FDA Drug Approval to Change its Ways?

Pharmacology Watch

In This Issue: FDA drug approval to change? Urinary incontinence in women; how metabolism of certain drugs can be predicted by genetic analysis; bowel preps may compromise renal function especially in the elderly according to a new study; FDA Actions.

Should the FDA change the way it approves drugs? With the number of drug withdrawals and black box warnings in the last 10 years, the FDA's approval process has come under scrutiny. Many have focused on the Prescription Drug User Fee Act (PDUFA), originally enacted in 1992 which transformed the FDA's drug approval process. At that time the FDA was underfunded and understaffed. PDUFA was negotiated with the pharmaceutical industry to help defray the cost of new drug approvals. Under this plan drug manufacturers would pay a user fee for each drug review to help cover the costs of FDA staff; however the FDA would be required to make a decision on each application within a fixed date after submission. Some have argued that this arrangement makes the FDA too beholden to the industry that it regulates. There has also been concern that the required deadline for approval has accelerated the approval process, perhaps at the expense of drug safety. A new study from Harvard in the March 27 New England Journal of Medicine looks at the relationship between drug review deadlines and safety issues—specifically whether drugs approved immediately before their deadlines are associated with a higher rate of post-marketing safety problems. As compared with drugs approved at other times, drugs approved within the two months before their PDUFA deadlines were more likely to be withdrawn for safety reasons (odds ratio 5.5; 95% CI, 1.3 to 27.8), and more likely to carry a subsequent black box warning (OR 4.4; 95% CI, 1.2 to 20.5), and more likely to have one or more dosage forms voluntarily discontinued by the manufacturer (OR 3.3; 95% CI, 1.5 to 7.5). The authors conclude that PDUFA deadlines have appreciably changed the approval decisions of the FDA, and drugs approved immediately before their deadline are more likely to have subsequent safety problems. They also state, "A plausible hypothesis is that relying more on staffing and less on deadlines could result in the same degree of review efficiency without increasing the risk (and resulting greater cost) of unanticipated drug-safety problems." (NEJM 2008; 358:1354-1361).

Help for Women with Urinary Incontinence

Urinary incontinence is a common problem in women, affecting one third of women over the age of 65, and up to 25% of younger women. The NIH has published a systematic review of nonsurgical treatments for urinary incontinence in women, reviewing the most commonly used modalities. Pelvic floor muscle training (Kegel exercises) plus bladder training resolved urinary incontinence compared with regular care. Different injectable blocking agents and medical devices all had similar improvement rates, while electrical stimulation failed to resolve urinary incontinence. Oral hormone administration improved urinary continence, however transdermal or vaginal estrogen results were inconsistent. Adrenergic drugs were ineffective. Oxybutynin (Ditropan) and tolterodine (Detrol) were both effective at resolving urinary incontinence compared with placebo, however duloxetine improved but did not resolve incontinence. The authors conclude that pelvic floor muscle training and bladder training are effective interventions for women with incontinence as are oxybutynin and tolterodine. Duloxetine improved but did not resolve incontinence and electrostimulation, medical devices, injectable blocking agents, and local estrogen therapy were inconsistent (Annals Int Med. 2008; 148: 459-473).

Human Genome Study Affects Pharmacology

Phamacogenetics and pharmacogenomics are terms that practicing physicians will have to get use to the next few years. The study of the human genome has led to many breakthroughs, not the least of which is the realization that metabolism of certain drugs can be predicted by genetic analysis. The FDA has recently altered the labels of both warfarin and carbamazepine to incorporate language encouraging health professionals to consider pharmacokinetic testing prior to prescribing these drugs in some situations. Some are calling this personalized medicine, but there are concerns ranging from the cost/benefit of these analyses to the potential for abuse of this information, including genetic discrimination. The March 19 issue of JAMA is entirely devoted to medical genomics (the study of how genes interact and influence the biology and physical characteristics of living things) and includes articles reviewing genetic analysis for cardiovascular risk, osteoporosis, post-traumatic stress disorder, deep venous thrombosis, and cancer. The issue includes a patient page "Genetics: the Basics" with a glossary of terms (good for patients and doctors alike!).

Bowel Preps and Renal Function in Elderly

Oral sodium phosphate solution (OSPS) bowel preps may compromise renal function especially in the elderly according to a new study. Researchers in Texas retrospectively reviewed 286 patients who received phosphorus containing bowel preps (Fleet Phospho-Soda, Accu-Prep, Visicol) for colonoscopy or sigmoidoscopy and 125 controls. Both groups had similar baseline characteristics, the mean age was 68, 85% were white, and 64% female. In patients treated with OSPS, the baseline glomerular filtration rate was 79 mL/min/1.73 m2 which declined to 73 mL/min/1.73 m2 at 6 months after exposure to OSPS. The GFR in the control group was stable at six months. A drop in GFR in the treatment group was still present one year later although to a lesser degree. Concomitant use of ACEIs or ARBs or the presence of diabetes were significant determinants of the fall in GFR after OSPS preps. The authors conclude that use of oral sodium phosphate solution bowel preps is an under-diagnosed cause of acute kidney injury and that if patients are to receive these preps, physicians should focus on adequate hydration and avoidance of ACEIs and ARBs, especially in diabetic patients (Arch Int Med. 2008; 168:593-597). The authors state that their health-care system has banned the routine use of OSPS as bowel cleansing agents for colonoscopies and has switched to polyethylene glycol agents for any patient with stage 3-5 CKD. An accompanying editorial points out that of the two most commonly used methods for colon preps, oral sodium phosphate solutions are often preferred over polyethylene glycol because of the lower volume and better tolerability. Oral phosphate solutions however have been associated with hypokalemia, hypophosphatemia, hypernatremia, and hypocalcemia. Although these are generally transient, acute phosphate nephropathy has also been described with OSPS. Based on the findings, caution should be exercised using phosphorus preps especially in those patients who are risk for renal failure (Arch Int Med. 2008; 168:565-567).

FDA Actions

The FDA has issued in early communication about an ongoing safety review of tiotropium (Spiriva), Boehringer Ingelheim's inhaler for bronchospasm associated with COPD. Ongoing safety monitoring has identified a possible increased risk of stroke associated with use of Spiriva. Based on data from 29 placebo-controlled studies the risk of stroke was 8 patients per 1000 treated for one year with Spiriva vs 6 patients per 1000 treated with placebo. The FDA has not confirmed this analysis and recommends the patient should not stop taking Spiriva before talking to their doctor.

The FDA has approved desvenlafaxine for the treatment of depression. The drug is a metabolite of venlafaxine (Effexor) which has recently gone generic in some formulations. Desvenlafaxine is a serotonin-norepinephrine inhibitor which may have less drug-drug interactions than venlafaxine. The drug will be marketed by Wyeth as "Pristiq."


This supplement was written by William T. Elliott, MD, FACP, Chair, Formulary Committee, Kaiser Permanente, California Division; Assistant Clinical Professor of Medicine, University of California-San Francisco. In order to reveal any potential bias in this publication, we disclose that Dr. Elliott reports no consultant, stockholder, speaker's bureau, research, or other financial relationships with companies having ties to this field of study. Questions and comments, call: (404) 262-5431. E-mail: iris.young@ahcmedia.com.