FDA announces efforts to tackle supply problems causing drug shortages

US Food and Drug Administration (FDA) Commissioner Scott Gottlieb, MD, today announced the formation of a new task force to address drug shortages and long-term strategies for preventing them.

In a statement, Gottlieb said though the number of new drug shortages has declined since 2011, the agency continues to see ongoing shortages of medically necessary products. He added that even short supplies of a small number of key drugs can put a serious burden on health providers, which sometimes impact patient care.

"While we've made progress to mitigate individual shortages, we haven't firmly impacted the underlying structural concerns that give rise to these recurring challenges," he said.

Lawmakers have urged the FDA to develop new proposals that have a longer-term impact on the shortages and have asked the FDA and other federal agencies if they need more authority to ensure that patients have the drugs they need and have requested recommendations for policy changes to address the shortages, Gottlieb said.

The Drug Shortages Task Force will be headed by Keagan Lenihan, the FDA's associate commissioner for strategic initiatives, and include senior leaders from the FDA and other federal agencies. Gottlieb said the group's mission is to look more deeply into the reasons for persistent shortages and for solutions that address the underlying causes. He noted that the task force's work will expand on a group created by the FDA Safety and Innovation Act of 2012, which gave the agency new authorities to address drug shortages.

Gottlieb emphasized that lasting solutions can't be addressed by the FDA alone, and he acknowledged that many drugs in short supply are low-profit generic medicines and sterile parenteral drugs that are challenging to make in an industry marked by consolidation. "This has resulted in fewer and fewer manufacturers for certain key products. The result is very little margin for error in this space," he said, adding that lack of investment in manufacturing creates conditions that lead to production stoppages.

Along with examining the FDA's authority, the group will also explore possible incentives to expand manufacturing capacity, whether it would be useful to develop a critical drug list that merits stronger interventions to prevent shortages, and the possibility of coupling regulations with financial incentives. To encourage feedback from the industry, other stakeholders, and the public, Gottlieb said the FDA will hold a public meeting sometime in the next several months.
Jul 12 FDA statement

 

Two phase 2 TB vaccine trials show reduction in sustained infections

Results from two tuberculosis (TB) vaccine candidate phase 2 trials show both were effective in reducing the rate of sustained infections in high-transmission settings, according to a study today in the New England Journal of Medicine, but H4:IC31, one of the candidate vaccines, did not reduce transmissions at a statistically significant rate.

The proof-of-concept study looked at two TB vaccine candidates, H4:IC31, a candidate subunit vaccine that consists of a recombinant fusion protein (H4) and IC31 adjuvant, and the primary bacille Calmette–Guerin (BCG) vaccine. The research was conducted in South Africa, where 930 children ages 12 to 17 who had already received BCG in infancy were either revaccinated with BCG or given H4:IC31. All trial participants tested negative for HIV and TB at the beginning of the trail.

The efficacy of the H4:IC31 vaccine for the prevention of sustained QuantiFERON-TB Gold In-tube assay (QFT) conversion was 30.5%. In the BCG group, the efficacy of revaccination for the prevention of sustained QFT conversion was 45.4%, and 48.2% efficacy was observed at the end of the trial. The results for H4:IC31 were deemed not statistically significant.

The authors conclude that their trials show a promising result in BCG revaccination in patients who are TB-free. Previous studies have shown a wide range of BCG efficacy against initial Mycobacterium tuberculosis infection, from 27% to 71%.  

"The efficacy of the primary BCG vaccine against disease is highly variable in different populations; efficacy is thought to be greatest in persons without previous mycobacteria exposure and may last for 10 years. Our findings suggest that BCG revaccination of QFT-negative adolescents may provide additional benefit," the authors said.
Jul 12 N Engl J Med study

 

Using fractional doses of yellow fever vaccine leaves many questions

In a letter today also published in the New England Journal of Medicine, three researchers tackle fractional dosing and the yellow fever vaccine.

First used in the Democratic Republic of the Congo (DRC) in 2016, fractional dosing involves inoculating recipients with one fifth of the yellow fever vaccine during an outbreak. The dose-saving measure helps stretch global supply of the vaccine, and was used in Brazil in 2017 during another outbreak of the flavivirus.

Existing yellow fever vaccines contain doses between 12,874 and 43,651 international units (IU), far above the WHO’s recommended minimum of 1,000 IU.

Until 2016, there were only three published studies on fractional dosing, but all showed overwhelming (98%) seroconversion among people who were seronegative at the time of vaccination. Follow-up studies published earlier this month showed that even small doses of the vaccine offered protection for up to 8 years.

But the authors, led by Kristen Vannice, PhD, MHS, say fractional dosing is a complex issue; WHO's recommended minimum dose is based on studies in animals rather than dose-finding studies in humans, and there is little known about fractional dosing in children.

"Although available evidence supports the use of fractional-dose vaccination when needed, a larger evidence base will be important to ensure optimal use and protection," the authors conclude.
Jul 12 N Engl J Med
letter
Jul 5 CIDRAP News scan on latest study

 

Scientists isolate influenza B virus in pigs, showing zoonotic threat

For the first time, scientists isolated naturally occurring influenza B viruses in pigs. Influenza and Other Respiratory Viruses published the report today.

Researchers isolated the virus from Taiwanese swine. From 2007 to 2017, 15,983 swine serum samples were collected from 1,039 farm visits under active surveillance. In 2014, three samples were positive for influenza B. Genetic analysis showed the viruses to be grouped with B/Taiwan/13/2013 and B/Taiwan/113/2014 in the same cluster of the B/Brisbane/60/2008 genetic clade of Victoria lineage.

In addition to the three positive samples, antibodies against swine influenza B viruses were detected in 31 serum samples.

"Public health concerns might arise from the finding that [influenza B viruses] could be transmitted naturally from humans to pigs, even cross-species infections are sporadic and accidental currently in Taiwan. It implies a cycle of human-swine-human transmission could be or might have been initiated as some of [influenza A viruses] did in human and swine populations," the authors concluded.
Jul 12 Influenza Other Respir Viruses study

 

Russia, Taiwan report more high-path H5 avian flu outbreaks

In the latest highly pathogenic avian flu developments, Russia reported eight more H5 outbreaks in backyard poultry in the west, and Taiwan reported one more H5N2 outbreak at a commercial poultry farm, according to notifications from the World Organization for Animal Health (OIE).

In Russia, the latest detections occurred in four oblasts: Orlov, Rostov, Kursk, and Nizhegorod. The outbreaks began from Jun 26 to Jul 9, killing 6,116 of 616,350 susceptible poultry. The outbreaks are part of ongoing avian flu activity in western Russia that began on early June.

Though the OIE report doesn't specify an H5 subtype, an updated risk assessment on Jul 9 from the UK Department for Environment, Food, and Rural Affairs (DEFRA) said H5N8 was involved in Russia's outbreaks.

Meanwhile, Taiwan's latest outbreak—part of activity under way since early 2015—struck a turkey farm in Yunlin County. The event began on Jul 2, killing 161 of 771 birds.
Jul 11 OIE report on H5 in Russia
Jul 9 DEFRA updated avian flu risk assessment
Jul 12 OIE report on H5N2 in Taiwan

In low-pathogenic avian flu developments, France reported an H7N7 detection at a mallard farm housing 10,000 ducks in Val-d'Oise department in the north central part of the country. The virus was found on Jun 6 during regular surveillance. The birds were contained, and repeat tests on Jul 5 were negative. The country's last outbreak involving low-path H7N7 was reported in January 2017.
Jul 9 OIE report on H7N7 in France

Stewardship / Resistance Scan for Jul 12, 2018

News brief

Study: Intervention reduces unnecessary antibiotic use for pneumonia

A new study by researchers with a health system in Detroit indicates that a small, behavioral "nudge" in microbiology reporting increased de-escalation and discontinuation of unnecessary broad-spectrum antibiotics in pneumonia patients. The results were reported in Open Forum Infectious Diseases.

In the study, researchers with the Henry Ford Health System evaluated antibiotic de-escalation and discontinuation in 210 patients treated with anti–methicillin-resistant Staphylococcus aureus (MRSA) and antipseudomonal antibiotics for respiratory infections. The quasi-experimental study was conducted over two periods: a 6-month period before implementation of an intervention to improve the clarity of microbiology results, and a corresponding 6-month period following the intervention.

In the intervention, respiratory cultures with no dominant organism growth and no Pseudomonas or S aureus were reported as "commensal respiratory flora only: No S aureus/MRSA or P. Aeruginosa." Prior to the intervention, these were reported as "commensal respiratory flora."

The researchers found that de-escalation/discontinuation was more commonly found in the intervention group than in the pre-intervention group (73% vs. 39%, P < 0.001). After adjusting for severity of illness and comorbidities, the intervention comment was associated with a 5.5-fold increased odds of de-escalation. Acute kidney injury was also reduced in the intervention group (14% vs. 31%, P = 0.003). No statistically significant difference in all-cause mortality was detected between the two groups (18% vs. 30%, P = 0.052).

"Our study demonstrates that a simple behavioral intervention to more clearly communicate respiratory culture results for normal flora can impact prescribing, and may reduce patient harm," the authors write.
Jul 10 Open Forum Infect Dis abstract

 

Meta-analysis finds 2nd-line therapy effective against MDR-TB in children

A meta-analysis of 28 studies involving children with multidrug-resistant tuberculosis (MDR-TB) determined that, in general, second-line MDR-TB antibiotics work well in this age-group, despite a high burden of severe disease, according to a study yesterday in PLoS Medicine.

The researchers analyzed data on 975 children from 18 countries; 731 (75%) had bacteriologically confirmed and 244 (25%) had clinically diagnosed MDR-TB. The median age was 7.1 years, and 39% were infected with HIV. When compared with clinically diagnosed patients, children with confirmed MDR-TB were more likely to be older, to be infected with HIV, to be malnourished, and to have severe TB on chest radiograph (P < 0.001 for all traits).

Overall, 764 of 975 (78%) had a successful treatment outcome at the conclusion of second-line therapy—75% among confirmed and 89% among clinically diagnosed children. Success dropped to 56%, however, among HIV-positive children who had bacteriologically confirmed TB and did not receive any antiretroviral treatment during MDR-TB therapy, compared with 82% in those who received ART.

In children with confirmed MDR-TB, the use of second-line injectable agents and high-dose isoniazid were associated with treatment success (adjusted odds ratio, 2.9 and 5.9, respectively), but the authors say the findings for high-dose isoniazid may have been skewed by site effect, as most of these patients came from Cape Town.
Jul 11 PLoS Med study

 

British group offers guidance to combat resistant Mycoplasma genitalium

The British Association for Sexual Health and HIV (BASHH) this week released new guidelines for managing infections with Mycoplasma genitalium, which is becoming increasingly antibiotic-resistant. The guidelines emphasize comprehensive testing, including for macrolide-resistance mutations, and point out that many clinics don't have such tests but should.

M genitalium infection is most often asymptomatic, but when they do occur they can mimic other sexually transmitted diseases like chlamydia and gonorrhea.

The highest-level recommendations in the guidance including testing all male patients who have non-gonococcal urinary tract infections, as well as all patients who have signs and symptoms of pelvic inflammatory disease. "Nucleic acid amplification tests (NAATs) that detect M. genitalium specific DNA or RNA in clinical specimens are the only useful diagnostic method," the guidelines state. "Several CE marked commercial tests are available, although none are currently FDA approved."

The authors also advise that, when possible, all M genitalium–positive specimens be tested for macrolide-resistance mediating mutations.

They state, "Whilst the guideline sets out recommendations for best practice according to current evidence, it is acknowledged that not all clinics will have access to M. genitalium testing at the time of guideline publication. The objective of this guideline is therefore also to assist clinics and laboratories in making the case for funding towards M. genitalium testing by underlining the importance of testing in relevant populations."

BASHH has opened the guidelines to feedback until Sep 1.
Jul 8 BASHH guidelines 

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