Addressing choice of law challenges in multi-state precision medicine research: experts' assessment of key factors.

Precision medicine research implicates numerous state laws that may affect participants' rights and protections and are not preempted by federal law. The choice of which state's laws apply, and under what circumstances, can have significant impact on research design and oversight. But neither of the traditional approaches to choice of law issues-contractual agreement or determination by a court after a dispute arises-fit the research context well. We hosted a series of workshops with choice of law experts and research law and ethics experts to identify factors that are most crucial to account for in a future choice of law precision medicine research framework. Our workshops focused on precision medicine 'places' and choice of law factors; there was consensus that 'place where the harm occurred' was relevant and best represented by where the participant resides and/or where the research/institution is located. Our experts identified factors that need to be accounted for in a future choice of law framework. They also identified potential approaches, including a federal law or model state law as ways of achieving more uniformity of protections and a comprehensive database of laws, which merit further consideration to provide IRBs and researchers the guidance they require.

Onapristone Extended Release: Safety Evaluation from Phase I-II Studies with an Emphasis on Hepatotoxicity.

INTRODUCTION: Antiprogestins have demonstrated promising activity against breast and gynecological cancers, but liver-related safety concerns limited the advancement of this therapeutic class. Onapristone is a full progesterone receptor antagonist originally developed as an oral contraceptive and later evaluated in phase II studies for metastatic breast cancer. Because of liver enzyme elevations identified during clinical studies, further development was halted. Evaluation of antiprogestin pharmacology and pharmacokinetic data suggested that liver enzyme elevations might be related to off-target or metabolic effects associated with clinical drug exposure. OBJECTIVE: We explored whether the use of a pharmaceutic strategy targeting efficacious systemic dose concentrations, but with diminished peak serum concentrations and/or total drug exposure would mitigate hepatotoxicity. Twice-daily dosing of an extended-release formulation of onapristone was developed and clinically evaluated in light of renewed interest in antiprogestin therapy for treating progesterone receptor-positive breast and gynecologic cancers. The hepatotoxic potential of extended-release onapristone was assessed from two phase I-II studies involving patients with breast, ovarian, endometrial, and prostate cancer. RESULTS: Among the 88 patients in two phase I-II studies in progesterone receptor-positive malignancies treated with extended-release onapristone, elevated alanine aminotransferase/aspartate aminotransferase levels were found in 20% of patients with liver metastases compared with 6.3% without metastases. Of five patients with grade 3 or higher alanine aminotransferase elevations with or without bilirubin elevations (four with breast cancer and one with endometrial cancer), four were assessed as unrelated to extended-release onapristone by the safety data review committee. Furthermore, while the fifth patient's liver enzyme elevations were considered possibly drug related by the study investigator, they were adjudicated as unlikely to be related (< 25% likelihood) by a subsequent independent hepatologist. CONCLUSIONS: These results suggest that the extended-release formulation by reducing drug exposure may be associated with a reduced risk of hepatotoxicity, and supports the continued clinical evaluation of extended-release onapristone for treating progesterone receptor-positive cancers.

Long-term acute care hospitals and Georgia Medicaid: Utilization, outcomes, and cost.

OBJECTIVES: Because most research on long-term acute care hospitals has focused on Medicare, the objective of this research is to describe the Georgia Medicaid population who received care at a long-term acute care hospital, the type and volume of services provided by these long-term acute care hospitals, and the costs and outcomes of these services. For those with select respiratory conditions, we descriptively compare costs and outcomes to those of patients who received care for the same services in acute care hospitals. METHODS: We describe Georgia Medicaid recipients admitted to a long-term acute care hospital between 2011 and 2012. We compare them to a population of Georgia Medicaid recipients admitted to an acute care hospital for one of five respiratory diagnosis-related groups. Measurements used include patient descriptive information, admissions, diagnosis-related groups, length of stay, place of discharge, 90-day episode costs, readmissions, and patient risk scores. RESULTS: We found that long-term acute care hospital admissions for Medicaid patients were fairly low (470 90-day episodes) and restricted to complex cases. We also found that the majority of long-term acute care hospital patients were blind or disabled (71.2%). Compared to patients who stayed at an acute care hospital, long-term acute care hospital patients had higher average risk scores (13.1 versus 9.0), lengths of stay (61 versus 38 days), costs (US$143,898 versus US$115,056), but fewer discharges to the community (28.4% versus 51.8%). CONCLUSION: We found that the Medicaid population seeking care at long-term acute care hospitals is markedly different than the Medicare populations described in other long-term acute care hospital studies. In addition, our study revealed that Medicaid patients receiving select respiratory care at a long-term acute care hospital were distinct from Medicaid patients receiving similar care at an acute care hospital. Our findings suggest that state Medicaid programs should carefully consider reimbursement policies for long-term acute care hospitals, including bundled payments that cover both the original hospitalization and long-term acute care hospital admission.

Redressing past wrongs: changing the common rule to increase minority voices in research.

Numerous diseases disproportionately affect African Americans across socioeconomic, age, gender, and geographic groups. Despite the need for research into these disparities, African Americans are often underrepresented in research. The Tuskegee Syphilis Study receives much of the blame for this problem, but other contributing factors have also been identified. To date, government policies seeking to increase African American participation have had limited success, and recently proposed changes to the Common Rule do not address this problem. Therefore, we have proposed 3 changes: treating racial minorities as vulnerable, requiring community consultation in minority research, and increasing minority representation on institutional review boards. Coupled with other efforts, these changes could help increase minority representation in researching health disparities.

Fourteen-day safety and acceptability study of the universal placebo gel.

OBJECTIVE: This study evaluated the effect of the so-called universal placebo compared to the polystyrene sulfonate (PSS) placebo on genital irritation. DESIGN: A single-center, Phase I, randomized, closed-label study was performed to evaluate the genital irritation of microbicide placebo gels. Thirty healthy, sexually abstinent women were randomly assigned to apply 3.5 mL of either the universal placebo or the PSS placebo gel intravaginally twice daily for 14 days. METHODS: Genital irritation was assessed by signs as seen on pelvic examination and colposcopy and reports of symptoms. Vaginal health was assessed by wet mounts, Gram stains for Nugent score and polymorphonuclear leukocytes, and semiquantitative vaginal cultures. Acceptability was assessed as reported on the follow-up questionnaire. RESULTS: The universal placebo was less irritating than the PSS placebo with a lower proportion of women experiencing signs and/or symptoms of genital irritation throughout follow-up (36% compared to 80%, p=.0253). The universal placebo was associated with few and mild genital symptoms, few and minor colposcopic findings and good vaginal health with no clinically significant changes in genital flora. Most participants found the feel of the universal placebo gel neutral or pleasant, and all participants found it odorless. CONCLUSIONS: The universal placebo appeared safe and acceptable when used twice daily for 14 days. The strategy of creating a de novo inert universal placebo is a successful approach. The universal placebo is appropriate for use as a placebo gel in HIV prevention trials with microbicide candidates.

Development and characterization of bioadhesive vaginal films of sodium polystyrene sulfonate (PSS), a novel contraceptive antimicrobial agent.

PURPOSE: Polystyrene sulfonate (PSS) is a novel noncytotoxic antimicrobial contraceptive agent. A gel formulation of PSS was found safe for vaginal administration in phase I clinical trials. The purpose of the current study was to develop and evaluate novel bioadhesive vaginal film formulations of PSS. METHODS: PSS films were prepared by solvent evaporation and optimized for various physical, mechanical, and aesthetic properties. Further, films were evaluated for various biological activities and safety. RESULTS: Vaginal films containing 300 mg PSS per unit have been developed, using generally regarded as safe (GRAS) listed excipients. The films are colorless, transparent, thin, soft, and tough, dissolve rapidly in physiologic fluid to form a smooth, viscous and bioadhesive solution that could be retained in the vagina for prolonged intervals. Sperm function inhibition (hyaluronidase and cervical mucus penetration) and antimicrobial activities against human immunodeficiency virus (HIV) and herpes simplex virus (HSV) by PSS films were found comparable to PSS. Also, films did not inhibit normal vaginal microflora (Lactobacillus) and were noncytotoxic as indicated by negligible sperm immobilization and cytotoxicity to host cell assays. CONCLUSIONS: Rapidly dissolving bioadhesive vaginal film formulation of PSS with desired physical, mechanical, aesthetic, and biological properties is a suitable candidate vaginal microbicide for prevention of sexually transmitted disease (STDs) and is ready for toxicological and clinical evaluation.

Contraception by Ushercell (cellulose sulfate) in formulation: duration of effect and dose effectiveness.

This study evaluated contraception by formulated Ushercell, a uniquely high-molecular-weight form of cellulose sulfate, in the rabbit. Variables included (1) dose effectiveness, (2) duration of effectiveness, and (3) formulation excipients. Vaginally applied carboxymethyl-cellulose-based Ushercell gel is contraceptive. A 6% gel is active for at least 18 h; partial activity is observed for at least 24 h. With an application-insemination interval of 0.5 h, Ushercell as low as 0.1% is contraceptive. Contraception is incomplete with 2% Ushercell and an application-insemination interval of 24 h. Ushercell formulations containing a relatively high concentration of Carbopol are ineffective contraceptives, whether the gel is applied before insemination or is premixed with spermatozoa before insemination. Contraceptive activity is restored in Ushercell formulations with lower Carbopol content. This study shows that formulated Ushercell is an effective, long-lasting contraceptive and, hence, is bioavailable when vaginally applied. Activity is dependent on the type and relative concentration of formulation excipients. These data support a projected successful outcome of further clinical trials.

Single and multiple exposure tolerance study of polystyrene sulfonate gel: a phase I safety and colposcopy study.

OBJECTIVES: To evaluate symptoms and signs of genital irritation, vaginal leakage and acceptability of polystyrene sulfonate (PSS), which is being studied as a vaginal contraceptive and microbicide. METHODS: Forty-nine women applied 2.5 mL of either 5% PSS, 10% PSS, PSS vehicle, or Conceptrol (a marketed spermicidal product containing 4% nonoxynol-9) for 6 consecutive days. RESULTS: All women completed the study except one in the Conceptrol group who experienced vaginal symptoms after her first use and was discontinued. After both the first use and after all uses, irritation was seen among more women in the Conceptrol group than in the PSS groups, reaching statistical significance with regard to any evidence of irritation, signs of irritation and product-related irritation. There were no adverse events that were serious, unexpected and related to product use in any group. The 5% concentration of PSS may be preferable in terms of leakage and acceptability. CONCLUSION: The results suggest that PSS has a safety profile comparable to that of the marketed nonoxynol-9 product, Conceptrol, and appears to be associated with less genital irritation.

Preclinical evaluation of sodium cellulose sulfate (Ushercell) as a contraceptive antimicrobial agent.

The spread of sexually transmitted infections (STIs) and limited methods for control of pregnancies presents high risks to the reproductive health of women. Methods controlled by women and directed toward disease prevention and contraception are needed. We report on preclinical studies of the biological properties of sodium cellulose sulfate (Ushercell) currently being developed for use as a topical contraceptive antimicrobial agent. Ushercell was evaluated with tests designed to identify its contraceptive and antimicrobial properties. Ushercell inhibits hyaluronidase (reversible; IC50 = 1.7 mg/mL), impairs sperm penetration of cervical mucus (approximately 70% inhibition at 1 mg/mL), and acts as a stimulus for acrosomal loss (IC50 = 52 ng/mL). It prevents conception in rabbits when added to spermatozoa (approximately 95% inhibition at 1 mg/mL) or when vaginally applied (complete contraception by 45 mg) before insemination. However, up to 50 mg/mL, Ushercell does not irreversibly immobilize spermatozoa, suggesting that Ushercell is not cytotoxic. Ushercell has a broad spectrum of antimicrobial activity in vitro. Inhibited microbes include human immunodeficiency viruses (different laboratory strains and clinical isolates; IC50 values range from 3 to 78 microg/mL), herpes viruses, HSV-1 (IC50 = 59 ng/mL) and HSV-2 (lC50 = 24 ng/mL), Neisseria gonorrhoeae (IC50 = 2 microg/mL), and Chlamydia trachomatis (IC50 = 78 microg/mL). In contrast, Ushercell does not inhibit growth of beneficial vaginal bacteria, Lactobacillus gasseri, at 5 mg/mL. These results suggest that the antimicrobial effects of Ushercell are selective, and not likely mediated by nonspecific cytotoxic mechanisms. These data provide the basis for further clinical development of Ushercell as a vaginal agent to prevent unplanned pregnancy and STIs.

Efficacy and safety of a new vaginal contraceptive antimicrobial formulation containing high molecular weight poly(sodium 4-styrenesulfonate).

Host cell infection by sexually transmitted disease (STD)-causing microbes and fertilization by spermatozoa may have some mechanisms in common. If so, certain noncytotoxic agents could inhibit the functional activity of both organisms. High molecular mass poly(sodium 4-styrenesulfonate) (T-PSS) may be one of these compounds. T-PSS alone (1 mg/ml) or in a gel (2% or 5% T-PSS) completely prevented conception in the rabbit. Contraception was not due to sperm cytotoxicity or to an effect on sperm migration. However, T-PSS inhibited sperm hyaluronidase (IC(50) = 5.3 microg/ml) and acrosin (IC(50) = 0.3 microg/ml) and caused the loss of acrosomes from spermatozoa (85% maximal loss by 0.5 microg/ml). T-PSS (5% in gel) also reduced sperm penetration into bovine cervical mucus (73% inhibition by 1 mg gel/ml). T-PSS (5% in gel) inhibited human immunodeficiency virus (HIV; IC(50)= 16 microg gel/ml) and herpes simplex viruses (HSV-1 and HSV-2; IC(50) = 1.3 and 1.0 microg gel/ml, respectively). The drug showed high efficacy against a number of clinical isolates and laboratory strains. T-PSS (5% in gel) also inhibited Neisseria gonorrhea (IC(50) < 1.0 gel/ml) and Chlamydia trachomatis (IC(50) = 1.2 microg gel/ml) but had no effect on lactobacilli. These results imply that T-PSS is an effective functional inhibitor of both spermatozoa and certain STD-causing microbes. The noncytotoxic nature should make T-PSS safe for vaginal use. T-PSS was nonmutagenic in vitro and possessed an acute oral toxicity of >5 g/kg (rat). Gel with 10% T-PSS did not irritate the skin or penile mucosa (rabbit) and caused no dermal sensitization (guinea pig). Vaginal administration of the 5% T-PSS gel to the rabbit for 14 consecutive days caused no systemic toxicity and only mild (acceptable) vaginal irritation. T-PSS in gel form is worthy of clinical evaluation as a vaginal contraceptive HIV/STD preventative.