In the news ... 2007

FDA Rejects Use of Serostim for
Treating HARS, a Form of Lipodistrophy

July 19, 2007

The FDA has rejected an application by SERONO for use of Serostim (human growth hormone/HGH) in the treatment of one type of lipodystrophy often seen in HIV positive people treated with highly active antiretroviral therapy. HARS (HIV-associated adipose redistribution syndrome) is commonly described as unusual large deposits of hard fats around the abdomen, called Visceral Adipose Tissue (VAT).

In the early days of protease inhibitor use, the condition was mistakenly called “Crix-belly” because it was often seen in people using Crixivan, the most popular protease inhibitor of the era. Such fat may also accumulate in the upper body, forming what is called “buffalo hump” at the back of the neck. This disfiguring redistribution of hard fat is very troubling to people with HIV even if it is not directly life threatening. To date, there have been no proven remedies for HARS other than to discontinue the use of the drugs believed to contribute to it (mostly boosted protease inhibitors).

Serono, manufacturer of a form of HGH (Serostim) which is approved for the treatment of AIDS wasting syndrome, conducted studies using the drug in hopes of reducing HARS. When the studies demonstrated significant reductions in VAT and HARS, the company applied to the FDA for a license to promote the drug for this use. Most physicians and activists familiar with the data seemed satisfied that the product worked, at least to a modest degree, though were disappointed that the benefits quickly faded unless the use of the drug was continued.

Consequently, it was something of a surprise on July 13 when the FDA rejected the application. Surprisingly though, while rejecting the application and forbidding the company from promoting the use of the drug for this purpose, the FDA at the same time required the company to publish a new label for the drug which included all the findings of the studies that had been submitted. This is surely going to be confusing to many physicians. The FDA seems to be saying to the company “you can’t sell the drug for this purpose” while also requiring the company to show physicians and patients all the data that shows that the product works for the treatment of HARS.

At this point, no one is quite sure what this means or how it will be interpreted. One difficult result of this action is that the company will be forbidden from letting patients apply for their Patient Assistance Program if they say they are planning to use the drug to treat HARS. To get assistance, patients would have to ask their physicians to lie about the intended use of the drug. It is likely that the company and the investigators from its studies will seek to meet further with the FDA to plead their case.

Commentary
The FDA hasn’t made any public statements explaining its action but some individual FDA representatives have said the agency was concerned that the benefits of the drug, while real, might not outweigh the risks associated with its use. In particular, they have cited concerns about the possibility that HGH would increase the risk of diabetes or heart disease in HIV-positive people.

There are already concerns that many HIV treatments contribute to heart disease and diabetes, so it isn’t clear why this one is being singled out. In the actual studies of the drug for treatment of HARS, the group receiving the placebo actually had a higher number of cases of new onset of diabetes than the groups receiving HGH. Other studies, however, have had different results, though none have shown major increases in diabetes. When heart disease or new onset diabetes (or insulin resistance) appear in people with HIV while on treatment, it is very difficult to determine the cause. Highly active antiviral treatment is believed by many to increase these risks. But the risks of heart disease and diabetes also increase with age; they are caused by dietary factors; and HIV itself may increase the risk. Thus, when an additional drug, such as HGH is added to the mix anything short of a dramatic increase in heart disease or diabetes is all but impossible to interpret.

Many physicians and regulators may prefer to err on the side of caution and take the position that unless they can be sure the additional drug isn’t responsible for such side effects, they recommend not using the product. The trade-off between risk and benefit, however, may look quite different to individual patients who have to live with the disfiguring effects of HARS. Since the earliest days, Project Inform has always argued in favor of letting the patient and his or her physician make the final judgment about risk and benefit.

The FDA is currently in an increasingly conservative state of mind. They have been heavily criticized, perhaps unfairly, for recent problems that have appeared in the long-term use of some drugs, such as Vioxx and the diabetes drug Aavandia. In both cases, long-term follow up and collective analysis of dozens of studies has identified heart disease problems that were not seen in individual studies.

Critics accuse the FDA of being too quick to approve new drugs. It’s is unclear though just how many studies, and for how long a new drug should be studied before allowing it to be sold. There may be a price to be paid for premature approval, but there is also a price for delaying or denying approval inappropriately. The pendulum swings back and forth at the FDA between safety and speed. At the moment, the emphasis is primarily on safety, and consequently, treatment for HARS will not be available any time soon. While it is not our concern whether the company gets to sell its drug more widely or make more profits, it is a concern that patients have now lost the possibility of access to the only drug that has shown any proven benefits against HARS.