Thinking straight about orphan drugs, Part 5.

In my last post, I canvassed two common ways that manufacturers game the Orphan Drug Act. Today I’ll cover the third—“salami slicing.”

Many common diseases have subtypes, and manufacturers can seek to approve a drug either for the broader disease or for those subtypes. When some of the subtypes can be characterized as orphan diseases, the manufacturer may be tempted to seek approval for one subtype after another, earning seven years of marketing exclusivity for each new approval. As a result, a drug that’s targeted at a population much larger than 200,000 people can call itself an orphan.

The practice is known as “salami slicing,” and FDA tries to guard against it by approving only medically plausible disease subsets. The challenge is that lots of disease subsets are medically plausible. Take cancer, for example. Physicians at Johns Hopkins recently wrote a cri de couer about how drug manufacturers strategically exploit variations in cancer etiology to secure approval of orphan indications.

[T]he convergence of [the organ and gene models of cancer] means that almost any cancer medication can be maneuvered into an orphan disease category. For example, the proto-oncogene HER2 is most commonly associated with breast cancer. However, HER2 can also be found in glioblastomas, non-small cell lung cancer, gastric tumors, adenoid cystic carcinomas of the parotid gland, pancreatic cancer, and ovarian cancer. Each one of these organ-based cancer types can be further substratified by classifying them into HER2+ and HER2- cancers.

So if you’re a drug manufacturer, you slice the cancer salami, securing approval after approval for “different” cancers. Take transtuzumab (Herceptin), for example, which has been approved to treat HER2+ breast cancer—not an orphan disease. But the drug has also been approved to treat HER2 pancreatic cancer and HER2 gastric cancer, both of which are orphans.

Salami slicing raises at least four concerns. First, granting seven years of market exclusivity for every new disease subset allows manufacturers to extend their drug monopolies. It’s not quite right to say, as the Johns Hopkins researchers do, that “extreme prices are made possible” by that exclusivity: the patent system already grants a monopoly to at least some of these drugs, so it’s also the patent system’s fault. But for drugs with weak patents or whose patents have lapsed, the Orphan Drug Act is to blame.

Second, a practice of seeking approval for disease subtypes will result in fewer clinical trials on whether a drug works for the disease as a whole. Without those trials, many patients who could benefit from the drug won’t receive treatment.

Third, Phase III clinical trials for orphan drugs are less intensive than for conventional drugs, enrolling about one-third as many patients. For true orphan drugs, that’s probably OK: reducing the stringency of FDA approval may encourage their development. But easing up on drugs that aren’t actually orphans will mean a general reduction in the quality of clinical trials.

Fourth, salami slicing may enable a manufacturer to maintain market exclusivity for off-label uses, even when the drug is no longer patented. When a cluster of orphan drug designations makes it difficult for a generic to get a toehold, generic manufacturers may lack adequate incentives to bring a competitor to market. And without generic competition, an orphan drug has a lock on the market for both approved and off-label uses.

So yes, drug manufacturers are systematically gaming the Orphan Drug Act. What can we do about it? I’ll turn to that soon.


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