Consumer watchdog group Public Citizen is criticizing the U.S. Food and Drug Administration’s decision to expand the approved use of Vanda Pharmaceutical’s sleep disorder drug Hetlioz (tasimelteon), a melatonin receptor agonist, to treat non-24-hour sleep-wake disorder. The group argues the FDA decision to approve its use beyond the medication’s original indication is in part because they believe blind people will have different side effects than people who have vision.
Background
Hetiloz (tasimelteon) was approved under FDA’s orphan drug pathway. Non-24-hour sleep-wake disorder is estimated to affect 100,000 people who are blind. The disorder is a chronic circadian rhythm disorder that causes problems with the timing of sleep. Non-24 occurs almost exclusively in persons who are completely blind. Light does not enter their eyes and they cannot synchronize their body clock to the 24-hour light-dark cycle. Hetiloz was the first FDA approval of a treatment for the disorder.
The drug was also reviewed in 2013 by the FDA’s Peripheral and Central Nervous System Drugs Advisory Committee. The committee agreed, almost unanimously, that the drug had been proven to be effective and safe for patients with non-24-hour sleep-wake disorder.
As we previously noted, Congress passed the Orphan Drug Act in 1983, recognizing that drug companies would incur a financial loss when developing important drugs for rare conditions. The Act offers incentives to induce companies to develop drugs and other medical products for the small markets of individuals with rare disorders, defined as diseases affecting fewer than 200,000 people in the U.S.
In its petition, Public Citizen’s asks FDA to (1) Require revision of the indication in the “Indications and Usage” section of the product labeling; (2) Require revision of the “Carcinogenesis,” “Mutagenesis,” and “Pregnancy” sections of the product labeling to include additional risk information from FDA’s pharmacology review; (3) Require distribution of a medication guide with each prescription of tasimelteon, informing patients of the newly narrowed indication of the drug’s risks; (4) Ask the sponsor to send a “Dear Doctor” letter notifying physicians and other health care providers of the corrected, narrower indication; (5) Mandate that the sponsor conduct a large, adequately powered postmarking clinical trial.
Discussion
Public Citizen reviewed FDA’s approval letters for the medication. It notes FDA’s press release on the second approval of tasimelteon stated its use in treatment for non-24-hour sleep-wake disorder in totally blind individuals. However, in the second approval letter, FDA expanded tasimelteon’s indication to include non blind individuals.
The petition considers this a “post-hoc rationale,” explained in an FDA letter published by Public Citizen, which includes three observations: (1) The sponsor had conducted trials in sighted individuals with jet lag disorder as well as in other models of circadian rhythm disruption; (2) There have been a few case reports of patients with severe brain damage in whom non-24-hour sleep-wake disorder seemingly resulted from interruption of circadian pathways while conscious visual pathways remained relatively intact, and treatment with melatonin was reported to be effective in at least some of these patients; and (3) There have been some reports that sighted individuals with non-24-hour sleep-wake disorder as a result of a lack of exposure to sunlight had been successfully treated with melatonin.
Public Citizen calls these observations “limited” and “insufficient” to support the expansion of the indication for tasimelteon beyond totally blind individuals as proposed in the NDA. Arguing that side effects would be different for blind patients in comparison to nonblind patients, the petition argues the FDA’s observations cannot offer “substantial evidence” that the drug is effective for the treatment of individuals with non-24-hour sleep-wake disorder who are not totally blind.
Public Citizen continues: “Viewed in their entirety, the FDA review documents cited … clearly indicate that the actual mistake by the agency was not in the wording of the indication in the first FDA approval letter for tasimelteon. Rather, the mistake was in the wording of the ‘Indications and Usage’ section of the product labeling initially approved by the agency that omitted the reference to blind individuals. The FDA compounded this mistake by issuing a second approval letter that changed this indication.” Public Citizen concludes FDA “should have required that the sponsor revise the label to include the correct indication, not issue a second approval letter asserting that the initial approval letter was in error.”
Conclusion
Public Citizen’s petition attempts to draw a distinction between blind and non-blind patients, arguing that lack of eyesight would significantly change a medication’s adverse effects. This is, as noted by Public Citizen’s own petition, in direct conflict with FDA’s conclusion that the medication would be beneficial to those who are not blind.
This is an example of the ludicrous level of scrutiny that organizations such as Public Citizen will draw against manufacturers and may be faced by orphan drug manufacturers in the future. It is hard to imagine how a drug that works on blind people for sleep disorder would not benefit non blind individuals. The FDA was correct in their assessment and these types of nuisance complaints highlight that you just can’t please some people.
Your arguments will appear to be valid to people who know little about circadian rhythm disorders — the vast majority of people, of course. It is very unfortunate that Non-24 in the blind and in the sighted share the same name, as the causes are entirely different while some of the observable symptoms are similar. This is understandable because the disorders were named before researchers knew about the differences.
Non-24 in the blind is secondary to their blindness. It is easily explained; you yourself explain it adequately in your article. The cause(s) of Non-24 in sighted people appear to be genetic, not yet understood or described, and the disorder is debilitating.
“Safe For Blind People, Not Safe For Others?” is your headline. The drug’s safety is not in question. It is, of course, being tried in sighted people; they are in dire need of help. There is no reason to believe that Hetlioz will be any more or less effective than the earlier melatonin receptor agonists, ramelteon (trade name Rozerem), agomelatine (trade names Valdoxan, Melitor, Thymanax) as well as the hormone melatonin itself.
I don’t know if PublicCitizen knows/understands any of the above information. They seem to be more interested in the formalities, that is, FDA not following its own rules.
A very thorough article about non-24-hour sleep-wake disorder in both the blind and the sighted is at NORD, National Organization for Rare Diseases: https://rarediseases.org/rare-diseases/non-24-hour-sleep-wake-disorder/