IAVI Report - March / April 2002

Julie Milstien is Coordinator of the Access to Technologies Team, Department of Vaccines and Biologicals at the World Health Organization (WHO) in Geneva. The team's mission is to remove barriers to making vaccines and immunization-related technologies widely accessible. Before joining WHO in 1988, she spent 14 years at the US Food and Drug Administration. Milstien has a PhD in Biochemistry from the University of Southern California and did postdoctoral work at the National Institutes of Health. Here she and IAVI Report editor Patricia Kahn discuss some of the regulatory issues that will arise in making an AIDS vaccine available worldwide.

How do vaccines developed in the USA or Europe get approved for use in developing countries that don't have domestic agencies to license them?
This can work by different mechanisms. Some vaccines—especially older ones like DTP [diptheria, tetanus and pertussis] or BCG, to some extent polio; oral polio—are also manufactured in certain developing countries, so they are eventually licensed there by national regulatory authorities. But those regulators don't really look at efficacy data based on their country's own epidemiological situation. Up to now they've just taken or adapted guidelines based on clinical data from the US or Europe.

For vaccines that reach developing countries through UN agencies—UNICEF, for instance, or the PAHO revolving fund—WHO is responsible for advising these agencies on which ones are acceptable to purchase. That involves an evaluation of the vaccine. But again, we find that for the most part, this evaluation is based on experience in the manufacturing country, not the countries importing the vaccine.

With some newer vaccines for example Hib, [Haemophilus influenzae type B] we're trying to ensure that the evaluating committees see clinical trials data reflecting local conditions—the immunization schedule that will be used locally; what other vaccines will be given at the same time; the local epidemic situation.

What kinds of regulatory obstacles or gaps could come into play with an AIDS vaccine?
I can't answer that question in general. It depends a lot on the circumstances. Without specific examples, it's difficult to ensure we've got all the gaps covered.

Here's one dilemma we have now: If an industrialized country makes a vaccine that will be used only in the developing world, how do you get it licensed?

The US and European agencies, the FDA and the EMEA, are responsible only for vaccines used in their domestic markets. Their mandate actually forbids them from giving marketing authorization to any vaccine that will not be marketed at home. So it's not for them to look into what happens with a vaccine used in African countries, for example.

Are there examples of vaccines that are now caught in this situation?
Not yet, although there is a potential example: vaccines based on a DTP [with whole cell pertussis] combination. These are manufactured in Europe but used only in one or two European countries. This is what keeps them licensed in Europe—although at the time they were licensed, nobody in Europe was planning to use them.

So how could they get licensed?
The EMEA decided to license them, since there was a possibility they might be used in Europe and because WHO thought this was really important. Just recently, EMEA renewed the license, because the vaccine is being used in Spain. But if Spain were to switch to acellular pertussis vaccine, then we would need another mechanism.

This is the real gap that could arise with a vaccine against AIDS or malaria.

What's being done to address this gap?
It's multi-pronged. First, WHO is working with the EMEA specifically to see if they will agree to consider giving, not a marketing authorization, but as near as they can come to one, to products that won't be sold in Europe. They recently agreed to this, and to assure ongoing regulatory oversight. Actually, when things go through the EMEA centrally, it's the country of manufacture that guarantees ongoing oversight.

This is a major step forward—it means that we have a solution for products made in Europe, provided that it holds up. We don't have it in writing yet.

For vaccines made in the US, the FDA says there really is no way they could do this. So we're looking at two alternatives. One is to better understand what are called the ‘Export Provisions'—the rules under which the Secretary of Health allows unlicensed vaccines to be exported. That can be done if someone else takes responsibility for demonstrating the product's safety and efficacy. So vaccines can be exported in this way to, I believe, 26 countries, including those in the EU and the European Economic Space, as well as Canada, Japan, Israel, South Africa and Australia.

What about countries without the capacity to evaluate vaccines?
There would have to be a demonstration that the country had some mechanism in place for looking at whether the vaccine is safe and effective. If not, we would need some other way to show this, and I don't know how that would work under the Export Provisions. We're still trying to pin down just when the Export Provisions would apply, and to understand all their in's and out's, and what kind of precedents have been set.

What would happen, then, if the first AIDS vaccine shown to work is based on a common East African subtype—so it probably wouldn't be licensed in industrialized countries—but the country that hosted the trial has no regulatory agency to license it?
Let's assume that most of these developing market vaccines would be bought by UNICEF or some other UN procurement agency. In that case, WHO has a responsibility to find a regulatory authority (RA), because our whole system of advising UNICEF depends on regulatory oversight. So we would find a way, somehow.

If it couldn't be licensed through the US, which it probably couldn't, then we would look at three other possibilities.

One is to export to another RA under the Export Provisions--for example South Africa, which has a full RA. But I don't mean to point to South Africa—we haven't discussed this with them or looked into it yet.

The second possibility is to look into licensing the vaccine as an orphan product. If there were a traveler's market in the US, or some kind of market—even a very small one—then it could be licensed in the US [and exported through WHO]. We haven't investigated this yet, but it's another possibility.

Another possibility is to work with manufacturers up front, looking carefully at how to plot the regulatory pathway for any promising vaccine down the line. The idea would be to make sure they have a partnership in a competent developing country that would do the filling, or finishing, or some other part of the manufacture, and then try to get the vaccine licensed there.

In all these cases, it's also essential to make sure that the licensing process includes expert input from the countries wanting to use the vaccine.

Are there efforts underway to build regulatory capacity in countries that lack licensing authorities?
WHO is very involved in strengthening National Regulatory Authorities (NRAs), through a relatively new system of assessments, based on indicators for evaluating

 how well an RA is functioning (see box). These, in turn, are based on the workings of WHO's Expert Committee on Biological Standardization plus inputs from 38 countries. The process includes a first assessment, followed by technical supports and training according to a plan that addresses the gaps, and then continued monitoring.

Between 1998 and April 2002 we've used this in 43 countries, and another 40-something assessments or follow-up are proposed for the next two years. The system has really been accepted by all the countries that have either supplied experts or been assessed.

Our first priority has been to assess countries that manufacture vaccines, because they're the ones with ultimate responsibility for products being exported, as well as used at home. Of the 48 countries that manufacture vaccines, 30 have been found through this process to have fully functioning NRAs—for example, Brazil, Korea, Indonesia, South Africa, Russia, India.

Then there's another group of 8 or 10 countries that are fairly close to being fully functional, who we think will be there within the next couple of years.

A lot of these assessments have been done as part of WHO's role in advising UNICEF on whether a vaccine is appropriate for purchase, since this decision requires an NRA assessment. And these vaccines are reassessed every two years, which includes seeing if anything has changed in the NRA.

What about having regional RA's?
We are trying to develop regional advisory committees, and regional expertise in areas like disease burden and demonstration of safety and efficacy, that would inform the regulatory decisions in individual countries. So if you had a vaccine to be used in Kenya, for example, and the RA of Kenya is not ready to go through the whole process, they could rely on the advice of another RA and be sure—because of the expertise on the advisory committee—that it had considered the needs of Kenya and its neighboring countries.

We may have a case soon: the conjugate meningitis-A vaccines being developed for Africa. We'll probably have to use one of these regulatory pathways.

How can people in developing countries acquire this expertise?
I'm so glad you asked that! We have something called the Global Training Network on Vaccine Quality (www.who.int/vaccinesaccess/vaccines/Vaccine_Quality/gtn/gtn.htm). Right now it has 13 centers around the world, and they provide training in activities relating to regulatory oversight. It's a little different than the usual WHO training, because it requires an institutional development plan based on an RA, which will then build on this assessment process. The needs it identifies are then discussed with the country, along with what possible training or technical inputs might be implemented.

What topics does your training cover?
We have curricula in GMP, licensing, lot release, lab quality systems, different lab testing methods, and monitoring and dealing with adverse events. Later this year we will add a new one on clinical evaluation.

Is there anything vaccine developers can do early on to minimize regulatory delays or complications later?
My recommendation is to map out a regulatory strategy up front. Once you know who will make the vaccine and what its basic characteristics will be, then you think through how it can be licensed. Because this will impact where your clinical trials are held, how you want them set up, where your IRB is going to be—all these kinds of things. •

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