NIH Halts Trial on Saline to Treat Shock The National Heart, Lung, and Blood Institute has stopped a clinical trial studying the benefits and safety of administering a highly concentrated form of saline solution in the ambulance (before hospital arrival) to trauma patients suffering from shock due to severe bleeding. The trial was stopped last month because patients who received the concentrated saline solutions were no more likely to survive than those who received a normal saline solution. A parallel study of concentrated saline for traumatic brain injury without shock continues.

Typically, in the crucial early minutes before blood transfusions can be safely administered in the hospital, trauma patients receive normal saline solution intravenously in the field to compensate for blood loss and buy time. Concentrated saline solution is believed to compensate for blood loss more effectively, lessen excessive inflammatory responses and prevent brain swelling. The trials of concentrated saline solutions are conducted through a network of clinical research sites in the United States and Canada called the Resuscitation Outcomes Consortium. A major focus of the ROC is to conduct randomized trials of promising new treatments for severe traumatic injury in real-world settings.

The NHLBI suspended enrollment into the concentrated saline (hypertonic) shock study on Aug. 25, 2008, due to concerns raised by ROC’s Data and Safety Monitoring Board (DSMB), an independent group monitoring the study. In the shock trial, the DSMB observed no difference among the treatment groups in 28-day mortality. However, more of the patients receiving hypertonic saline died before reaching the hospital or in the emergency department, while more of the patients receiving normal saline died during the remainder of the 28-day follow-up period.

The DSMB requested further analysis of these observations. The additional analysis looked at in-hospital data (following saline administration in the field) from 545 patients in the largest enrolling hospital from each site. The results, presented to the DSMB on Feb. 25, 2009, confirmed the previous findings that deaths occurred earlier in patients who received hypertonic saline and that there was no significant difference in cumulative mortality between the hypertonic and normal saline groups at 28 days. However, the new analysis did not fully explain the mortality findings. The investigators are completing analyses of these results and will submit them for publication in a peer-reviewed scientific journal.

Although there were no similar concerns about earlier mortality in the traumatic brain injury trial, this trial was also temporarily and voluntarily suspended last August so that emergency medical service personnel could be retrained to enroll only brain-injury patients, not those who would have been eligible for the shock study. The traumatic brain injury study resumed in late November 2008.

In both the shock and traumatic brain injury ROC hypertonic saline trials, patients were randomly selected to receive either approximately 8 ounces of intravenous normal saline, which has nearly the same concentration of salt as blood and is considered standard care; approximately 8 ounces of hypertonic saline, which has a higher salt concentration; or about 8 ounces of hypertonic saline with dextran, a carbohydrate which can prolong the effect of the hypertonic saline. The stopped trauma shock study tested whether hypertonic solutions improve survival by 28 days after injury, compared to usual care with normal saline.

The now-resumed trial of brain-injured patients continues to investigate whether the hypertonic solutions improve both survival and brain function in patients 6 months after traumatic injury. As the traumatic brain injury study continues, ROC investigators hope that hypertonic saline will prove beneficial for this application.

FDA Amends Action on Opioids The Food and Drug Administration last month amended its March 30, 2009, action warning manufacturers to stop the production and distribution of certain unapproved prescription opioids. The amendment allows the continued marketing and distribution of one particular type of opioid—a high concentrate morphine sulfate oral solution—on an interim basis.

The FDA took the action in response to concerns from patients and healthcare professionals in the palliative care community that the March 30th action would cause a shortage of 20 mg/mL morphine sulfate oral solution. This product is widely used to alleviate pain in terminally ill patients. The agency has determined that this dosage form is medically necessary, and should remain on the market until an approved alternative becomes available to the patients who need it.

“While the FDA remains committed to ultimately ensuring that all prescription drugs on the market are FDA approved, we have to balance that goal with flexibility and compassion for patients who have few alternatives for the alleviation of their pain,” said Douglas Throckmorton, M.D., deputy director, FDA’s Center for Drug Evaluation and Research in a statement. “In light of the concerns raised by these patients and their healthcare providers, we have adjusted our actions with regard to these particular products.”

To address the needs of palliative care patients, the FDA will allow companies that are currently manufacturing and distributing versions of this unapproved prescription product to continue to do so on an interim basis until an FDA-approved version of this product or another acceptable alternative therapy becomes available for this patient population.

Last month’s decision only affects the high concentrate morphine sulfate solution. According to FDA, companies that received warning letters from the FDA on March 30 concerning other unapproved prescription opioid products will still be required to cease production and distribution of those products within the timeframes set out in those letters. The other products affected by the enforcement action are: immediate release tablets containing morphine sulfate, hydromorphone and oxycodone.

The March 30 action is part of the FDA’s Unapproved Drugs Initiative, which seeks to ensure that all drugs available on the U.S. market have met FDA’s standards for safety, efficacy, and quality.

Benefit of Exercise for Patients with Chronic Heart Failure Confirmed Regular exercise is safe for heart failure patients and may slightly lower their risk of death or hospitalization, according to results from the largest and most comprehensive clinical trial to examine the effects of exercise in chronic heart failure patients. Supported by the National Heart, Lung, and Blood Institute, the study also found that heart failure patients who add regular, moderate physical activity to standard medical therapy report a higher quality of life compared to similar patients who receive medical therapy only. Researchers with HF-ACTION (Heart Failure—A Controlled Trial Investigating Outcomes of Exercise Training) published two papers in the April 8, 2009, issue of the Journal of the American Medical Association. The study was conducted at 82 centers in the United States, Canada and France.

Earlier, smaller clinical trials have suggested that exercise is beneficial for heart failure patients, and clinical guidelines recommend moderate exercise for this condition. Nonetheless, safety concerns have persisted. HF ACTION followed 2,331 patients with moderate-to-severe systolic heart failure (average age 59) for up to four years (average of 2.5 years). About one-half of the participants were randomly assigned to receive usual care alone, which included medical and device therapy as prescribed by their physicians and educational materials on disease management. They were also asked to engage in 30 minutes of moderate physical activity on most days of the week.

The other half of the participants were in the exercise training group, and they received usual care plus 36 sessions of group-based, supervised aerobic exercise training (walking or stationary cycling) of up to 35 minutes three times per week. These participants were asked to transition to home-based training at the same intensity five times per week for the remainder of the study and received a treadmill or stationary bike for home use and a heart rate monitor.

Compared to the usual care group, the exercise training group had slightly fewer (statistically non-significant) deaths or hospitalizations from any cause. When researchers adjusted the findings (as specified in the study design) for the strongest predictors of death or hospitalization—initial exercise capacity, history of atrial fibrillation, depression, cardiac pumping function and cause of heart failure—exercise training was linked to an 11 percent lower risk of all-cause death or hospitalization and a 15 percent lower risk of cardiovascular-related death or heart failure hospitalization. In addition, there was no significant difference in serious adverse events between the two groups, such as an abnormal heart rhythm, hip fracture or hospitalization related to exercise, suggesting that exercise training was well tolerated and safe.

The researchers noted that the benefit of exercise may be underestimated by the observed study results because many of the usual care participants also exercised. In addition, adherence to prescribed exercise in the exercise training group was below goal in the majority of participants. Overall, the exercise training was well tolerated.

Furthermore, after training, participants in the exercise group scored significantly higher than those in the usual care group on a standard, self-administered quality-of-life questionnaire. Participants reported fewer physical and social limitations and symptoms, and improved quality of life after three months. The improvements persisted throughout the follow-up period and were consistent regardless of sex, race, or age.

FDA To Review Last of Pre-1976 Medical Devices The Food and Drug Administration last month announced that manufacturers of 25 types of medical devices marketed prior to 1976 must submit safety and effectiveness information to the agency so that it may evaluate the risk level for each device type. Devices found by the FDA to be of high risk to consumers will be required to undergo the agency’s most stringent premarket review process.

These 25 device types were marketed in the U.S. prior to the Medical Device Amendments to the Food, Drug, and Cosmetic Act of 1976. That law authorized the FDA to review new medical devices. Last month’s announcement is FDA’s first step toward completing the review of Class III device types predating the 1976 law, as was recommended by the U.S. Government Accountability Office in a January 2009 report to Congress.

The FDA classifies medical devices into three categories according to their level of risk. Class III devices represent the highest level of risk and generally require a showing of safety and effectiveness before they may be marketed. Class III devices include heart valves and intraocular lenses. Class I and Class II devices pose lower risks and include devices such as adhesive bandages and wheelchairs. Most Class II devices and some Class I devices are marketed after submission of premarket notifications establishing their substantial equivalence to legally marketed devices that do not require premarket approval.

After Congress enacted the medical device law in 1976, the FDA classified these 25 devices types into Class III (premarket approval). Under the law, these devices were not immediately required to undergo the premarket approval process. The law required the FDA to issue a rule subjecting the devices to that requirement. Until that time, new devices within those device types have been cleared through the premarket notification process, in which the agency determines whether they are substantially equivalent to legally marketed devices not requiring premarket approval.

Devices that present a new intended use or include new technology that presents new questions of safety or effectiveness may not be found substantially equivalent and require premarket approval.

As of 1994, there were approximately 149 Class III, pre-1976 types of medical devices that had not yet been subject to premarket approval. Since then, the FDA has made significant progress in reviewing and issuing new regulations for all but 27 of those device types, including the review of 55 types since January 2000. The FDA has already initiated this process for two device types, which will be completed separately.

Manufacturers of the 25 remaining device types must submit the requested information within 120 days. The FDA will review the submitted data and, based on the risk level, issue regulations for each device type that either will require manufacturers to submit premarket approval applications or will re-classify the devices into Class I or Class II.

Researchers Invited to Design Experiments for Space Station The National Institutes of Health and NASA are partnering to conduct biomedical experiments that astronauts could perform on the International Space Station. In a notice to scientists at universities, medical centers and companies across the United States, the NIH announced its willingness to fund highly meritorious biomedical experiments that could utilize the unique environment in space and produce breakthroughs to improve human health on Earth. The International Space Station provides a special microgravity and radiological environment that Earth-based laboratories cannot replicate. Congress opened the U.S. portion of the International Space Station to other federal agencies and university and private sector researchers when it designated the U.S. resources as a National Laboratory in 2005.

The NIH solicitation is the next step in a new partnership to apply the National Laboratory to research that complements NASA’s space exploration efforts. Already, biomedical experiments conducted on the International Space Station have addressed how bone and muscle deteriorate, how humans fight infectious disease and how cancers grow and spread. The NIH-NASA program is designed to encourage a new cadre of health researchers from a variety of disciplines to incorporate the space environment into their experiments, and will support them as they prepare their experiments for launch and analyze their data following a mission.

In addition to NIAMS, other sponsors of the announcement include the National Cancer Institute; the National Center for Research Resources; the National Heart, Lung, and Blood Institute; the National Institute on Aging; the National Institute on Alcohol Abuse and Alcoholism; the National Institute of Biomedical Imaging and Bioengineering; the National Institute of Child Health and Human Development; and the National Institute of Neurological Disorders and Stroke.