty
                                                                                  l   -
                                                            Local co
                                            RECs
                                                                      mmu
                                                                            nity
                  Sends                   Do ethical
                protocol for               review.
                 approval.                              Potential
                                                        trial site
              Sponsor
      Starts, manages and/or
           finances trial.
                                     Council for Genetically
       Sends relevant                 Modified Organisms
        protocols for                   do GMO review.
          approval.

     Parties involved in approving clinical trials.


     The tables on the next few pages briefly describe the role of each
     party involved in approving HIV vaccine trials. Remember that
     early and ongoing consultation with community stakeholders is an
     important part of the research process.

                 Name of party                                  Role in approving
                                                                HIV vaccine trials

      The Sponsor: This is the                          •   The Sponsor takes overall
      company, institution or                               responsibility for designing
      organisation that takes                               the trial and for submitting the
      responsibility for initiating,                        trial protocol to the regulatory
      managing and/or financing                             authorities (e.g. the MCC),
      a clinical trial. This could be                       and the REC/s for review and
      a pharmaceutical company,                             approval to begin the trial.



22
                                HIV VACCINES FACILITATOR'S MANUAL




          Name of party                         Role in approving
                                                HIV vaccine trials

the principal investigator (PI),        • The Sponsor must make sure
a vaccine manufacturer, or                that there is enough safety
a funding body. Examples of such          and efficacy data about the
parties are the pharmaceutical            vaccine from the preclinical
company Merck, the South                  studies and/or clinical trials to
African AIDS Vaccine Initiative           support testing or continuing
(SAAVI) – a lead programme of             to test the HIV vaccine in
the Medical Research Council              humans.
(MRC); and the HIV Vaccine Trials       • The Sponsor must also make
Network (HVTN) which is funded            sure that there is insurance
and supported by the US-based             cover, in accordance with
National Institutes of Health             the MCC requirements, for
(NIH).1                                   injury and damages to trial
                                          participants if this happens as
                                          a result of the trial.

The Regulatory Authority/ies:           •   The MCC reviews protocols
This is an independent body/                for clinical trials for
ies that may be set up by the               non-registered medicines and
government. In South Africa,                for new uses of registered
the medicines regulatory authority          medicines. It also reviews
for clinical trials on drugs and            applications to license a
vaccines is the Medicines Control           medicine, including drugs
Council (MCC). It follows the               or vaccines for public
Guidelines for Good Practice                distribution.
in the Conduct of Clinical Trials       •   This scientific review of
in Human Participants in South              applications, including the
Africa to do scientific review of           research protocol and or
applications for clinical trials. The       supporting data, ensures that
research, as described in the               all medicines, including
protocol, must meet the criteria            vaccines, used in the country
given in the guidelines.                    are safe, effective and of high
                                            quality.
                                                                              KEY WORD
                                        In multi-country trials, regulatory   Multi-country trial:
                                        authorities from all participating    The same trial
                                        countries should review the           happening in many
                                        protocol and decide on approval       different countries.
                                        of the trial. In the United States,
                                        the regulatory authority is the
                                        Food and Drug Administration
                                        (FDA).




                                                                                                     23
                              MODULE 4: HIV VACCINE RESEARCH AND DEVELOPMENT




                                          Name of party                           Role in approving
                                                                                  HIV vaccine trials

                               Research Ethics Committee                  • RECs review protocols to
KEY WORDS                      (REC) (sometimes called an                   ensure that the research is
Informed consent:              Institutional Review Board or IRB):          ethical; that the human rights,
Consent by a person            A trial site is usually linked to a          safety and well-being of trial
to a surgical or medical       university or research institute             participants are respected and
procedure or to                that has an REC. This is an                  protected; and that there is
participate in a clinical      independent committee that                   informed consent.2
study after achieving an       includes several academics and             • It also reviews certain trial-
understanding of the           lay or community members. It is              related documents before the
relevant medical facts         a main mechanism through which               research can start, e.g. the
and the risks involved.        communities can ensure that                  informed consent forms.
Genetically modified           the trial is ethical and respects          • In trials involving different
organisms (GMO):               people’s human rights. The REC               countries, the protocol is
GMOs occur when                is guided by relevant laws and               reviewed by RECs from all
technology is used             guidelines when making their                 participating institutions.
to change the genetic          decisions.1
make-up of living
organisms like animals,
plants, viruses or             In HIV vaccine trials, the                 Its main role is to ensure
bacteria. This is done         Council for Genetically Modified           responsible development,
to produce desired             Organisms may also need to                 production, use, application and
characteristics for            approve the clinical trial. In South       release of GMOs in accordance
example, drought-              Africa, this body is based within          with the Genetically Modified
resistant maize, or            the Department of Agriculture.             Organism Act 15 of 1997. This
vaccine designs which          Its Executive Council includes             applies to some HIV vaccine
can combat HIV.                officers from different national           designs that include genetically
                               departments who study the                  modified parts. It can approve or
                               potential impact of genetically            reject the use in clinical trials of
                               modified organisms (GMOs)                  HIV vaccine designs that include
Informed consent is also
                               relevant to their area.                    genetically modified parts.
discussed in Modules
5, 6 & 7. Community
involvement is discussed
in Module 7.
                              1. In South Africa, the National Health Act, 2003 makes provision for a National
                                 Health Research Ethics Council (NHREC) that will have the overall responsibility to:
For more information             • register and audit RECs;
on biotechnology and             • set the norms and standards for how RECs should work and for how the
                                     research should be conducted;
genetic modification, visit      • ensure and monitor that approved RECs in South Africa fulfil the relevant
the Public Understanding             legislation, regulations and guidelines; and
of Biotechnology website         • hear complaints about the functioning of RECs and make decisions about
at www.pub.ac.za.                    what to do.
                              2. They do this by reviewing and providing comment on: the qualifications and
                                 experience of investigator(s), the facilities, methods, recruitment strategies,
                                 payment and compensation of trial participants, and the forms and procedures
                                 used to obtain informed consent.




24
                                              HIV VACCINES FACILITATOR'S MANUAL




  Take 5 minutes …
     If you are not from South Africa, do you know which parties in
     your country are involved in giving approval for HIV vaccine
     trials? Try to find out who the parties are and their major
     responsibilities or roles.

  Parties involved in running HIV vaccine clinical trials
  The parties involved in running and managing HIV vaccine clinical
  trials may differ from trial to trial, but generally include those in the
  following diagram:


                                       Applies for
                                                                       DOH
                                      and/or gets
                                                                Registers the trial
                                      a clinical trial
                                                                  and gives it a
                                       registration
                                                               registration number.
                                         number.
                     In

                       O lti-c
                        m
                        ve en
                          u

                            ra tre




                                                                                           CAG
                              ll
                                 PI tria




                                                                                      Represent local
                                                                                      community. Link
                                         l.




                                                                                       researchers &
              Appoints                                                                  community.
Sponsor     Pl/s who are                       Trial Site/s
             responsible
                                                         Site Staff
             to them for
                                                         • Principal Investigator (PI)
            managing the
                                                         • Trial site director/Study
                 trial.
                                                           coordinator
                                                         • Medical officers
                                                         • Pharmacists                            Consult
                                                         • Trial nurses
                                                         • Counsellors
                  Laboratories                           • Community outreach team
                                                         • Data managers
                                                         • Laboratory technicians
                                                         • Trial participants




  Parties involved in running clinical trials.


  The tables on the next few pages give examples of typical bodies
  that are involved in a larger clinical trial. In smaller trials, people
  often play more than one role. Also, a party may have a different
  name or title to the one listed, depending on the trial.




                                                                                                            25
                              MODULE 4: HIV VACCINE RESEARCH AND DEVELOPMENT




KEY WORDS                              Name of party                         Role in running HIV
Serious adverse                                                             vaccine clinical trials
event (SAE):
An AE that results in one     The Sponsor                           •   Appoints suitably qualified
or more of the following:                                               staff to design the protocol,
death; a life-threatening                                               to supervise the trial, to handle,
condition; hospitalisation;                                             verify and analyse data, and to
an ongoing or significant                                               write trial reports.
disability/incapacity; or a                                         •   Supplies the test HIV vaccine/s
birth defect.                                                           and the comparative products
                                                                        or placebo to the principal
Adverse Event (AE):
                                                                        investigator (PI) with written
Any untoward medical
                                                                        procedures on how to handle
occurrence in a patient
                                                                        and store them. This information
or trial participant who is
                                                                        is given to all involved parties
given a pharmaceutical
                                                                        e.g. pharmacists, Monitor etc.
product. The untoward
                                                                    •   Takes responsibility for ongoing
medical occurrence is
                                                                        safety evaluation of these
not necessarily caused
                                                                        product(s) throughout the trial.
by the pharmaceutical
                                                                    •   Ensures trial activities and
product. So an AE can
                                                                        outcomes are regularly reported
be any unfavourable
                                                                        to the regulatory authorities and
and unintended sign
                                                                        the REC.
(including an abnormal
                                                                    •   Should submit to the regulatory
laboratory finding),
                                                                        authority and appropriate ethics
symptom, or disease,
                                                                        committee/s all safety updates
temporarily associated
                                                                        and periodic reports to meet the
with the use of an
                                                                        relevant regulatory requirements.
investigational product,
                                                                    •   Ensures that reports on serious
whether or not these
                                                                        or unexpected adverse events
signs are related to the
                                                                        (SAEs) are immediately sent to all
investigational product.
                                                                        concerned PIs, institutions, RECs
                                                                        and the regulatory authorities.

                              The Principal Investigator            • Takes sole or joint responsibility
                              (PI): This is usually, but not          for the design, conduct, analysis
                              always, a medical doctor who            and reports of the trial.
                              is appropriately qualified to         • Ensures that approval for the trial
                              carry out a clinical trial. Usually     has been given by the regulatory
                              he or she is appointed by, and          authorities and the RECs, and
                              is responsible to, the Sponsor.         that a clinical trial registration
                                                                      number is given before starting
                              In a multi-country trial involving      the trial.
                              South Africa, there must be           • Ensures that all necessary staff,
                              a local PI living in the country        facilities, equipment and finances
                              to oversee the conduct of               are in place for the trial.
                              the clinical trial at the trial       • Follows the protocol, appropriate
                              site/s here.                            legislation and related guidelines,
                                                                      and ensures that all trial site staff
                                                                      know and also follow them.



26
                                  HIV VACCINES FACILITATOR'S MANUAL




          Name of party                       Role in running HIV
                                             vaccine clinical trials

PI cont'd:                             •   Takes responsibility for the       KEY WORDS
In the case of a multi-site trial          management and use of              Multi-site trial:
in South Africa, there may be an           the HIV vaccine/s at the           More than one trial site
overall PI who oversees the PIs            trial site.                        in a clinical trial.
at the various trial sites.            •   Develops mechanisms to
                                                                              Trial site:
                                           ethically obtain informed
                                                                              The place at which the
                                           consent from trial participants.
                                                                              trial takes place – usually
                                       •   Takes responsibility for
                                                                              a clinic, hospital or
                                           collecting, recording, and
                                                                              research institution.
                                           maintaining source data.
                                       •   Ensures adequate plans to
                                           address any unexpected AEs.
                                       •   Reports and sends relevant
                                           information about any SAEs
                                           to the Sponsor, who forwards
                                           the relevant information to the
The Principal Investigator (PI)
                                           appropriate parties.
                                       •   Submits progress reports and
                                           a final report, as required by
                                           the Sponsor, to the REC/s and
                                           regulatory authority.
                                       •   Submits reports of adverse
                                           drug reactions (ADRs) that are
                                           both serious and unexpected
                                           immediately to all concerned
                                           parties, e.g. MCC, REC and
                                           Sponsor.

                                       •   Together with the PI, takes
                                           responsibility for carrying out
                                           the trial and addressing any
Trial site director or study               problems during the trial.
co-ordinator: The most senior          •   Makes sure that the trial site
person at the site who could also          functions efficiently and helps
be a PI. This person is usually a          in the day-to-day running of
professional health care worker,           the trial.
e.g. a doctor.                         •   Ensures that these activities
                                           are carried out with scientific
                                           thoroughness and expertise.
                                       •   Ensures that the trial is
                                           managed according to
                                           the protocol, the relevant
                                           guidelines and legislation.
                                       •   Ensures that trial participants
                                           undergo and have given
                                           informed consent.
                                       •   Ensures that confidentiality
                                           is kept.


                                                                                                     27
                                  MODULE 4: HIV VACCINE RESEARCH AND DEVELOPMENT




                                           Name of party                         Role in running HIV
                                                                                vaccine clinical trials

KEY WORDS                         Medical officers or study             • Do medical check-ups of
Case Report Forms/                investigators: They are                 volunteers and trial participants,
Files (CRFs):                     qualified doctors.                      and make clinical decisions.
Printed or electronic                                                   • Evaluate laboratory results.
pages that are designed                                                 • Report and follow up Serious
to record all the                                                         Adverse Events (SAEs).
information required                                                    • Refer volunteers and/or trial
by the protocol.                                                          participants for appropriate care,
                                                                          if necessary.
Source documents:
All the original documents        Trial nurse: Assists the trial site   • Deals with trial participants in
and basic or source data          director, co-ordinator, medical         all examinations and follow-up
that are necessary to             officers/study investigators and        visits.
recreate and evaluate             study co-ordinators in the day-       • Takes blood and vital signs,
a clinical trial, e.g. original   to-day running of the trial.            e.g. measure blood pressure.
laboratory reports.                                                     • Completes Case Report
Product inventory:                                                        Forms (CRFs) by using source
List of products, e.g. a                                                  documents.
record of each bottle                                                   • May counsel trial participants.
delivered and used,
where each bottle has             Pharmacist: The PI may assign         • Keeps records of the
gone, and number                  some of the responsibilities and        product inventory.
of unused products,               duties for the investigational        • Dispenses the products.
or unused products                product(s) to a pharmacist or         • Explains how to administer or
returned to the Sponsor.          any other appropriate person at         take the investigational
                                  the trial site.                         product/s, and regularly checks
Dispenses:                                                                that these instructions are being
Prepares and gives                                                        followed.
out medicines.
Retention:
Maintaining trial                                                       •   Processes CRFs and data.
participants and making                                                 •   Creates a database and
efforts not to lose them          Data manager                              other tools to assist in quality
from the study.                                                             control and retention of trial
                                                                            participants.
Risk-reduction
counselling:                                                            • Does HIV, and pregnancy risk-
For example, counselling          Counsellor                              reduction counselling, and pre-
people about ways                                                         and post-test HIV counselling.
to reduce their risk of                                                 • Collects personal information
getting HIV or STIs.                                                      from trial participants, when
                                                                          necessary.
                                                                        • Counsels trial participants
                                                                          about personal challenges and
                                                                          problems that they experience
                                                                          due to the trial.
                                                                        • Helps with the informed consent
                                                                          sessions.


28
                                HIV VACCINES FACILITATOR'S MANUAL




          Name of party                        Role in running HIV
                                              vaccine clinical trials

Community outreach personnel            •   Take responsibility for
(sometimes called community                 communication between the
liaison officers): Can include              trial site and the community.
nurses, social scientists,              •   Recruit trial participants.
counsellors and community               •   Work closely with the
vaccine educators. They are led             community advisory group
by the trial site co-ordinator or the       (CAG) if there is one.
community outreach co-ordinator.        •   Work on retention of trial
                                            participants, especially during
                                            large trials, such as phase
                                            III trials.
                                        •   Social scientists research
                                            issues such as willingness
                                            to participate, recruitment,
                                            retention, and barriers to
                                            HIV testing.

                                        • Processes samples and
Laboratory technician                     prepares them for transfer
                                          to other laboratories.
                                        • May test and analyse blood
                                          and other types of samples
                                          obtained from trial participants,
                                          at the trial site.

The Community Advisory Group            • Forms an important and
or Board (CAG): A group of                ongoing communication
volunteers who live and work in           and advisory link between           For more information on
and around the area from which            the researchers and                 CAGs and community
trial participants are recruited.         the community.                      involvement refer to
They represent the interests of the     • Should become equal                 Module 7.
community, and encourage and              partners in the research and
facilitate community involvement          development process, and
in the research process.                  should ideally participate in
                                          all decision making to do
We prefer to use the term                 with the trials that affects the
Community Advisory Group                  community.
(CAG), rather than Board because
in South Africa the term ‘Board’
carries legal responsibilities that
are beyond what is expected
from the CAG members.




                                                                                                  29
     MODULE 4: HIV VACCINE RESEARCH AND DEVELOPMENT




                Name of party                        Role in running HIV
                                                    vaccine clinical trials

      Laboratories                           Routine laboratories provide
      Laboratories are used in the           commercially available and
      general public to run tests on e.g.    routinely used tests, e.g. HIV
      blood or urine samples. These          antibody tests, blood counts, and
      tests check a specific aspect of       so on. Trial sites may use them
      a person’s health, such as the         to do these standard tests on
      amount of sugar in the blood of        samples from trial participants.
      someone with diabetes.
                                             Research laboratories run tests
      Laboratory technicians at the          that are designed for a specific
      HIV vaccine trial site may run         HIV vaccine trial. These tests are
      certain tests at the trial site. The   not used in the general public
      types of tests that they would         and cannot be done at routine
      run are similar to those done          laboratories. An example of a
      at the Routine laboratories (see       test like this would be one that
      next column). Where the trial site     detects the immune response
      laboratory is not equipped to          that takes place in participants
      do certain tests, the laboratory       in a clinical trial for a specific HIV
      technicians will prepare and send      vaccine design.
      samples to outside laboratories
      for results. There are two types
      of outside laboratories. These
      include routine laboratories and
      research laboratories.




     Take 5 minutes …
        If you are not from South Africa, do you know which parties and
        individuals in your country are involved in running clinical trials?
        Try to find out who they are and what their major responsibilities
        or roles are.




30
                                  HIV VACCINES FACILITATOR'S MANUAL




Parties involved in quality assurance of HIV vaccine
                                                                                             KEY WORDS
clinical trials
                                                                                             Quality assurance (QA):
Quality assurance of clinical trials in South Africa is done through                         All those planned and
monitoring, audits and inspections, and ensures that:                                        systematic actions
   the rights and well-being of trial participants are protected;                            that ensure that the
   the reported data is accurate, complete and can be checked                                trial is performed
   against the source documents; and                                                         and the data is generated,
   the trial is carried out and reported according to the                                    documented (recorded),
   approved trial protocol, GCP guidelines, and any applicable                               and reported in
   regulatory requirements.                                                                  compliance with GCP
                                                                                             and the applicable
                                                                                             regulatory requirement(s).
                                                                South
                        Regulatory authority                              Afri               Regulatory
                              – MCC.                                   natio can s
                                                                             nal    o        requirements:
                                                      Can inspect trial          lev ciet
                                                     site & laboratories.           el y -   Generally in South
                                   In

                                     O lti-c




                                                                                             Africa this refers to all
                                      m
                                      ve en
                                        u




                                                                      Loca
                                          ra tre




         Ensures regular                                                  l co               applicable laws, e.g.
                                            ll




                                                                               mm
                                               PI tria




      reports & safety data
            are sent.
                                 RECs                                            un          the National Health
                                                                                   it y
                                                                                             Act (2003) that impose
                                                       l.




                                                Trial site/s                  CAG
                                             PI sends regular                                requirements for the
                                                                          Help to ensure
  Sponsor       Appoints                   reports & safety data           community         approval, running
                Monitor,                    to relevant parties.          concerns are       and monitoring of
                Auditor &                                                  addressed.
                 IDMC
                                                                                             clinical research.
                                  Laboratories




Parties involved in quality assurance.


The following tables briefly explain the parties involved in quality assurance.


            Name of party                          Role in quality assurance of
                                                    HIV vaccine clinical trials

 The Sponsor                                   • Implements and maintains
                                                 quality assurance (QA) and
                                                 quality control (QC) systems.
                                                 This includes appointing a
                                                 Monitor, and sometimes an
                                                 Independent Data Monitoring
                                                 Committee (IDMC), and
                                                 sometimes an Auditor.
                                               • Develops written standard
                                                 operating procedures (SOPs)
                                                 to ensure that data is collected
                                                 and reported according to the
                                                 relevant requirement(s).




                                                                                                                    31
                            MODULE 4: HIV VACCINE RESEARCH AND DEVELOPMENT




                                    Name of party                      Role in quality assurance
                                                                      of HIV vaccine clinical trials

                            The Sponsor (cont'd)                 • Must get agreement from all
                                                                   involved parties to allow direct
KEY WORD
                                                                   access to all trial-related sites,
Concerned parties:                                                 source data/documents and
Usually includes the PIs,                                          reports. This access enables
the regulatory authority                                           monitoring and auditing, and
and the relevant ethics                                            inspection by regulatory authorities.
committees.                                                      • Informs the regulatory authority and
                                                                   appropriate ethics committee/s of
                                                                   possible serious violation/s of GCP
                                                                   during the trial.
                                                                 • Is ultimately responsible for the
                                                                   quality and integrity of the trial data.

                                                                 • Allows monitoring and auditing
                                                                   of the trial and inspection by the
                                                                   regulatory authority/ies.
                            The Principal Investigator           • The PI should be available for
                            (PI)                                   regular visits by the Monitor. Here
                                                                   the PI verifies with the Monitor
                                                                   that the trial site, staff and facilities
                                                                   comply with the protocol and the
                                                                   Sponsor’s SOPs.

                            The Monitor: Appointed by            •   Mainly responsible to oversee and
                            the Sponsor. He or she is an             report on the progress of a trial.
                            important communication              •   Visits the trial sites regularly to
                            link between the Sponsor                 ensure the trial is carried out and
                            and the PIs. The Monitor                 reported according to the protocol,
                            should have adequate                     SOPs and appropriate legislation.
                            medical, pharmaceutical and/         •   Checks that the informed consent
                            or scientific qualifications. S/he       documents are properly signed and
                            should be available at all times         dated.
                            for consultation or reporting of     •   Checks that records, files and
                            SAEs. The role of Monitor is             CRFs are complete and follows up
                            sometimes done by a Clinical             on missing information.
                            Research Organisation (CRO),         •   Visits laboratories used in the trial
                            which is appointed by the                to ensure they are appropriately
                            Sponsor. The Monitor must                accredited and, to check their
                            understand the investigational           quality assurance.
                            product (HIV vaccine), the           •   Informs the Sponsor and trial
                            clinical research procedures and         management of any problems at
                            the requirements of the protocol         the trial sites or laboratories.
                            and related documents.




32
                                 HIV VACCINES FACILITATOR'S MANUAL




    Name of party                     Role in quality assurance
                                     of HIV vaccine clinical trials
                                                                               KEY WORDS
The Auditor:                •   Does an in-depth examination to evaluate       GLP:
An independent                  trial conduct, and whether or not the trial    Good Laboratory
individual,                     meets the terms of the protocol, SOPs,         Practice
organisation or                 GCP, GLP, GPP and appropriate regulatory       GPP:
group appointed by              requirements.                                  Good Pharmacy Practice
the Sponsor and
suitably qualified to       Examples of what is audited include:
audit the clinical trial.   • how and where data was recorded;
                            • how the investigational product/s were
                               delivered, stored and managed;
                            • how trial participants were recruited and
                               whether informed consent was obtained
                               appropriately;
                            • whether AEs were reported and
                               appropriately addressed; and
                            • whether REC approvals and notifications
                               were documented.

What happens if there are problems?
The Sponsor must take immediate action if the Monitor or Auditor find
any problems with compliance to the protocol, GCP, etc. If any serious
and/or ongoing problems are identified with the PI, then the Sponsor
may need to end the trial.

If a trial is stopped or suspended, the Sponsor must immediately inform
the PIs and the regulatory authority(ies), including the reasons. The REC
must also be informed by the Sponsor or PI.

The Research                They should frequently and regularly review
Ethics Committees           and monitor each trial to identify the following
(RECs)                      from an ethics and human rights point of view:
                            • relevant PI trial progress reports;
                            • change(s) to the protocol during trials; and
                            • reports of SAEs.

                            The review may lead to the need for the trial
                            site to update the informed consent forms, or
                            to the trial being stopped.

What happens if there are problems?
• The REC must contact the PI, who is responsible, to address
  the issue.
• During the trial, trial participants may lay complaints about ethical
  or human rights concerns with the REC. They could also complain
  to the CAG who would follow it up or alert the REC.




                                                                                                 33
                        MODULE 4: HIV VACCINE RESEARCH AND DEVELOPMENT




                                  Name of party                      Role in quality assurance of
                                                                      HIV vaccine clinical trials

                        The Independent Data                     Reviews data at various points
                        Monitoring Committee (IDMC)              during the trial to assess trial
                        or Data and Safety Monitory              progress. Data reviewed includes:
                        Board (DSMB): A committee                • safety data; and
                        of independent clinical                  • efficacy data – how well the
                        researchers sometimes                       test HIV vaccine works in
                        appointed by the Sponsor.                   comparison to the outcomes
                                                                    or end-points that researchers
                        In a double-blind study, they are           want, e.g. they find that a
For more information    the only group that can review              vaccine is 65% effective in
on HIV vaccine trial    the data in such a way that they            preventing infection when the
end-points, see pages   know which group of people                  end-point was hoped to be a
2– 4 of this module.    received the test HIV vaccine and           vaccine that is 75% effective.
                        which group of people did not.
                                                                 Based on the review, the DSMB
                                                                 recommends to the Sponsor
                                                                 whether to continue, change
                                                                 or stop the trial.




                        The Community Advisory Group             •   Are a mechanism to ensure
                        or Board (CAG)                               that any human rights issues
                                                                     and other personal concerns
                                                                     raised by the community are
                                                                     addressed.

                        Medicines regulatory authority:          • Can do on-site inspections at
                        The Medicines and Related                  any time to see how a clinical
                        Substances Act, 1965 prescribes            trial is being carried out.
                        that the medicines regulatory            • Compares the procedures and
                        authority in South Africa, the             practices that the PI uses with
                        MCC, may inspect the conduct               those given in the protocol and
                        of a clinical trial by on-site visits.     in reports submitted to
                        The Sponsor, trial site, facilities        the MCC.
                        and laboratories, and all data and
                        related documentation must be
                        available for inspection.




34
                                         HIV VACCINES FACILITATOR'S MANUAL




               Name of party                            Role in quality assurance of
                                                         HIV vaccine clinical trials

    Medicines regulatory authority
    (cont'd): Inspections may be
    carried out randomly or for
    specific reasons. Usually they
    only happen if there is reason to
    believe that the competency of
    the trial site needs to be reviewed,
    or there is evidence that GCP is
    not being followed.

    What if there are problems?
    If there are any serious problems then the MCC has the power to close
    a trial. This is to ensure high-quality trials.


  The Sponsor, the PI and the trial site staff must consult with
  government and community members throughout the trial to ensure
  community involvement and participation. (Refer to Module 7 for
  more on community involvement and the community entry process.)

  The diagram below is a summary of all the parties involved in
  clinical trials:

                                                      DOH
                                              Department of health
                                            provides a trial registration
                                                                                               Sou
                                                     number.                                      th
                                                                                                      A
                                                                                                  n a f ri c
                                                                                                     tio an
                                                                            ration                      na
                                                                                                           l l soc
                                                                     regist
                              Regulatory
                                                              e s for rial.                                   ev ie
                              authorities                Appli f the t                                          el
                                                                o
                                                                                                                  ty




                             e.g. MCC do
                                                                                                                      -




                            scientific review.                        Can inspect trial site
                                                                       and laboratories.
                                                   In

                                                    O lti-c
                                                     m
                                                     ve en




                                                                                                    Lo
                                                       u




   Sends protocol for
                                                         ra tre




                                                                                                       ca
                                                           ll




    approval. Ensures                                                                                    lc
                                                              PI tria




 regular reports & safety                                                                                  om
                                        RECs                                                                    m
      data are sent.                                                                                             un
                                                                      l.




                                      Do ethical
                                                               Trial Site/s
                                                                                                                  it




                                       review.
                                                                                                                      y




                                                            PI and site staff.
   Sponsor                                                                                              CAG
                   Appoints Pls,                          PI is responsible for
Starts, manages                                                                                  Link community and
                    and parties                           managing the trial &
and /or finances                                                                                  researchers. Help
                   to do quality                          regularly reports to
      trial.                                                                                      ensure community
                    assurance                               relevant parties.
                                                                                                     concerns are
                     at sites &
                                                                                                      addressed.
                   laboratories.            Laboratories




  Summary of parties involved in clinical trials.


                                                                                                                          35
                             MODULE 4: HIV VACCINE RESEARCH AND DEVELOPMENT




                             So far we have looked at the roles and responsibilities of all those
                             involved in setting up, implementing and quality assuring the HIV
                             vaccine clinical trials. Let’s now examine how trial sites are chosen.

                             6. HOW ARE TRIAL SITES CHOSEN?
                             In Module 7 we look in detail at the process involved in entering a
                             community to get ‘buy in’ or agreement for research to happen in
                             the area. Sponsors and researchers also look at a number of issues
                             to help them identify appropriate HIV vaccine trial sites or areas
                             where the research will take place.
KEY WORD
Baseline information:        Baseline information
Information collected
                             Baseline information is collected by researchers in an area before
at the initial stages of
                             a trial site is chosen. This information tells researchers, if they use
a project. This usually
includes facts and figures   the site, whether they can answer the questions in their study, e.g.
that provide a basis         is the number of new HIV infections high enough in the area to see
against which future         if a preventative test HIV vaccine works? If researchers establish a
measurements can             trial site there, then any future information can be compared to the
be compared. These           baseline information to see what progress has been made, or to
are used to measure          see if the test HIV vaccine is making a difference.
progress in achieving
project aims and             Let’s take an example of researchers who want to carry out a
objectives.                  phase III trial of a preventative test HIV vaccine in a group of
                             thousands of healthy adults (over 18 years old), at high risk of HIV
                             infection. They need to collect the following baseline information
                             about the community and the potential trial site area. This is to see
                             if there are enough people in the area from which to draw suitable
                             trial participants who meet the trial criteria:
                                 Information about the community (demographics):
                                 Researchers look at the various characteristics of a certain
                                 population or community, e.g. population size and density, age
                                 distribution, percentage of men and women, and levels
                                 of literacy.
                                 Biological factors: This includes information about HIV
                                 infections in the area, e.g. the rate of new HIV infections, the
                                 prevalence of HIV infections – how many infections there are
                                 altogether, which HIV subtypes are common, the age and sex of
                                 those infected, etc.
                                 Attitude to research in the community: The research is bound
                                 to fail if people from the community or other stakeholders, e.g.
                                 local government do not want an HIV vaccine to be tested
                                 in the community. So researchers must measure people’s
                                 attitudes to HIV vaccine research in that area before choosing
                                 and investing in a particular trial site. Early and ongoing
                                 consultation with community stakeholders is an important part
                                 of this research process and should begin prior to, or as part of,



36
                              HIV VACCINES FACILITATOR'S MANUAL




   this process. (See Module 7 for more on community involvement
   and consultation.)

Practical and logistical factors
Apart from baseline information, researchers also need to collect
information to understand the practical and logistical factors in the
potential trial site area. In particular they need to understand:
    Access to transport and other facilities: Researchers need to
    determine the following:
    –     Does the community have access to good medical facilities
          to cope with any adverse events?
    –     Is the trial site close to where the majority of trial
          participants might work or live, so that they do not have
          far to travel for visits? The research team also needs to
          be closeby to the site to deal with any SAEs quickly and
          effectively.
    –     HIV vaccine trials often require specialised laboratory tests
          which need to be done soon after samples are drawn. So is
          there a good laboratory network within reasonable distance
          from the potential site, or one that is reachable through
          efficient transport, to ensure proper testing and storage of
          samples? Or is it possible to establish these facilities nearby?
    – Are there well maintained facilities and equipment, or is it
         possible to build and buy the necessary equipment? This
         could be one of the benefits of having a trial in a community.
    – Are there facilities or the possibility of establishing facilities
         for long-term document storage and retrieval?
    Research capacity: There must be an adequate number
    of qualified staff available for all trial-related activities, e.g.
    experienced investigators and research staff. Researchers
    must also have access to an REC that operates in
    accordance with GCP.
    Urban and rural trial sites: Researchers might
    need to choose some trial sites in urban areas
    and others in rural areas. This is to ensure
    that various communities and groups have the
    opportunity to take part in the trials and to benefit
    from them through improved healthcare facilities,
    capacity development, and so on. Look at
    Module 5 to see why this is an ethical issue.
    Requirements for different phases of trials: Is
    the given population or community of the area
    suitable for the criteria required (see next page)
    for the particular phase of the intended trials?
    The following are examples of these criteria:
                                                           Are there facilities and equipment that are well maintained?




                                                                                                                 37
                           MODULE 4: HIV VACCINE RESEARCH AND DEVELOPMENT




                              –    Phase I preventative HIV vaccine trials need healthy,
                                   HIV-negative, low-risk participants.
                              –    Currently for South African trials, people need at least 12
                                   years of education to participate in phase I and II
                                   HIV vaccine trials.
KEY WORD
                              –    Phase IIb and III preventative HIV vaccine trials need healthy,
Infrastructure:
This includes facilities
                                   HIV-negative, high-risk participants.
and services such             –    Phase III trials also need a big enough population from
as transport, roads,               which to draw participants. Also a greater infrastructure
laboratories, telephone            is needed in phase III trials to accommodate thousands of
lines, etc.                        participants.
                              –    For larger trials it is also better to have more trial sites to
                                   relieve the burden on the researchers and the communities
                                   of having only one site. It is also important that marginalised
                                   groups are not left out of the trials, i.e. groups who
                                   are usually powerless and do not have a ‘voice’ in the
                                   community, e.g. the poor, the illiterate, and the uneducated.

                           Finally, let’s look at where HIV vaccine trials are happening in
                           the world.

                           7. WHERE ARE HIV VACCINE TRIALS HAPPENING?
                           Take 5 minutes…
                           Look carefully at the world map on page 39.
                              In which countries have phase I trials been happening?
                              In which countries have phase II trials been happening?
                              In which countries have phase IIb trials happening?
                              In which countries have phase III trials been happening?

                           Notice the following on the map:
                             Most of the trials are small phase I studies – the first phase of
                             clinical trials in humans. Phase II trials have also been happening
                             in Peru, USA, Canada, the Dominican Republic, Haiti, Puerto
                             Rico, France, the United Kingdom, Kenya and Australia. Phase
                             IIb trials have also begun in countries like South Africa, Canada
                             and the United States. Finally, only one phase III study has
                             occurred so far – the AIDSVAX trial mentioned earlier in this
                             Module - in Thailand during 2003. Other trial sites are also in the
                             process of being established.

                           Take 5 minutes…
                              Do you know which trials have or are taking place in
                              South Africa?




38
                                                                                                                                                                  Sweden (I)
                                                                                                                                                                                                                                   Russian Federation (I)
                                                                                                                                                       Finland
                                                                                                                                                       (I, II)




     end of page 40.
                                                                                                                                       Germany (I)
                                                                                                                   Canada (II, IIb)
                                                                                                                                          UK (I)
                                                                                                                                      Belguim (I)
                                                                                                                                Switzerland (I)
                                                                                                                                 France (I,II)
                                                                                                                                     Italy (I)
                                                                                                                USA (I, II, IIb)
                                                                                                        Haiti (I, II, IIb)
                                                                                                          Dominican Republic (I, IIb)                                                                                                                   China (I)
                                                                                                                   Puerto Rico (I, II)

                                                                                  Jamaica (I)
                                                                                                                                                                                         India (I)
                                                                                                                                                                                            Uganda (II)      Thailand
                                                                                                                                                                                        Kenya (I)              (I, III)
                                                                                    Peru (I, II, IIb)                                                                                   Rwanda (I)
                                                                                                                                                                                        Tanzania (I)
                                                                                                                                      Brazil (I, II)
                                                                                                                                                                                        Malawi (I)

                                                                                                                                                                           Botswana (I)
                                                                                                                                                                          South Africa (I, II, IIb)       Australia (I, II, IIb)




     This map was compiled from information found on the websites listed at the
                                                                                                                                 Key
                                                                                                                                                                                                                                                                    HIV VACCINES FACILITATOR'S MANUAL




                                                                                                                                      Phase I
                                                                                                                                      Phase II
                                                                                                                                      Phase IIb
                                                                                                                                      Phase III
                                                                                                                                                                 2006/7




39
                              MODULE 4: HIV VACCINE RESEARCH AND DEVELOPMENT




                              At present, the major sponsors of HIV vaccine trials in
                              South Africa are:
                                 SAAVI: South African AIDS Vaccine Initiative
                                 HVTN: HIV Vaccine Trials Network, which is funded and supported
                                 by the US National Institutes of Health (NIH)
                                 IAVI: International AIDS Vaccine Initiative.

                              The following are examples of HIV vaccine trials that have, or are
                              currently taking place in South Africa:
                                 Venezuelan Equine Encephalitis (VEE), phase I – preventative HIV
                                 vaccine trial:
                                 – Collaboration between Alphavax, HVTN and SAAVI.
                                 – Started in United States (US), July 2003 and in South Africa
                                      (SA), November 2003.
                                 – Replicon vaccine design using VEE.
                                 – Subtype C (most common in SA).

                                 Adenovirus (cold virus), phase IIb – preventative HIV vaccine trial:
                                 – Developed by Merck. Known as the Phambili trial.
                                 – Merck, HVTN, SAAVI clinicians involved in sponsoring and/or
                                    testing the vaccine.
                                 – Began in SA, February 2007.
                                 – Vector vaccine design using the adenovirus.
                                 – Subtype B is being tested.

                                 FIT Biotech’s HIV DNA Vaccine, phase II – first therapeutic HIV
                                 vaccine trial in South Africa:
                                 – Collaboration between the Perinatal HIV Research Unit
                                      (PHRU) of the University of Witwatersrand, the National
                                      Institute of Communicable Diseases (NICD), AVIP, FIT Biotech.
                                 – Began with recruitment in SA in February 2006.
                                 – DNA vaccine using a plasmid design.
                                 – Multiple subtype vaccine.

                              To date, most of the trials in South Africa have been preventative HIV
                              vaccine trials.

                              To keep up to date with the latest HIV vaccine clinical trials you may
                              want to visit the following websites:
For more information on          SAAVI: www.saavi.org.za
participating in a clinical      IAVI database of clinical trials: www.iavi.org
trial, please see                IAVI, India website: www.iavi.org.in
Module 7.                        EuroVacc Programme website: www.eurovacc.org
                                 AIDS Clinical Trials Group: aactg.org/clinicaltrials_research.asp
                                 US National Institutes of Health web page on clinical trials:
                                 www.clinicaltrials.gov
                                 HVTN web page on global trial sites: www.hvtn.org/about/sites.html
                                 Pipeline Project: www.chi.ucsf.edu/vaccines
                                 Ending AIDS website: www.endingaids.org


40
                             HIV VACCINES FACILITATOR'S MANUAL




TO SUM UP
  A successful HIV vaccine is a substance that teaches the
  body to recognise and defend itself against the HI virus that
  causes AIDS.
  Most vaccines already in public use, and most HIV vaccines
  currently being tested in clinical trials, are preventative vaccines.
  Preventative HIV vaccines are those that are meant to protect
  people from HIV infection or, if infection occurs, to slow disease
  progression. They are tested in people who are HIV-negative
  where information on how to fight the virus becomes part of
  the person’s immune system memory. This enables the immune
  system to remember how to fight back if the person encounters
  HIV at a later date.
  Researchers are, however, also interested in therapeutic HIV
  vaccines. This type of vaccine is meant to strengthen or boost
  the immune response of those people who are already infected
  with HIV, helping to stop or slow disease progression.
  Researchers would prefer a preventative HIV vaccine that works
  in 100% of those vaccinated. However, there is no vaccine in
  general use today that is 100% effective, so this is unlikely with
  any new vaccine. The next best end-points or outcomes include
  a vaccine where:
  – if a person is infected, then the vaccine will help the immune
     system to clear the infection; or
  – if a person is infected, then the vaccine will keep the virus
     under better control because of the vaccine’s effect on the
     immune response. This could mean that:
     – the vaccine helps to slow down disease progression –
        the time it takes to develop AIDS; and/or
     – the vaccine helps to reduce a person’s level of
        infectiousness by helping to control the level of virus (viral
        load) in the blood. The lower the viral load in a person’s
        blood, the less chance there is of the person infecting
        others with HIV. This means that if we find a successful
        preventative vaccine and we use it to vaccinate a large
        percentage of the population, then all those who are
        vaccinated will be less infectious and will have a smaller
        chance of infecting others with HIV. The number of new
        infections in the wider community or population would
        come down.
  Currently, HIV vaccine designs are not made using the traditional
  vaccine approaches – whole-killed or live-attenuated designs –
  because of the danger that using these designs for HIV vaccines
  might cause HIV infection.
  Current HIV vaccine designs do not include any whole or live
  HIV, and so they cannot cause HIV infection. HIV vaccine
  designs include only a few laboratory-made HIV proteins or


                                                                          41
     MODULE 4: HIV VACCINE RESEARCH AND DEVELOPMENT




        peptides (bits of proteins), or one or more HIV genes to cause an
        immune response. Due to vaccination, these bits of HIV cause
        the immune system to create B and/or T- memory cells that stay
        on guard in a person’s body, and will be triggered causing a
        much quicker immune response (antibodies and/or killer T cells)
        if the person is exposed to HIV in the future. This is aimed to
        prevent HIV infection or to slow disease progression.
        An HIV vaccine follows the same stages of development and
        phases of clinical trials as other new drugs and vaccines.
        There are various parties involved in approving, running
        and quality assuring HIV vaccine clinical trials (see pages 22–35).
        In addition to all the policies, laws and guidelines that apply to
        clinical trials in general, the UNAIDS Ethical considerations in
        preventive HIV vaccine research, and more recently, the MRC
        Guidelines for medical research: HIV preventive vaccine research
        (Book 5) also apply specifically to HIV vaccine clinical trials.
        Funders and researchers look at baseline information as well
        as practical and logistical concerns when identifying a potential
        trial site.
        Different types of HIV vaccine clinical trials are happening around
        the world including South Africa (see map on page 39).

     BIBLIOGRAPHY
     Bass E. IIb or not IIb? AIDS vaccine trial sponsors weigh the merits of
       intermediate-size efficacy trials, IAVI Report; 8(1): 1–5.

     Website addresses
     You will find the UNAIDS Ethical considerations in preventive
       HIV vaccine research at: http://www.unaids.org/en/default.asp
     You will find the MRC Guidelines for medical research: Book 1 and
       Book 5 at: http://www.sahealthinfo.org/ethics/index.htm




42
                             HIV VACCINES FACILITATOR'S MANUAL




Section 2: Activities to help you present                                 NOTE
information on HIV vaccine research and                                   For copies of the HIV
development to others                                                     Vaccines Learner's
                                                                          Handbook or overheads for
                                                                          the Activities, please contact
OVERALL OUTCOMES
                                                                          Masikhulisane who will send
By the end of these activities, workshop participants should be           you an electronic copy of the
able to:                                                                  document. You can use the
1. Explain the difference between a preventative and a therapeutic        document to print the pages
   HIV vaccine, how an HIV vaccine works, what is meant by an             that you need as this may be
   ‘effective’ HIV vaccine, and the different test HIV vaccine designs.   easier and less costly than
2. Explain the four stages in the HIV vaccine research and                photocopying notes from
   development process.                                                   Section 1 of the Manual.
3. Outline the four phases of an HIV vaccine clinical trial.
4. Describe which type of study design is used for HIV vaccine trials
   and why it is used.
5. Discuss what policies, guidelines and laws apply to HIV vaccine
   research and development.
6. Explain which parties are involved in approving, running and
   quality assuring HIV vaccine clinical trials.
7. Explain how HIV vaccine trial sites are chosen.
8. Identify where HIV vaccine clinical trials are happening
   in the world.


    NOTE
    Module 3 gives you and your workshop participants general and background information
    about science and research. Module 4 takes this general knowledge and applies it to
    HIV vaccine research and development. This means that some of the information from
    Module 3 is repeated in Module 4. It is a good educational principle to repeat or
    recycle information, so if you have time to do both modules with the same group
    of participants, then do them. However, if you do not have time, then you will need
    to integrate or combine the information and activities from both modules into one
    workshop.



ACTIVITY 1: WHAT IS A PREVENTATIVE
AND A THERAPEUTIC HIV VACCINE?

OUTCOMES OF THIS ACTIVITY
By the end of this activity, workshop participants should be able to:
   Explain how an HIV vaccine works.
   Explain the difference between a preventative and a therapeutic
   HIV vaccine.
   Explain what is meant by an ‘effective’ HIV vaccine.
   Explain the different HIV vaccine designs.




                                                                                                   43
                           MODULE 4: HIV VACCINE RESEARCH AND DEVELOPMENT




                           MATERIALS NEEDED
REMEMBER!
                              See the checklist of resources needed on page 7 of Module 1.
Check which pages you
could refer participants      Try to ensure that each workshop participant has an HIV
to in the HIV Vaccines        Vaccines Learner’s Handbook to work through.
Learner’s Handbook or         Use overheads on the definition of HIV vaccines, how they work,
photocopy the relevant        what is an effective HIV vaccine and the different HIV vaccine
pages from Section 1          designs.
of this module for
each activity.             TIME: 30–40 minutes


                           PREPARATION
                              Read through Section 1, pages 2–10 of this module and make
                              your own notes.
                              Make photocopies of any handouts needed (see process notes).

                           PROCESS
                           1. Have a general discussion to draw out what workshop
                              participants already know about HIV vaccines and to prepare
                              participants for the input that follows. You can ask questions like:
                              What is a vaccine and how does it work? How do you think an
                              HIV vaccine works? What are some of your concerns about test
                              HIV vaccines? What do you think the difference is between a
                              preventative HIV vaccine and a therapeutic HIV vaccine?
                           2. Then give input from pages 2–10 of Section 1. Explain what a test
                              HIV vaccine is, how it works and how it is designed. Emphasise
                              that current HIV vaccine designs generally use laboratory-made
                              materials, for example, a few laboratory-made (artificial) proteins,
                              peptides, or genes from HIV. There is no whole HIV or live HIV
                              used in these designs, and so there is no chance that anyone will
                              get infected with HIV from having the vaccine.
                           3. Some participants may confuse antiretrovirals and HIV vaccines.
                              So explain the difference between ARVs, preventative HIV
                              vaccines and therapeutic HIV vaccines. Use information from
                              Module 2 to explain ARVs.
                           4. Ask what a preventative HIV vaccine should do to be considered
                              effective, e.g. should it prevent infection in everyone who receives
                              it, or shoud we still use it if it only works in 50% of the people?
                              Or, if it doesn’t prevent HIV infection but slows down the time it
                              takes to get AIDS, should it be considered successful? Give input
                              from pages 2–4 of this module on what scientists are hoping
                              preventative and therapeutic HIV vaccines will achieve. Stress
                              that an HIV vaccine which is tested as a preventative vaccine
                              may turn out to be of therapeutic use instead if it is shown to
                              delay disease progression in those who become HIV infected.
                           5. Ask: If a successful preventative HIV vaccine is found, but it
                              does not prevent infection in everyone who receives it, then in
                              addition to having the vaccine, what other things can people


44
                             HIV VACCINES FACILITATOR'S MANUAL




   do to prevent themselves from becoming infected? Encourage
   people to discuss the need to continue safer sex even if they
   are vaccinated as it is unlikely that researchers will find an HIV                    Stage 1:
   vaccine that is completely protective. Explain that we need to                        Discovery
   use many different approaches to prevent HIV infection and to
   control the AIDS epidemic. Refer to Module 2, page 26 for the list
   of approaches used to prevent HIV infection and to page 35–36                         Stage 2:
                                                                                         Exploration
   for information on how to try to keep healthy to slow disease
   progression to AIDS.
6. Sum up and refer participants to the HIV Vaccines Learner’s
   Handbook or give them copies of pages 2–10 of Section 1 for
   information covered in this activity.

ACTIVITY 2: WHAT HAPPENS IN EACH STAGE OF HIV
VACCINE RESEARCH AND DEVELOPMENT?

OUTCOME OF THIS ACTIVITY
By the end of this activity, workshop participants should be able to:   Stage 3: Clinical trials in
   Explain the four stages in the HIV vaccine research and              humans
   development process.

MATERIALS NEEDED
   See the checklist of resources needed on page 7 of Module 1.
   Try to ensure that each workshop participant has an HIV
                                                                        Stage 4: Licensure
   Vaccines Learner’s Handbook to work through.
   Use overheads on the stages of HIV vaccine research
   and development.

TIME: 15 minutes
                                                                        Phase IV: Performance on a
PREPARATION                                                             large scale.
   Read through Section 1, pages 10–12 and 18–19, and make
   your own notes.
   Make photocopies of any handouts needed (see process notes).

PROCESS
1. Ask participants what they remember from Module 3 about the
   four stages in the research and development of a new drug or
   vaccine.
2. Write up their feedback on flipchart paper. You can also use the
   relevant overheads from Module 3 to remind participants about
   the four stages.
3. Add to this information with input from pages 10–12 and
   pages 18–19 (remember that we are focusing only on the
   stages here and not on the four phases of clinical trials). Focus
   specifically on how each stage relates to HIV vaccine research
   and development.

                                                                                                  45
     MODULE 4: HIV VACCINE RESEARCH AND DEVELOPMENT




     Another way to do this activity
     1. Divide participants into groups of four and give each group notes
        on the four stages in HIV vaccine research and development. Give
        one stage to each group to present on after 20 minutes.
     2. They must present their information back to the whole group.
     3. Summarise and add to their input where necessary.
     4. Refer participants to the HIV Vaccines Learner’s Handbook
        or give them copies of pages 10–12 and 18–19 of Section 1 for
        information covered in this activity.

     ACTIVITY 3: WHAT HAPPENS IN EACH PHASE
     OF AN HIV VACCINE CLINICAL TRIAL?

     OUTCOMES OF THIS ACTIVITY
     By the end of this activity, workshop participants should be able to:
        Outline the four phases of an HIV vaccine clinical trial, including
        the aims of each phase, the number and criteria for trial
        participants in each phase, and the length of each phase.
        Explain briefly the reasons for a phase IIb trial, and the similarities
        and differences to a phase III trial.

     MATERIALS NEEDED
        See the checklist of resources needed on page 7 of Module 1.
        Try to ensure that each workshop participant has an HIV
        Vaccines Learner’s Handbook to work through.
        Use the overheads on the phases of an HIV vaccine trial.

     TIME: 90 minutes


     PREPARATION
        Read Section 1, pages 11–20 and make your own notes.
        Make photocopies of any handouts needed (see process notes).

     PROCESS
     1. Work in four groups. Give each group a different phase of HIV
        vaccine clinical trials to work on. Give them a photocopy of
        the pages on their phase from Section 1 or refer them to the
        Learner's Handbook. Also give the group working on phase II
        trials information on phase IIb trials. If they did the activity, remind
        participants to look at the posters or pamphlets they made when
        they covered the four phases in clinical trials in Module 3 (Activity 4).
     2. Ask each group to prepare a 5–10 minute presentation on their
        phase for the other groups. However, get each group to do their
        presentation in an interesting and dynamic way, e.g. it could be a
        radio interview for a community radio station; or a role-play




46
                             HIV VACCINES FACILITATOR'S MANUAL




   in which a researcher explains the points to a potential trial
                                                                         Refer to Module 1
   community; or they could prepare a diagram with the different         for information on
   points and speak to this in their presentation. They must cover       using flipcharts.
   the key points.
3. Sum up by going through the relevant overheads. Remember
   to point out the differences in the aims and criteria between
   therapeutic and preventative HIV vaccine trials.
4. Refer participants to the HIV Vaccines Learner’s Handbook
   or give them copies of the handouts used in this activity.

ACTIVITY 4: WHAT TYPE OF RESEARCH DESIGN
IS USED FOR HIV VACCINE TRIALS?

OUTCOME OF THIS ACTIVITY                                                 Read through Activity 2
By the end of this activity, workshop participants should be able to:    in Module 3. If relevant,
   Describe which type of research design is generally used for          combine parts of
                                                                         the two activities,
   HIV vaccine trials, namely a randomised, double-blind, placebo-
                                                                         focussing especially on
   controlled trial design, and why it is used.
                                                                         randomised, placebo-
                                                                         controlled, double-blind
MATERIALS NEEDED                                                         studies.
   See the checklist of resources needed on page 7 of Module 1.
   Try to ensure that each workshop participant has an HIV
   Vaccines Learner’s Handbook to work through.
   Copies of the case study on pages 48– 49.
   Use the overheads from Modules 3 and 4 on clinical research
   designs, and on types of research designs used for HIV vaccine
   clinical trials.

TIME: 25 minutes


PREPARATION
   Read through pages 20 –21 of Section 1 and make your
   own notes. Also refer to your notes from Activities 1 and 3.
   Make photocopies of any handouts needed (see process notes).

PROCESS
1. Use your overheads to explain that the HIV vaccine trials generally
   make use of randomised, double-blind, placebo-controlled trials.
2. Read through the case study that follows with participants.
   Explain any new words and terms. Hand out copies of the case
   study or refer participants to the Learner's Handbook.
3. Ask workshop participants to work in pairs. They should read
   the case study again and then prepare a role-play to explain the
   study (see the instructions on page 49).




                                                                                               47
                                      MODULE 4: HIV VACCINE RESEARCH AND DEVELOPMENT




Refer to Module 1                     4. Give participants some time to prepare the role-play and then
for more information                     give each pair 10 minutes to present different points in their role-
on role-plays.                           play, i.e. do not repeat the same explanations unless the pairs
                                         have given the wrong information.
                                      5. Record important points on the flipchart.
You may want to look
at the steps involved in
                                      6. Sum up and add any information you think is important.
participating in a clinical           7. Refer participants to the HIV Vaccines Learner’s Handbook
trial in Module 7. This                  or give them copies of pages 20–21 of Section 1 for more
case study may also be                   information covered in this activity.
useful to refer to when
doing Activity 10 in                  FOR PAIRED WORK
Module 7.                             Read the case study. Then read the activity that follows.


              CASE STUDY: A PHASE I, SAFETY AND IMMUNOGENICITY TRIAL OF
              A REPLICON HIV-1 SUBTYPE C VACCINE IN HEALTHY HIV-1 UNINFECTED
              ADULT PARTICIPANTS

              Purpose of the study: To assess the safety of a test HIV vaccine called a replicon,
              HIV-1 subtype C vaccine. To assess how the immune system responds to the vaccine.

              Expected total enrollment (number of trial participants required): 96
              Study start date: October 2004
              Last follow-up: June 2006

              About the study
              HIV-1 subtype C is the most common subtype of HIV in sub-Saharan Africa and especially
              in southern Africa. So it is very important to develop a preventative subtype C vaccine
              to control the spread of HIV in this part of the world.

              In this study we will look at the safety and immunogenicity of a HIV-1 subtype C vaccine
              that comes from an attenuated virus called Venezuelan Equine Encephalitis (VEE).

              About the trial participants
              Who can become a trial participant?
              They should be (inclusion criteria):
              • HIV-negative people;
              • who are 18–50 years;
              • either male or female;
              • at low risk for HIV infection;
              • willing to receive HIV test results;
              • in good general health;
              • using contraception;
              • Hepatitis B negative; anti-hepititis C (anti-HCV) negative or negative HCV PCR
                if anti-HCV is positive; and
              • at the correct educational level for the study.

              They should not (exclusion criteria):
              • have been in a previous HIV vaccine or placebo trial;
              • have been using medication that suppresses the immune system, or be on blood
                products, or using immunoglobulin, or have had a live-attenuated vaccine in the last

48
                                HIV VACCINES FACILITATOR'S MANUAL




      30 days, or be using other investigational research agents, or have had a subunit or
      killed vaccine in the last 14 days, or be on allergy treatment with antigen injections,
      or be on TB preventative medication or treatment;
    • have suffered from any serious adverse reactions to a vaccine;
    • have any specific diseases, such as autoimmune disease, active syphilis, asthma,
      diabetes, thyroid disease, angioedema, hypertension, bleeding disorder, cancer, seizures,
      mental illness; and
    • be pregnant or breastfeeding.

    Where from? Trial participants will be recruited from the United States, South Africa
    and Botswana.

    What will happen?
    There will be four different groups of participants. They will be randomly put into either
    the intervention or the control group. The intervention group will receive the vaccine
    while the control group will receive a placebo.

    Participants will first have a full medical history assessment, a complete physical
    examination, HIV testing and counselling and will have blood and urine taken. They will
    be interviewed and asked to complete a questionnaire.

    After this, there will be eight visits – at each visit participants will fill out a questionnaire,
    they will have a physical examination and more HIV testing and counselling, and more
    blood and urine will be taken.

    (adapted from: Clinical Trial: Safety of and Immune Response to an HIV-1 Subtype C Vaccine,
    http://clinicaltrials.gov/ct/action/GetStudy




Work in pairs. Prepare a role-play. One person is recruiting trial
participants for the above study and the other is a community
member. In the role-play, the community member must ask
questions and the person recruiting must explain what the
following means:
    the four different phases in an HIV vaccine clinical trial, and
    which phase you are recruiting trial participants for in this study;
    what the purpose of the study is;
    what HIV subtype is being targeted and why;
    in which countries the study will take place;
    how many people will be involved;
    what a preventative HIV vaccine aims to do;
    what is meant by safety and what is meant by immunogenicity;
    what is a replicon, a vector and an attenuated virus design (refer
    to the notes on HIV Vaccine designs);
    who can and who cannot become a trial participant;
    what a randomised, double-blind, study means;
    what a placebo is; and
    what will happen in the study.

                                                                                                         49
                           MODULE 4: HIV VACCINE RESEARCH AND DEVELOPMENT




                           ACTIVITY 5: WHAT ARE THE POLICIES, GUIDELINES
If you have limited
time, then combine this
                           AND LAWS THAT APPLY TO HIV VACCINE RESEARCH?
activity with Activity 5   OUTCOME OF THIS ACTIVITY
in Module 3.
                           By the end of this activity, workshop participants should be able to:
                              Name the ethical, legal and clinical guidelines that apply to HIV
                              vaccine research and development.

                           MATERIALS NEEDED
                              See the checklist of resources needed on page 7 of Module 1.
                              Try to ensure that each workshop participant has an HIV
                              Vaccines Learner’s Handbook to work through.
                              Use overheads on the policies, guidelines and laws that apply to
                              HIV vaccine clinical research.

                           TIME: 40 minutes


                           PREPARATION
                              Read through Section 1, page 21 and make your own notes.
                              Make photocopies of any handouts needed (see process notes).

                           PROCESS
                           1. Recap relevant information from Module 3. What is a research
                              protocol? What kind of information do you get in a research
                              protocol and why is it important to have one?
                           2. Then ask the group to quickly name the policies and guidelines
                              that apply to clinical trials in general, (see Module 3). Together,
                              quickly write up the names of the ethical, legal and clinical
                              policies and guidelines discussed in Module 3 or use the relevant
                              overheads.
                           3. Explain that these policies and guidelines also apply to HIV
                              vaccine research including clinical trials, but that there are
                              additional guidelines that apply specifically to preventative HIV
                              vaccine research.
                           4. Tell participants that although therapeutic HIV vaccine trials
                              are different, many of the same principles that are addressed
                              in ethical guidelines for preventative HIV vaccine trials, will also
                              apply. An example would be the need for informed consent.
                           5. Sum up and refer participants to the HIV Vaccines Learner’s
                              Handbook or give them copies of page 21 of Section 1 for
                              information covered in this activity.




50
                             HIV VACCINES FACILITATOR'S MANUAL




ACTIVITY 6: WHICH PARTIES ARE INVOLVED IN
APPROVING, RUNNING AND QUALITY ASSURANCE OF
HIV VACCINE CLINICAL TRIALS?

OUTCOME OF THIS ACTIVITY
By the end of this activity, workshop participants should be able to:
   Name and explain the role of the parties involved in approving,
   monitoring and quality assuring HIV vaccine clinical trials.

MATERIALS NEEDED
   See the checklist of resources needed on page 7 of Module 1.
   Try to ensure that each workshop participant has an HIV
   Vaccines Learner’s Handbook to work through.
   Photocopy and enlarge the diagrams of the parties involved in
   each of the three processes of clinical trials - the parties involved
   in approving the trials, the parties involved in running the trials
   and the parties involved in quality assurance of the clinical trials
   – see pages 59 to 62.
   Photocopies of the Exercises for Group 1, Group 2 and Group 3.
   Use overheads on the parties involved in approving, running and
   quality assurace of HIV vaccine clinical trials and their roles.

TIME: 30 minutes

PREPARATION
   Read through Section 1, pages 22–35 and make your
   own notes.
   Make photocopies of any other handouts (see process notes).
   e.g. the diagrams on pages 59 to 62, and of the Exercises and
   answers to the Exercises on pages 52 to 55.

PROCESS
1. Use the overheads and your notes to explain information
   about the different parties involved in approving, running and
   quality assuring clinical trials. Go through each party, explaining
   their role in each process. As you do this, use overheads of the
   diagrams on pages 59 –62 to summarise and clarify information.
2. Ask participants to work in three groups:
   Group 1 will look at the parties involved in approving HIV vaccine
   clinical trials.
   Group 2 will look at the parties involved in running HIV vaccine
   clinical trials.
   Group 3 will look at the parties involved in quality assuring HIV
   vaccine clinical trials.
3. Give each group one of the diagrams on pages 59 –62, and the
   matching Exercise from pages 53 –55.




                                                                           51
     MODULE 4: HIV VACCINE RESEARCH AND DEVELOPMENT




     4. Ask each group to do their Exercise. Ask them to match up the
        name of the party with the description of their role. They can do
        this by drawing a line between the name of the party and the
        correct description for that party. Or they can match the letter,
        e.g. a., to the relevant number of the description that they have
        chosen. For the answers to each Exercise, please see below.
     5. Once groups have finished, check the answers together. Now
         ask the groups to prepare a presentation in which they will
         explain to the plenary, the name of each party and the role that
         that party plays in the process, e.g. approval of clinical trials, that
         they covered in their Exercise. Give them copies of the enlarged
         diagrams to demonstrate as they explain. Group 1 should
         present first, and Group 3 should present last.
     6. Once the groups have presented, sum up and fill in any gaps
         in the information. Refer workshop participants to the relevant
         pages in the HIV Vaccine Learner’s Handbook or give them
         copies of the diagrams on pages 59–62, and copies of all the
         tables in Exercises 1-3 plus the answers below.

     Answers for Exercises
     Exercise for Group 1
     1. and c.
     2. and d.
     3. and b.
     4. and a.

     Exercise for Group 2
     1. and d.
     2. and c.
     3. and e.
     4. and b.
     5. and a.
     6. and j.
     7. and l.
     8. and g.
     9. and h.
     10. and k.
     11. and i.
     12. and f.

     Exercise for Group 3
     1. and c.
     2. and a.
     3. and f.
     4. and b.
     5. and d.
     6. and h.
     7. and e.
     8. and g.

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                                 HIV VACCINES FACILITATOR'S MANUAL




Exercise for Group 1
In the table below the parties and their roles are jumbled up. Match
the role with the correct party responsible for carrying out approval
of clinical trials. Draw a line between the role and the correct party;
or match the number to the letter.


               Role in approving HIV vaccine trials                               Name of party

 1. Takes responsibility for initiating, managing and/or financing       a. The Council for Genetically
    the clinical trial. Submits the trial protocol to the correct           Modified Organisms
    parties for approval.
 2. They review the protocols to ensure that the research is             b. Research Ethics Committee
    scientifically sound. They must give approval for the clinical          (REC)
    trial to proceed.
 3. They review the protocols to ensure that the research is ethical
                                                                         c. The Sponsor
    and that the rights, safety and well-being of trial participants
    are protected. They must give ethical approval for the trial to
    proceed.
 4. This party approves or rejects the testing, in clinical trials, of
                                                                         d. The Regulatory Authority/ies
    HIV vaccine designs that include genetically modified parts.
                                                                            (e.g. the MCC)
    It ensures responsible development, production, and use of
    GMOs in South Africa.




                                                                                                           53
                                      MODULE 4: HIV VACCINE RESEARCH AND DEVELOPMENT




                                      Exercise for Group 2
                                      In the table below the parties and their roles are jumbled up. Match
                                      the role with the correct party responsible for running the clinical
                                      trials. Draw a line between the role and the correct party; or
                                      match the letter to the number.


                      Role in running the clinical trials                                Name of party

     1.   Together with the PI, this person takes responsibility for           a. The Sponsor
          carrying out the trial and addressing any problems during the
          trial. He or she ensures that the trial site functions efficiently
          and co-ordinates the day-to-day running of the trial.
     2.   Responsible for communication between the trial site and             b. Counsellors
          the community; actively recruit trial participants. Work closely
          with the CAG.
     3.   Represent the community interests and concerns and form
          an ongoing communication and advisory link between the               c. Community outreach
          researchers and the community. Participate in all                       personnel
          decision-making to do with the trial that affects the
          community.
     4.   Do pre- and post-test counselling, risk-reduction and
          pregnancy reduction counselling. Assist with gathering               d. The trial site director or study
          personal information and giving counselling. Help with                  co-ordinator
          informed consent sessions.
     5.   Appoints suitably qualified staff to design the protocol, to         e. Community Advisory Group
          supervise the trial, to manage and analyse data, and to write
          trial reports.
     6.   Keeps records of product inventory. Gives out or dispenses           f. Routine and research
          the product and explains how to administer or take it.                  laboratories
     7.   Deals directly with trial participants in all examinations and       g. Medical officer
          follow-ups. Takes blood. Completes Case Report Forms and
          may counsel trial participants.
     8.   Qualified doctor who performs medical check ups; makes
          clinical decisions; evaluates laboratory results; and reports        h. The PI
          any Serious Adverse Events and follows them up.
     9.   This person is appointed by the Sponsor and takes sole
                                                                               i. Laboratory technician
          or joint responsibility for designing, carrying out, analysing
          and reporting on the clinical trial. He or she ensures that
          approval is given by the regulatory authority and the REC/s
          before beginning the trial, and that all the staff, facilities and
          equipment are in place.
     10. Processes Case Report Forms and data. Creates a                       j. Pharmacist
         database to help with quality control.
     11. May test and analyse blood and other samples. Prepares                k. Data manager
         samples for transfer to other laboratories.
     12. Tests and analyses blood and other samples that the site is           l. Trial nurses
         not equipped to do themselves.
54
                                  HIV VACCINES FACILITATOR'S MANUAL




Exercise for Group 3
In the table below the parties and their roles are jumbled up. Match
the role with the correct party responsible for quality assurance in
clinical trials. Draw a line between the role and the correct party;
or match the letter to the number.


            Role in quality assurance of clinical trials                            Name of party

 1. Is an important ongoing communication link between                    a. The Auditor
    researchers and the community. Are a mechanism to ensure
    that any human rights issues and other personal concerns
    raised by the community are addressed.
 2. Appointed by the Sponsor. Does an in-depth examination of
    the trial to see that it meets the terms of the protocol, GCP,        b. RECs
    GLP and GPP and all regulatory requirements.
 3. Reviews data at various points during the trial to
    assess progress.                                                      c. Community Advisory Groups

 4. Ongoing review and monitoring of the trial from an ethics
    and human rights viewpoint.                                           d. The Sponsor

 5. Implements and maintains quality assurance and quality
    control systems. This includes appointing a Monitor,                  e. The PI
    sometimes an Independent Data Monitoring Committee
    (IDMC), and sometimes the Auditor.
 6. Appointed by the Sponsor. Mainly oversees and reports on
    the progress of a trial. Visits the trial sites regularly to ensure   f. Independent Data Monitoring
    that the trial is carried out and reported in accordance with            Committee (IDMC)
    the protocol, SOPs and appropriate legislation. Informs the
    Sponsor and trial management of any problems at the trial
    sites or laboratories.
 7. Should allow monitoring, auditing and inspection by the
    regulatory authority of the trial. Verifies with the Monitor          g. Medicines regulatory authority
    that the trial site complies with the protocol and the
    Sponsor's SOPs.
 8. Can do on-site inspections at any time. Compares the                  h. The Monitor
    practices of the trial site with those in the protocol and in
    reports sent to the MCC.




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     MODULE 4: HIV VACCINE RESEARCH AND DEVELOPMENT




     ACTIVITY 7: HOW ARE TRIAL SITES CHOSEN?
     OUTCOMES OF THIS ACTIVITY
     By the end of this activity, workshop participants should be able to:
        Describe the baseline information as well as the practical and
        logistical factors in choosing an HIV vaccine trial site.
        Imagine what it is like to be a researcher in an HIV vaccine trial.

     MATERIALS NEEDED
        See the checklist of resources needed on page 7 of Module 1.
        Try to ensure that each workshop participant has an HIV
        Vaccines Learner’s Handbook to work through.
        Bring pictures or posters of different natural environments,
        e.g. rocky mountains, flat grassland areas, a desert, a river and
        its banks.
        Use overheads on how trial sites are chosen.

     TIME: 60 minutes


     PREPARATION
        Read through Section 1, pages 36–38 of this module and make
        your own notes.
        Try to ensure that each participant has an HIV Vaccines
        Learner’s Handbook to work through.
        Make photocopies of any handouts needed (see process notes).

     PROCESS
     1. Show participants the pictures of different natural environments.
        Ask: In which area would you prefer to build your house? Why?
     2. Use their answer to lead into a discussion about the practical,
        logistical factors in choosing a trial site as well as other baseline
        factors. Or ask participants to imagine that they are a group of
        researchers who want to do a preventative HIV vaccine trial
        in South Africa. Ask them how they would go about choosing
        a trial site and what factors they would consider.
     3. Give input from pages 36–38 of Section 1 once they have finished
        with the feedback, filling in any gaps or misunderstandings using
        your overheads. Emphasise that ideally researchers should
        consult with the community and with relevant stakeholders, e.g.
        government officials and community leaders, when they get
        baseline information about the potential community. Explain that
        you will cover this in the module on Community Involvement.
     4. Sum up and refer participants to the HIV Vaccines Learner’s
        Handbook, or give them copies of pages 36–38 of Section 1,
        for information covered in this activity.




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                             HIV VACCINES FACILITATOR'S MANUAL




ACTIVITY 8: WHERE ARE HIV VACCINE CLINICAL
TRIALS HAPPENING?

OUTCOME OF THIS ACTIVITY
By the end of this activity, workshop participants should be able to:
   Explain where HIV vaccine clinical trials are happening in
   the world.

MATERIALS NEEDED
   See the checklist of resources needed on page 7 of Module 1.
   Try to ensure that each workshop participant has an HIV
   Vaccines Learner’s Handbook to work through.
   Make copies of the map on page 39 of Section 1, showing
   where HIV vaccine clinical trials are happening around the world.
   Use overheads on where clinical trials are happening in the
   world.

TIME: 30 minutes


PREPARATION
   Read through Section 1, pages 38–40 and make your
   own notes.
   Prepare copies of the map as handouts or one large copy
   for everyone to see. You can also use your overhead.
   Make photocopies of any handouts needed (see process notes).

PROCESS
1. Ask participants to look at the map carefully.
2. Have a quiz. Divide the group into two teams. Explain that each
   team will be asked a question. If they answer it correctly, they
   get two points. If it is incorrect then the second team has a
   chance to answer the question and score the two points. Ask
   questions like:
        Are trials taking place in one country or are they spread
        across the world?
        Which countries are involved?
        Are the trials mostly in developing or in developed
        countries?
        Which phase of clinical trials is most common?
        In which countries are phase I trials happening?
        In which countries are phase II trials happening?
        In which countries are phase IIb trials happening?
        In which countries are phase III trials happening?
        If these trials are successful, what phase of trials do you
        think will be happening in the majority in five years time?
   You can also ask each team to set their own five questions
   to ask the other team.

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     MODULE 4: HIV VACCINE RESEARCH AND DEVELOPMENT




     3. You may want to end the activity with a short presentation
        on the latest news on clinical trials taking place in South Africa.
     4. Refer participants to the HIV Vaccines Learner’s Handbook
        or give them copies of pages 38–40 of Section 1, for information
        covered in this activity.


      SUM UP
      Ask workshop participants:
      1. How does an HIV vaccine work and what is the difference
          between a preventative and a therapeutic HIV vaccine?
      2. What is meant by an effective HIV vaccine?
      3. What HIV vaccine designs are there, and generally how do
          they work?
      4. Can an HIV vaccine cause you to become infected with HIV?
      5. What are the four stages in the HIV vaccine research and
          development process?
      6. What are the four phases of HIV vaccine clinical trials?
      7. Which type of research is used for HIV vaccine trials? Why?
      8. What are some policies, guidelines and laws that apply to
          HIV vaccine research and development?
      9. Who are the different parties and what are they responsible
          for in approving HIV vaccine clinical trials?
      10. Who are the parties and what are they responsible for in
          running HIV vaccine clinical trials?
      11. Who are the parties and what are they responsible for in
          quality assuring HIV vaccine clinical trials?
      12. What do researchers look at when choosing an HIV vaccine
          trial site?
      13. Currently, which phase of trials is most common in the
          world?

      Use all the overheads to sum up the whole workshop, as well
      as the points under To sum up, on pages 41–42 of Section
      1. If you do not have copies of the HIV Vaccines Learner's
      Handbook, you can give copies of pages 41–42 to the
      workshop participants.




58
                                                                                     59
HIV VACCINES FACILITATOR'S MANUAL




                                    Parties involved in approving clinical trials.
                                                    MODULE 4: HIV VACCINE RESEARCH AND DEVELOPMENT




     Parties involved in running clinical trials.




60
                                                                             61
HIV VACCINES FACILITATOR'S MANUAL




                                    Parties involved in quality assurance.
MODULE 4: HIV VACCINE RESEARCH AND DEVELOPMENT




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                                                                              Summary of parties involved in clinical trials.




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