1. Republicans and Pharmaceutical Industry Target the FDA
2. Low Key Dual Combo Appears First to Achieve the Unimaginable

Gregg Gonsalves, TAG's Policy Director and Washington watchdog, has just returned from a week in our nation's capitol, on the heels of a major defeat in the Senate on an FDA reform bill known as S. 830. In the pages that follow, Gregg explains why the proposed reforms are cynically crafted and pernicious, and how they end up putting the foxes in the questionable role of protecting the henhouse. "Instead of modernizing the FDA," he writes, "the bill really takes us back to a past where unsafe and ineffective drugs regularly threatened the public health."

As Congress reconvenes for its autumn semester this year, one of the first bills likely to be considered on the Senate floor is the Food and Drug Administration (FDA) Modernization and Accountability Act [S. 830]. Groups representing the pharmaceutical and medical device industries are championing this legislation claiming it will "bring safe and effective new medicines to people sooner." Appropriating the language of AIDS activism, industry is urging its supporters to tell Congress to approve the bill and "to cut the red tape that is delaying cures." However, the FDA Modernization and Accountability Act has little support from groups representing patients, consumers and health care professionals. AIDS organizations are roundly opposed to the bill because it erodes the FDA's ability to evaluate the safety and efficacy of new drugs and allows industry to make claims about drugs without substantial evidence to support their claims.

Senator James Jeffords (R-VT), an erstwhile GOP moderate, crafted the bill behind closed doors with industry representatives. There have been no public hearings on the bill although it will effect the health and well-being of millions of Americans. The bill also endangers the reauthorization of another piece of legislation that everyone, patients and industry alike, agrees has speeded up the drug approval process: the Prescription Drug User Fee Act (PDUFA). PDUFA has cut drug approval times in half at the FDA by allowing the agency to use industry contributions or users' fees to hire additional reviewers. The act expires this fall and needs to be renewed in order to allow the FDA to retain staff hired under the legislation's authority. What are some of the provisions of the FDA Modernization and Accountability Act that make it so hazardous to the health of people with HIV infection and other serious and life threatening conditions?

Weakening the Efficacy Standard

One of the major goals of the proposed legislation is to reduce the number of clinical trials needed for the approval of new drugs from two to one. Industry is pushing for this provision because it would require them to do less clinical research before receiving approval to market new agents. This would reduce their own research and development costs while allowing them to get their products on pharmacy shelves faster than ever before. However, the FDA already has regulatory authority to approve drugs in special circumstances based on the results of one clinical study with confirmatory evidence. Moreover, the FDA has already shown great flexibility in approving drugs, especially for AIDS. We can now count the time it takes to approve AIDS drugs in days and weeks, rather than months and years. After years of effort by AIDS activists and others, the agency has finally found a way to maintain the delicate balance between expeditious review of new drugs and a rigorous evaluation of their safety and efficacy. In a shameless capitulation to industry greed, The FDA Modernization and Accountability Act recklessly tips the balance away from careful oversight. By completely removing the ability of the FDA to require two clinical trials for marketing, patients will know less and less about the safety and efficacy of drugs they are putting in their bodies. Instead of modernizing the FDA, the bill really takes us back to a past where unsafe and ineffective drugs regularly threatened the public health. Instead of holding industry accountable for the safety and efficacy of its products, the bill promotes corporate irresponsibility by weakening the requirements companies must fulfill to sell their goods.

The Fox Guarding the Henhouse

Not content with gutting the efficacy standard, the bill's sponsors have included provisions that allow medical device companies to directly contract with private reviewing firms to recommend approval of their products. This means a maker of a new pacemaker or any "implantable, life-sustaining or supporting device," could handpick, hire and pay a for-profit company to review its new device application and recommend approval to the FDA. This is a ludicrous invitation to conflict of interest. Device manufacturers would seek out review companies with the most relaxed appraisal standards and for-profit review companies looking for their business would have no incentive to provide an exacting evaluation of new products. Consumer groups like the Patients' Coalition (of which TAG is a member) have suggested a more reasonable alternative. The Patients' Coalition recommend the institution of medical device users' fees modeled on the drug users' fees collected by the FDA under PDUFA. This would allow the agency to hire additional reviewers to expedite the approval of new devices without compromising the health of the American public.

Unfettered Promotion of Off-Label Drug Use

One of the most difficult provisions of the bill for AIDS treatment advocates is a proposed amendment that would allow off-label promotion for unapproved uses of prescription drugs. Off-label drug use for treating HIV is common. In a study by Carol L. Brosgart of the Community Consortium in San Francisco, Brosgart and her coworkers found that in a cohort of over 1,100 patients, 81 percent received at least one drug off-label and that 40 percent of all reported drug use was off-label. The bulk of the off-label drug use was for the treatment and prevention of HIV-related opportunistic infections. Despite widespread off-label drug use in HIV infection, AIDS groups are opposed to the amendment that would allow companies to promote drugs for uses that are not approved by the FDA.

While supporting the right of doctors and patients to use drugs off-label, AIDS groups do not support the right of drug companies to market their drugs for these unofficial indications. The Patients' Coalition and others have argued that off-label promotion provides "a disincentive for drug companies to conduct research into new efficacious and safe uses of approved products." In HIV infection, the optimal use of many drug regimens is still to be determined. For instance, we do not know when to start combination antiretroviral therapy or which combination is best to begin with. We also do not have a full picture of the complex interactions of the protease inhibitors with many other common medications. Many of the unanswered questions about these drugs are about their use in off-label indications. AIDS advocates argue that the right to market and promote drugs for expanded indications must be linked to the completion of studies that confirm the clinical benefit of these broader uses. Otherwise, people with HIV infection will be forced to make important treatment decisions without adequate information to guide their judgments.

Accelerated Approval: Republican Style

Several years ago, in the quest to expedite the approval for drugs for patients with serious or life-threatening conditions, the FDA enacted regulations that allowed for the approval of drugs based on surrogate endpoints. However, this accelerated form of approval is contingent on the completion of post-marketing studies confirming the clinical benefit of the surrogate effect.

The FDA Modernization and Accountability Act would codify the accelerated approval process but without requiring post-marketing studies. This provision would essentially allow approval of drugs for serious and life-threatening conditions without evidence of their ability to extend the health and life of patients. The accelerated approval regulations reasonably balanced the need for quicker approval for drugs for AIDS and other serious illnesses with the need for information on the clinical effects of these agents. However, Senator Jeffords' bill would endanger the lives of people with HIV infection by depriving them of the most basic knowledge about the drugs that they are taking.

AIDS advocates are urging that provisions be included in the legislation that actually enhance the ability of the FDA to require post-marketing studies of new drugs to elucidate their clinical effects. The Patients' Coalition has proposed that the Secretary of Health and Human Services be allowed to impose civil fines on companies that do not conduct post-approval research. This would strengthen the accelerated approval regulations instead of watering them down.

Epilogue

The FDA Modernization and Accountability Act would radically transform the regulation of drugs, medical devices, food and cosmetics in the United States. Currently, the FDA enjoys wide support among the American public for its role in protecting patients from unsafe and ineffective drugs. The American public is clearly not clamoring for the kinds of drastic changes in the agency that the FDA Modernization and Accountability Act would provide.

Why then has Senator Jeffords decided to champion the narrow, commercial interests of the pharmaceutical and medical device industries over the wider interest of protecting the public health of all Americans? Clearly, the Senator has been led down this path by the powerful pharmaceutical industry lobby. But he is not alone. Important Democratic senators like Christopher Dodd of Connecticut and Barbara Mikulski of Maryland are co-sponsoring the bill as well. On this bit of legislation, there seems to be a bipartisan willingness to feed at the trough of the drug and medical device companies. Meanwhile, the Clinton Administration refuses to oppose all but the most noxious provisions of the act. As TAGline went to press, the Senate overwhelmingly approved the FDA Modernization and Accountability Act, 98 to 2. The two lone voices of opposition to the bill were Democratic Senators Edward Kennedy of Massachusetts and Jack Reed of Rhode Island. The bill is now rapidly moving through the House and will in all likelihood be signed into law by the President.

In a recent issue of Nature Medicine, a group of immunologists make two obvious but rarely discussed observations about the limitations of current triple drug cocktails for HIV infection: First: If, upon cessation (or failure) of treatment the level of virus in the blood rebounds to the same level as before treatment, then the immune system clearly hasn't "learned" anything new about controlling the infection during this treatment-induced temporary cease-fire. Secondly, If, after being "undetectable" for a couple of years (blood, lymph nodes, the whole gamut), viral load still surges back within 2-4 weeks of stopping therapy, then there must be cells in the body that current therapies are not reaching.

A couple of months ago, Aaron Diamond's first eradication candidate was scheduled to stop his therapy. After some two years on a triple combination (AZT+3TC+ ritonavir), the Aaron Diamond team could find no detectable HIV RNA in his body. Neither could they culture virus from any of his cells. "Dodge," as the patient was called, was featured on a special Friday Nightline segment. "Just one name," the reporter explained, "like Madonna or Prince." The show was called "The First Cure." But the first cure was not to be. Just as they were about to take Dodge off his unpalatable potion to test whether or not the 'cure' had worked, scientists at Johns Hopkins called with disappointing news. After artificially stimulating some of Dodge's cells in the lab, they were able to make his cells grow HIV anew. If it could happen in a petri dish, they argued, it could happen in Dodge's body. Withdrawal of Dodge's treatment would have to be postponed.

What the Nightline program didn't tell its riveted audience (didn't know) was that a similar experiment had already been conducted in France -- and with much more stunning results. As part of an on-going study with the combination of ddI and the 30-year old cancer chemotherapy drug hydroxyurea, an Argentinean physician based in Lyon (Dr. Jorge Vila) had identified 2 patients who, after 12 months of treatment with ddI and hydroxyurea, had no detectable HIV-RNA in their lymph nodes or blood. Low levels of proviral DNA, however, (believed to be incapable of producing new virus) were detected in some of the cells of each patient. Although the quantitation tests in these 2 patients might have been less rigorous (or less thorough) than those in the Aaron Diamond case, the patients agreed to stop therapy. That was in 1995. One year later, Vila and his colleagues report no rebound of HIV. Neither can they detect infectious virus after in vitro cell activation. The study was published as a letter to The Lancet at the end of August (vol. 350:635-6).

Although clearly very interesting, what this all means is still unclear. The fact that there was no viral rebound for an entire year after only one year of treatment with this dual combination is remarkable. (Recent revisions of earlier mathematical models estimate that fully suppressive therapy would need to be given for a minimum of 6 years - and perhaps for life.) The authors propose that hydroxyurea's success is due to its ability to permeate into the viral reservoirs of HIV infection: so-called "resting" T-cells and macrophages where the popular triple combos can't reach. Others posit the moderate immunosuppressive activity of hydroxyurea as a possible explanation for its unique effect in the setting of HIV infection. (Remember Jean-Marie Andrieu's prednilisone paper and Fauci's cyclosporin-A experiments?)

Rather than targeting HIV directly, hydroxyurea is said to inhibit HIV replication by acting upon the cellular enzyme ribonucleotide reductase, which HIV needs to assure a continual supply of nucleotides in order to successfully assemble a DNA chain from its viral RNA. A drug from the same pharmaceutical house that brought us ddI and d4T, hydroxyurea is little promoted for one very simple reason: Bristol Myers' patent on it expired in 1995. So no one's gonna get rich on this. Bristol Myers said it has no interest in financing further research with hydroxyurea, and recently pulled out of an on-going study of the drug within AmFAR's community-based clinical trials network (CBCT).

Exciting as all this is, it would be inaccurate to say that HIV has been eradicated from these two patients. Both still harbor cells with fully integrated HIV-DNA. No one can be certain that these cells, upon bumping into their assigned antigen months or years from now, won't become activated and begin again to pump out millions and millions of copies of new HIV. The authors of the study propose that this HIV DNA is defective and incapable of producing infectious virus, and that is a plausible hypothesis. It's less clear, at least for the time being, that the results achieved in these 2 patients can be reproduced in larger numbers of patients.

To begin with, both patients were recently infected. No one has yet done this hydroxyurea experiment with individuals with chronic HIV infection. Secondly, Dr. Vila's patients had not been treated with any other HIV medicines prior to going on the ddI+hydroxyurea combination. Will the same results be achievable in drug-experienced patients? Thirdly, both patients had extremely low viral loads (676 and 1,120 copies/mL) even before therapy. (Some critics question whether the individuals were even productively infected, although HIV-antibody seropositivity was confirmed by ELISA and Western blot.) Various other experiments with ddI+ hydroxyurea have shown that at most 30-40% of patients become "undetectable" on this combination. Patients with relatively high viral loads will almost certainly not. Will hydroxyurea perform as well in combination with, for example, 3TC, nevirapine or the protease inhibitors? Lastly, it's entirely possible that these two individuals might have cleared their HIV infection on their own. Maybe there was something special about their immune responses.

A third intriguing anecdote was delivered by Franco Lori (Research Institute for Genetic and Human Therapy, Pavia, Italy) at the Gallo meeting in Baltimore, MD on September 16th. An HIV-infected German man with baseline HIV-RNA viral load of some 85,000 copies is reported to have driven the virus down to "undetectable" levels with the combination of indinavir+ddI+hydroxyurea. After 144 days on the treatment, an acute case of hepatitis A caused him to stop his medications for 3 weeks. Before restarting them, his physicians checked the amount of virus in his blood. It was still undetectable -- and has remained so for 9 months.