AIDS TREATMENT NEWS Issue # 77, April 21, 1989
John S. James

One long-term survivor and treatment expert noted recently that almost nothing was being done to save lives. And a leading AIDS physician commented off the record that the research community had convinced itself it would take ten years to cure this disease, and that "they want to milk the grants and appropriations."

AIDS TREATMENT NEWS has long criticized the treatment-research establishment for having written off those now ill with AIDS or HIV, and for the remarkable lack of urgency about saving lives. Recently we have had more contact than previously with this establishment, and we have found the situation even worse than we had realized. So entrenched and near-universal is the commitment to unworkable viewpoints, approaches, and programs, that in meetings and conversa- tions we must temporarily suspend our own view of what is happening, and operate from the prevailing mindset in order to allow any communi- cation to take place. The real issues of how to save lives in this epidemic are so far removed from the conventional wisdom of the research and regulatory professionals, that if these issues are put forward in meetings, no dialog is possible. Many professionals as individuals would want to challenge the prevailing ideas; but they have lacked a conceptual infrastructure that is developed enough to hold its own against the conventional views -- views which started with the inevitable deaths of those now ill, accepted a priori without looking at facts or doing any analysis.

Here we will outline the real issues as we see them, and suggest analytical tools for bringing these issues out of their current limbo and into the light of day, where they can be considered openly and decided on their own merits.

In particular, this article will:

* Show that, barring a miracle, fifty thousand unnecessary deaths over the next several years is a conservative estimate of the cost of continuing with current policies and directions.

* Provide a simple mathematical model which anyone can use to calculate the number of unnecessary deaths caused by any given treatment research and access delays. We will also show how to use this model to analyze proposals for regulatory reform, how to do the arithmetic to determine whether or not a given proposal could possibly help to prevent these deaths, even if it worked perfectly.

* Show that even if an AIDS "penicillin" is developed -- a dramatically successful new treatment -- all bureaucratic incentives would be not to release it, but rather to conceal it for as long as possible. We will show that such concealment of dramatic break- throughs may have happened already.

* Explain the crucial scientific dispute which underlies these problems. We will show that the research establishment is right, of course, in its own terms -- but wrong in its choice of these terms, and in its uses of them. We will show that the fundamental dispute is not a scientific but a human one -- rooted in the failure of academic researchers to acknowledge that at least for now and for some time to come, patients and physicians must and do make decisions under uncer- tainty -- and that trials designed to statistically prove isolated drugs safe and effective after several years may serve the interests of drug companies, the regulatory system, and research professionals, but that there are much better research strategies for supporting the actual decisions which must be made now in the course of medical practice.

* Suggest examples of the kinds of research which need to be done. We will show that much of it is legally possible in the United States today, and can be done very economically, without the financial support of the research establishment, with money raised directly from the community. We will also show that some of the research needed cannot be done in the United States under the current regulatory climate -- and that the AIDS community must let the world know that other nations cannot rely on the United States to do anything in these areas, but must do their own work independently.

* Show where to start in building a coalition to bring the real issues in AIDS research into the open, to force an open choice: a research effort oriented to saving lives vs. writing people off a priori.

Estimating Unnecessary Deaths: A Mathematical Model

How many deaths are caused by each month or year that red tape, malice, or unworkable policies or systems delay AIDS treatment development? A simple mathematical model provides rational estimates. We propose this model as an intellectual tool to help in analyzing the costs and benefits of public policies (or lack of policies).

AIDS deaths have increased approximately at a geometric progression -- meaning that they tend to double, and then double again, and so on, during the same fixed amount of time. (Fortunately the doubling time for AIDS deaths had increased somewhat over time, meaning that the death rate is not exactly a geometric progression; this variation does not greatly affect our model, however.) We have not looked up the latest epidemiological figures, but an estimate of national (or world) AIDS deaths doubling every 18 months is close enough for the purpose of illustrating this model.

In any geometric progression (or any other sequence which doubles repeatedly), it turns out that the last doubling accounts for at least half of the cumulative total -- no matter how long the sequence has gone. To illustrate with simple arithmetic, if we take the geometric progression 1, 2, 4, 8, 16, 32, 64, 128, 256, the last value, 256, is very close to half of the total of all the numbers, which is 511. No matter where we stop the sequence, the last doubling will account for half of the grand total of all the numbers.

How does this model apply to AIDS deaths? Someday there will be a cure or effective treatment. What the model shows is that no matter when the cure is found, the last doubling before that time (about 18 months) will account for half of the cumulative total of AIDS deaths throughout the entire epidemic.

Therefore, a delay of 18 months anywhere in the treatment research and development process will account for half of the total deaths of the epidemic. An unnecessary delay of 18 months, anywhere in the political mobilization, funding, coordination of research, conducting of the trials themselves, analysis of the data, or regulatory approval, means that half of the total deaths which will ever be due to AIDS will be unnecessary. A delay as long as 36 months (3 years) in treatment development will cause three quarters of all the deaths of the epidemic -- deaths which would otherwise not have occurred.

If there is no single cure, but instead a gradual, incremental improvement of treatments which brings the deaths to an end, then the calculations become more difficult, but the bottom-line result of the model does not change.

There have been fifty thousand AIDS deaths in the United States so far. No major drugs are likely to come out of the regulatory pipeline for at least another 18 months -- during which time an additional fifty thousand deaths will occur. Therefore, the cost of any unneces- sary 18-month delay, in research or in patient access to whatever treatment turns out to be effective, can be estimated at fifty thousand lives.

But what delays are unnecessary? The research establishment tells the public that there are none -- that we are going as fast as we can, that the only issue is whether to compromise the standards of Good Science, due to public impatience, and replace it with Bad Sci- ence. Researchers who break with this party line will jeopardize their future projects and future careers, so few will speak out. Journalists, politicians, and others involved with public education and public policy naturally tend to follow the consensus of recognized scientists on scientific questions -- especially since one could oth- erwise be accused of wanting to weaken the standards of science. Good Science, like God, patriotism, and the flag, are rhetorical devices designed to be impossible to argue against -- devices often used in the absence of a good case on the merits.

Later in this article we will show how the most important drugs in the pipeline could be tested and made available in weeks or months, not the years which will be required under present procedures. First, however, we must provide some additional background necessary for the defense of this statement, which understandably may seem preposterous to the reader. How, one might ask, could drugs be tested properly in weeks, when the scientific establishment has said that such testing takes years?

What Will Happen When a Cure Is Found?

Researchers have told us that if an AIDS "penicillin" is discovered -- a drug which works dramatically well -- it will be made available to patients very quickly. However, it is hard for us to understand how all existing procedures will suddenly be suspended, in favor of a new set of procedures which so far as we know have never been written down or even thought through, let alone implemented as public policy. Governments, corporations, and professional bodies seldom work that way.

In fact, all bureaucratic incentives would be not to release such a drug, but rather to conceal it. To release it would mean that some person or institution would have to take responsibility for a momen- tous decision, with little preparation or lead time -- something bureaucracies seldom do. It would be very difficult to develop a con- sensus to abandon all existing procedures and move into uncharted ter- ritory.

But another consensus would be easy to reach. Almost by definition, the research and political establishments agree that underground, unauthorized use of a treatment is undesirable. And unless the treatment could be tightly controlled, a large grassroots use of it would be inevitable if the public knew that the drug clearly worked. There would also be extensive political activity, which would be trou- blesome to the establishment.

This means that the incentives built into the system would be to conceal an effective drug from the public, not to release it.

Large-scale clinical trials cannot be hidden, because too many patients are involved. Successful concealment is only possible at the early stages of a treatment's development, before anyone knows for sure that it works. Phase I trials could either be postponed, or drawn out. We are not suggesting that anyone would do this deli- berately to have people killed. But institutional pressures lead inexorably toward this kind of institutional denial, motivated by the normal bureaucratic fear of making major decisions and being forced unprepared into uncharted territory.

Long-term concealment of major advances in AIDS treatment may have happened already. One example is Compound Q. On April 18 The New York Times reported that "The researchers were so afraid of raising false hopes in people with AIDS that they did not disclose their findings for two years, until they were ready to test the drug in peo- ple." One of the researchers explained, "If I told you that we had found a drug that selectively kills HIV-infected cells in a single dose but then told you that it won't be available for two years, you'd go nuts." However, a version of the drug was already available and in routine use in China; it could easily have been tested in people two years ago, as soon as it was found to work in the test tube. But in fact, the secrecy around the Compound Q research largely ended on the day the patent for it was issued -- suggesting that the wait for patent approval may have been what really held up not only release of the laboratory results, but also the testing in people with HIV (which could not have been kept secret) for as long as two years. (FDA rules would have accounted for some portion of this time even if the patent were not an issue.)

Companies normally keep their work secret until they receive a patent. Otherwise, rivals could learn what they were doing and file their own patent application. While the original party would normally be protected because it filed first, its application might be found to be defective and thrown out, losing its priority and perhaps losing the patent to the rival. The time taken to receive a patent is vari- able, because there may be negotiation with the patent office over specific claims.

During the approximately two years of quiet development of compound Q, laboratory and animal research did proceed. But in view of the prior human experience in China, where the same active ingredient is given by injection in comparable doses, laboratory work has little practical relevance to the safety and usefulness of the drug as an AIDS treatment. Only tests in patients can show how well it can work. Such tests will start now, with tiny, useless doses of the proprietary drug, much as they could have been done two years ago with active doses of the Chinese version.

If Compound Q does work as well as some people think that it might, this delay in its development could by itself account for half of the total deaths to date (see the mathematical model above). We should not blame the developers, who seldom have control over the key decisions. The fault is with the lack of national will to treat the epidemic as an emergency and make the system work.

And if, as expected, it takes yet another two years go get compound Q through clinical trials before it becomes widely available, then we can add another 50,000 unnecessary deaths, from this second delay alone. For if the drug does have dramatic effects, it would take only weeks at most to discover that fact. And long-term toxicity is little danger in a drug already widely used in humans elsewhere without any such problems. Certainly it is less of a danger than untreated AIDS.

Of course, compound Q may turn out not to work at all. But even- tually, whatever drug finally does work will face the same kinds of delays. The public policies in effect today make the massive unneces- sary deaths which we have predicted inevitable, regardless of whether compound Q or some other substance turns out to be the particular occasion where the delays cause the deaths.

Another example of a major advance in AIDS treatment concealed from the public and from many physicians is fluconazole (an antifungal for opportunistic infections, not a treatment for HIV or AIDS itself). When AIDS TREATMENT NEWS first reported about fluconazole over 18 months ago (September 25, 1987), it was so little known in the United States that few physicians had heard of it. Yet even at that time two thousand persons in Europe had used the drug. Today fluconazole is approved in England; yet in the United States many physicians have never heard of it, and few know how to get it for their patients if they need it.

A third example of deadly concealment of treatment information is pneumocystis prophylaxis. This treatment, using aerosol pentamidine, bactrim, or other drugs, is now becoming the standard of care for per- sons with AIDS. But what few people realize is that pneumocystis pro- phylaxis (with bactrim) was already the required standard of care for persons at risk for pneumocystis for any reason except AIDS -- ever since the 1970s, before AIDS was known. A few physicians have used this treatment all through the epidemic, and their patients are among the long-term AIDS survivors today. Most patients, however, were never told about this option.

The point of these examples is that major AIDS treatment advances can be and are concealed from the public, and sometimes from the medical and scientific communities, at major cost in loss of human lives.

Many people believe that the commercial pressures of capitalism are driving drug research and development as fast as it can safely go. In fact, even today the AIDS market is considered too small to be very profitable. Companies are better off waiting for this market to expand. They know that nothing will beat them to the market, because they can see for months or years ahead what is coming (or not coming) through the clinical-trials pipeline. This long pipeline delay, required by FDA rules, rationalizes and protects the investments of the entire pharmaceutical industry. This is why the clinical-trials pipeline is not being seriously shortened, although empty "reforms" (those which in practice could not save lives in the foreseeable future, even if everything went right and the reforms worked exactly as they were designed to) may be provided as public-relations diver- sions.

AZT, the only AIDS drug ever allowed to move rapidly through the clinical-trials pipeline, was unique in that there was no competitive product ahead of it to be threatened. However, there will never be such a slot again.

(Note: Part II of this article will appear later.)

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