Trial by "Firsts": Clinical Trial Design and Regulatory Considerations in the Development and Approval of the First AAV Gene Therapy Product in the United States.

Given the therapeutic potential of supplying a normal copy of a mutant gene to the correct target tissue, gene therapy holds extraordinary promise for the treatment of genetic disease. Like other novel classes of therapeutics however, gene therapies must overcome a range of clinical, regulatory, and manufacturing hurdles to reach regulatory approval. This paper reviews key aspects of clinical trial design, development, and evaluation of a novel primary end point, and regulatory interactions that resulted in the first approval by the U.

Multiyear Factor VIII Expression after AAV Gene Transfer for Hemophilia A.

Background: The goal of gene therapy for patients with hemophilia A is to safely impart long-term stable factor VIII expression that predictably ameliorates bleeding with the use of the lowest possible vector dose.

Methods: In this phase 1-2 trial, we infused an investigational adeno-associated viral (AAV) vector (SPK-8011) for hepatocyte expression of factor VIII in 18 men with hemophilia A. Four dose cohorts were enrolled; the lowest-dose cohort received a dose of 5  × 10 vector genomes (vg) per kilogram of body weight, and the highest-dose cohort received 2 × 10 vg per kilogram.

Durability of Voretigene Neparvovec for Biallelic RPE65-Mediated Inherited Retinal Disease: Phase 3 Results at 3 and 4 Years.

Purpose: To determine whether functional vision and visual function improvements after voretigene neparvovec (VN; Luxturna [Spark Therapeutics, Inc]) administration in patients with biallelic RPE65 mutation-associated inherited retinal disease are maintained at 3 to 4 years and to review safety outcomes.

Design: Open-label, randomized, controlled phase 3 trial.

Participants: Thirty-one individuals were enrolled and randomized 2:1 to intervention (n = 21) or control (n = 10).

The Natural History of Inherited Retinal Dystrophy Due to Biallelic Mutations in the RPE65 Gene.

Purpose: To delineate the natural history of visual parameters over time in individuals with biallelic RPE65 mutation-associated inherited retinal dystrophy (IRD); describe the range of causative mutations; determine potential genotype/phenotype relationships; and describe the variety of clinical diagnoses.

Design: Global, multicenter, retrospective chart review.

Methods: Study Population: Seventy individuals with biallelic RPE65 mutation-associated IRD.

Synthetic conjugated estrogens-B and postmenopausal nocturnal vasomotor symptoms: a randomized controlled trial.

Objective: To evaluate two doses of oral synthetic conjugated estrogens-B tablets compared with placebo on the frequency of awakenings resulting from nocturnal vasomotor symptoms in postmenopausal women over a 12-week treatment period.

Methods: A double-blind, randomized, placebo-controlled multicenter study enrolled a total of 157 women who were experiencing daytime vasomotor symptoms and a minimum of at least three nocturnal awakenings per night as a result of hot flushes. Participants were evenly randomized to one of three treatment groups (0.

Body weight does not impact pregnancy rates during use of a low-dose extended-regimen 91-day oral contraceptive.

Background: This study evaluated the impact of weight on efficacy during use of an extended oral contraceptive (OC).

Study Design: Data were from a Phase 3 clinical trial evaluating the efficacy of a low-dose 91-day extended regimen of 100 mcg levonorgestrel/20 mcg ethinyl estradiol (LNG/EE; 84 days)+10 mcg EE (7 days) for the prevention of pregnancy. Crude pregnancy rates were calculated for weight and body mass index (BMI) deciles.

A look at the long-term safety of an extended-regimen OC.

Background: Oral contraceptives (OCs) are the most widely used method of reversible contraception. Recent alterations of the standard 28-day regimen have included shortening the traditional hormone-free interval (HFI), supplementing the HFI with low-dose estrogen, or increasing the number of active pills administered, thus extending the time between withdrawal bleeding episodes by a variable number of months. In light of these changes in regimens, clinicians may be seeking evidence that the new regimens are safe and will not result in unexpected adverse events.

The efficacy and safety of a low-dose, 91-day, extended-regimen oral contraceptive with continuous ethinyl estradiol.

Background: This clinical trial was conducted to demonstrate the efficacy and safety of a 91-day extended-regimen, low-dose combination oral contraceptive (OC) consisting of 84 days of ethinyl estradiol (EE) 20 mcg/levonorgestrel (LNG) 100 mcg, followed by 7 days of 10 mcg EE in place of placebo.

Study Design: A multicenter open-label, single-treatment, Phase 3 study evaluated women aged 18 through 40 years over a treatment period of up to 1 year (four 91-day extended cycles). All subjects completed daily paper diaries to monitor compliance, bleeding and additional forms of contraception used during the course of the study.

Adding low-dose estrogen to the hormone-free interval: impact on bleeding patterns in users of a 91-day extended regimen oral contraceptive.

Background: A cross-study analysis of contraceptive clinical trials for two different 91-day oral contraceptive (OC) regimens was performed to examine the impact on bleeding patterns when supplementing the 7-day hormone-free interval with 10 mcg ethinyl estradiol (EE) daily.

Study Design: Two separate 1-year Phase 3 clinical programs were conducted using similar study designs. The percentages of subjects reporting bleeding and spotting using electronic diaries for each 91-day cycle were compared.

Twice-weekly synthetic conjugated estrogens vaginal cream for the treatment of vaginal atrophy.

Objective: The aim of this study was to evaluate low-dose synthetic conjugated estrogens A (SCE-A) cream administered twice weekly for the treatment of moderate to severe vulvovaginal atrophy (VVA) in a symptomatic postmenopausal population.

Methods: In a multicenter, double-blind, randomized, placebo-controlled study, 305 women with symptoms of VVA were treated with either 1 g SCE-A cream (n = 150) or matching placebo (n = 155) for a period of up to 12 weeks. Participants had to have a vaginal pH of greater than 5, less than or equal to 5% superficial cells on a vaginal smear, and at least one of five symptoms of VVA (dryness, soreness, irritation, pain with intercourse, and bleeding after intercourse) that was moderate or severe in intensity.

Effectiveness of a novel home-based testing device for the detection of rupture of membranes.

We evaluated the ability of a testing panty liner (TPL) embedded with a pH/ammonia indicator polymer to differentiate amniotic fluid leakage from urine. A multicenter, open-label study in which 339 pregnant women (age 18 to 45 years, minimum 16 weeks' gestation, presenting with unexplained vaginal wetness) were enrolled. The TPL was worn and the results read by the subject and a health care provider (HCP) who was blinded to the subject's reading.

Understanding the menopausal experiences of professional women.

Objective: To assess how menopause affects the lives of busy female executives by evaluating how they view their overall health and how specific symptoms affect their lives and to gain insight into their knowledge and general perspective of hormone therapy as treatment for menopause-related symptoms.

Design: In this survey, 961 members of the National Association of Female Executives aged 35 years and older completed an Internet survey about the impact of menopausal symptoms and general knowledge and understanding of hormone therapy. Subgroups within this survey included women who were premenopausal (n = 118), perimenopausal (n = 239), menopausal (n = 297), and postmenopausal (n = 307).

Measuring symptom relief in studies of vaginal and vulvar atrophy: the most bothersome symptom approach.

Objective: To assess the importance and usefulness of self-reported symptom data, especially the most bothersome symptom, in the evaluation of treatment for vulvovaginal atrophy.

Design: This was a double-blind, placebo-controlled multicenter study. Women rated symptoms associated with vaginal atrophy (vaginal dryness, vaginal/vulvar irritation/itching, vaginal/vulvar soreness, and dyspareunia) before and during treatment and selected one moderate to severe symptom as the most bothersome.

Efficacy and safety of a 28-day oral contraceptive with 7 days of low-dose estrogen in place of placebo.

Background: The study was conducted to evaluate the efficacy and safety for the prevention of pregnancy of a 28-day oral contraceptive (OC) containing 150 mcg desogestrel (DSG)/20 mcg ethinyl estradiol (EE) for 21 days followed by 7 days of 10 mcg EE (Cette-28).

Study Design: A 6-month, prospective, multicenter, single-arm study was conducted in 1302 women aged 18-45 years.

Results: Over six cycles of treatment, the cumulative risk of pregnancy among all treated subjects (n=1262) was 0.

Evaluation of pituitary-ovarian axis suppression with three oral contraceptive regimens.

Background: The study was conducted to evaluate follicular development and hormone patterns with three oral contraceptive (OC) regimens before, during and after the 7-day hormone-free interval (HFI) or 7-day ethinyl estradiol (EE)-supplemented interval.

Study Design: The study is a single-center, open-label, prospective, randomized trial to evaluate pituitary-ovarian suppression with three OC regimens containing identical hormones: 30 mcg of EE and 150 mcg of levonorgestrel (LNG).

Methods: After a standard 21/7 OC baseline cycle, subjects were randomized to one of three treatment groups: (1) three 21/7-day cycles of 150 mcg LNG/30 mcg EE for 21 days followed by 7 days of placebo (n=10); (2) one 84/7-day cycle of 150 mcg LNG/30 mcg EE for 84 days followed by 7 days of placebo (n=12) and (3) one 84/7EE-day cycle of 150 mcg LNG/30 mcg EE for 84 days followed by 7 days of 10 mcg EE (n=11).

Endometrial effects of a 91-day extended-regimen oral contraceptive with low-dose estrogen in place of placebo.

Background: The study was conducted to evaluate the effects of a 91-day extended-regimen oral contraceptive (OC) containing levonorgestrel (LNG) with low-dose ethinyl estradiol (EE) in place of placebo on endometrial histology.

Study Design: Endometrial biopsies were obtained prior to initiation and posttreatment, between cycle Days 60 and 84 (during combination EE/LNG tablets), between cycle Days 85 and 91 (during low-dose EE tablets) or after completion of therapy.

Results: Paired endometrial biopsy samples obtained before and after treatment were available for 63 subjects.

Effects on serum hormone levels of low-dose estrogen in place of placebo during the hormone-free interval of an oral contraceptive.

Background: The study was conducted to evaluate the effects of low-dose estrogen compared to placebo on ovarian activity during the traditional 7-day hormone-free interval (HFI) of an oral contraceptive (OC).

Study Design: Women were randomized to placebo or low-dose estrogen for 7 days during the HFI. Serum levels of estradiol, follicle-stimulating hormone (FSH), luteinizing hormone and inhibin B were obtained before, during and after treatment.

Randomized, multicenter, double-blind, placebo-controlled trial to evaluate the efficacy and safety of synthetic conjugated estrogens B for the treatment of vulvovaginal atrophy in healthy postmenopausal women.

Objective: To evaluate the safety and efficacy of synthetic conjugated estrogens B (SCE-B; 0.3 mg/d) for 12 weeks in the treatment of vulvovaginal atrophy in symptomatic, postmenopausal women.

Design: Prospective, randomized, multicenter, double-blind, placebo-controlled trial.

Effects of synthetic conjugated estrogens A on sleep quality in postmenopausal women with nocturnal diaphoresis and/or hot flushes: a pilot study.

In a single-center, double-blind, placebo-controlled pilot study, patients who received 0.625 mg daily of synthetic conjugated estrogens A experienced a statistically significant reduction in the average number of hot flushes and galvanic skin responses. The polysomnographic change in sleep measures did not reach statistical significance, but the data suggest an overall improvement in sleep quality in the treatment group.

Current contraceptive research and development.

The approval of various new contraceptive products in recent years has resulted in broadening the options available to women. Trends in contraceptive research for hormonal products include variations in dose and dosing regimens, introduction of novel compounds, evaluation of products for noncontraceptive indications, and development of nonoral delivery systems and male contraceptives. Nonhormonal areas of research include microbicidal products, dual protection methods, and contraceptive vaccines.