On March 3, 2017, the US Food and Drug Administration (FDA) approved desmopressin nasal spray (Noctiva) for the “treatment of nocturia due to nocturnal polyuria in adults who awaken at least 2 times per night to void.”1 According to the product manufacturer, Serenity Pharmaceuticals, nocturia is a common condition affecting “over 89 million adults in the U.S.”2
However, nocturia is a symptom, rather than a disease. Nocturia can be due to an adverse effect of a drug (eg, diuretics) or can be a marker of both benign conditions (eg, overactive bladder, benign prostatic hypertrophy, low bladder capacity) and more serious conditions (eg, congestive heart failure, diabetes mellitus, pituitary disorders). In the case of desmopressin acetate, the FDA has indicated that its use should be considered only after these and other causes of nocturia are evaluated and nocturnal polyuria is confirmed with a 24-hour urine collection.
The active pharmaceutical ingredient in Noctiva is a slight modification of desmopressin acetate, a drug originally approved by the FDA as an intranasal solution in 1978, labeled for the treatment of primary nocturnal enuresis in children, and still labeled for the treatment of central diabetes insipidus.3 The slight modification was the addition of cyclopentadecanolide, an excipient designed to enhance absorption of desmopressin across the nasal mucosa. Serenity first opened an investigational new drug application with the FDA in June 2008.3 The drug was tested in 2 double-blind, placebo-controlled, randomized phase 3 trials but failed to demonstrate efficacy in decreasing episodes of nocturia.3 Thus, 2 subsequent trials were designed using higher doses.
These 2 trials were also double-blinded and placebo-controlled.3 Patients were included if they were 50 years or older and reported 2 or more episodes of nocturia per night. The exclusion criteria included unstable diabetes mellitus, congestive heart failure, renal impairment, hyponatremia, and about 19 other criteria.3 Among the 1045 study participants, the mean age was 67 years, approximately 60% were men, and many had more than 1 etiology identified for their nocturia. The primary end points of the trials were change in mean number of episodes of nocturia per night from baseline during the 12-week treatment period.1,3 The average number of episodes of nocturia was about 3.3 per night, which decreased to about 2.1 per night with placebo and 1.9 per night with desmopressin.3
While the benefit of desmopressin was modest, the risks were substantial. The product was approved with a black-box warning for potentially life-threatening hyponatremia.1 In the clinical trials, 15 of 695 patients (2.2%) who received desmopressin experienced moderate hyponatremia (126-129 mmol/L) compared with 0 of 349 patients who received placebo, and 5 of 695 patients (0.7%) who received desmopressin experienced severe hyponatremia (≤125 mmol/L) compared with 1 of 349 patients (0.3%) who received placebo.1,3 All of the patients who had severe hyponatremia were older than 65 years. There were also 5 deaths during the clinical trials of Noctiva or their follow-up extension studies.3 All deaths occurred among patients in the desmopressin group and none occurred in the placebo group, although 3 deaths were deemed by the FDA to be unrelated to the medication.
Also of concern regarding the drug’s potential safety is that the FDA removed the indication of primary nocturnal enuresis for children 6 years or older from the label of the previously approved version of desmopressin in 2007. This was in response to 61 cases of hyponatremia-related seizures reported to the FDA, 2 of which resulted in death.4 However, the primary postmarketing requirement that appears to have been placed on the new formulation was to conduct a pharmacokinetic trial comparing systemic exposure with different doses of the nasal sprays in healthy adults. This was surprising, since the risk of hyponatremia was apparent within a narrowly defined and highly selected patient population that was closely monitored throughout the trial, with serum sodium levels tested every other week.
In October 2016, an advisory committee meeting was called by the FDA to discuss the desmopressin data.5 The meeting was attended by patients, Serenity Pharmaceuticals representatives, members of the FDA, invited physicians and researchers, and the advisory committee members. The meeting concluded with an open public hearing. Of the 6 participants who spoke during the hearing, 5 spoke in favor of Noctiva (all declared that Serenity had paid for their trip to attend), and the sixth indicated that the risks of the medication outweighed its benefits.5
Overall, the advisory committee considered the risk of hyponatremia to be rare and determined that the benefits outweighed the risks. Some committee members expressed concern that the drug would be used in patient populations excluded from the trials (eg, patients living in nursing homes) and patients underrepresented in trials (eg, patients older than 80 years) who may be at highest risk of hyponatremia.5 Regardless, the committee voted in favor 17 to 1 that desmopressin was effective and 14 to 4 that the benefits of the medication outweighed its risks.5
The recent approval of desmopressin highlights some important, but often overlooked, aspects of drug development and approval. First, there are inherent risks in recommending medications that treat a symptom without consideration of the underlying disease process. A patient with severe hyperglycemia, for example, may have fewer episodes of nocturia if prescribed desmopressin, but use of this medication also could delay appropriate treatment and may adversely affect patient care. Other examples of medications later demonstrated to be unsafe that are widely used entirely for symptom relief (eg, opioids for noncancer chronic pain) or those that did not address the underlying pathophysiology (eg, cerebral vasodilators for dementia) highlight some of the problems with this approach.
Second, the Food, Drug, and Cosmetic Act only requires that a new drug show “substantial evidence of efficacy” before the drug can be authorized for widespread use; evidence of substantial effectiveness is not required. Often, this means that manufacturers can demonstrate at the P < .05 level that the drug, compared with placebo, reduces (or increases) the primary end point. But this change may not translate into meaningful clinical effectiveness. In the case of desmopressin acetate, the placebo group had a similar numeric decrease in the number of episodes of nocturia compared with the active treatment group. These nuances are rarely communicated in the advertising or news releases accompanying drug approval, so physicians or patients would only be able to understand the limited potential benefits offered by the drug if they closely read the drug’s label or any associated publications. To address this issue, some investigators have recommended including a prominent “drug fact box” that describes the actual utility of the product.6
A drug’s ability to gain regulatory approval based on statistical significance rather than clinical significance is particularly problematic when the effect size is small, when the medication poses important risks, or both. The risks of a new medication are initially derived from outcomes during the clinical trials leading up to its approval. Desmopressin acetate nasal spray, for example, increased episodes of hyponatremia among patients in its pivotal trials as compared with placebo, albeit rarely. But in the case of desmopressin, the active ingredient has been widely used for decades. Because of this, it would be an ideal scenario in which to have performed observational cohort studies in actual practice settings to assess drug safety and to report the results along with the pivotal trial results in the drug’s label.
With its new formulation of desmopressin, Serenity is likely to receive years of guaranteed market exclusivity, permitting the company to charge a high price (although the price has not yet been announced, it will be interesting to compare the price of the newly approved drug with that of the off-patent version of desmopressin, which has a retail price of about $1 per day). In its official labeling (which few prescribers ever read), the FDA restricted the drug's indication from “nocturia” in general to “nocturia due to nocturnal polyuria.” But this subtlety may not be adequate to prevent misuse. This will be of particular concern if or when the drug is marketed through a direct-to-consumer advertising program.
The example of desmopressin shows that in the modern era of ever more permissive drug approvals, it is becoming increasingly important for physicians to critically examine the underlying data and communicate the totality of the expected benefits to patients. The risks of desmopressin did not outweigh the benefits for the FDA or its advisory committee, but they might keep more than a few physicians and patients up at night.
Corresponding Author: Michael Fralick, MD, 1620 Tremont St, Ste 3030, Boston, MA 02120 (email@example.com).
Published Online: April 6, 2017. doi:10.1001/jama.2017.4316
Conflict of Interest Disclosures: The authors have completed and submitted the ICMJE Form for Disclosure of Potential Conflicts of Interest. Dr Kesselheim reported receiving unrelated grants from the FDA Office of Generic Drugs and Division of Health Communication. Dr Fralick reported no disclosures.
Funding/Support: Dr Kesselheim’s work is supported by the Laura and John Arnold Foundation, with additional support from the Harvard Program in Therapeutic Science. Dr Kesselheim is a Greenwall Faculty Scholar in Bioethics. Dr Fralick receives funding from the Eliot Phillipson Clinician-Scientist Training Program, the Clinician Investigator Program at the University of Toronto, and the Detweiller Traveling Fellowship funded by the Royal College of Physicians and Surgeons of Canada.
Role of the Funders/Sponsors: The funders had no role in the preparation, review, or approval of the manuscript and the decision to submit the manuscript for publication.
Fralick M, Kesselheim AS. FDA Approval of Desmopressin for Nocturia. JAMA. Published online April 06, 2017. doi:10.1001/jama.2017.4316