Statement of the American Sleep Apnea Association
to the Food and Drug Administration
by Christin L. Engelhardt, Executive Director
September 25, 2003
Good afternoon. My name is Christin Engelhardt, and I am the Executive Director of the American Sleep Apnea Association, a non-profit organization dedicated to seeing that all people with sleep apnea are diagnosed and treated properly. Thank you for letting the ASAA present its view on Cephalon's application at today's hearing. In the interest of full disclosure, I first want to acknowledge that the ASAA has received some support from Cephalon for our activities over the last four fiscal years but only less than $4000 per fiscal year. All activities, such as exhibiting at medical meetings and National Sleep Apnea Awareness Day, have been initiated by the ASAA, never by any company. I personally hold no stock in Cephalon or any other company in the sleep field, other than what may be in a retirement mutual fund.
Sleep-disordered breathing-including sleep apnea and upper airway resistance syndrome-is a common disorder that affects millions of Americans of all ages. Yet it is relatively rarely diagnosed, in part because the most common symptoms-snoring and falling asleep easily and/or sometimes inappropriately-are not recognized as symptoms of a potentially serious medical disorder. Consequences of untreated sleep apnea may be significant and include sleepiness, high blood pressure and other cardiovascular disease, morning headaches, feelings of depression, impotence, and memory problems. Once diagnosed, the patient can be prescribed a course of treatment. Treatment options include oral appliances, weight loss, positional therapy, surgery, and the use of a Continuous Positive Airway Pressure (CPAP) device. Medications may also be prescribed for central sleep apnea. Which treatment option is best for the patient depends upon the severity of the sleep apnea and other aspects of the patient's medical history.
The gold standard and most consistently effective therapy is the CPAP machine. CPAP works by pushing air (via tubing that connects the CPAP machine to an interface that touches the patient's face) through the airway passage at a pressure high enough to keep the airway open. The pressure is set according to the patient's sleep apnea; pressure that is too low will not be as effective in eliminating the apneas and hypopneas. While effective, CPAP may be difficult to use. Hence published compliance rates can be suboptimal. Of course, adherence to any therapy for any chronic disorder is typically suboptimal; for example, adherence to pharmacological therapy is approximately 50%. Moreover, it is possible-and important-to improve adherence to CPAP. Our publication "If Your Patient Is Not Complying with CPAP" was written for professionals precisely for this purpose, and I should note that Cephalon has,
through its support of our presence at medical meetings, helped us to distribute this to physicians and other health care professionals.
Comfort is often an issue with CPAP, and sadly patients may not get all the equipment and/or assistance they need to utilize this effective treatment all night, every night. For example, patients need access to all available options in the mask and machine features so they can find the best one for them, hence the ASAA publications "Choosing a CPAP" and "Choosing a Mask and Headgear." (There are many masks on the market now and manufacturers constantly work to develop more comfortable masks, but there is no one best mask or machine; each patient has different personal preferences.) In addition, some patients need to be desensitized to the mask. It often takes a skilled health care professional to enable a patient to adhere to CPAP therapy, yet unfortunately it can be difficult, if not impossible, for all patients to gain access to this expertise. Even patients who are assertive and persistent have been known to give up on treatment before they find a comfortable option. Thus proper treatment of sleep-disordered breathing does not always follow the diagnosis. The ASAA finds this state of affairs unacceptable.
The three main causes of sleepiness are sleep deprivation (endemic in our country), untreated sleep disorders, and circadian rhythm misalignment caused by factors such as jet lag and night work. Alcohol and certain medications may also cause sleepiness, as can depression and certain illnesses. Numerous studies show that untreated sleep apnea causes sleepiness and that CPAP-even when not used all night, every night-reduces sleepiness. Likewise, there are studies that show that patients with inadequately treated sleep apnea are likely to remain sleepy. One may also have treated sleep apnea and be sleepy from sleep deprivation or night work. Studies also show that patients who appear to have well-treated apnea may have residual sleepiness. Regardless of the cause, sleepiness can have adverse consequences and requires attention.
Modafinil was originally approved by the Food and Drug Administration to improve wakefulness in patients with excessive daytime sleepiness associated with narcolepsy. It has also been investigated to treat residual sleepiness in patients with treated sleep apnea (defined in one study as using CPAP on a regular basis at least four hours a night on five nights per week, not all night, every night). Modafinil has been shown to be safe in clinical studies and in clinical use. It is thought to be safer than amphetamines which have also been prescribed for residual sleepiness in sleep apnea. Still it is not benign; no drug is.
As noted earlier, some sleep apnea patients experience residual sleepiness despite getting sufficient sleep and having effective therapy for the apnea. Because of this, based on the limited available data, the ASAA can support the narrow use of modafinil in patients whose sleep apnea is being treated appropriately and sufficiently and whose other causes of sleepiness, including sleep deprivation, insufficient CPAP pressure, or mask leak, have been addressed or excluded. It is worth noting that to our knowledge, no published study looked at the role of sleep deprivation in the sleepiness. Yet the ASAA believes modafinil has a role, albeit a minimal one, in managing sleep apnea, and the absence of a relevant indication for the drug can be a barrier for patients to get insurance coverage for a medically necessary medication.
Still we cannot emphasize enough that prior to prescribing medication for sleepiness after a
patient has been treated for sleep apnea, the physician must examine and address other possible causes of the patient's sleepiness, particularly CPAP adherence. As Dr. Jed Black wrote in his editorial "Pro: Modafinil Has a Role in Management of Sleep Apnea" published in the American Journal of Respiratory and Critical Care Medicine, one unpublished study found that two-thirds of (31 of 46) CPAP patients who were sleepy after being on CPAP for at least six months were no longer sleepy "following 30 days of subsequent 'upgraded' CPAP use." At the same time, fifteen of the 46 subjects still had residual sleepiness and underwent a trial of modafinil. It however must be remembered that this pharmacological approach treats only the symptom of sleepiness, not the underlying cause of sleepiness. It does not prevent apneas and the consequential oxygen desaturation and sleep fragmentation that may lead to cardiac disease and other health problems. So while it may be easier for physicians to prescribe and for patients to take modafinil, both must know that taking modafinil does not render CPAP unnecessary. This point must be made clear on the labeling and in any advertising, particularly as one study found a statistically significant reduction in CPAP use among subjects given modafinil compared to the control group.
In addition, in cases of extreme sleepiness thought to be from untreated sleep apnea, modafinil may have a short-term role to minimize the direct risk of sleepiness until definitive treatment is initiated and found to be effective. While we are aware of no formal studies on the use of modafinil as "bridge therapy," the doctor must make a clinical judgment on the potential benefits and risks of prescribing modafinil and of not prescribing modafinil. Sleepiness does carry risks. Yet modafinil must not be seen as a panacea; the drug must not hinder appropriate diagnosis and treatment of the underlying cause for the sleepiness.
The ASAA is clearly committed to seeing that modafinil, should it be approved for additional indications, be prescribed appropriately. We believe Cephalon as the manufacturer must vigilantly educate the public and prescribing physicians about the appropriate role of modafinil. The ASAA remains willing to continue to work with Cephalon and with other interested parties on our common goal of helping people with sleep disorders.
Again, thank you very much for this opportunity to speak to the panel today.
Given its mission, the ASAA can comment only on the use of modafinil for sleep-disordered breathing and only in adults: because it is riskier to use in children medications with a central nervous system effect with an unknown mechanism of action, in the absence of sufficient data the ASAA can comment only on the use of modafinil in adults.
