As if the whole AIDS crisis hasn't been fought with enough controversies a couple new and rather complex ones are on the horizon that are threatening much of the antiviral/immunomodulary clinical research underway in the country. One issue is the ethicalness of placebo controlled drug trials involving HIV (AIDS virus) infected individuals. The other involves a recent Food and Drug Administration (PDA) ruling by Commissioner Frank Young allowing individuals to import into the country small quantities of unapproved drugs for personal use.
Research subjects in drug trial testing today fall into two general categories: those individuals already ill (AIDS/severe ARC) and those with only relatively minor HIV related problems usually having T-helper cells between 200-500.
Many drug trials (AZT, dextran sulfate, Imuthiol, etc.) currently going on in the country are double blind and placebo controlled. This means that neither the researcher nor the study participant knows whether or not they are getting the real drug or a placebo ("sugar pill"). Often 50% will be getting the drug and 50% the placebo. Some studies have three groups for example with two groups getting different doses of the real drug and one group getting placebo.
A placebo controlled trial for the very ill and/or those carrying a diagnosis of AIDS or severe ARC (Kaposi sarcoma is sometimes an exception) is rare. Criteria for enrollment into these studies usually include a T-cell count below 200 and significant symptoms. More and more studies though are looking at trying to prevent progression of the infection to the severe ARC or AIDS stage. These trials look for individuals who have greater than 200 T-cells and have experienced only minor HIV-related symptoms. Many of these trials have a placebo group. Most studies have slightly different criteria and there are many drugs being studied. For the most complete listing available of current drug trials and their inclusion criteria check out the American Foundation for AIDS Research (Am Far) Directory of Experimental Treatments (Phone 212-333-3118).
Doing placebo controlled trials with those who have already experienced severe illness as a result of their HIV infection and/or have a profoundly depressed immune system is generally recognized as inhumane and that is why many drug trials for people with AIDS and severe ARC are now comparing different dosages of the same drug between randomized groups or comparing different drugs and drug combinations in similarly matched populations.
Placebo control trials, in the population with more than 200 T-cells and "mild" ARC, are quite common though and are viewed by many in the research establishment as the quickest and most scientifically sound way of proving or disproving a drug's usefulness. This would then speed PDA approval of the drug for use in the populations being affected and allow for third party reimbursement (insurance, medicaid, federal assistance grants, etc.). AZT, for example (the only example!), is currently licensed to be used only when T-cells are below 200 and there are significant symptoms indicative of HIV infection present. In the real world though just about anybody can get a prescription for AZT with little trouble - getting someone to pay for it if you don't fit current PDA recommended guidelines is another story, however.
The object of the earlier stage research is to try and keep people from getting ill by intervening early with a certain drug, an antiviral or an immune booster. This is done by giving it to some people and not to others and seeing if those who do not get the drug progress to illness faster and/or in greater numbers than those who are receiving the real thing. In plain English some people would need to get ill who are not on the drug and ideally all those getting it would stay healthy. The largest placebo controlled studies in this country involve AZT. Denver has a version of this study and essentially it is the same format as most other AZT trials going on in the country.
The end point or reason for study termination is what is proving most controversial about these trials. Generally a person needs to have a T-cell count dip below 200 and stay there (T-cells bounce up & down a lot) for several months and in addition a couple of new HIV related symptoms, defined in the study protocol, need to develop. To keep anyone on study beyond this point would be truly unethical since they now meet approved criteria for the drug and if third party payment is available it is now possible. Most of these studies also prohibit pneumocystis carinii pneumonia (PCP) prophylaxis (preventive therapy). The development of PCP is rare in people with greater than 200 T-cells, but becomes a real possibility once the count has consistently dropped below 200.
The belief held by many and reinforced with studies presented in Stockholm this past June, is that a high percentage of people infected with HIV will eventually get AIDS, unless an effective intervention is developed. A real ethical issue exists here especially if it is true that it is only a matter of time until all infected people become ill. Placebo controlled studies may well be the cleanest and most efficient way to provide data on various treatment interventions - an approach that in the long run may benefit the whole while in the short run sacrificing the individual. The researcher would say there is only one sure way to find out what works and doesn't work and that is through rigidly controlled clinical trials.
As an individual infected with the virus who believes he will someday, sooner or later, have to make some difficult treatment decisions, the thought of joining a placebo controlled trial is a difficult one indeed. Even though my number one priority is my own survival I might be willing to take a certain amount of risk if the potential payoff was the cure for AIDS. Whether or not I am willing to shoot my altruistic wad on AL721, AZT, or Ampligen or dextran sulfate is another matter.
Before exploring a couple of possible compromise solutions to this problem I'll address the other issue raised about the PDA allowing private shipments of unapproved drugs into the country. The major drug this is having an effect on is Dextran Sulfate ( a large sugar molecule plus some sulfur that keeps virus from binding to white blood cells). The drug is currently imported from Japan. Researchers in San Francisco (see Science 9 Sept. '88) are bemoaning the possibility that easy access to unapproved drugs will make it impossible to do any meaningful research in the future. Donald Abrams, AIDS researcher in San Francisco, had this to say: "The FDA turned its back on us. They're making clinical trials impossible.", (Science 9 Sept. 88). I think this is a bit of an overstatement, but there are changes that are going to have to be made in how clinical research is conducted around HIV or much of it is doomed to never get off the ground or churn out worthless data.
The quite understandable reluctance to participate in a placebo controlled study and the fact that many people are obtaining and using unapproved drugs while on studies or just combining several treatments on their own is creating a situation that is threatening to throw all AIDS drug research into chaos. However, to ask desperate people in desperate situations to act altruistically, possibly at their own expense, is unrealistic and isn't going to happen.
All the energy currently being devoted to getting more research dollars and faster drug testing will be useless if study designs and treatment interventions are not modified to address the real issues confronting those infected and ill. Studies that can't attract participants or churn out muddy, contaminated data will be useless. The possibility of not knowing much about the efficacy and/or toxicity of various treatments under investigation today several years from now is a frightening possibility.
Several possible solutions to the above problems have been suggested primarily by clinicians dealing with large populations of HIV infected individuals and various progressive HIV-advocacy groups. An urgent need exists for a nationally coordinated dialogue on these vital issues involving clinicians, researchers and the various HIV-advocacy groups.
One possible solution for dealing with the problems around placebo controlled trials is to make changes in the end point or stage at which a person is taken off the study. Even though the significance of such indices as rising Beta? microglobulin levels, falling T-cells, persistent p24 antigenemia, urine neopterin levels, positive viral cultures, and certain early ARC symptoms are not completely understood perhaps they could be used in some combination as a point at which to stop study participation, rather than using more serious clinical developments (PCP for example!). Making PCP prophylaxis routine on these studies for people with T-cells consistently below 200 could also be added.
Another option would be to not do placebo controlled trials at all. Give everyone on a particular study the drug, varying the dose or perhaps comparing different drugs in similarly matched groups. Historical controls could be used to determine effectiveness of the therapy. What this means is that you could project that in a certain group of infected people at such and such a stage of HIV infection a certain percentage would get sick without intervention over say a two year period. If no one or very few people get sick or progress to serious illness on the study you could deduce that the treatment is effective. This is obviously not as good a data and another potential problem is that the PDA may not consider data generated using historical controls adequate enough to license the drug for general use.
Another possibility for monitoring and perhaps generating useful information on the treatment of HIV infection was suggested by a New York physician named Nathaniel Pier in a recent issue of John James1 AIDS Treatment News. Dr. Pier suggested setting up a national data bank that clinicians seeing many HIV positive patients could feed information into on various treatments being used in their practices. Blood work and clinical information would be included and updated on an ongoing basis. The success of such a venture implies a nationally coordinated effort which certainly doesn't exist at this time!
One more possibility to speed research would be an expansion of the community based trials. These community based trials represent an integration of scientific trials and normal medical practice. These sorts of trials are best suited for testing potential therapies that already have records of human use. The new designer drugs, CD-4 as an example, or drugs with known toxicities are better studied in large medical centers. For a list of candidate therapies for community based trials and a more detailed description of this research approach see AIDS TREATMENT NEWS issue #66, September 7, 1988.
Any AIDS treatments that move counter-to, challenge or would not benefit the very powerful forces of corporate drug companies, ambitious research scientists and/or bureaucratic intertia are going to have to struggle to get off the ground. Screaming and yelling about genocide and homophobia may feel good but change in these areas is going to take hard work. To simply point out the obvious in dramatic fashion is of little value, results in very little change and can initiate reactionary backlash. A sadly sobering statistic is a recent poll result showing that nearly 70% of the American public has "no sympathy" for gay men with AIDS in this country - I.V. drug users didn't even do that well!
Groups such as Project Inform and Documentation of AIDS Issues & Research (DAIR) and the diligent work of such people as John James have made great strides in raising important treatment issues and offering alternative ways of getting AIDS research in this country off dead center. Local community organizing by an HIV positive advocacy group focusing specifically on treatment issues and options could dovetail nicely right now in Denver in conjunction with the current Buyers Club effort. A major educational effort is needed to start bringing the knowledge level, particularly in the minority communities in Denver, up to a point where more educated choices can be made. The work of Ann Shields at the Colorado AIDS Project has been one bright spot in this process, but more work especially grassroots is desperately needed.
Joining a placebo controlled study may not be a bad decision at all especially in an area of few options (and that's Colorado!). Often the medical monitoring provided in these studies is excellent, but to maximize the situation's potential the individual must be well informed and knowledgeable about their HIV infection.
A fantastic article by Patrick Mulcahey, information services manager at Project Inform, entitled Staying Well is the Best Revenge was published recently in the San Francisco Sentinel. He had this to say about certain drug trials: "If you find yourself quitting a trial early, or cheating by taking disallowed drugs, the fault could be partly in the design of the study, which should not place your best interests at odds with its own. But distorting the study's findings or delaying its finish places you on the hit parade of those slowing down the approval process. The problem can be avoided by doing adequate research on your own ahead of time to examine whether the trial's goals suit yours and how solid the case for the treatment being studied is. Pay particular attention to how sick you have to get before other treatment is allowed." Very sound advice for those in the market for a drug research study!
Be well !!!