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MI Conference Series
No. 10 June 10, 2004


The Campaign to Fight AIDS: Ensuring Access to the Best Medicines

How to Make Quality Drugs Available

DR. ROBERT GOLDBERG: Thanks to enormous private-sector investment in health care, we are on the verge of great public health breakthroughs that will extend the promise of healthier, longer, and better lives not just for rich nations but for each and every individual on this planet. But the quest for health improvements on a global scale requires us to look beyond ideological partisanship and face the most compelling public health challenges and opportunities before us with faith, ingenuity, and honesty. Surely, one of the most pressing-and most contentious-global health challenges is the epidemic of HIV/AIDS in Africa. Our conference today is designed to help policymakers learn what resources are needed by those who must set up, run, and sustain programs in Africa intended to prevent HIV and treat those who are infected with that deadliest of diseases.

We made a decision when we organized this conference to invite African health-care providers who actually treat patients, rather than relying on abstract conjecture or statistics. We think that it is critically important to give the people on the ground who are actually treating this epidemic a real voice in our deliberations. In an era when technology can practically eliminate communication barriers, provide high-quality scientific information in real time, and accelerate the creation of sophisticated health-delivery networks, health-care professionals in developing countries are demanding direct control over how funds are allocated, how drugs are used, and how medicines are evaluated. The era when any one international agency or donor organization or drug company or NGO can dictate to HIV organizations in developing countries what their priorities are is over.

We are also going to discuss the scientific and economic challenges ahead as we seek to develop medicines to fight infectious diseases, particularly emerging pathogens, and provide a vaccine to combat HIV. The reality is that these treatments will not emerge without substantial private-sector investments, along with an expectation of substantial return on that investment. To suggest that these products can be developed without private-sector investment is not only shortsighted; it will cost lives. But the need for private-sector investment does not suggest that cutting-edge medicines cannot be made available to Africa and other developing countries for little or no cost. They can, they should, and they must be made available at affordable prices, and our speakers today are going to discuss how this can be done.

I would now like to introduce the speakers from our first panel. Our first speaker today will be Dr. Scott Gottlieb, who is a physician and the senior advisor for medical technology to the Centers for Medicare and Medicaid Services Administrator, Dr. Mark McClellan. Before holding that position, Dr. Gottlieb was the Director of Medical Policy Development at the Food and Drug Administration. In addition to his official duties, Dr. Gottlieb still serves as an emergency-room physician.

Our next panelist will be Jerry Norris, an adjunct fellow at the Hudson Institute in Washington, D.C., working on global HIV/AIDS issues. Before holding that position, Mr. Norris was Senior Director for International Operations for the WebMD Foundation, where he was developing a joint UN private-sector partnership to bridge the digital divide in public health. His research now focuses on trying to find ways to ensure a steady, affordable supply of quality medicines to developing nations.

Following Mr. Norris will be Dr. Robert Orina Nyarango, a pharmacist responsible for coordinating the antiretroviral treatment program at Gertrude's Garden Children's Hospital in Nairobi, Kenya. Gertrude's Garden is the only pediatric hospital in east and central Africa and is the primary referral hospital in that part of Africa.

Our final panelist is Segolame Ramotlhwa, who is Deputy Operations Manager for the National Anti-Retroviral Therapy Project as well as head of the Botswana Essential Drugs Action Program at the Botswana Ministry of Health. As the pharmacist in the ART Project Team, Mr. Ramotlhwa is also responsible for coordination of the pharmaceutical component of the project.

DR. SCOTT GOTTLIEB: I want to start by talking about a policy that we instituted at the FDA about a month ago. I recently moved over from the FDA, as Bob mentioned, to work with Dr. McClellan at the Centers for Medicare and Medicaid Services, but I was at the FDA at the time that this policy was developed.

A very high-level group of officials from the Department of Health and Human Services recently returned from a trip to South Africa and India, where they spoke to some of the companies that have expressed interest in developing follow-on versions of existing drugs but in fixed-dose combinations, so that they would be producing new drugs by combining some currently marketed drugs into one pill. These companies are Aspen in South Africa and Ranbaxy and Cipla in India.

I've been told that those discussions went well, and I think that this trip demonstrates opportunities that are going to be created as a result of the new policy promulgated by the FDA. That policy consisted of a guidance document that articulated a very fast pathway for the approval of fixed-dose-combination drugs through the FDA, and committed the FDA to unprecedented timelines for review of these drugs—as fast as several weeks.

The fixed-dose-combination drugs, as many of you know, are combinations of existing patented HIV medications. So rather than taking six different pills a day representing three different medicines, in some cases you can combine all those different medications into one pill and take a regimen that's as easy as one pill once a day.

The guidance that we put forward has several components, and I don't want to go through every detail, but I do want to highlight four essential elements of that policy that I think make this policy unique. It is an unprecedented step forward from the agency's standpoint. It's important to know that there's nothing really new as far as policy: we didn't require any new regulations or new laws and were able to articulate all these pathways in one document.

The first element of our new policy was to articulate four processes by which fixed-dose-combination drugs can get FDA approval. Some of these processes represent the typical pathways that a branded company or a generic company would use to get approval for a product through FDA, but the issue that emerged was that there were products developed by Indian companies (Ranbaxy and Cipla, in particular) that were being used on the ground in Africa yet had not gone through any formal approval process-certainly not the FDA's approval process. There also might be some desire to use funds from the President's Emergency Plan for AIDS Relief to procure those products. Naturally, we wanted a method by which those products could be brought under some form of scientific review to ensure that they were safe and effective.

So one element of the guidance policy was a process by which these Indian and South African companies could file for formal approval with the FDA under a mechanism known as 505B2. They can go through a formal evaluation and get tentative approval, which would be sufficient for the purposes of procurement by the president's fund. They couldn't get full approval, because patents would block them in the United States. But for the purposes of procuring these products for the countries where the branded companies have already waived their patents under the Trade-Related Aspects of Intellectual Property Rights (TRIPs) agreements-principally, Africa and the Caribbean-tentative approval would be sufficient. But these companies would still go through a process analogous to any scientific review that the FDA does, albeit on a very expedited timetable.

The second element of the policy was a proactive listing by the FDA of where the clinical data already exist to allow this very expedited process. Specifically, to obtain approval for these products, you need two things: first, you need to demonstrate that the combinations themselves-the three drugs used in combination-are actually effective for the treatment of HIV, and that requires clinical evidence where these three drugs have been used in combination in actual patients and have resulted in attenuating viral loads. Second, you need a lot of chemical data to demonstrate that the products don't break down in the sun, that they get into the bloodstreams at adequate levels for treatment, and that they get into the bloodstream in reproducible ways. In short, we need to ensure that every pill that reaches a patient is the same. The first thing usually requires many years of clinical data. We actually have to give the drug to patients and see how the patients do. The second thing can be done very quickly because much of it is chemical data. You can test for bioavailability in a laboratory, where you can actually monitor the drug in the bloodstream with a small group of patients.

So we listed 25 or 30 combinations for which we believe that the clinical data already exist to prove that the drugs would be effective if used in combination. Therefore, if a sponsor wanted to come in with a fixed-dose-combination drug, all it would need to do for those listed combinations would be to provide bioequivalence and chemical stability data, which can be done in a very short time. I could find only one other instance in which the agency proactively listed a case in which it felt that the clinical data were sufficient for a sponsor to come in with an application for a drug without going through the clinical trials-the normal process of giving the drug to patients and watching for the clinical effectiveness.

The third element of our policy was an articulation of the bioequivalence in the composition that would be needed for approval. This is what the FDA does on a day-in and day-out basis—it looks at bioequivalence and stability of drugs. But here, again, we were proactively articulating what the threshold would be for the approval of these combination products.

The fourth and final element was a pledge on time frames-that the FDA would review these products in time frames as short as three to six weeks.

Shortly after we announced these guidelines, companies expressed interest in developing new combination products. In particular, two groups of branded companies issued press releases expressing interest in developing fixed-dose-combination drugs. We're hopeful that other companies will step forward as well.

Despite the innovative steps taken by the FDA, an enormous political debate surrounded the announcement of our new policy. As many of you know, there was a lot of talk about the Indian companies that were developing fixed-dose-combination drugs—principally, Cipla's product, which consisted of Sustiva, Nevirapine, and Lamivudine. The discussion focused on whether the U.S. would use the president's fund to procure these products. The reason that people in the AIDS community, particularly in the international AIDS community, wanted us to use our funds to procure these products is because they were cheap fixed-dose combinations. The fact that they were fixed-dose combinations is not debatable, and the fact that fixed-dose-combination drugs will probably offer some benefit in a Third World environment without a lot of health-care infrastructure probably isn't debatable, either. The assertion that these drugs were cheaper than other available options is probably very debatable, but I won't get into that today, since it is not my direct area of expertise.

What I would like the audience here today to think about is the value of a one-size-fits-all drug in Africa and other similar markets. I have talked to many public health officials about this and have heard are various opinions. There is a presumption that these products-particularly, the Sustiva, Nevirapine, and Lamivudine combination-would be a very good pill to introduce into the African market because it is, in many respects, a one-size-fits-all pill, meaning that it can be used in men as well as in women. In women, the medical community wants to be able to offer a product that can prevent maternal-to-fetal transmission, and the inclusion of Nevirapine in this product does just that.

Consequently, if you are looking for a very easy way to procure one product and do not have access to the kind of health-care infrastructure in which you can tailor different kinds of treatment regimens to different kinds of patients, this is the product to use, according to many people. But one thing that we need to think through carefully from a public health standpoint is the limitation of introducing a one-size-fits-all product into any market.

Here in the United States, treatment regimes are highly tailored; a drug would probably have limited market potential here for that very reason. The best case is the situation in which clinicians can tailor treatment regimes to an individual's response to different kinds of medications to ensure that they are responding positively to treatment and avoiding severe adverse effects. For instance, if a patient has liver disease, physicians want the option to give the patient drugs that aren't as toxic to the liver. If the patient is a young woman, you might prescribe a certain drug that prevents maternal-to-fetal transmission. In short, there are numerous considerations that illustrate the limitations of a one-pill-treats-all approach.

Clinicians in the U.S. can avoid that problem because we have the health-care infrastructure to assess patients on a regular basis. That is obviously not true around the world, and that is what makes a combination product like Cipla's attractive in some people's minds. But you also have to realize the shortcomings of that approach. You are, by necessity, accepting a certain percentage of treatment failures and a certain amount of toxicity from the product itself. In particular, we know that Nevirapine is highly toxic. About 0.5 to 1 percent of people develop a very severe rash called Stevens-Johnson Syndrome, which can be fatal, particularly if you don't have sophisticated health-care support. A much higher percentage of patients will develop liver toxicity that isn't necessarily self-limiting-for example, it doesn't stop once you withdraw the drug. As a result, it is quite possible that a not-unsubstantial number of those patients could go on to develop fatal liver disease.

The unpleasant reality that not many people want to acknowledge is that if you saturate this product in a population without a lot of health-care support, you're going to obligate a small percentage of those people to die just from the treatment, not the disease. Here in the United States, when we use Nevirapine we titrate it on very slowly to patients over the course of a couple weeks and monitor them very closely for liver toxicity. But in an environment where you're using a fixed-dose-combination pill, you don't have the opportunity to titrate it up. It is, by definition, a fixed-dose combination, and you're starting them on the maximum clinical dose right from the start. This means that you are going to have a certain amount of toxicity that's going to be even higher than our experience in the United States with this drug.

I raise this problem to ask the question: What should be our goal? Should the goal be to get patients on durable treatments in settings where they could continue to be successfully treated, or should the goal be to start as many people on treatment as quickly as possible? If your goal is the latter, you want a very cheap drug that doesn't require substantial infrastructure to support. If your goal is to get people on durable treatments, you probably need many different kinds of drugs. This is not to deny that there is a very important place for the fixed-dose-combination drugs, but you need backup drugs to support people who fail on that treatment, and you probably need to tailor your regimens a bit better to men and women and young people and old people and people who might have other comorbidities.

The ultimate question is which treatment scenario will save more lives. I'm not sure that it is a foregone conclusion that starting many more people on fixed-dose treatments is better than taking the time to develop treatments that could be more sustainable in the long run. There is a real sense of crisis attending this problem, and rightfully so. But we cannot allow our sense of crisis to blind us to the therapeutic trade-offs and alternatives that are available. If we do that, we may wind up regretting our decisions a few years down the road.

MR. JERRY NORRIS: I would like to discuss the fixed-dose-combination conference that was held in Botswana, March 29-31. But before that, I would like to go back to October 2003 because it has an effect on the conference itself.

Last October, I wrote an analysis of the scientific dossier for the drug Triomune, which is the fixed-dose-combination product that most of us will be referring to today. About a month later, I was invited to participate in a telephone conversation with the CEO of Cipla, the company that produces Triomune. In that conversation, the CEO, Dr. Hamied, started off by saying that the analysis that I had written was causing the WHO to delay the approval of Triomune, so he wanted to correct the inaccuracies in my analysis.

He said that I was inaccurate in stating that the drug could only be administered by registered medical practitioners. I replied that I was only quoting from his scientific dossier. After a couple of minutes of dueling assertions, in which he kept asserting that there was no such dossier on his company's drug, I said, "I have it in my hand. It is a six-by-nine brochure, three colors. On the back cover, which is blue, in very small white print, it says, 'only for use only by registered medical practitioners.' " After I pointed this out to him, there was a long silence on his end of the line. Finally, he asked, "How did you get it? It's confidential."

At that moment, I was bemused that a copy-drug manufacturer, who reverse-engineers someone else's intellectual property, was concerned that his property rights had been compromised. So indeed, there was a scientific dossier on his drug. At the end of the conversation, he asked, "Is there anything else that I could show you?" So I asked if he could send the approval from the Indian drug-regulatory authority. He replied that not only would he send it, but that he would send it by DHL. And indeed he did: it arrived a few days later. This document was more revealing than the scientific dossier. It isn't an approval, but rather a permission to produce the drug-manufacture the drug-and it's from the Drugs Controller General of India, which is India's centralized version of the FDA. There were five conditions that I found significant in the approval. One is just what we talked about, that there must be a box-warning label that it can only be used under prescription by registered medical practitioners. Second was that it was for adult patients only. Third was that it is for patients who have been on Nevirapine. The patients must have been stabilized before they are administered Cipla's triple-dose drug. Fourth, the permission to produce the drug was good for a period of two years beginning July 26, 2001, and we were in the end of that approval period. And fifth, which I found puzzling, was the restriction that there shall be no reference in the advertisement or medical literature that the Indian government has approved this drug. None of these restrictions saw the light of day when the WHO prequalified the drug or when the World Bank approved purchase of the drug in its procurement mechanism.

None of these conditions has been publicized, but all of them are very, very critical to our discussion today. In terms of the drug approval in India: I went back to Dr. Hamied and said, "You must have gotten it renewed by the Drugs Controller General." And he said no, that I didn't understand their system and that he would send me their new approval. And the new approval is from the State Authority-Maharashtra State. So it's gone from the central regulatory agency to a state regulatory agency. Apparently, there are 28 different state authorities in India after it goes through the two-year initial process at the central level.

So now let's go to the Botswana conference. As many of you know, it was cosponsored by World Health Organization, UNAIDS, the Southern Africa Development Community, and the U.S. Department of Health and Human Services. The purpose of the conference was to try to draft scientific and technical principles for fixed-dose-combination products, so it was basically a scientific meeting. And it was an open meeting: anyone could attend. In the week or ten days prior to the conference, there was an incessant drumbeat of articles in the media and letters to the president of the United States calling for its cancellation. These letters claim that the intent of the conference was to subordinate the World Health Organization's prequalification system and to stop the purchase of least-cost fixed-dose combinations (FDCs) from India. Behind it all, they claimed, was the silent hand of the U.S. pharmaceutical industry, the largest financial supporters of the president's reelection campaign. But the media barrage was to avail. The conference went forward. But having failed to stop it, NGOs in particular were able to read prepared statements at the end of the conference, and these statements were picked up by the media, which were quick to claim that the conference had failed to reach consensus.

What the media did not report were the voices from Africa that were at that conference. Let's hear just a few of those African delegates: "We are holding all drugs to the same high standard," said the delegate from Botswana. "Yes, people are dying in Africa, but should we throw out standards and buy anything?" said the delegate from the Food and Drug Board in Ghana. "Poor quality means poor access," said the delegate from the Medicines Control Council, South Africa. "African regulators are not being unreasonable by demanding that generic companies show them the data on their drugs," noted the delegate from Botswana. On April 12, the Financial Times carried an article by the director of the Institute of Public Policy in Nigeria, who wrote: "HIV medicines, whether original or generic, should meet the most stringent, rigorous, clinical and testing reviews. If the proposed drugs are rejected by pharmacies in Brussels, London, Tokyo, Geneva, or Washington, accepting the use of the same drugs in Africa with little resources and lack of equipment to do a proper clinical and scientific evaluation may further compound the woes of HIV/AIDS victims."

The FDCs suddenly captured everyone's imagination over the past six months. But I find it astonishing how quickly these FDCs could gain ascendancy in so many quarters as the silver bullet for AIDS treatment among Africa's poorest. Much of the enthusiasm started in October 2003, when the Clinton Foundation announced its historic pricing agreement with Indian pharmaceutical companies. The Indian companies said that they would be able to produce this triple-dose combination treatment for $140 per year per person. That's an amazing price, and the press naturally picked this story up and ran with it. On December 1, 2003, the World Health Organization announced its support for these drugs as the cornerstone of its plan to treat 3 million people by 2005. Subsequently, the WHO listed these same fixed-dose combinations in its prequalification system for the first time. All this happened over the course of just a few months, and it was what propelled the conference in Botswana. The NGOs jumped on the fixed-dose bandwagon, sending a blizzard of letters to Congress, the State Department, and Secretary Tommy Thompson at Health and Human Services. They claimed that millions of patients would die because the U.S. government would not approve the purchase of cheap fixed-dose-combination products.

The reason that the NGOs asserted for U.S. non-approval? They trotted out the scapegoat of the U.S. pharmaceutical industries and asserted that the WHO prequalification system was just as scientific and just as rigorous as that of the FDA. But when you look closely at the FDA and the WHO, you see that they are not really comparable. The FDA is, for the most part, the gold standard when it comes to pharmaceutical data and approval.

The NGOs also asserted that copy drugs are two to three times less expensive than patented products, and so they seemed-until someone did a comparative study. On May 12, the Hudson Institute released a report called "Myths and Realities on Prices of AIDS Drugs." Hudson found that the average price of the patented product (and these data were taken from Doctors Without Borders publications where they list prices of drugs) was $404. The average price of the copy drug was $494. Of the 13 most commonly used AIDS drugs, eight copy drugs are less expensive, and the next several are marginally more expensive. The real price differential is found in Nevirapine, which is much more expensive. But Nevirapine is produced by a German company, and the Doctors Without Borders pricing report did not mention-or did not compensate for-the fact that the German company donates this drug absolutely free in mother-to-child transmission prevention programs around the world. When it comes to fixed-dose-combination drugs, the patented version is $659 and the copy drug is $1,178.

At the Botswana conference, something occurred that was significant to the WHO prequalification process. One of the co-chairs was from the Office of Essential Drugs and Medicines Policy in Geneva, and I had been puzzled as to why in 14 separate editions of the prequalification exercise they listed a disclaimer saying that these drugs were not warranted for safety or efficacy in the treatment of AIDS patients. So I asked at the conference of the WHO representative: Why there was a disclaimer noted in the prequalification for these drugs? This was a public meeting, so I was very surprised when he said that he would only answer that question in private. So I moved on, and followed up with another question: How does the WHO intend to ensure informed consent to patients in its plan to treat 3 million people by 2005? Again, he told me that he would only answer that question in private.

Later, during the coffee break, he told me that the reason for the disclaimer for safety and efficacy of these drugs was that it is the responsibility of the manufacturer to ensure those attributes. In terms of informed consent, it's the responsibility of the home government in question.

In the first case, all the drugs shipped out of India are priced freight-on-board, and once the drugs leave Indian shores the companies have no concern about those products and do no post-surveillance or marketing studies to see if there are any adverse side effects with their drugs. Consequently, I don't understand how the World Bank, the WHO, and even the Vatican leap onto the FDC bandwagon and pretend that these drugs are the silver bullet for AIDS in Africa. I remind everyone here today that this is not a silver bullet that we're willing to use in the West. We're only willing to use it in poor African countries, and that's the shame of it.

DR. ROBERT ORINA NYARANGO: The purpose of my presentation today is to relate the Kenyan experience with antiretroviral therapy (ART) and to focus on what the requirements are in our situation. The mission of antiretroviral therapy in Kenya is to ensure the best clinical outcomes and to place as many patients as possible on ART. I must emphasize the first part, of ensuring the best clinical outcomes, because that is what is missing in most of our programs. The idea currently is to place as many people as possible on ARVs (antiretrovirals), as opposed to monitoring the outcome of the treatment.

We have five objectives: to ensure availability of quality and affordable ARVs; to provide a policy framework and structures through which ARVs should be given; to ensure availability of trained personnel to run the program (that is a very big challenge to us); to implement and coordinate the program; and to put into place a sustainable resource fund for the program. The last objective is critical because if we are relying more on donors-if we have a supply of ARVs for, say, only two years and we don't have funds for the following year(s)-we will have a severe problem in continuing that program.

The components of our program are very complex, and I will highlight only a few. Quality political and technical relationships are very important, especially in our setting because from a political standpoint, the government may want to make as many ARVs available as possible without taking into regard the technical aspects of their delivery. But the technical aspect is very important because the political leadership has to be in check. What political objectives are driving the choice of which ARV drugs you bring in? How useful are the drugs for the patients? Has there been adequate quality analysis of these drugs? How do we evaluate the process through which these drugs are given to patients? These questions are very important, and most of the answers are missing.

Right now, we cannot adequately monitor treatment outcomes. Once we place these patients on ARVs, how do we monitor them? How do we know that they are benefiting from them? At what stage do we decide to move from one regimen to another? That also requires input. We need quality logistical management information. We must have a tracking system to know which patients are using which drugs and how they are benefiting from particular regimens.

The situation in Kenya is as follows. We have 2.1 million infected people, 315,000 of whom are eligible for ARTs (that number could be higher because we don't know exactly what parameters the government is using to decide who is eligible for treatment), but only 18,600, or 0.9 percent, of those who are eligible for treatment are actually on ART programs-about 8,000 in the government and the rest in the private sector. The government has two bodies coordinating the ARV program: one in the Office of the President; and one in the Ministry of Health. We should have only one, in the Ministry of Health, but there must have been political considerations for this setup. With all due respect to our ambassador to the UN, who is here today, I don't see why we should have one in the Office of the President because it's duplicative-money that could be used elsewhere, which gives political leverage to whoever is in power.

We also have about thirteen donor communities involved with our programs. The sad thing is that every one of those groups is doing its own thing-coming into our country with its own drugs and running its own programs. The goals, methods, and standards of these groups are all very different, and the outcomes will be very different in that kind of setting. The quality of all the products and the processes are not assured because they are not evaluated in any centralized way. There are no uniform policies for product quality; the government is relying more on the WHO prequalifications.

But I come from the private sector, and we have a small unit of antiretroviral therapy. We try as a hospital to have our own way of deciding which products to use. Thus far, we rely on FDA approval, but the government says that you have to place so many people on ARVs, so then we have to use the WHO prequalification instead, which is a problem because the product quality is not as assured as it would be with FDA approval. There are no national guidelines for ARV use in pediatrics and in pregnant women. The government has some guidelines, but they're not adequate. There is no national curriculum for training and certification of ARV providers, which is a very big problem. If there is any curriculum, it is still being developed. There is very little funding for human-resource development. You can bring in all the ARV drugs you need, but if you don't have people who know how to use them, the drugs aren't useful.

The government has trained about 500 people, but at least 2,500 are now necessary. Our hospital is a pediatric-referral hospital, so we have pediatricians practicing-and 90 percent of the prescriptions that we receive are from one pediatrician. This means that most pediatricians are not well versed in the use of ARVs. Some 60 percent of all prescriptions that we receive require pharmacist intervention in terms of wrong combination, wrong dosage, drug interactions, food interactions, and so on. That is why I emphasize the need for human-resource development. If this is happening in the private sector, imagine what is happening in the public sector. There are huge funding gaps, especially for human-resource development.

About 90 percent of our pediatric patients pay from their own pockets. There are no HMOs or insurance under the funding pool for ARVs. Less than 10 percent of patients have laboratory checks at least every three months to confirm that the ARVs are working or to monitor them for adverse reactions and so on. There are 12 sites for dispensing ARVs in a country with 30 million inhabitants, and there is inadequate information technology and infrastructure (warehousing, transportation facilities, and so forth).

Right now, the crucial goal should be to balance clinical outcomes with scaling up our ARV treatment programs. The ARVs that are available or that should be given must address the need for appropriate structures for delivery. That is very important. We need adequate monitoring of the relations of other products and the process and the human resources. Pharmaceuticals need, as much as possible, OD and BD dosing for the drugs for the obvious reason of adherence. FDCs (fixed-dose combinations)-I don't say which manufacturer-are good in our setting in terms of improving adherence, reducing pill burden, and possibly reducing cost.

Forty to 70 percent of our children are on adult formulations-capsules and tablets, because syrups are very expensive. If you have to put children on ARVs, you need to put the medication, say, in a tablet that you break and crush-and you can anticipate the problems that arise with that. More liquid formulations for pediatrics are necessary. FDCs are most desirable. They should fit in with the work schedules of the parents and of the patients. They could improve adherence and reduce pill burden, but we need a way of certifying that they're working correctly and certifying the quality of the FDCs. The formulation should come with assurance of quality and efficacy. There should be more choice in the FDC regimes available (not just the one triple dose available now among the innovator brands).

FDCs must be developed with the clinical requirements of administration in mind. About 60 percent of our patients are also infected with tuberculosis. If you're putting them on a Nevirapine FDC, I don't know how you're going to manage the interactions that are going to occur with the TB treatment regime.

Ninety percent of our patients are on first-line therapy. I guess that applies to most of Africa. So if we have to develop FDCs, we should keep that in mind. FDC formulations should also allow for dose titrations. Dr. Gottlieb mentioned the toxicity of Nevirapine. If you had to titrate it for two weeks to check liver toxicity, how are you going to do it if it comes in a fixed-dose combination?

There is a pressing need for monitoring product quality and safety, and we need to revamp our national laboratories for doing that. There is a need for monitoring the patient outcomes, the drug effects, resistance testing, toxic effects, and so on. Resistance testing is a very big problem because it's a major hurdle to change from one combination to another without resistance testing. We've had a big problem with resistant malaria and TB strains in Africa, and we don't want to repeat the problems with HIV.

We need to put into place a management institution for ARVs, and we need government as well as private-sector collaboration. The government will provide leadership and coordination and will mobilize funds while the private sector will provide the human resources. I've just broken it down from the Minister of Health to private sector to commercial distribution and to donor funding with the Ministry of Health's doing a lot of the policy work, development of systems, and logistics and coordination, and the private sector providing personnel, distribution points, and dispensing, education, and training. We need commercial distribution-I prefer commercial distribution because if they're distributing through the government, a lot of bureaucracy slows down the process. And, of course, we need donor funding and logistical and technical support. As the drugs and the funding go through the pipeline to patients, we need to have a way of moving information up from the patients to the doctors and then to the government and to the donors. We need that distribution network working in both directions. We need national, regional, and district distribution centers. We need a way of transport to rush those drugs to the patients. We need equipment-computers, refrigerators, and a computer system that is able to track the product and the patients. We need to upgrade our quality laboratories for monitoring both the quality of the drug and the treatment outcomes of the patient. And human-resource development-it costs about $2 million a year. We need a national curriculum and technical aid.

Central distribution, regional distribution, dispensing sites, information system management, personnel and training, transport, quality-control centers, monitoring laboratories, treatment guidelines: these are the hurdles we face, and the cost of these elements is more substantial than the cost of just buying the ARVs. The funds go more to ARVs than to information, logistics, or training, but we should focus more on developing the structures and the human resources before we move into mass ARV provision. With the ARVs, the approach is to have revolving funding. We need to have a way of sustaining the process of ARV provision over time.

In conclusion, we need private-sector NGO and public-sector collaboration, with the Ministries of Health taking a lead. We need donor funding. We should address the priority areas-human-resource development, systems and infrastructure, and subsidizing for ARV costs. We need to create revolving ARV funds to sustain the provision of ARVs, and we need to develop drugs that address the needs we face-adherence, cost, safety, and efficacy.

In our hospital, our first priority should be orchestrating our programs using more technical criteria than the need to provide just the ARVs to patients. What we have learned is that we need to have a more objective way of deciding who should be on ARVs in terms of diagnosis and balancing between long- and short-term effects. We have managed as a hospital to develop pediatric guidelines for ARVs, and we think that the government can work out something similar in the public sector. We have a method of training personnel without a well-developed curriculum. It is a great challenge to us, but there is some interest from donors in developing such a curriculum. USAID has shown interest in this area. We have a strict way of monitoring adherence, which includes having to spend the hospital's money to call up the parents and find out how they are administering the drugs to their children. We are now able at least to collect some data. And 80-90 percent of our prescriptions, as I said, are from one pediatrician, 60 percent require pharmacist intervention, and 6 percent of the patients in our hospital who need to be on ARVs are actually on the program, which means that about 94 percent are going without treatment. The average cost of our prescription is up to $200 per month for each patient. The government and private practitioners have shown interest in our training programs. A few groups have also expressed interest in terms of funding.

MR. SEGOLAME RAMOTLHWA: I would first like to recognize members of the diplomatic corps present today. I'm going to be talking about our program in Botswana. We call it "Masa," which means "dawn." The name was chosen to reflect our situation at the time; before this program, it was as though the sun had set for people who were living with HIV/AIDS. But with the introduction of this program, the sun began to rise and there was new hope for people living with AIDS. The program in Botswana was initially launched in 2001 after a series of activities and considerations by government.

Initially, like everyone else, we focused primarily on prevention. But because the epidemic was hitting us so hard, the idea of treatment kept cropping up among those responsible for such decisions. From a study done by the Bank of Botswana that examined the economic impact of HIV if left unchecked or untreated, it became clear that without any intervention that targeted the virus itself, there were going to be many problems. There have indeed been many developments in the technical field; in the mid- to late 1990s, the newer class of antiretrovirals-the protease inhibitors-came onto the market. The results from these drugs were encouraging, which made it interesting to consider what it would take to actually introduce antiretroviral therapy. Indeed, the government eventually asked the Ministry of Health what it would take to introduce antiretroviral therapy. A study was conducted to examine two things: First, what would be the demand, or what could be the demand, for antiretroviral therapy if it were to be introduced in the country at that time? Second, what resources would be required to service that demand?

By 2001, we were already in the middle of a mature epidemic, with many people infected and many people dying from the disease. At that time, it was projected that about 300,000 people were infected with the virus, based on an estimate that at least 35 percent of cohort aged 15-49 would test positive. Based on an eligibility criterion of a CD4 cell count of 200 and below or the presence of an AIDS-defining illness, it was projected that the demand for antiretroviral therapy would be 110,000 people.

But it is important to interpret the figures that 300,000 people are living with HIV/AIDS, and 110,000 of those people are eligible for ARV treatment in the right context. These numbers were based only on projections and not necessarily on people who were actually waiting at the door that day who had already been tested and were ready to be started on ART. In fact, at that time, over 90 percent of the people didn't even know their HIV status. So in order for people to benefit from this program, they would have to start with testing, to learn their HIV status. Given the 110,000 people who are thought to be eligible for antiretroviral therapy, it became clear that our health-delivery system could not immediately service that demand; thus the decision to introduce the ARV program in phases or stages. It was not the easiest of decisions, because we are talking about people dying in large numbers. But given the vastness of the country, there obviously were those eligible people who didn't have immediate access to the program. We were faced with a situation whereby we felt that it was better to start small and do something rather than nothing.

What was of great concern to us was the human resources required for the program. We recognized that we needed to increase the number of health-care providers in our facilities and to train them appropriately, including those who were already in the system. The infrastructure and the treatment that are required to service a problem of this magnitude forced us to assess the resources that we would need. Previously, our policies were centered on prevention; with the introduction of a program like this, we needed to review our policies and systems.

This included confidentiality, which, with respect to HIV, had reached the stage of secrecy rather than confidentiality. I'm saying this because as health-care providers, we are trained in patient confidentiality. But when it came to HIV, it was a completely different ball game because of the social and cultural issues involved. As a country, we introduced routine HIV testing in January 2004 as part of a comprehensive management of the epidemic with a specific intention of facilitating access to ART by those in need. This is one area where people become uncomfortable. But if we had to address the HIV epidemic comprehensively, we needed to be honest about the confidentiality issues involved and do all we could to win the war against HIV/AIDS.

We needed to revisit our information, education, and communication (IEC) strategies so that we could come up with a strategy that would be dedicated to a program of this type. ART and prevention were viewed as mutually reinforcing, and our IEC messages were deliberately designed to reflect this.

A program like this needs a well-organized and functioning monitoring and evaluation component, which meant that we had to implement a nationwide IT (information technology) system that included testing and evaluation on site. We were starting from a situation where our health-care system was not computerized and our IT literacy level was very, very low. We had people who didn't even know how to turn on a computer, so you can appreciate the challenges that we were facing.

Currently, we have about 14 or 15 centers with a total of about 15,000 patients from the public sector and another 7,000 or so from the private sector. So the total number of patients who are now on antiretroviral therapy is about 22,000. We have a mortality rate of, on average, about 10 percent. In our view, that's quite a success because we were initially dealing with very, very sick patients with advanced disease-stage three, stage four of the disease-and we did not expect that we would get that sort of results. An average of 10 percent mortality is very good when we are dealing with patients with such advanced disease.

Currently, there are about 22,000 people enrolled in our program, with just under 15,000 people receiving ARV treatment. As I mentioned, after treatment we are averaging about 10 percent mortality rate, with another 7 percent experiencing toxicity, which requires them to switch treatment regimes.

In terms of monitoring, one issue has always been gender. Some 64 percent of our patients are women. For whatever reason, women tend to enter the ARV program in greater numbers. Perhaps in our situation, women tend to seek medical treatment more often than men do.

When we started, CD4 cell counts, on average, at the time of intervention were about 50. But that figure has increased to about 86. So we are still dealing with very, very sick patients. The monitoring of CD4 cell count and viral load are among the important parameters for patient monitoring. Thanks to the effort that we put into this particular program, we have adequate patient follow-up, which is currently over 90 percent. In monitoring patient follow-up or adherence, we record every deviation: we do not tolerate any deviation whatsoever. For instance, when a patient is supposed to come in for a checkup today, but she comes the following day, even if she still took the drugs as prescribed we record that as non-adherence. In terms of patients taking the drugs under a zero-tolerance policy, our adherence rate is at least 85 percent, and it is a lot higher if one looks at whether the patient actually takes the medications.

When we started this program, one of the biggest unknowns was the toxicity issue. Initially, we thought that important drug toxicity requiring a change of therapy would be more common and thus make implementation of the program very difficult. But our experience so far is that toxicity occurs in less than 10 percent of cases, that is, toxicity requiring a change of treatment from one drug to another. And primarily, we are talking about anemia-related sickness, where the patient has to be switched from AZT to another drug because of anemia. But if you remember that the majority of the patients were anemic already because of their advanced disease, this is a figure we can live with. So in this particular area, we don't feel that there's much of a problem. Best of all, at about six months we find that we have at least 85 percent of patients with complete viral-load suppression. That tells us that our program has been highly successful even in terms of therapeutic outcomes.

We are currently scaling the program and rolling it out to the rest of the country. Our aim is to have a nationwide ARV program by the end of 2004. We only have about 17 sites remaining now. There are a several areas for which we need support from development partners; one is the strengthening of monitoring and evaluation, which includes IT system improvements. This is one area where we think we may need outside expertise. We do have a system in place that has served us well to this point, but with the rollout and expansion of the program, we will certainly need to strengthen this component.

With the expansion of the program and as the program evolves, we think we might see other problems related to implementation-for instance, development of disease resistance in the next few years. We need the expertise that will help us monitor and manage that inevitable development. Management and coordination is another area that needs strengthening, which could be done with the support from our development partners. In the Anti-Retroviral Therapy (ART) program, you need to ensure that you optimal utilize all available resources. The support and contributions from development partners should be coordinated, including those efforts from the private sector and NGOs, if you are to get everyone moving in the same direction so that we actually get synergy.

Staff recruitment, especially key staff such as doctors, pharmacists, and laboratory scientists, is one very important area where support from partners will be highly valuable. One big challenge is that we don't have the ability to locally train the key health professionals urgently needed for the rollout of the program, such as doctors and pharmacists; all doctors and pharmacists practicing in Botswana obtained their degrees outside the country. A further complication is that the majority of doctors and pharmacists in the country are actually noncitizens and therefore work as expatriates; thus we compete for these professionals with the rest of the world, including developed countries, which often offer far better packages than we can afford as a developing country.

Training is a major component of our program because we have health-care providers who graduated in the early 1980s who were never trained to administer antiretroviral therapy. That means that we have to train each and every health-care provider in the system. You cannot say that you want only to train a certain number of people because of the prevalence of HIV in our population. The HIV infection is going to be the single largest morbidity factor in our health system for years to come. So the largest group of patients who will be visiting our health facilities are going to be HIV-positive. If about 35 percent of the population is infected, health facilities will tell you that about 50 percent of the patients they see are going to be HIV-infected. If you are a doctor, it means that when a patient enters your consulting room there's about a 50 percent chance that the person is going to be HIV-positive. All of our health-care practitioners have to be prepared to deal with those patients.

As far as laboratory and testing, we know the special tests that we have to do as a result of this program: CD4 cell and viral-load testing. In addition, we have to put a lot of effort into our existing testing capabilities for other areas, such as hematology and chemistry. We need to strengthen our capacity to meet the increasing demand for these laboratory services.

Space procurement and upgrading is another area where the support of our development partners will be highly valued. The need for adequate facilities is challenging as well, but is a lesser challenge than that of adequate human resources. Human resources are the most dynamic of all the resources that we need, so it is the biggest ongoing challenge. This is so because of all the issues that I've raised during this presentation.

There are several challenges that we face as we move forward. One is the fact that most people in the country, including those who are infected, don't know their HIV status; we all know that knowing one's HIV status is a prerequisite for accessing all available care and support services for infected individuals. Because we began the ART program amid a mature epidemic, we're facing an initial burden of very sick patients. In our experience, there is a tendency for the general public to wait until they are very sick before they seek medical assistance. It takes far more resources to stabilize bedridden patients than those who are up on their feet. And, of course, there are also social and cultural factors that delay members of the public to seek treatment, such as going to the traditional practitioner first and only going to the hospital when the condition has gotten worse. Fear and stigma remain the biggest challenges in terms of people accessing the HIV/AIDS programs that could help them; the result is that people only go for an HIV test very late and eventually access services late-if they survive long enough.

Another challenge to our national ART program in Botswana is the fact that there is limited civil society activity and NGO capacity. This means that we have to strengthen these organizations so that they can increase or expand their capacity and play a more meaningful role in the fight against the epidemic.

Adherence and drug security-another very important area. Initially, you are dealing with very few patients, but as you expand the program, non-adherence may be a consequence of drug security or lack thereof. There are people who may start sharing drugs with friends or relatives or even diverting ARV drugs to unintended markets. As a country, we have put measures into place, which we continuously review and adapt, to prevent these potential problems. It is critical that drugs are kept under secure storage, fully accounted for, with definite mechanisms and procedures for assessing adherence. The consequences of non-adherence in this particular program are far-reaching; if people don't adhere, you are going to get rapid development of drug-resistant HIV strains and thus start dealing with a completely new strain or strains of the virus. Once you start dealing with the new strains of the virus, your nationwide ARV treatment program is going to be challenged as the new strain spreads, and the new strains can start spreading very quickly.

Management and communications become very important in this scenario because you have to coordinate within the health system and within all the sectors that are involved in the provision of ART. You need to get everyone involved, including the private sector-even in terms of seeing how the private sector can be brought on board to play that part, because in this program you need a multi-sectoral approach; you cannot leave it to the Ministry of Health. It has to involve everyone if you are to reach out to all the people who need to be put on this program and cater for all their needs, some of which may be outside the mandate of the Ministry of Health.

Capacity building is critical. Ironically, you start with less experienced people, but as they gain experience suddenly they're able to enroll more patients in treatment within a short time. Then it reaches a phase where your capacity to treat patients is saturated. If you don't augment that capacity as you proceed, your patient enrollment is going to stagnate, which may create problems. As you augment capacity, it picks up again. All sites tend to experience the same problems, and our experience is that there is no gain in starting one site at a time once you have passed the pilot phase.

Initially, the sickest patients come first, but it takes a lot more time to stabilize a bedridden patient. In terms of cost, we found that it takes at least three times more resources, especially human resources, to stabilize the sickest patients. So it is important that while you are attending to the sickest patients, you also look at those who are still up on their feet so that you can enroll those who are healthy and maintain them in a productive state while you're also addressing those who are bedridden. If you don't do that, you will face a constant stream of very sick patients and you won't be able keep up with the epidemic.

Another  issue that is often viewed as controversial is confidentiality. We think that if you are to address this problem comprehensively, you need to look at routine testing. When we talk of routine testing, some people think that we mean mandatory testing. But we are simply saying that if, for example, a patient comes to your clinic or consulting room and has a sexually transmitted infection, in Botswana that means that there's a much greater chance of that person being HIV-positive. So you need to talk to the patient about getting an HIV test. You want to emphasize the importance of getting the patients tested while you are treating the infection that they already have. If someone comes to you with TB, you have to be aware that 75 percent of our patients with TB are HIV-positive. So it is not adequate management of that particular patient if you're not going to be thinking about HIV testing. We are not saying to do routine testing for the sake of doing it. Do it so that you can provide for that particular patient; voluntary counseling and testing (VCT) centers and services will continue, as has always been the case. Once you institute routine testing, you can also test patients who are still up on their feet and stabilize them on antiretroviral therapy before they become seriously ill. And when you stabilize them on that antiretroviral therapy, you keep them productive. They can continue to provide for their families and contribute to the community, pay taxes, and therefore fund their own antiretroviral therapy. And that is one of the objectives of this program.

continued>>

 


Center for Medical Progress.

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MICS 10 PDF (435 kb)

SUMMARY:
How can wealthy nations best help save lives in developing countries, particularly those nations struggling with widespread HIV/AIDS infections? The U.S. government has embarked on a new plan to rapidly approve and help distribute low-cost combination anti-retroviral therapy (ART) pills to treat HIV in developing nations. Speakers at this conference concluded that controlling HIV/AIDS in developing nations requires balancing access to less expensive treatments with financial incentives for companies to invest in new medicines; giving assurance to developing nations that generic medicines are as safe and effective as patented drugs sold in wealthy countries; and expanding healthcare infrastructure in poor nations to deliver new treatments and monitor patient health.

How to Make Quality Drugs Available

Moderator:

Robert Goldberg, Ph.D., Senior Fellow and Director, Center for Medical Progress at the Manhattan Institute

Panelists:

Dr. Scott Gottlieb, Senior Adviser to the Administrator, Centers for Medicaid and Medicare Services

Jerry Norris, Adjunct Fellow, Hudson Institute

Dr. Robert Orina Nyarango, Head Pharmacist, ARV Programme, Gertrude’s Garden Children’s Hospital, Nairobi, Kenya

Dr. Segolame Ramotlhwa, Director of Pharmacy, Botswana Government HIV Program

Patents and the Availability of Medicines in the Third World

Dr. Amir Attaran, Associate Professor, University of Ottawa

Drugs and Vaccines Against Global Diseases: The Next Generation

Moderator:

Robert Goldberg, Ph.D., Senior Fellow and Director, Center for Medical Progress at the Manhattan Institute

Panelists:

Karen Bush, Vice President, Anti-Bacterial Research, Johnson & Johnson

Dr. Emilio Emini, Senior Vice President, Vaccine Development, International AIDS Vaccine Initiative

Professor Frank Lichtenberg, Courtney C. Brown Professor, Columbia University School of Business Administration

Luncheon Address

Dr. Mark Dybul, Office of Global AIDS Coordinator, U.S. Department of State

Co-sponsored by: Institute for Policy Innovation, Center for Medical Progress, International Policy Network

 


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