FDA/CDC

Rozlytrek (entrectinib) has been approved to treat cancers with neurotrophic tyrosine receptor kinase (NTRK) gene fusion defects in adults and adolescents for whom there are no effective treatments, the Food and Drug Administration announced in a press release.

Olivier Le Moal/Getty Images

Entrectinib was also approved for the treatment of adults with metastatic non–small cell lung cancers that are ROS1-positive.

“We are in an exciting era of innovation in cancer treatment as we continue to see development in tissue-agnostic therapies, which have the potential to transform cancer treatment. We’re seeing continued advances in the use of biomarkers to guide drug development and the more targeted delivery of medicine,” FDA Acting Commissioner Ned Sharpless, MD, said in the release.

This is the third time the agency has approved a cancer treatment based on a common biomarker across different types of tumors rather than on the original tumor’s location. The previous tissue-agnostic indications approved by the FDA were pembrolizumab (Keytruda) for tumors with microsatellite instability-high (MSI-H) or mismatch repair deficient (dMMR) tumors in 2017 and larotrectinib (Vitrakvi) for NTRK gene fusion tumors in 2018.

The approval of entrectinib was granted to Genentech. “Rozlytrek is the first FDA-approved treatment that selectively targets both ROS1 and NTRK fusions, and, importantly, has also shown responses in these rare cancer types that have spread to the brain,” Sandra Horning, MD, chief medical officer and head of global product development for Genentech, said in a separate press release.

Foundation Medicine will submit Foundation One CDx to the FDA for approval as a companion diagnostic for entrectinib, according to the Genentech release; an FDA-approved companion diagnostic for entrectinib is not available at this time.

“Today’s approval includes an indication for pediatric patients, 12 years of age and older, who have NTRK fusion–positive tumors by relying on efficacy information obtained primarily in adults,” said Richard Pazdur, MD, director of the FDA’s Oncology Center of Excellence and acting director of the Office of Hematology and Oncology Products in the FDA’s Center for Drug Evaluation and Research. “Efficacy in adolescents was derived from adult data and safety was demonstrated in 30 pediatric patients.”

Entrectinib was evaluated in four clinical trials that included 54 adults with NTRK fusion–positive tumors. The overall response rate was 57%, with 7.4% of patients having complete disappearance of the tumor. Among the 31 patients with tumor shrinkage, 61% had tumor shrinkage persist for 9 months or longer. The most common cancer locations were the lung, salivary gland, breast, thyroid, and colon/rectum.

Clinical studies evaluated 51 adults with ROS1-positive lung cancer. The overall response rate was 78%, with 5.9% of patients having complete disappearance of their cancer. Among the 40 patients with tumor shrinkage, 55% had tumor shrinkage persist for 12 months or longer.

The most serious side effects of entrectinib are heart failure, central nervous system effects, changes in sleep pattern, skeletal fractures, hepatotoxicity, hyperuricemia, QT prolongation, and vision disorders. Females of reproductive age and males with a female partner of reproductive potential are advised to use effective contraception during treatment; the drug may cause harm to a developing fetus or newborn baby.

Genentech must provide additional clinical trial data to the FDA as a condition of the approval.

mdales@mdedge.com

Rozlytrek (entrectinib) has been approved to treat cancers with neurotrophic tyrosine receptor kinase (NTRK) gene fusion defects in adults and adolescents for whom there are no effective treatments, the Food and Drug Administration announced in a press release.

Olivier Le Moal/Getty Images

Entrectinib was also approved for the treatment of adults with metastatic non–small cell lung cancers that are ROS1-positive.

“We are in an exciting era of innovation in cancer treatment as we continue to see development in tissue-agnostic therapies, which have the potential to transform cancer treatment. We’re seeing continued advances in the use of biomarkers to guide drug development and the more targeted delivery of medicine,” FDA Acting Commissioner Ned Sharpless, MD, said in the release.

This is the third time the agency has approved a cancer treatment based on a common biomarker across different types of tumors rather than on the original tumor’s location. The previous tissue-agnostic indications approved by the FDA were pembrolizumab (Keytruda) for tumors with microsatellite instability-high (MSI-H) or mismatch repair deficient (dMMR) tumors in 2017 and larotrectinib (Vitrakvi) for NTRK gene fusion tumors in 2018.

The approval of entrectinib was granted to Genentech. “Rozlytrek is the first FDA-approved treatment that selectively targets both ROS1 and NTRK fusions, and, importantly, has also shown responses in these rare cancer types that have spread to the brain,” Sandra Horning, MD, chief medical officer and head of global product development for Genentech, said in a separate press release.

Foundation Medicine will submit Foundation One CDx to the FDA for approval as a companion diagnostic for entrectinib, according to the Genentech release; an FDA-approved companion diagnostic for entrectinib is not available at this time.

“Today’s approval includes an indication for pediatric patients, 12 years of age and older, who have NTRK fusion–positive tumors by relying on efficacy information obtained primarily in adults,” said Richard Pazdur, MD, director of the FDA’s Oncology Center of Excellence and acting director of the Office of Hematology and Oncology Products in the FDA’s Center for Drug Evaluation and Research. “Efficacy in adolescents was derived from adult data and safety was demonstrated in 30 pediatric patients.”

Entrectinib was evaluated in four clinical trials that included 54 adults with NTRK fusion–positive tumors. The overall response rate was 57%, with 7.4% of patients having complete disappearance of the tumor. Among the 31 patients with tumor shrinkage, 61% had tumor shrinkage persist for 9 months or longer. The most common cancer locations were the lung, salivary gland, breast, thyroid, and colon/rectum.

Clinical studies evaluated 51 adults with ROS1-positive lung cancer. The overall response rate was 78%, with 5.9% of patients having complete disappearance of their cancer. Among the 40 patients with tumor shrinkage, 55% had tumor shrinkage persist for 12 months or longer.

The most serious side effects of entrectinib are heart failure, central nervous system effects, changes in sleep pattern, skeletal fractures, hepatotoxicity, hyperuricemia, QT prolongation, and vision disorders. Females of reproductive age and males with a female partner of reproductive potential are advised to use effective contraception during treatment; the drug may cause harm to a developing fetus or newborn baby.

Genentech must provide additional clinical trial data to the FDA as a condition of the approval.

mdales@mdedge.com

Rozlytrek (entrectinib) has been approved to treat cancers with neurotrophic tyrosine receptor kinase (NTRK) gene fusion defects in adults and adolescents for whom there are no effective treatments, the Food and Drug Administration announced in a press release.

Olivier Le Moal/Getty Images

Entrectinib was also approved for the treatment of adults with metastatic non–small cell lung cancers that are ROS1-positive.

“We are in an exciting era of innovation in cancer treatment as we continue to see development in tissue-agnostic therapies, which have the potential to transform cancer treatment. We’re seeing continued advances in the use of biomarkers to guide drug development and the more targeted delivery of medicine,” FDA Acting Commissioner Ned Sharpless, MD, said in the release.

This is the third time the agency has approved a cancer treatment based on a common biomarker across different types of tumors rather than on the original tumor’s location. The previous tissue-agnostic indications approved by the FDA were pembrolizumab (Keytruda) for tumors with microsatellite instability-high (MSI-H) or mismatch repair deficient (dMMR) tumors in 2017 and larotrectinib (Vitrakvi) for NTRK gene fusion tumors in 2018.

The approval of entrectinib was granted to Genentech. “Rozlytrek is the first FDA-approved treatment that selectively targets both ROS1 and NTRK fusions, and, importantly, has also shown responses in these rare cancer types that have spread to the brain,” Sandra Horning, MD, chief medical officer and head of global product development for Genentech, said in a separate press release.

Foundation Medicine will submit Foundation One CDx to the FDA for approval as a companion diagnostic for entrectinib, according to the Genentech release; an FDA-approved companion diagnostic for entrectinib is not available at this time.

“Today’s approval includes an indication for pediatric patients, 12 years of age and older, who have NTRK fusion–positive tumors by relying on efficacy information obtained primarily in adults,” said Richard Pazdur, MD, director of the FDA’s Oncology Center of Excellence and acting director of the Office of Hematology and Oncology Products in the FDA’s Center for Drug Evaluation and Research. “Efficacy in adolescents was derived from adult data and safety was demonstrated in 30 pediatric patients.”

Entrectinib was evaluated in four clinical trials that included 54 adults with NTRK fusion–positive tumors. The overall response rate was 57%, with 7.4% of patients having complete disappearance of the tumor. Among the 31 patients with tumor shrinkage, 61% had tumor shrinkage persist for 9 months or longer. The most common cancer locations were the lung, salivary gland, breast, thyroid, and colon/rectum.

Clinical studies evaluated 51 adults with ROS1-positive lung cancer. The overall response rate was 78%, with 5.9% of patients having complete disappearance of their cancer. Among the 40 patients with tumor shrinkage, 55% had tumor shrinkage persist for 12 months or longer.

The most serious side effects of entrectinib are heart failure, central nervous system effects, changes in sleep pattern, skeletal fractures, hepatotoxicity, hyperuricemia, QT prolongation, and vision disorders. Females of reproductive age and males with a female partner of reproductive potential are advised to use effective contraception during treatment; the drug may cause harm to a developing fetus or newborn baby.

Genentech must provide additional clinical trial data to the FDA as a condition of the approval.

mdales@mdedge.com

The Centers for Disease Control and Prevention has updated its recommendation for serologic detection of Lyme disease, according to CDC investigators.

At the 1994 Second National Conference on Serologic Diagnosis of Lyme Disease, several groups and organizations convened, recommending a two-test methodology for Lyme disease detection. First, an enzyme immunoassay (EIA) or immunofluorescence assay should be used, followed by a western immunoblot assay for specimens yielding positive or equivocal results. The guideline advised that all future tests should be evaluated against a challenge panel, and that new assays should only move forward if their specificity, sensitivity, and precision equaled or surpassed the performance of tests used in the recommended two-test procedure.

On July 29, 2019, the Food and Drug Administration approved several Lyme disease serologic assays with new indications for use based on a modified two-test methodology, with a second EIA replacing the western immunoblot assay.

“Clearance by FDA of the new Lyme disease assays indicates that test performance has been evaluated and is ‘substantially equivalent to or better than’ a legally marketed predicate test,” the CDC investigators noted (MMWR Morb Mortal Wkly Rep. 2019 Aug 15;68(32):703).

The recommendation advises that FDA-cleared “serologic assays that utilize EIA rather than western immunoblot assay in a two-test format are acceptable alternatives for the laboratory diagnosis of Lyme disease.”

lfranki@mdedge.com

The Centers for Disease Control and Prevention has updated its recommendation for serologic detection of Lyme disease, according to CDC investigators.

At the 1994 Second National Conference on Serologic Diagnosis of Lyme Disease, several groups and organizations convened, recommending a two-test methodology for Lyme disease detection. First, an enzyme immunoassay (EIA) or immunofluorescence assay should be used, followed by a western immunoblot assay for specimens yielding positive or equivocal results. The guideline advised that all future tests should be evaluated against a challenge panel, and that new assays should only move forward if their specificity, sensitivity, and precision equaled or surpassed the performance of tests used in the recommended two-test procedure.

On July 29, 2019, the Food and Drug Administration approved several Lyme disease serologic assays with new indications for use based on a modified two-test methodology, with a second EIA replacing the western immunoblot assay.

“Clearance by FDA of the new Lyme disease assays indicates that test performance has been evaluated and is ‘substantially equivalent to or better than’ a legally marketed predicate test,” the CDC investigators noted (MMWR Morb Mortal Wkly Rep. 2019 Aug 15;68(32):703).

The recommendation advises that FDA-cleared “serologic assays that utilize EIA rather than western immunoblot assay in a two-test format are acceptable alternatives for the laboratory diagnosis of Lyme disease.”

lfranki@mdedge.com

The Centers for Disease Control and Prevention has updated its recommendation for serologic detection of Lyme disease, according to CDC investigators.

At the 1994 Second National Conference on Serologic Diagnosis of Lyme Disease, several groups and organizations convened, recommending a two-test methodology for Lyme disease detection. First, an enzyme immunoassay (EIA) or immunofluorescence assay should be used, followed by a western immunoblot assay for specimens yielding positive or equivocal results. The guideline advised that all future tests should be evaluated against a challenge panel, and that new assays should only move forward if their specificity, sensitivity, and precision equaled or surpassed the performance of tests used in the recommended two-test procedure.

On July 29, 2019, the Food and Drug Administration approved several Lyme disease serologic assays with new indications for use based on a modified two-test methodology, with a second EIA replacing the western immunoblot assay.

“Clearance by FDA of the new Lyme disease assays indicates that test performance has been evaluated and is ‘substantially equivalent to or better than’ a legally marketed predicate test,” the CDC investigators noted (MMWR Morb Mortal Wkly Rep. 2019 Aug 15;68(32):703).

The recommendation advises that FDA-cleared “serologic assays that utilize EIA rather than western immunoblot assay in a two-test format are acceptable alternatives for the laboratory diagnosis of Lyme disease.”

lfranki@mdedge.com

Paclitaxel-coated devices, which are used to treat peripheral artery disease (PAD), appear to have a nearly 60% higher mortality risk than uncoated devices, according to a letter to health care providers from the Food and Drug Administration.

This letter updates details about long-term follow-up data and panel conclusions reviewed by the Food and Drug Administration, as well as recommendations from the agency regarding these devices. On Jan. 17, 2019, the FDA notified providers regarding an apparent increased late mortality risk seen with paclitaxel-eluting stents and paclitaxel-coated balloons placed in the femoropopliteal artery in patients with PAD. The agency issued an update March 15.

In a public meeting June 19-20, the Circulatory System Devices Panel of the Medical Devices Advisory Committee discussed long-term follow-up data that demonstrated a 57% relative increase in mortality among PAD patients treated with paclitaxel-coated devices when compared with those receiving uncoated devices. The panel concluded that the late mortality signal was real and warranted further study and action, a conclusion with which the FDA has concurred.

Among other recommendations issued by the FDA, health care professionals should continue to closely monitor patients who’ve already received the devices and fully discuss the risks and benefits of these devices with patients. The FDA has decided that, given the demonstrated short-term benefits of these devices, clinical studies may continue and should collect long-term safety and effectiveness data.

The magnitude of this late mortality signal should be interpreted with caution, the FDA noted in the update, because of the wide confidence intervals (although the relative risk was 1.57, the 95% confidence interval was 1.16-2.13, which translates to 16%-113% higher relative risk), pooling studies of different devices that weren’t meant to be combined, missing data, and other reasons.

The full letter, including more detailed data and the full list of recommendations, is available on the FDA’s website.

cpalmer@mdedge.com

Paclitaxel-coated devices, which are used to treat peripheral artery disease (PAD), appear to have a nearly 60% higher mortality risk than uncoated devices, according to a letter to health care providers from the Food and Drug Administration.

This letter updates details about long-term follow-up data and panel conclusions reviewed by the Food and Drug Administration, as well as recommendations from the agency regarding these devices. On Jan. 17, 2019, the FDA notified providers regarding an apparent increased late mortality risk seen with paclitaxel-eluting stents and paclitaxel-coated balloons placed in the femoropopliteal artery in patients with PAD. The agency issued an update March 15.

In a public meeting June 19-20, the Circulatory System Devices Panel of the Medical Devices Advisory Committee discussed long-term follow-up data that demonstrated a 57% relative increase in mortality among PAD patients treated with paclitaxel-coated devices when compared with those receiving uncoated devices. The panel concluded that the late mortality signal was real and warranted further study and action, a conclusion with which the FDA has concurred.

Among other recommendations issued by the FDA, health care professionals should continue to closely monitor patients who’ve already received the devices and fully discuss the risks and benefits of these devices with patients. The FDA has decided that, given the demonstrated short-term benefits of these devices, clinical studies may continue and should collect long-term safety and effectiveness data.

The magnitude of this late mortality signal should be interpreted with caution, the FDA noted in the update, because of the wide confidence intervals (although the relative risk was 1.57, the 95% confidence interval was 1.16-2.13, which translates to 16%-113% higher relative risk), pooling studies of different devices that weren’t meant to be combined, missing data, and other reasons.

The full letter, including more detailed data and the full list of recommendations, is available on the FDA’s website.

cpalmer@mdedge.com

Paclitaxel-coated devices, which are used to treat peripheral artery disease (PAD), appear to have a nearly 60% higher mortality risk than uncoated devices, according to a letter to health care providers from the Food and Drug Administration.

This letter updates details about long-term follow-up data and panel conclusions reviewed by the Food and Drug Administration, as well as recommendations from the agency regarding these devices. On Jan. 17, 2019, the FDA notified providers regarding an apparent increased late mortality risk seen with paclitaxel-eluting stents and paclitaxel-coated balloons placed in the femoropopliteal artery in patients with PAD. The agency issued an update March 15.

In a public meeting June 19-20, the Circulatory System Devices Panel of the Medical Devices Advisory Committee discussed long-term follow-up data that demonstrated a 57% relative increase in mortality among PAD patients treated with paclitaxel-coated devices when compared with those receiving uncoated devices. The panel concluded that the late mortality signal was real and warranted further study and action, a conclusion with which the FDA has concurred.

Among other recommendations issued by the FDA, health care professionals should continue to closely monitor patients who’ve already received the devices and fully discuss the risks and benefits of these devices with patients. The FDA has decided that, given the demonstrated short-term benefits of these devices, clinical studies may continue and should collect long-term safety and effectiveness data.

The magnitude of this late mortality signal should be interpreted with caution, the FDA noted in the update, because of the wide confidence intervals (although the relative risk was 1.57, the 95% confidence interval was 1.16-2.13, which translates to 16%-113% higher relative risk), pooling studies of different devices that weren’t meant to be combined, missing data, and other reasons.

The full letter, including more detailed data and the full list of recommendations, is available on the FDA’s website.

cpalmer@mdedge.com

The Food and Drug Administration’s Antimicrobial Drugs Advisory Committee backed the fixed dose combination of emtricitabine and tenofovir alafenamide (TAF; Descovy, Gilead) for pre-exposure prophylaxis (PrEP) against HIV for men and transgender women who have sex with men.

In a discussion after a 16-2 vote, committee members cited analysis by the study’s sponsor and the FDA showing efficacy and a generally good safety profile in the DISCOVER trial, the single new clinical trial conducted to support TAF’s use for pre-exposure prophylaxis (PrEP).

However, this trial included no cisgender women; the sponsor asked for approval based primarily on extrapolation from the DISCOVER results and previous results with tenofovir disoproxil fumarate (TDF) in cisgender women. Both formulations of tenofovir are prodrugs and converted to tenofovir diphosphate intracellularly in peripheral blood mononuclear cells, though many aspects of their pharmacokinetics differ.

The committee voted 10-8 against the proposition that these data supported an indication of TAF for PrEP in cisgender women, in a narrowly worded question from the FDA.

Many members who voted on either side of the question had strongly worded reservations about the lack of data for cisgender women. Said committee chair Lindsey R. Baden, MD, director of the infectious disease service at Dana-Farber Cancer Institute, Boston, who voted against the indication for cisgender women, “We’ve failed women. To be at this point and not have the data to guide decision-making is a shame on all of us.”

Ighovwerha Ofotokun, MD, who voted yes, concurred: “I agree it is a terrible failure that the agency, as well as the sponsor, would come to this committee with a lack of data on women.” But for Dr. Ofotokun, a professor of infectious diseases at Emory University, Atlanta, not including cisgender women in the approval was a distasteful proposition. “Creating a two-tier prevention and treatment hierarchy would not be helpful. We should remind ourselves that there are more women living with HIV in the world than there are men, and the risk of new HIV infection is higher among women than among men, if you look at this globally,” he said.

“I find it disrespectful and an issue of research equity. Women deserve the same quality of data about the safety and efficacy of the drugs they are exposed to that men get and that is not the situation we find ourselves in at the moment,” said Dawn K. Smith, MD, MPH, a lead scientist at the Centers for Disease Control and Prevention (CDC), Atlanta, who voted against approval for cisgender women.

Michael Green, MD, MPH, professor of pediatrics, surgery and clinical and translational science at the University of Pittsburgh, echoed the frustration of many committee members when he said, “I voted yes, almost abstained, then almost voted no.” He, along with all who voted yes, emphasized the importance of mandatory postmarketing studies in cisgender women to ensure efficacy data are obtained.

Transgender women made up only about 1% of the DISCOVER population, a fact that also gave many committee members pause.

If TAF is approved, labeling and package materials should be clear that the data support only noninferiority, not superiority, compared with TDF, said several advisory committee members who voted for approval for men and transgender women who have sex with men. “My expectation of this approval is that it should be marketed responsibly from the perspective of not creating these disparities and having Truvada be a drug for poor people and Descovy be a drug for rich people,” said Demetre Dasklalakis, MD, assistant commissioner of the Bureau of HIV/AIDS Prevention and Control at the city of New York’s Department of Health and Hygiene, and of the Icahn School of Medicine at Mount Sinai, N.Y. Truvada is slated to be offered as a generic drug in 2020, according to a Securities and Exchange Commission filing by Gilead Sciences.

The CDC reported earlier in 2019 that rates of new HIV infections have plateaued in recent years. Uptake of PrEP has been particularly low among at-risk members of minority populations, in rural areas, and in the South, according to a CDC report.

The DISCOVER trial is a 96-week ongoing trial to test TAF’s noninferiority to a fixed-drug combination of emcitrabine and tenofovir dimethyl fumarate (TDF; Truvada, Gilead) for PrEP. Both drugs are already approved to treat HIV infection, and TDF is approved for PrEP. Non-inferiority was preestablished at a rate ratio of HIV incidence of 1.62 (TAF:TDF) between the two study arms.

DISCOVER has enrolled 5,387 men and transgender women who have sex with men and are deemed at high risk for HIV, and found an incidence rate ratio of 0.47, with the upper bound of the confidence interval at 1.15. Since this figure was less than the prespecified noninferiority margin, both Gilead presenters and the FDA agreed, TAF’s noninferiority for efficacy was established.

Characteristics were similar between patients in the TAF arm (N = 2,694) and the TDF arm (N = 2,693). About 60% of patients in each arm reported having receptive anal sex with at least two partners in the previous 12 weeks, and recent rectal gonorrhea, syphilis, and chlamydia rates were 9-13% at baseline. Two thirds of participants reported recreational drug use, and about one in four reported binge drinking.

Sexual behavior and sexually transmitted infection rates continued generally unchanged from baseline during the study period.

The median age was 34 years, and most participants (84%) were white. Black participants made up 9% of the study population, and about 25% were of Hispanic or Latin ethnic origin.

Known decreases in bone mineral density occur with TDF; these were not seen with TAF, and bone mineral density increased while on TAF for the DISCOVER population aged 19-25 years.

Renal biomarkers of concern with TDF included two proteins linked with proximal tubule dysfunction, as well as estimated glomerular filtration rate. According to the sponsor’s analysis, eGFR fell by 2.3 mL/min for the TAF group, compared with a 1.8 mL/min rise while on TDF (P less than .001). Changes of similar statistical significance were seen for proximal tubular proteinuria. Also, improvements were seen in renal measures for the subset of patients enrolled who were on TDF PrEP at baseline but switched to TAF, in a prespecified subgroup analysis.

However, patients who were on TDF had a significant decrease in total cholesterol and both low- and high-density lipoprotein cholesterol compared with those on TAF, who had minimal changes or slight increases in lipids (P less than .001 for all). Triglycerides rose for those on TAF and remained unchanged for those on TDF (P = .002).

The PrEP indication sought by Gilead includes adults and adolescents, defined as those who weigh more than 35 kg. A nonvoting question put before the committee asked whether the totality of tenofovir data supported an indication of TAF for cisgender men who have insertive vaginal sex; though this extrapolation didn’t give the committee as much pause as the request for approval in cisgender women, they cited similar concerns and noted that cervicovaginal mucosa are different in many ways from rectal mucosa.

The study included no cisgender women, for a host of reasons cited by the sponsor and the FDA. These included high nonadherence rates among this population, relatively lower HIV infection rates among cisgender women in the United States, and mixed efficacy results in previous tenofovir clinical trials; the latter point made establishing a noninferiority margin problematic, according to the FDA.

For Dr. Baden, “The optics of approval for population A but not for population B are problematic.” Speaking to both the sponsor and the FDA, he said, “Everyone agrees there needs to be actual data. Please do the study as quickly as possible.” What’s needed is the collective will to make it happen, he added: “I don’t accept that it’s too big, too hard, too difficult.”

The FDA usually follows the recommendations of its advisory committees.

koakes@mdedge.com

This article was updated 8/8/19.

The Food and Drug Administration’s Antimicrobial Drugs Advisory Committee backed the fixed dose combination of emtricitabine and tenofovir alafenamide (TAF; Descovy, Gilead) for pre-exposure prophylaxis (PrEP) against HIV for men and transgender women who have sex with men.

In a discussion after a 16-2 vote, committee members cited analysis by the study’s sponsor and the FDA showing efficacy and a generally good safety profile in the DISCOVER trial, the single new clinical trial conducted to support TAF’s use for pre-exposure prophylaxis (PrEP).

However, this trial included no cisgender women; the sponsor asked for approval based primarily on extrapolation from the DISCOVER results and previous results with tenofovir disoproxil fumarate (TDF) in cisgender women. Both formulations of tenofovir are prodrugs and converted to tenofovir diphosphate intracellularly in peripheral blood mononuclear cells, though many aspects of their pharmacokinetics differ.

The committee voted 10-8 against the proposition that these data supported an indication of TAF for PrEP in cisgender women, in a narrowly worded question from the FDA.

Many members who voted on either side of the question had strongly worded reservations about the lack of data for cisgender women. Said committee chair Lindsey R. Baden, MD, director of the infectious disease service at Dana-Farber Cancer Institute, Boston, who voted against the indication for cisgender women, “We’ve failed women. To be at this point and not have the data to guide decision-making is a shame on all of us.”

Ighovwerha Ofotokun, MD, who voted yes, concurred: “I agree it is a terrible failure that the agency, as well as the sponsor, would come to this committee with a lack of data on women.” But for Dr. Ofotokun, a professor of infectious diseases at Emory University, Atlanta, not including cisgender women in the approval was a distasteful proposition. “Creating a two-tier prevention and treatment hierarchy would not be helpful. We should remind ourselves that there are more women living with HIV in the world than there are men, and the risk of new HIV infection is higher among women than among men, if you look at this globally,” he said.

“I find it disrespectful and an issue of research equity. Women deserve the same quality of data about the safety and efficacy of the drugs they are exposed to that men get and that is not the situation we find ourselves in at the moment,” said Dawn K. Smith, MD, MPH, a lead scientist at the Centers for Disease Control and Prevention (CDC), Atlanta, who voted against approval for cisgender women.

Michael Green, MD, MPH, professor of pediatrics, surgery and clinical and translational science at the University of Pittsburgh, echoed the frustration of many committee members when he said, “I voted yes, almost abstained, then almost voted no.” He, along with all who voted yes, emphasized the importance of mandatory postmarketing studies in cisgender women to ensure efficacy data are obtained.

Transgender women made up only about 1% of the DISCOVER population, a fact that also gave many committee members pause.

If TAF is approved, labeling and package materials should be clear that the data support only noninferiority, not superiority, compared with TDF, said several advisory committee members who voted for approval for men and transgender women who have sex with men. “My expectation of this approval is that it should be marketed responsibly from the perspective of not creating these disparities and having Truvada be a drug for poor people and Descovy be a drug for rich people,” said Demetre Dasklalakis, MD, assistant commissioner of the Bureau of HIV/AIDS Prevention and Control at the city of New York’s Department of Health and Hygiene, and of the Icahn School of Medicine at Mount Sinai, N.Y. Truvada is slated to be offered as a generic drug in 2020, according to a Securities and Exchange Commission filing by Gilead Sciences.

The CDC reported earlier in 2019 that rates of new HIV infections have plateaued in recent years. Uptake of PrEP has been particularly low among at-risk members of minority populations, in rural areas, and in the South, according to a CDC report.

The DISCOVER trial is a 96-week ongoing trial to test TAF’s noninferiority to a fixed-drug combination of emcitrabine and tenofovir dimethyl fumarate (TDF; Truvada, Gilead) for PrEP. Both drugs are already approved to treat HIV infection, and TDF is approved for PrEP. Non-inferiority was preestablished at a rate ratio of HIV incidence of 1.62 (TAF:TDF) between the two study arms.

DISCOVER has enrolled 5,387 men and transgender women who have sex with men and are deemed at high risk for HIV, and found an incidence rate ratio of 0.47, with the upper bound of the confidence interval at 1.15. Since this figure was less than the prespecified noninferiority margin, both Gilead presenters and the FDA agreed, TAF’s noninferiority for efficacy was established.

Characteristics were similar between patients in the TAF arm (N = 2,694) and the TDF arm (N = 2,693). About 60% of patients in each arm reported having receptive anal sex with at least two partners in the previous 12 weeks, and recent rectal gonorrhea, syphilis, and chlamydia rates were 9-13% at baseline. Two thirds of participants reported recreational drug use, and about one in four reported binge drinking.

Sexual behavior and sexually transmitted infection rates continued generally unchanged from baseline during the study period.

The median age was 34 years, and most participants (84%) were white. Black participants made up 9% of the study population, and about 25% were of Hispanic or Latin ethnic origin.

Known decreases in bone mineral density occur with TDF; these were not seen with TAF, and bone mineral density increased while on TAF for the DISCOVER population aged 19-25 years.

Renal biomarkers of concern with TDF included two proteins linked with proximal tubule dysfunction, as well as estimated glomerular filtration rate. According to the sponsor’s analysis, eGFR fell by 2.3 mL/min for the TAF group, compared with a 1.8 mL/min rise while on TDF (P less than .001). Changes of similar statistical significance were seen for proximal tubular proteinuria. Also, improvements were seen in renal measures for the subset of patients enrolled who were on TDF PrEP at baseline but switched to TAF, in a prespecified subgroup analysis.

However, patients who were on TDF had a significant decrease in total cholesterol and both low- and high-density lipoprotein cholesterol compared with those on TAF, who had minimal changes or slight increases in lipids (P less than .001 for all). Triglycerides rose for those on TAF and remained unchanged for those on TDF (P = .002).

The PrEP indication sought by Gilead includes adults and adolescents, defined as those who weigh more than 35 kg. A nonvoting question put before the committee asked whether the totality of tenofovir data supported an indication of TAF for cisgender men who have insertive vaginal sex; though this extrapolation didn’t give the committee as much pause as the request for approval in cisgender women, they cited similar concerns and noted that cervicovaginal mucosa are different in many ways from rectal mucosa.

The study included no cisgender women, for a host of reasons cited by the sponsor and the FDA. These included high nonadherence rates among this population, relatively lower HIV infection rates among cisgender women in the United States, and mixed efficacy results in previous tenofovir clinical trials; the latter point made establishing a noninferiority margin problematic, according to the FDA.

For Dr. Baden, “The optics of approval for population A but not for population B are problematic.” Speaking to both the sponsor and the FDA, he said, “Everyone agrees there needs to be actual data. Please do the study as quickly as possible.” What’s needed is the collective will to make it happen, he added: “I don’t accept that it’s too big, too hard, too difficult.”

The FDA usually follows the recommendations of its advisory committees.

koakes@mdedge.com

This article was updated 8/8/19.

The Food and Drug Administration’s Antimicrobial Drugs Advisory Committee backed the fixed dose combination of emtricitabine and tenofovir alafenamide (TAF; Descovy, Gilead) for pre-exposure prophylaxis (PrEP) against HIV for men and transgender women who have sex with men.

In a discussion after a 16-2 vote, committee members cited analysis by the study’s sponsor and the FDA showing efficacy and a generally good safety profile in the DISCOVER trial, the single new clinical trial conducted to support TAF’s use for pre-exposure prophylaxis (PrEP).

However, this trial included no cisgender women; the sponsor asked for approval based primarily on extrapolation from the DISCOVER results and previous results with tenofovir disoproxil fumarate (TDF) in cisgender women. Both formulations of tenofovir are prodrugs and converted to tenofovir diphosphate intracellularly in peripheral blood mononuclear cells, though many aspects of their pharmacokinetics differ.

The committee voted 10-8 against the proposition that these data supported an indication of TAF for PrEP in cisgender women, in a narrowly worded question from the FDA.

Many members who voted on either side of the question had strongly worded reservations about the lack of data for cisgender women. Said committee chair Lindsey R. Baden, MD, director of the infectious disease service at Dana-Farber Cancer Institute, Boston, who voted against the indication for cisgender women, “We’ve failed women. To be at this point and not have the data to guide decision-making is a shame on all of us.”

Ighovwerha Ofotokun, MD, who voted yes, concurred: “I agree it is a terrible failure that the agency, as well as the sponsor, would come to this committee with a lack of data on women.” But for Dr. Ofotokun, a professor of infectious diseases at Emory University, Atlanta, not including cisgender women in the approval was a distasteful proposition. “Creating a two-tier prevention and treatment hierarchy would not be helpful. We should remind ourselves that there are more women living with HIV in the world than there are men, and the risk of new HIV infection is higher among women than among men, if you look at this globally,” he said.

“I find it disrespectful and an issue of research equity. Women deserve the same quality of data about the safety and efficacy of the drugs they are exposed to that men get and that is not the situation we find ourselves in at the moment,” said Dawn K. Smith, MD, MPH, a lead scientist at the Centers for Disease Control and Prevention (CDC), Atlanta, who voted against approval for cisgender women.

Michael Green, MD, MPH, professor of pediatrics, surgery and clinical and translational science at the University of Pittsburgh, echoed the frustration of many committee members when he said, “I voted yes, almost abstained, then almost voted no.” He, along with all who voted yes, emphasized the importance of mandatory postmarketing studies in cisgender women to ensure efficacy data are obtained.

Transgender women made up only about 1% of the DISCOVER population, a fact that also gave many committee members pause.

If TAF is approved, labeling and package materials should be clear that the data support only noninferiority, not superiority, compared with TDF, said several advisory committee members who voted for approval for men and transgender women who have sex with men. “My expectation of this approval is that it should be marketed responsibly from the perspective of not creating these disparities and having Truvada be a drug for poor people and Descovy be a drug for rich people,” said Demetre Dasklalakis, MD, assistant commissioner of the Bureau of HIV/AIDS Prevention and Control at the city of New York’s Department of Health and Hygiene, and of the Icahn School of Medicine at Mount Sinai, N.Y. Truvada is slated to be offered as a generic drug in 2020, according to a Securities and Exchange Commission filing by Gilead Sciences.

The CDC reported earlier in 2019 that rates of new HIV infections have plateaued in recent years. Uptake of PrEP has been particularly low among at-risk members of minority populations, in rural areas, and in the South, according to a CDC report.

The DISCOVER trial is a 96-week ongoing trial to test TAF’s noninferiority to a fixed-drug combination of emcitrabine and tenofovir dimethyl fumarate (TDF; Truvada, Gilead) for PrEP. Both drugs are already approved to treat HIV infection, and TDF is approved for PrEP. Non-inferiority was preestablished at a rate ratio of HIV incidence of 1.62 (TAF:TDF) between the two study arms.

DISCOVER has enrolled 5,387 men and transgender women who have sex with men and are deemed at high risk for HIV, and found an incidence rate ratio of 0.47, with the upper bound of the confidence interval at 1.15. Since this figure was less than the prespecified noninferiority margin, both Gilead presenters and the FDA agreed, TAF’s noninferiority for efficacy was established.

Characteristics were similar between patients in the TAF arm (N = 2,694) and the TDF arm (N = 2,693). About 60% of patients in each arm reported having receptive anal sex with at least two partners in the previous 12 weeks, and recent rectal gonorrhea, syphilis, and chlamydia rates were 9-13% at baseline. Two thirds of participants reported recreational drug use, and about one in four reported binge drinking.

Sexual behavior and sexually transmitted infection rates continued generally unchanged from baseline during the study period.

The median age was 34 years, and most participants (84%) were white. Black participants made up 9% of the study population, and about 25% were of Hispanic or Latin ethnic origin.

Known decreases in bone mineral density occur with TDF; these were not seen with TAF, and bone mineral density increased while on TAF for the DISCOVER population aged 19-25 years.

Renal biomarkers of concern with TDF included two proteins linked with proximal tubule dysfunction, as well as estimated glomerular filtration rate. According to the sponsor’s analysis, eGFR fell by 2.3 mL/min for the TAF group, compared with a 1.8 mL/min rise while on TDF (P less than .001). Changes of similar statistical significance were seen for proximal tubular proteinuria. Also, improvements were seen in renal measures for the subset of patients enrolled who were on TDF PrEP at baseline but switched to TAF, in a prespecified subgroup analysis.

However, patients who were on TDF had a significant decrease in total cholesterol and both low- and high-density lipoprotein cholesterol compared with those on TAF, who had minimal changes or slight increases in lipids (P less than .001 for all). Triglycerides rose for those on TAF and remained unchanged for those on TDF (P = .002).

The PrEP indication sought by Gilead includes adults and adolescents, defined as those who weigh more than 35 kg. A nonvoting question put before the committee asked whether the totality of tenofovir data supported an indication of TAF for cisgender men who have insertive vaginal sex; though this extrapolation didn’t give the committee as much pause as the request for approval in cisgender women, they cited similar concerns and noted that cervicovaginal mucosa are different in many ways from rectal mucosa.

The study included no cisgender women, for a host of reasons cited by the sponsor and the FDA. These included high nonadherence rates among this population, relatively lower HIV infection rates among cisgender women in the United States, and mixed efficacy results in previous tenofovir clinical trials; the latter point made establishing a noninferiority margin problematic, according to the FDA.

For Dr. Baden, “The optics of approval for population A but not for population B are problematic.” Speaking to both the sponsor and the FDA, he said, “Everyone agrees there needs to be actual data. Please do the study as quickly as possible.” What’s needed is the collective will to make it happen, he added: “I don’t accept that it’s too big, too hard, too difficult.”

The FDA usually follows the recommendations of its advisory committees.

koakes@mdedge.com

This article was updated 8/8/19.

Abbott Laboratories has issued a recall of all Ellipse Implantable Cardioverter Defibrillators manufactured between April 5, 2019, and May 29, 2019, because of exposed aluminum wires within the device, potentially preventing defibrillation.

The Ellipse Implantable Cardioverter Defibrillators, formerly manufactured by St. Jude Medical (now a wholly-owned subsidiary of Abbott), provide pacing for patients with bradycardia and electric shock or pacing for patients with tachycardia. The device is implanted under the skin in the upper chest area with leads running into the heart.

The recall has been issued because electrical failures have occurred; Abbott has determined that these failures are caused by a faulty manufacturing process that left some aluminum wires in the leads partially exposed. Wires without proper insulation are likely to short, leaving the device without the ability to provide high voltage therapy.

Abbott is aware of no related reports of electrical failure in any of the devices that have already been implanted, the Food and Drug Administration announced, and no reports of patient harm, adverse events, or death have occurred. All affected devices that were implanted have either been replaced or are scheduled to be replaced, the agency said.

lfranki@mdedge.com

Abbott Laboratories has issued a recall of all Ellipse Implantable Cardioverter Defibrillators manufactured between April 5, 2019, and May 29, 2019, because of exposed aluminum wires within the device, potentially preventing defibrillation.

The Ellipse Implantable Cardioverter Defibrillators, formerly manufactured by St. Jude Medical (now a wholly-owned subsidiary of Abbott), provide pacing for patients with bradycardia and electric shock or pacing for patients with tachycardia. The device is implanted under the skin in the upper chest area with leads running into the heart.

The recall has been issued because electrical failures have occurred; Abbott has determined that these failures are caused by a faulty manufacturing process that left some aluminum wires in the leads partially exposed. Wires without proper insulation are likely to short, leaving the device without the ability to provide high voltage therapy.

Abbott is aware of no related reports of electrical failure in any of the devices that have already been implanted, the Food and Drug Administration announced, and no reports of patient harm, adverse events, or death have occurred. All affected devices that were implanted have either been replaced or are scheduled to be replaced, the agency said.

lfranki@mdedge.com

Abbott Laboratories has issued a recall of all Ellipse Implantable Cardioverter Defibrillators manufactured between April 5, 2019, and May 29, 2019, because of exposed aluminum wires within the device, potentially preventing defibrillation.

The Ellipse Implantable Cardioverter Defibrillators, formerly manufactured by St. Jude Medical (now a wholly-owned subsidiary of Abbott), provide pacing for patients with bradycardia and electric shock or pacing for patients with tachycardia. The device is implanted under the skin in the upper chest area with leads running into the heart.

The recall has been issued because electrical failures have occurred; Abbott has determined that these failures are caused by a faulty manufacturing process that left some aluminum wires in the leads partially exposed. Wires without proper insulation are likely to short, leaving the device without the ability to provide high voltage therapy.

Abbott is aware of no related reports of electrical failure in any of the devices that have already been implanted, the Food and Drug Administration announced, and no reports of patient harm, adverse events, or death have occurred. All affected devices that were implanted have either been replaced or are scheduled to be replaced, the agency said.

lfranki@mdedge.com

Turalio (pexidartinib) capsules have been approved for the treatment of adult patients with symptomatic tenosynovial giant cell tumor (TGCT) that is associated with severe morbidity or functional limitations not responsive to improvement with surgery, the U.S. Food and Drug Administration announced.

Olivier Le Moal/Getty Images

Turalio is the first therapy to be approved for the rare joint tumor and is available only through the Turalio Risk Evaluation and Mitigation Strategy (REMS) Program. The FDA granted the approval of Turalio to Daiichi Sankyo.

“TGCT can cause debilitating symptoms for patients such as pain, stiffness and limitation of movement,” Richard Pazdur, MD, director of the FDA’s Oncology Center of Excellence and acting director of the Office of Hematology and Oncology Products in the FDA’s Center for Drug Evaluation and Research, said in a statement. “Surgery is the primary treatment option, but some patients are not eligible for surgery, and tumors can recur, even after the procedure.”

The approval was based on results of a study of 120 patients, 59 of whom received placebo. After 25 weeks of treatment, the overall response rate was 38% (15% complete responses and 23% partial responses) in those who received pexidartinib; no responses occurred in patients who received placebo. The response persisted in 22 of 23 responders who had been followed for a minimum of 6 months, and in 13 of 13 responders who had been followed for a minimum of 12 months.

Turalio comes with a Boxed Warning about the risk of serious and potentially fatal liver injury. Liver tests should be performed prior to beginning treatment and the results monitored at specified intervals during treatment. Patients who develop abnormal results may need to withhold therapy, reduce the dose, or discontinue therapy depending on the severity of the liver injury.

Common side effects for patients were increased levels of lactate dehydrogenase, aspartate aminotransferase, alanine aminotransferase, and cholesterol. Loss of hair color also occurred in some patients.

Additional side effects included neutropenia, increased alkaline phosphatase levels, decreased lymphocytes, eye edema, decreased hemoglobin levels, rash, dysgeusia, and decreased phosphate levels.

Females of reproductive age and males with a female partner of reproductive potential should use effective contraception during treatment with pexidartinib. Pexidartinib may cause harm to a developing fetus or newborn baby.

Pexidartinib must be dispensed with a patient Medication Guide that describes important information about the drug’s uses and risks.

mdales@mdedge.com

Turalio (pexidartinib) capsules have been approved for the treatment of adult patients with symptomatic tenosynovial giant cell tumor (TGCT) that is associated with severe morbidity or functional limitations not responsive to improvement with surgery, the U.S. Food and Drug Administration announced.

Olivier Le Moal/Getty Images

Turalio is the first therapy to be approved for the rare joint tumor and is available only through the Turalio Risk Evaluation and Mitigation Strategy (REMS) Program. The FDA granted the approval of Turalio to Daiichi Sankyo.

“TGCT can cause debilitating symptoms for patients such as pain, stiffness and limitation of movement,” Richard Pazdur, MD, director of the FDA’s Oncology Center of Excellence and acting director of the Office of Hematology and Oncology Products in the FDA’s Center for Drug Evaluation and Research, said in a statement. “Surgery is the primary treatment option, but some patients are not eligible for surgery, and tumors can recur, even after the procedure.”

The approval was based on results of a study of 120 patients, 59 of whom received placebo. After 25 weeks of treatment, the overall response rate was 38% (15% complete responses and 23% partial responses) in those who received pexidartinib; no responses occurred in patients who received placebo. The response persisted in 22 of 23 responders who had been followed for a minimum of 6 months, and in 13 of 13 responders who had been followed for a minimum of 12 months.

Turalio comes with a Boxed Warning about the risk of serious and potentially fatal liver injury. Liver tests should be performed prior to beginning treatment and the results monitored at specified intervals during treatment. Patients who develop abnormal results may need to withhold therapy, reduce the dose, or discontinue therapy depending on the severity of the liver injury.

Common side effects for patients were increased levels of lactate dehydrogenase, aspartate aminotransferase, alanine aminotransferase, and cholesterol. Loss of hair color also occurred in some patients.

Additional side effects included neutropenia, increased alkaline phosphatase levels, decreased lymphocytes, eye edema, decreased hemoglobin levels, rash, dysgeusia, and decreased phosphate levels.

Females of reproductive age and males with a female partner of reproductive potential should use effective contraception during treatment with pexidartinib. Pexidartinib may cause harm to a developing fetus or newborn baby.

Pexidartinib must be dispensed with a patient Medication Guide that describes important information about the drug’s uses and risks.

mdales@mdedge.com

Turalio (pexidartinib) capsules have been approved for the treatment of adult patients with symptomatic tenosynovial giant cell tumor (TGCT) that is associated with severe morbidity or functional limitations not responsive to improvement with surgery, the U.S. Food and Drug Administration announced.

Olivier Le Moal/Getty Images

Turalio is the first therapy to be approved for the rare joint tumor and is available only through the Turalio Risk Evaluation and Mitigation Strategy (REMS) Program. The FDA granted the approval of Turalio to Daiichi Sankyo.

“TGCT can cause debilitating symptoms for patients such as pain, stiffness and limitation of movement,” Richard Pazdur, MD, director of the FDA’s Oncology Center of Excellence and acting director of the Office of Hematology and Oncology Products in the FDA’s Center for Drug Evaluation and Research, said in a statement. “Surgery is the primary treatment option, but some patients are not eligible for surgery, and tumors can recur, even after the procedure.”

The approval was based on results of a study of 120 patients, 59 of whom received placebo. After 25 weeks of treatment, the overall response rate was 38% (15% complete responses and 23% partial responses) in those who received pexidartinib; no responses occurred in patients who received placebo. The response persisted in 22 of 23 responders who had been followed for a minimum of 6 months, and in 13 of 13 responders who had been followed for a minimum of 12 months.

Turalio comes with a Boxed Warning about the risk of serious and potentially fatal liver injury. Liver tests should be performed prior to beginning treatment and the results monitored at specified intervals during treatment. Patients who develop abnormal results may need to withhold therapy, reduce the dose, or discontinue therapy depending on the severity of the liver injury.

Common side effects for patients were increased levels of lactate dehydrogenase, aspartate aminotransferase, alanine aminotransferase, and cholesterol. Loss of hair color also occurred in some patients.

Additional side effects included neutropenia, increased alkaline phosphatase levels, decreased lymphocytes, eye edema, decreased hemoglobin levels, rash, dysgeusia, and decreased phosphate levels.

Females of reproductive age and males with a female partner of reproductive potential should use effective contraception during treatment with pexidartinib. Pexidartinib may cause harm to a developing fetus or newborn baby.

Pexidartinib must be dispensed with a patient Medication Guide that describes important information about the drug’s uses and risks.

mdales@mdedge.com

On the 1-year anniversary of the newest outbreak of Ebola in the Democratic Republic of the Congo (DRC), despite all of the international efforts, “currently the outbreak continues at the same pace, so we don’t see evidence of slowing,” according to Henry Walke, MD, director of the Division of Preparedness and Emerging Infections and Incident Manager, 2018 CDC Ebola Response, Centers for Disease Control and Prevention.

He added that new cases of Ebola have been seen in Goma, which is outside the initial outbreak area. Goma is the largest city in the eastern part of the DRC and a major trading port.

Dr. Walke made his remarks in a telephone media briefing Aug. 1 by the U. S. Department of Health and Human Services outlining the current state of the U.S. response to the outbreak.

World Bank/Vincent Tremeau/CCBY-NC-ND 2.0

He described the efforts of the CDC to provide support to the DRC both from Atlanta and in the field. These efforts included support for vaccination activities in DRC’s North Kivu and Ituri provinces for the population and for at-risk health-care workers in the DRC and neighboring countries. In addition, the United States is involved in the testing of experimental therapeutics and vaccines in the DRC in an effort to aid in this and future outbreaks.


“There are no cases of Ebola in the United States,” said Dr. Walke, and the CDC believes the risk to the United States from the outbreak is low. He cited the limited number of travelers from DRC. “There [are] about 16,000 from the DRC to the U.S. on an annual basis, and only about 100 from Goma itself. There aren’t direct flights and we have at the Goma airport both entry and exit screening.”

According to a World Health Organization report, this Ebola outbreak is the second deadliest on record and has killed 1,750 people out of around 2,518 confirmed cases as of July 23.

Efforts to control the epidemic are severely hampered by civil unrest in the area, public mistrust of the government and health care workers, and a comparative lack of international aid compared to previous Ebola outbreaks.

mlesney@mdedge.com

On the 1-year anniversary of the newest outbreak of Ebola in the Democratic Republic of the Congo (DRC), despite all of the international efforts, “currently the outbreak continues at the same pace, so we don’t see evidence of slowing,” according to Henry Walke, MD, director of the Division of Preparedness and Emerging Infections and Incident Manager, 2018 CDC Ebola Response, Centers for Disease Control and Prevention.

He added that new cases of Ebola have been seen in Goma, which is outside the initial outbreak area. Goma is the largest city in the eastern part of the DRC and a major trading port.

Dr. Walke made his remarks in a telephone media briefing Aug. 1 by the U. S. Department of Health and Human Services outlining the current state of the U.S. response to the outbreak.

World Bank/Vincent Tremeau/CCBY-NC-ND 2.0

He described the efforts of the CDC to provide support to the DRC both from Atlanta and in the field. These efforts included support for vaccination activities in DRC’s North Kivu and Ituri provinces for the population and for at-risk health-care workers in the DRC and neighboring countries. In addition, the United States is involved in the testing of experimental therapeutics and vaccines in the DRC in an effort to aid in this and future outbreaks.


“There are no cases of Ebola in the United States,” said Dr. Walke, and the CDC believes the risk to the United States from the outbreak is low. He cited the limited number of travelers from DRC. “There [are] about 16,000 from the DRC to the U.S. on an annual basis, and only about 100 from Goma itself. There aren’t direct flights and we have at the Goma airport both entry and exit screening.”

According to a World Health Organization report, this Ebola outbreak is the second deadliest on record and has killed 1,750 people out of around 2,518 confirmed cases as of July 23.

Efforts to control the epidemic are severely hampered by civil unrest in the area, public mistrust of the government and health care workers, and a comparative lack of international aid compared to previous Ebola outbreaks.

mlesney@mdedge.com

On the 1-year anniversary of the newest outbreak of Ebola in the Democratic Republic of the Congo (DRC), despite all of the international efforts, “currently the outbreak continues at the same pace, so we don’t see evidence of slowing,” according to Henry Walke, MD, director of the Division of Preparedness and Emerging Infections and Incident Manager, 2018 CDC Ebola Response, Centers for Disease Control and Prevention.

He added that new cases of Ebola have been seen in Goma, which is outside the initial outbreak area. Goma is the largest city in the eastern part of the DRC and a major trading port.

Dr. Walke made his remarks in a telephone media briefing Aug. 1 by the U. S. Department of Health and Human Services outlining the current state of the U.S. response to the outbreak.

World Bank/Vincent Tremeau/CCBY-NC-ND 2.0

He described the efforts of the CDC to provide support to the DRC both from Atlanta and in the field. These efforts included support for vaccination activities in DRC’s North Kivu and Ituri provinces for the population and for at-risk health-care workers in the DRC and neighboring countries. In addition, the United States is involved in the testing of experimental therapeutics and vaccines in the DRC in an effort to aid in this and future outbreaks.


“There are no cases of Ebola in the United States,” said Dr. Walke, and the CDC believes the risk to the United States from the outbreak is low. He cited the limited number of travelers from DRC. “There [are] about 16,000 from the DRC to the U.S. on an annual basis, and only about 100 from Goma itself. There aren’t direct flights and we have at the Goma airport both entry and exit screening.”

According to a World Health Organization report, this Ebola outbreak is the second deadliest on record and has killed 1,750 people out of around 2,518 confirmed cases as of July 23.

Efforts to control the epidemic are severely hampered by civil unrest in the area, public mistrust of the government and health care workers, and a comparative lack of international aid compared to previous Ebola outbreaks.

mlesney@mdedge.com

The Food and Drug Administration has approved pembrolizumab (Keytruda) for patients with recurrent, locally advanced, or metastatic esophageal squamous cell carcinoma (ESCC) whose tumors express PD-L1, as determined by an FDA-approved test, with disease progression after one or more prior lines of systemic therapy.

Wikimedia Commons/FitzColinGerald/Creative Commons License

FDA approval was based on results of two clinical trials: KEYNOTE-180 and KEYNOTE-181. KEYNOTE-181 was a randomized, open-label, active-controlled trial of 628 patients with recurrent, locally advanced, or metastatic esophageal cancer who progressed on or after one prior line of systemic treatment for advanced or metastatic disease. Patients who received pembrolizumab had a median overall survival of 10.3 months, compared with 6.7 months for patients who received control drugs.

In KEYNOTE-180, a single-arm, open-label trial of 121 patients with esophageal cancer who progressed after two prior lines of treatment, patients who had a PD-L1 combined positive score of at least 10 had an overall response rate of 20%, with response durations ranging from 4.2 to over 25.1 months, and with 71% of those patients having a response time over 6 months.

Adverse reactions reported in KEYNOTE-180 and –181 were similar to those in previous trials involving pembrolizumab in patients with melanoma and non–small cell lung cancer. The most common reactions were fatigue, musculoskeletal pain, decreased appetite, pruritus, diarrhea, nausea, rash, pyrexia, cough, dyspnea, constipation, pain, and abdominal pain.

The PD-L1 IHC 22C3 pharmDx kit was approved as the companion diagnostic device, the FDA said.

Find the full press release on the FDA website.

The Food and Drug Administration has approved pembrolizumab (Keytruda) for patients with recurrent, locally advanced, or metastatic esophageal squamous cell carcinoma (ESCC) whose tumors express PD-L1, as determined by an FDA-approved test, with disease progression after one or more prior lines of systemic therapy.

Wikimedia Commons/FitzColinGerald/Creative Commons License

FDA approval was based on results of two clinical trials: KEYNOTE-180 and KEYNOTE-181. KEYNOTE-181 was a randomized, open-label, active-controlled trial of 628 patients with recurrent, locally advanced, or metastatic esophageal cancer who progressed on or after one prior line of systemic treatment for advanced or metastatic disease. Patients who received pembrolizumab had a median overall survival of 10.3 months, compared with 6.7 months for patients who received control drugs.

In KEYNOTE-180, a single-arm, open-label trial of 121 patients with esophageal cancer who progressed after two prior lines of treatment, patients who had a PD-L1 combined positive score of at least 10 had an overall response rate of 20%, with response durations ranging from 4.2 to over 25.1 months, and with 71% of those patients having a response time over 6 months.

Adverse reactions reported in KEYNOTE-180 and –181 were similar to those in previous trials involving pembrolizumab in patients with melanoma and non–small cell lung cancer. The most common reactions were fatigue, musculoskeletal pain, decreased appetite, pruritus, diarrhea, nausea, rash, pyrexia, cough, dyspnea, constipation, pain, and abdominal pain.

The PD-L1 IHC 22C3 pharmDx kit was approved as the companion diagnostic device, the FDA said.

Find the full press release on the FDA website.

The Food and Drug Administration has approved pembrolizumab (Keytruda) for patients with recurrent, locally advanced, or metastatic esophageal squamous cell carcinoma (ESCC) whose tumors express PD-L1, as determined by an FDA-approved test, with disease progression after one or more prior lines of systemic therapy.

Wikimedia Commons/FitzColinGerald/Creative Commons License

FDA approval was based on results of two clinical trials: KEYNOTE-180 and KEYNOTE-181. KEYNOTE-181 was a randomized, open-label, active-controlled trial of 628 patients with recurrent, locally advanced, or metastatic esophageal cancer who progressed on or after one prior line of systemic treatment for advanced or metastatic disease. Patients who received pembrolizumab had a median overall survival of 10.3 months, compared with 6.7 months for patients who received control drugs.

In KEYNOTE-180, a single-arm, open-label trial of 121 patients with esophageal cancer who progressed after two prior lines of treatment, patients who had a PD-L1 combined positive score of at least 10 had an overall response rate of 20%, with response durations ranging from 4.2 to over 25.1 months, and with 71% of those patients having a response time over 6 months.

Adverse reactions reported in KEYNOTE-180 and –181 were similar to those in previous trials involving pembrolizumab in patients with melanoma and non–small cell lung cancer. The most common reactions were fatigue, musculoskeletal pain, decreased appetite, pruritus, diarrhea, nausea, rash, pyrexia, cough, dyspnea, constipation, pain, and abdominal pain.

The PD-L1 IHC 22C3 pharmDx kit was approved as the companion diagnostic device, the FDA said.

Find the full press release on the FDA website.

Officials at the U.S. Department of Health and Human Services have announced a new plan that they say would lay the foundation for safe importation of certain medications, with the aim of expanding drug access and lowering prescription costs for patients.

Jan Mika/iStockphoto

The action plan, unveiled July 31, outlines two pathways for drug importation from foreign markets. The first route would authorize states, wholesalers, or pharmacists to propose pilot demonstrations on how they would import drugs from Canada into the United States, provided these are versions of drugs already approved by the Food and Drug Administration. Similarly, a second pathway would allow manufacturers that sell in foreign countries the opportunity to import drugs that are versions of FDA-approved medications.

HHS Secretary Alex M. Azar II said the action plan is part of President Trump’s drug-pricing blueprint and is intended to combat the sky-high price tags on many prescription medications.

“President Trump has been clear: For too long American patients have been paying exorbitantly high prices for prescription drugs that are made available to other countries at lower prices,” Mr. Azar said in a statement. “[The] announcement outlines the pathways the administration intends to explore to allow safe importation of certain prescription drugs to lower prices and reduce out of pocket costs for American patients. This is the next important step in the administration’s work to end foreign freeloading and put American patients first.”

Wikimedia Commons/WWsgConnect/CC-SA 4.0

Under the first pathway, HHS would review plans submitted by states, pharmacists, or drugmakers that outline how the entities would import Health Canada–approved drugs that are in compliance with the federal Food, Drug, and Cosmetic Act. The importation would occur in a manner that assures the drug’s validity and meets the cost requirements of federal rule making, according to an HHS fact sheet.

Demonstration projects would be time-limited and require regular reporting to ensure safety and cost conditions are being met.

Under the second pathway, manufacturers of FDA-approved drug products would be able to import versions of those drugs that they sell in foreign countries through a special process to be outlined by the agency. As part of the process, drugmakers would need to establish that the foreign version is the same as the U.S. version. The FDA would then allow the drug to be labeled for sale in the U.S. and imported, according to the fact sheet. HHS officials said they believe that manufacturers would use this pathway to offer U.S. patients lower-cost versions of their drugs and the medications affected could potentially include those used to treat diabetes, rheumatoid arthritis, cardiovascular disorders, and cancer.

“In recent years, multiple manufacturers have stated (either publicly or in statements to the Administration) that they wanted to offer lower cost versions but could not readily do so because they were locked into contracts with other parties in the supply chain,” HHS officials stated in the fact sheet. “This pathway would highlight an opportunity for manufacturers to use importation to offer lower-cost versions of their drugs.”

HHS plans to introduce its action plan through a formal notice of proposed rulemaking, which has not yet been finalized. Some elements of the final proposal may differ from its initial descriptions to reflect further consideration of the relevant issues, the agency noted.

Acting FDA Commissioner Ned Sharpless, MD, said the agency has a unique role to play in promoting competition that can help reduce drug prices and improve access to medicine for Americans.

“Driving down drug prices requires a comprehensive approach and we must continue to look at all innovative solutions to this challenge,” Dr. Sharpless said in a statement. “[The] proposal is the result of the hard work by the dedicated staff of the FDA, in close collaboration with HHS and the White House, to identify potential pathways we can pursue to support the safe importation of certain prescription drugs.”

Sen. Lamar Alexander (R-Tenn.), chair of the Health, Education, Labor and Pensions committee, said the administration’s proposal sounds promising as long as the plan ensures the safety and efficacy of imported medications.

“This is the first administration to take concrete steps to allow importation of prescription drugs to reduce their cost and I welcome it,” Sen. Alexander said in a statement. “The key for me is whether this plan preserves the Food and Drug Administration’s gold standard for safety and effectiveness. Millions of Americans every day buy prescription drugs relying on the FDA’s guarantee of quality.”

agallegos@mdedge.com

Officials at the U.S. Department of Health and Human Services have announced a new plan that they say would lay the foundation for safe importation of certain medications, with the aim of expanding drug access and lowering prescription costs for patients.

Jan Mika/iStockphoto

The action plan, unveiled July 31, outlines two pathways for drug importation from foreign markets. The first route would authorize states, wholesalers, or pharmacists to propose pilot demonstrations on how they would import drugs from Canada into the United States, provided these are versions of drugs already approved by the Food and Drug Administration. Similarly, a second pathway would allow manufacturers that sell in foreign countries the opportunity to import drugs that are versions of FDA-approved medications.

HHS Secretary Alex M. Azar II said the action plan is part of President Trump’s drug-pricing blueprint and is intended to combat the sky-high price tags on many prescription medications.

“President Trump has been clear: For too long American patients have been paying exorbitantly high prices for prescription drugs that are made available to other countries at lower prices,” Mr. Azar said in a statement. “[The] announcement outlines the pathways the administration intends to explore to allow safe importation of certain prescription drugs to lower prices and reduce out of pocket costs for American patients. This is the next important step in the administration’s work to end foreign freeloading and put American patients first.”

Wikimedia Commons/WWsgConnect/CC-SA 4.0

Under the first pathway, HHS would review plans submitted by states, pharmacists, or drugmakers that outline how the entities would import Health Canada–approved drugs that are in compliance with the federal Food, Drug, and Cosmetic Act. The importation would occur in a manner that assures the drug’s validity and meets the cost requirements of federal rule making, according to an HHS fact sheet.

Demonstration projects would be time-limited and require regular reporting to ensure safety and cost conditions are being met.

Under the second pathway, manufacturers of FDA-approved drug products would be able to import versions of those drugs that they sell in foreign countries through a special process to be outlined by the agency. As part of the process, drugmakers would need to establish that the foreign version is the same as the U.S. version. The FDA would then allow the drug to be labeled for sale in the U.S. and imported, according to the fact sheet. HHS officials said they believe that manufacturers would use this pathway to offer U.S. patients lower-cost versions of their drugs and the medications affected could potentially include those used to treat diabetes, rheumatoid arthritis, cardiovascular disorders, and cancer.

“In recent years, multiple manufacturers have stated (either publicly or in statements to the Administration) that they wanted to offer lower cost versions but could not readily do so because they were locked into contracts with other parties in the supply chain,” HHS officials stated in the fact sheet. “This pathway would highlight an opportunity for manufacturers to use importation to offer lower-cost versions of their drugs.”

HHS plans to introduce its action plan through a formal notice of proposed rulemaking, which has not yet been finalized. Some elements of the final proposal may differ from its initial descriptions to reflect further consideration of the relevant issues, the agency noted.

Acting FDA Commissioner Ned Sharpless, MD, said the agency has a unique role to play in promoting competition that can help reduce drug prices and improve access to medicine for Americans.

“Driving down drug prices requires a comprehensive approach and we must continue to look at all innovative solutions to this challenge,” Dr. Sharpless said in a statement. “[The] proposal is the result of the hard work by the dedicated staff of the FDA, in close collaboration with HHS and the White House, to identify potential pathways we can pursue to support the safe importation of certain prescription drugs.”

Sen. Lamar Alexander (R-Tenn.), chair of the Health, Education, Labor and Pensions committee, said the administration’s proposal sounds promising as long as the plan ensures the safety and efficacy of imported medications.

“This is the first administration to take concrete steps to allow importation of prescription drugs to reduce their cost and I welcome it,” Sen. Alexander said in a statement. “The key for me is whether this plan preserves the Food and Drug Administration’s gold standard for safety and effectiveness. Millions of Americans every day buy prescription drugs relying on the FDA’s guarantee of quality.”

agallegos@mdedge.com

Officials at the U.S. Department of Health and Human Services have announced a new plan that they say would lay the foundation for safe importation of certain medications, with the aim of expanding drug access and lowering prescription costs for patients.

Jan Mika/iStockphoto

The action plan, unveiled July 31, outlines two pathways for drug importation from foreign markets. The first route would authorize states, wholesalers, or pharmacists to propose pilot demonstrations on how they would import drugs from Canada into the United States, provided these are versions of drugs already approved by the Food and Drug Administration. Similarly, a second pathway would allow manufacturers that sell in foreign countries the opportunity to import drugs that are versions of FDA-approved medications.

HHS Secretary Alex M. Azar II said the action plan is part of President Trump’s drug-pricing blueprint and is intended to combat the sky-high price tags on many prescription medications.

“President Trump has been clear: For too long American patients have been paying exorbitantly high prices for prescription drugs that are made available to other countries at lower prices,” Mr. Azar said in a statement. “[The] announcement outlines the pathways the administration intends to explore to allow safe importation of certain prescription drugs to lower prices and reduce out of pocket costs for American patients. This is the next important step in the administration’s work to end foreign freeloading and put American patients first.”

Wikimedia Commons/WWsgConnect/CC-SA 4.0

Under the first pathway, HHS would review plans submitted by states, pharmacists, or drugmakers that outline how the entities would import Health Canada–approved drugs that are in compliance with the federal Food, Drug, and Cosmetic Act. The importation would occur in a manner that assures the drug’s validity and meets the cost requirements of federal rule making, according to an HHS fact sheet.

Demonstration projects would be time-limited and require regular reporting to ensure safety and cost conditions are being met.

Under the second pathway, manufacturers of FDA-approved drug products would be able to import versions of those drugs that they sell in foreign countries through a special process to be outlined by the agency. As part of the process, drugmakers would need to establish that the foreign version is the same as the U.S. version. The FDA would then allow the drug to be labeled for sale in the U.S. and imported, according to the fact sheet. HHS officials said they believe that manufacturers would use this pathway to offer U.S. patients lower-cost versions of their drugs and the medications affected could potentially include those used to treat diabetes, rheumatoid arthritis, cardiovascular disorders, and cancer.

“In recent years, multiple manufacturers have stated (either publicly or in statements to the Administration) that they wanted to offer lower cost versions but could not readily do so because they were locked into contracts with other parties in the supply chain,” HHS officials stated in the fact sheet. “This pathway would highlight an opportunity for manufacturers to use importation to offer lower-cost versions of their drugs.”

HHS plans to introduce its action plan through a formal notice of proposed rulemaking, which has not yet been finalized. Some elements of the final proposal may differ from its initial descriptions to reflect further consideration of the relevant issues, the agency noted.

Acting FDA Commissioner Ned Sharpless, MD, said the agency has a unique role to play in promoting competition that can help reduce drug prices and improve access to medicine for Americans.

“Driving down drug prices requires a comprehensive approach and we must continue to look at all innovative solutions to this challenge,” Dr. Sharpless said in a statement. “[The] proposal is the result of the hard work by the dedicated staff of the FDA, in close collaboration with HHS and the White House, to identify potential pathways we can pursue to support the safe importation of certain prescription drugs.”

Sen. Lamar Alexander (R-Tenn.), chair of the Health, Education, Labor and Pensions committee, said the administration’s proposal sounds promising as long as the plan ensures the safety and efficacy of imported medications.

“This is the first administration to take concrete steps to allow importation of prescription drugs to reduce their cost and I welcome it,” Sen. Alexander said in a statement. “The key for me is whether this plan preserves the Food and Drug Administration’s gold standard for safety and effectiveness. Millions of Americans every day buy prescription drugs relying on the FDA’s guarantee of quality.”

agallegos@mdedge.com

The Food and Drug Administration has approved darolutamide for nonmetastatic, castration-resistant prostate cancer.

Olivier Le Moal/Getty Images

The approval was based on improved metastasis-free survival (MFS) in the randomized ARAMIS trial of 1,509 patients with nonmetastatic, castration-resistant prostate cancer.

Median MFS was 40.4 months (95% confidence interval, 34.3 months to not reached) for patients treated with darolutamide, compared with 18.4 months (95% CI, 15.5-22.3 months) for those receiving placebo (hazard ratio, 0.41; 95% CI, 0.34-0.50; P less than .0001), according to the FDA.

MFS is defined as the time from randomization to first evidence of distant metastasis or death from any cause within 33 weeks after the last evaluable scan, whichever occurred first.

In ARAMIS, patients were randomized 2:1 to receive either 600 mg darolutamide orally twice daily (n = 955) or matching placebo (n = 554). All patients received a gonadotropin-releasing hormone analog concurrently or had a previous bilateral orchiectomy. Twelve patients with previous seizure histories were treated on the darolutamide arm.

Overall survival data is not yet mature, the FDA said.

The most common adverse reactions in patients who received darolutamide were fatigue, extremity pain, and rash. Ischemic heart disease (4.3%) and heart failure (2.1%) were more common on the darolutamide arm, while seizure incidence was similar in the two arms (0.2%).

The recommended darolutamide dose is 600 mg (two 300-mg tablets) administered orally twice daily with food. Patients should also receive a gonadotropin-releasing hormone analog concurrently or should have had bilateral orchiectomy, the FDA said.

Darolutamide is marketed as Nubeqa by Bayer HealthCare Pharmaceuticals.

 

The Food and Drug Administration has approved darolutamide for nonmetastatic, castration-resistant prostate cancer.

Olivier Le Moal/Getty Images

The approval was based on improved metastasis-free survival (MFS) in the randomized ARAMIS trial of 1,509 patients with nonmetastatic, castration-resistant prostate cancer.

Median MFS was 40.4 months (95% confidence interval, 34.3 months to not reached) for patients treated with darolutamide, compared with 18.4 months (95% CI, 15.5-22.3 months) for those receiving placebo (hazard ratio, 0.41; 95% CI, 0.34-0.50; P less than .0001), according to the FDA.

MFS is defined as the time from randomization to first evidence of distant metastasis or death from any cause within 33 weeks after the last evaluable scan, whichever occurred first.

In ARAMIS, patients were randomized 2:1 to receive either 600 mg darolutamide orally twice daily (n = 955) or matching placebo (n = 554). All patients received a gonadotropin-releasing hormone analog concurrently or had a previous bilateral orchiectomy. Twelve patients with previous seizure histories were treated on the darolutamide arm.

Overall survival data is not yet mature, the FDA said.

The most common adverse reactions in patients who received darolutamide were fatigue, extremity pain, and rash. Ischemic heart disease (4.3%) and heart failure (2.1%) were more common on the darolutamide arm, while seizure incidence was similar in the two arms (0.2%).

The recommended darolutamide dose is 600 mg (two 300-mg tablets) administered orally twice daily with food. Patients should also receive a gonadotropin-releasing hormone analog concurrently or should have had bilateral orchiectomy, the FDA said.

Darolutamide is marketed as Nubeqa by Bayer HealthCare Pharmaceuticals.

 

The Food and Drug Administration has approved darolutamide for nonmetastatic, castration-resistant prostate cancer.

Olivier Le Moal/Getty Images

The approval was based on improved metastasis-free survival (MFS) in the randomized ARAMIS trial of 1,509 patients with nonmetastatic, castration-resistant prostate cancer.

Median MFS was 40.4 months (95% confidence interval, 34.3 months to not reached) for patients treated with darolutamide, compared with 18.4 months (95% CI, 15.5-22.3 months) for those receiving placebo (hazard ratio, 0.41; 95% CI, 0.34-0.50; P less than .0001), according to the FDA.

MFS is defined as the time from randomization to first evidence of distant metastasis or death from any cause within 33 weeks after the last evaluable scan, whichever occurred first.

In ARAMIS, patients were randomized 2:1 to receive either 600 mg darolutamide orally twice daily (n = 955) or matching placebo (n = 554). All patients received a gonadotropin-releasing hormone analog concurrently or had a previous bilateral orchiectomy. Twelve patients with previous seizure histories were treated on the darolutamide arm.

Overall survival data is not yet mature, the FDA said.

The most common adverse reactions in patients who received darolutamide were fatigue, extremity pain, and rash. Ischemic heart disease (4.3%) and heart failure (2.1%) were more common on the darolutamide arm, while seizure incidence was similar in the two arms (0.2%).

The recommended darolutamide dose is 600 mg (two 300-mg tablets) administered orally twice daily with food. Patients should also receive a gonadotropin-releasing hormone analog concurrently or should have had bilateral orchiectomy, the FDA said.

Darolutamide is marketed as Nubeqa by Bayer HealthCare Pharmaceuticals.