AIDS Treatment News #163, November 23, 1992
John S. James

Better AIDS Drugs: The Biggest Obstacle

To improve AIDS/HIV treatment and save lives of those already infected, the greatest need by far is better antiretroviral drugs. And the main reason progress in new drugs has been so disappointingly slow concerns obstacles near the beginning of the drug "pipeline" -- in the late preclinical and early clinical stages of drug development. This part of the development process has been overlooked, not because of scientific disagreements but because of systemic political and commercial snafus. It urgently needs more attention:

* Because of improvements by the FDA, the blockage near the end of the drug pipeline has been greatly reduced; ddI, ddC, and now d4T have been made available. The problem is that no major anti-HIV drugs are now in the pipeline, except for some, like tat and protease inhibitors, which are still very early in clinical trials. Therefore, no important advances are likely from the mainstream drug-development pipeline for at least several years.

(An FDA press release dated October 19, 1992 said that the FDA had "received" more than 500 IND applications "to test drugs or biologics that may have potential in treating AIDS and other HIV-related conditions." But when the press release listed "potential AIDS therapies publicly acknowledged by their sponsors to be under study," it had to stretch considerably to include any anti-HIV drugs. The following is the FDA's list of "INDs for experimental antiviral agents": compound Q, N-butyl DNJ, ribavirin, ddC, beta interferon, d4T, and AZDU. None of these is likely to be a major advance in HIV treatment, and some appear to be dead. Vaccines, which can also be HIV treatments, are listed separately; but there is considerable debate about whether any therapeutic vaccine has shown clinical benefit or is ready for large trials. And as for the drugs the FDA could not name because they had not been publicly acknowledged by their sponsors, none could have progressed to large human trials without being well known. In short, no important HIV drugs will emerge for some time. The image of hope and competence projected by the press release is an illusion.)

* Dozens if not hundreds of potential anti-HIV drugs or lead chemicals have been produced in university and other laboratories, tested in viral cultures or in animals, and published in major, peer-reviewed journals. Usually development stops there, since no one involved has the money to finish the preclinical development required or to begin human tests. Since no public agency takes responsibility for shepherding these compounds into further development if justified, they usually wait indefinitely unless some pharmaceutical company picks them up -- unlikely when there is no data on biological activity in humans.

* The existing AIDS trials networks (ACTG, CPCRA, CBCT) are focused on a later stage of research. Today they are often conducting dubious trials because they have no compelling drugs to study.

* Some people believe that the National Cooperative Drug Discovery Group program (NCDDG-HIV) is addressing this problem. We have not attended their meetings, but we hear that they focus on theories of rational drug design -- which clearly will be the ultimate future of drug development, but so far has not been effective for AIDS. (Much of the focus is on improving high-tech tools such as computer imaging systems, but the drugs produced with those tools have not worked.) For the current epidemic, we also need empirical development of the most promising leads available, even those resulting from chance discoveries instead of high-tech science. But this work is undervalued because it is usually routine and not glamorous.

* The bottom line is that we are suffering a serious imbalance in research, because the drugs which most need attention now for saving lives are not well positioned to build the constituency needed to motivate their continued development. Drugs which are already marketed, or almost ready for marketing, can develop industrial, medical, and public constituencies. Rational drug design generates both industrial and academic support. But no constituency champions a drug developed by one scientist or academic team, with no pharmaceutical sponsor, and with no human tests.

Recommendations

* The executive branch must take responsibility for proactively shepherding critical drugs through the development process -- not just wait for some pharmaceutical company to move.

* The U. S. National Cancer Institute has shown that government can successfully carry out early human drug development when necessary. Both legislative and executive branches should expand this work.

* The executive branch should set up a medical research ombuds office, where anyone who knows about research snafus of any sort can report them, and can expect to get action when appropriate. Most of the problems which block clinical trials or other research are red-tape accidents which could be cleared up by a few phone calls from an office with the president's authority behind it. When broader policy issues are involved, the office should research and prepare recommendations for the executive branch, for Congress, and for foundations, companies, and other private organizations.

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