Prescribers can soon expect to see prescription drug labels with clearer descriptions of the conditions and patient populations for which an FDA-approved drug is indicated, under draft guidance for industry that the FDA released Friday.
Although the agency didn’t indicate specific problems with existing labels that may have prompted the new guidance, some of the examples of preferred language give clues. For instance, “if a study evaluating a drug in adults enrolled patients of a certain age range … the indication should be worded to reflect the broader age group (i.e., ‘in adults’) rather than the exact ages studied,” the guidance stated, as long as there is no reason to believe the drug is unsafe in adults outside that range.
Overall, the agency’s goal with the new guidance is to give prescribers more precise yet also more understandable information on which conditions a drug is approved to treat, and which patients are appropriate to receive it.
In addition to suggesting the information labels should include, the guidance also indicates what they should omit — mainly, information so obvious that it merely clutters the label. As one example, the document said, “if an indication is clearly worded as being approved for use in combination with another drug, there is no need for a limitation of use stating that the subject drug should be used only in combination and not as monotherapy.”
Likewise, labels need not “address the absence of data in populations in which the drug was not studied” when it’s clear the drug isn’t indicated for those populations. For example, the label for an anti-rejection drug indicated for heart transplant patients doesn’t have to state that there is no data on its use in lung transplant patients.
“We believe this guidance will help healthcare providers identify appropriate treatment options for their patients,” said Jacqueline Corrigan-Curay, MD, MD, director of the Office of Medical Policy in FDA’s Center for Drug Evaluation and Research, in announcing the draft guidance.
The agency will accept comments on the draft guidance for 60 days, after which it will issue a final version. FDA guidance documents are non-binding but manufacturers typically pay close attention to them.
Clinicians will now have an easier time finding out how some of their Medicare patients with diabetes are doing, thanks to a change in Medicare’s coverage policy for continuous glucose monitors (CGMs) that use smartphone apps to transmit data.
In January 2017, the Centers for Medicare & Medicaid Services (CMS) announced that certain continuous glucose monitors would be covered by Medicare. In its announcement, the agency noted that “Medicare does not cover CGMs approved by the FDA for use as adjunctive devices to complement, not replace, information obtained from [fingerstick] blood glucose monitors. In our view, such devices are not used for making diabetes treatment decisions, such as changing one’s diet or insulin dosage … and therefore, have not been covered under Medicare.”
However, CMS added, “the FDA recently approved expanding the indications of one CGM product to include replacement of blood glucose monitors for diabetes treatment decisions.” It was that product — the Dexcom G5 CGM — that CMS approved coverage for. (Abbott’s FreeStyle Libre CGM is now also covered.) But the coverage came with a caveat: the device would only be covered if patients didn’t use the smartphone app to transmit information about their glucose readings.
According to a March 23, 2017 article from Medicare contractor CGS explaining the new coverage policy, “Coverage of the CGM system supply allowance is limited to those therapeutic CGM systems where the beneficiary ONLY uses a [CGM data] receiver classified as DME [durable medical equipment] to display glucose data. If a beneficiary uses a non-DME device (smartphone, tablet, etc.) as the display device, either separately or in combination with a receiver classified as DME, the [CGM supplies are] non-covered by Medicare.”
“That effectively eliminated the opportunity to use a smartphone together with, or on different days than, the receiver,” explained James Scott, president and CEO of Applied Policy, a consulting firm in Alexandria, Va.
The new policy, announced last month by CMS but not yet finalized, eliminates that caveat. “CMS heard from numerous stakeholders who shared their concerns that Medicare’s CGM coverage policy limited their use of CGMs in conjunction with their smartphones, preventing them from sharing data with family members, physicians, and caregivers,” the agency said. “After a thorough review of the law and our regulations, CMS is announcing that Medicare’s published coverage policy for CGMs will be modified to support the use of CGMs in conjunction with a smartphone, including the important data-sharing function they provide for patients and their families.”
“This is good news for everybody and it’s the right thing to do,” said Scott, whose clients include Dexcom and who lobbied to get the policy changed. “Most of all, it’s a victory for people with diabetes who are now able to access the full functionality of a CGM system, particularly alerts and alarms that can share unusually high or low readings with a loved one. For example, if [people with diabetes] have a high or low blood sugar while they’re asleep, the app can alert their partner who can wake them up” in time to take action.
The change will also make it easier for patients to share the information with doctors “to the extent that doctors want that information,” he continued. “For the right patients and their doctor who wants to closely watch [their readings] for a period of time … this is a big benefit.”
“This really should have happened when they [first] announced they would cover CGMs,” said Joanne Rinker, RD, CDE, director of practice and content development at the American Association of Diabetes Educators, in Chicago. “This helps the elderly who have caretakers, so they can keep up with what’s happening throughout the day.”
It also helps clinicians because “you could have a person with diabetes call their diabetes educator and say, ‘Can you look at my CGM for the last 2 days? Everything is acting crazy,’ and we can talk it through over the phone,” she said. “It gives that opportunity to be able to help in real time.”
The change will affect Medicare claims for CGMs submitted on or after June 7, 2018, according to an update from contractor CGS. CMS said it would issue a revised policy article “in the near future.”
A novel treatment for squamous cell carcinoma (SCC) using HPV vaccine could some day prove useful in patients who are poor surgical candidates, have multiple lesions, or who defer surgery, researchers reported.
A single case report of an elderly woman with multiple, inoperable cutaneous basaloid SCC, showed that systemic and direct intratumoral injection of 9-valent HPV vaccine resulted in complete regression of all cutaneous malignant tumors, according to Anna J. Nichols, MD, PhD, of the University of Miami Miller School of Medicine in Miami, and colleagues.
All tumors resolved 11 months after the first injection of vaccine, they reported in JAMA Dermatology.
No systemic adverse effects were reported, they added, and at the patient’s last follow-up visit 24 months after the first intratumoral dose of the HPV vaccine, there was no clinical evidence of SCC recurrence.
“The marked regression of numerous SCCs after initiation of the intratumoral injections eliminated the need for additional treatment,” the authors wrote. “Tumors not directly injected with the vaccine also regressed, possibly by local dispersion of the vaccine or its effects on immune-mediated mechanisms. These findings suggest that the 9-valent HPV vaccine can provide a therapeutic option for inoperable cutaneous SCCs, in addition to its approved use to prevent anogenital HPV infection.”
The mechanisms for the vaccine’s therapeutic efficacy in cutaneous malignant tumors are not yet clear, they acknowledged. Similarly, it is not known whether systemic use of the vaccine played a therapeutic role.
“The potent therapeutic benefit may reflect a combination of immunologic, antiviral, and antitumor effects of 9-valent HPV vaccine,” they suggested.
Nichols’ group pointed out that in patients with SCC and basal cell carcinoma (BCC), surgery remains the standard of care. For patients who are poor surgical candidates, or who have multiple lesions, or who defer surgery, alternate treatment options are limited.
The investigators noted that the 9-valent HPV vaccine is currently used to treat including recalcitrant cutaneous warts and oral papillomas. In a previous study, they showed that vaccination against HPV in immunocompetent patients could prevent the development of SCC and BCC.
“This, combined with the fact that other types of vaccines delivered directly into tumors elicit immune responses capable of eradicating tumor cells, led to our using a combination of systemic and intratumoral HPV vaccine for this patient,” Nichols told MedPage Today.
Nichols confirmed that her group did not test for the presence of HPV DNA in the patient’s tumors. “There is evidence that HPV proteins may modify the cellular response to UV exposure, possibly augmenting UV-induced DNA damage,” she added.
Looking ahead, this therapeutic approach may have broader applications in the treatment of SCC skin cancer, Nichols said. “Our multidisciplinary team is preparing to expand on this report by conducting a small proof-of-concept clinical trial in the near future.”
Adam Friedman, MD, of George Washington School of Medicine and Health Sciences in Washington, called the case report “interesting,” but said he did not see this approach being widely adopted or undergoing clinical testing.
“My impression from this case is that the efficacy is a result of immunostimulation induced by the HPV vaccine, rather then a direct immune response to HPV,” Friedman, who was not involved in the case report, told MedPage Today.
The report also did not discuss cost, “as insurance will surely not cover this treatment,” noted Friedman, who is a fellow of the American Academy of Dermatology. It also didn’t discuss “the potential adverse effects associated with the immune activation,” he said.
“It is important to realize that HPV may be involved in some squamous cell carcinoma, but basal cell carcinoma is four to five times more common,” pointed out Whitney A. High, MD, of the University of Colorado School of Medicine in Boulder.
“In basal cell carcinoma, HPV seems to be much much less involved that it is in squamous cell carcinoma,” noted High, who was not involved with the case report.
High also said she found the case report interesting. “I am quite glad the authors shared the experience, for it may trigger additional critical work in the area, which might, potentially, lead to additional management strategies.”
However, she emphasized that “far more study would be necessary before we routinely relied upon this as a treatment regimen.”
In the case report, a female patient in her 90s was treated at a university-based outpatient dermatology clinic from March 17, 2016, through Feb. 27, 2017. She was then followed until May 21, 2018.
The patient was initially treated with two doses of intramuscular HPV vaccine given 6 weeks apart. Three weeks after the second intramuscular dose, three of the largest tumors were treated intratumorally with 9-valent HPV vaccine (0.5 mL) diluted with sterile saline (2.5 mL).
Over the next 8 months, three similar doses of the HPV vaccine were administered intratumorally, resulting in complete resolution of the tumors.
Although the patient received no further treatment, histopathologic analysis of a single, small, pink, scaly papule on her right leg, where the tumors had been, revealed mild cellular atypia of basal keratinocytes with hyperkeratosis.
Nichols disclosed no relevant relationships with industry. Some co-authors disclosed a patent pending for this application of HPV vaccine.
Reviewed by Robert Jasmer, MD Associate Clinical Professor of Medicine, University of California, San Francisco
While BAN2401 failed to show a significant difference from a placebo in a 12-month Phase 2 study, the companies said an 18-month study yielded a significant effect in patients treated with the highest doses of the drug. This caused Biogen’s share price to rise nearly 20 percent.
Adam F’s Take
Feuerstein, a renowned biotech reporter, warned investors not to get overly excited. The details released concerning the study are surface-level; Feuerstein called the report “a sliver of positive news” that leaves “lots of unresolved questions.” Still, he welcomes any glint of hope in Alzheimer’s treatment, which he described as having a historical “100-percent failure rate.”
He said BAN2401 is like Biogen’s “back-up drug.” Another Alzheimer’s candidate from Biogen, aducanumab, is undergoing Phase 3 clinical trials.
Feuerstein said something like this Biogen news “could get people more interested” in larger-cap biotech stocks, but warned of cautiousness in general moving forward.
You can listen to Adam’s full interview on the Benzinga YouTube page by following this link. Adam’s appearance begins at the 9:05 mark.
Looking Ahead
While the July 5 report didn’t provide in-depth data, which Feuerstein noted wasn’t unusual, investors should be on the lookout for Alzheimer’s conferences in the coming months where Biogen will likely present a more complete trial report. The Alzheimer’s Association International Conference begins on July 22 and the American Neurological Association’s annual meeting begins Oct. 21.
Akorn’s (AKRX) trial with Fresenius (FSNUY) over the companies’ $4.3B merger agreement is set to begin on July 9 in Delaware Chancery Court and analysts at RBC Capital and Deutsche Bank are weighing the risks and rewards. AKORN FILES COMPLAINT: In April, Akorn filed a complaint in court asking that Fresenius Kabi be required to fulfill its obligations under the companies’ definitive merger agreement. Akorn said at that time that “Fresenius’ attempt to terminate the transaction on the pretext that the findings from the ongoing investigation are a breach of the merger agreement is completely without merit. The previously disclosed ongoing investigation, of which we have voluntarily notified and are in regular communication with the Food and Drug Administration, has not found any facts that would result in a material adverse effect on Akorn’s business and therefore there is no basis to terminate the transaction…We intend to vigorously enforce our rights, and Fresenius’ obligations, under our binding merger agreement.” Akorn had agreed to be acquired by Fresenius in April 2017 for approximately $4.3B, or $34 a share, plus the assumption of approximately $450M of debt. In February, Fresenius began an investigation into alleged FDA data breaches at Akorn and in April, the company decided to terminate the merger agreement saying the decision was “based on, among other factors, material breaches of FDA data integrity requirements.” Following Akorn’s filing in court, Fresenius said its probe uncovered fraud and accused the company of submitting phony data to the FDA on its antibiotic drug. RBC SEES ‘PATH TO CLOSING’: In a note published this Monday, RBC Capital analyst Randall Stanicky said the trial should bring some clarity to the ongoing deal uncertainty. He said he continues to see a path to closing and notes risk and reward are both high, as Akorn’s stock is trading at $16-$17 versus the $34 deal price. The analyst added he has not yet seen persuasive evidence justifying the deal break based on his review of litigation documents and a call with legal experts. AKORN UPSIDE/DOWNSIDE ‘LOOKS INTERESTING’: On Tuesday of this week, Deutsche Bank analyst Gregg Gilbert noted that Akorn is seeking a ruling that Fresenius be required to complete its acquisition per the merger agreement. The analyst believes the upside versus downside profile for Akorn from the current price is worth considering. He sees three potential scenarios: Fresenius is required to acquire Akorn for $34 per share, representing 102% upside; the deal breaks and Akorn trades down to single digits on a standalone basis, or 69% downside; the companies settle for a price below $34 but well above the current stock price, which could yield more upside than downside. Gilbert believes Akorn’s upside/downside “looks interesting” ahead of the key event, he told investors. PRICE ACTION: Akorn was up 3.5% to $18.15, while Fresenius rose 1.4% to $20.41 in late morning trading on Friday. The trial is set to begin on Monday and is scheduled to last through Friday July 13 at this point, RBC recently told investors. “Before the Move” is The Fly’s recurring series of exclusive stories that identify potentially market moving events, along with analyst predictions, ahead of the news.
In an experimental setting involving healthy volunteers, stimulating the prefrontal cortex with mild electrical current reduced aggressive impulses and brought moral judgments more into line with societal norms, researchers said.
Active transcranial direct current stimulation (tDCS) reduced the likelihood of intent to commit a physical assault by about half, and intent to commit sexual assault by 70%, reported Olivia Choy, MD, of the Nanyang Technological University in Singapore, and colleagues.
Approximately 31% of the results can be attributed to participants believing that the acts of assault were morally wrong, the researchers added.
“Understanding the etiology of aggression and the development of new interventions are paramount to a public health approach to violence reduction,” Choy and colleagues wrote. “This first known application of prefrontal tDCS to intentions to commit aggression takes a modest step towards advancing knowledge about the neural mechanisms that regulate aggression.”
“I think our approach to solving crime and violence is social,” study co-author Adrian Raine, PhD, of the University of Pennsylvania in Philadelphia, told MedPage Today.
“People blame [crime and violence] on poverty or racial discrimination, and those things are important, but I think what we’re saying is that there is another side of the coin that so far has been ignored: the biological part of the equation,” said Raine. “We hope we will open a new door to benign approaches to changing biology in a sensible manner in order to change behavior and reduce violence and victimization.”
In the study, published in the Journal of Neuroscience, 81 adults (36 males, 45 females) were randomly assigned to active or sham tDCS, and followed up 1 day after the experimental session. Participants were shown images of physical and sexual assault (e.g., smashing a beer bottle over a person’s head) and asked to rate their likelihood of acting them out for real, on a scale of 0-10, as well as the “moral wrongfulness” of doing so. In another exercise, conducted on a computer screen, they were shown a doll representing a partner or friend and were told they could “release negative energy” by sticking as many pins as they wished into the doll.
Participants in the active group received tDCS treatment targeting the dorsolateral prefrontal cortex, at 2 mA for 20 minutes, while the control group received current for only 30 seconds but remained hooked up to the stimulator device for the remaining time. Participants’ and experimenters’ guesses at study end about treatment assignments indicated that blinding was preserved.
Of the 86 participants, those who received tDCS reported an average score of 1.15 for committing a physical assault, compared with 2.19 for those in the placebo group. Similarly, the active group reported a score of 0.26 for intent to commit an act of sexual assault, compared with 0.86 for those in the placebo group.
The reductions in the active group can be at least partly explained by higher ratings of moral wrongfulness (b=-0.51, 95% CI -1.14 to -0.10, P<.05, in the aggressive acts; and b=-0.34, 95% CI -1.11 to -0.03, P<.05 in the sexual assaults), the authors said.
Active electrical stimulation did not appear to affect outcomes in the doll-based task.
For this study, the team targeted the dorsolateral prefrontal cortex, although aggressive behavior has also been tied to other sub-regions such as the ventromedial prefrontal cortex and the anterior cingulate cortex, Choy and colleagues explained.
While the control group contained equal parts males and females (21 of 42), the active group had more females (24 of 39). All subjects were over the age of 18 and in order to participate, could not have any contraindications to brain stimulation such as having metallic implants; neurological, cardiovascular, or psychiatric illness; or a history of adverse reactions to tDCS.
The researchers also adjusted for factors such as childhood placement in a foster home, parental divorce and unemployment, and having used food stamps in their youth.
Study limitations, the team said, were first, that the sample was taken from a healthy population, excluding subjects diagnosed with mental or physical health disorders. Second, the study measured moral judgment and aggression concurrently and did not establish a control region of the brain to test alongside dorsolateral prefrontal cortex stimulation. Lastly, since the aggression levels were measured just 1 day after the intervention, only short-term effects were evaluated.
“A stronger evidence base which includes more consistent findings, documentation of long-term beneficial effects, and a comprehensive effort to rule out potentially aversive side effects is required before this technique can be considered in practice to reduce aggression perpetration,” Choy and colleagues concluded.
The authors reported having no competing financial interests.
Reviewed by F. Perry Wilson, MD, MSCEAssistant Professor, Section of Nephrology, Yale School of Medicine and Dorothy Caputo, MA, BSN, RN, Nurse Planner
The FDA will move away from testing all donated blood and blood products for Zika virus, the agency said Friday.
Citing the decrease in Zika cases in the U.S., as well as cost effectiveness and a desire to make the process less burdensome, the FDA revised its interim guidance from August 2016, which stated that all blood and blood products should be tested for the virus.
The agency released a revised final guidance document explaining the new policy. They stated “in order to comply with applicable testing regulations, blood establishments must continue to test all donated Whole Blood and blood components for Zika virus using a nucleic acid test.” But they added that pooled donation using an FDA-licensed screening test may be sufficient, unless there is a higher risk of local mosquito-borne transmission of the virus in a specific geographic area, which would trigger the need for individual donation testing.
“When Zika virus first emerged, the unknown course of the epidemic and the observed severe effects from the disease indicated that individual donor testing was needed to ensure the continued safety of the blood supply,” Peter Marks, MD, PhD, director of FDA’s Center for Biologics Evaluation and Research, said in a statement. “Now, given the significant decrease in cases of Zika virus infection in the U.S. and its territories, we are moving away from testing each individual donation to testing pooled donations.”
When the interim guidance emerged, the U.S. was less than a month removed from the first cases of locally transmitted Zika virus in south Florida. But the Red Cross protested these interim guidelines at a meeting that November with the FDA, saying that this was cost prohibitive and burdening hospitals, and that the process had uncovered only “a handful” of donations that tested positive for the virus.
Bolstering this argument was a study published in the New England Journal of Medicinein May that found just nine confirmed positive cases of Zika among almost four million donations, and that the projected annual cost for national screening would be $137 million.
The FDA said they will “continue to monitor the situation closely, and as appropriate, and will reconsider what measures are needed to maintain the safety of the blood supply,” Marks said.
