Regulatory challenges of new male contraceptive methods.

INTRODUCTION: Progress in male contraception development faces the challenge of a lack of regulatory precedent and guidelines on the evidence (trial design and primary endpoint) required for marketing approval. Moreover, the development of a male contraceptive is complicated by the fact that the clinical treatment effect; prevention of pregnancy, is not measured in the patient receiving the intervention. DISCUSSION: Regulatory precedent and guidelines exist for female hormonal contraceptives but their applicability to male contraceptive products likely varies based on the mode of action and the anticipated pharmacodynamic effects of the product. The unique attributes of male contraceptives, including the frequent delay between the intervention (e.g., vasectomy and hormonal methods) and ultimate contraceptive effect, sperm suppression near azoospermia, and pregnancy prevention need to be addressed. CONCLUSION: This article describes the regulatory challenges faced by developers of male contraceptive products and offers proposals, paving the way for the development of both hormonal methods and non-hormonal approaches. Our article intends to suggest the directions but cannot substitute for the advice of regulatory agencies.

Variability of semen parameters with time in placebo treated men.

PURPOSE: We describe the variability of semen parameters with time in normal men receiving placebo. We also report the impact of season and geographic region, among other variables, on these parameters. MATERIALS AND METHODS: Data from the placebo arms of 5 randomized, controlled trials were pooled. All trials set minimum standards for semen parameters as an eligibility criterion for entry. Semen parameters examined include volume, density, motility, total count, total motile count and morphology. Mixed model repeated measure analysis was used for statistical analysis. Coefficients of variation for each semen parameter and the percent change from baseline were calculated. RESULTS: The mean within-subject coefficient of variation for each semen parameter ranged from a low of 10% to a high of almost 50%. The contribution of season and region to variability was negligible. The reduction in variability with an increasing number of samples per time point had decreasing returns beyond 2 samples. CONCLUSIONS: There was considerable variation in semen parameters with time in subjects who received placebo. Variation could not be attributed to season or region. We observed a general negative trend in semen parameters in this population selected for normal baseline semen parameters, which was likely due to the placebo response or to regression toward the mean.

Use of biomarkers to assess tissue specific androgen adequacy: defining male hypogonadism.

PURPOSE: The criteria for normal testosterone have been established by expert consensus rather than by evidence. We determined whether a cutoff point for normal could be established using biomarkers. MATERIALS AND METHODS: We performed an exploratory investigation of 1,492 hypogonadal men pooled from 7 registration trials. Serum testosterone, prostate specific antigen and hematocrit were measured at baseline and after 90 days of continuous testosterone replacement therapy. RESULTS: Baseline prostate specific antigen, percent change in prostate specific antigen and hematocrit appeared to be most strongly related to baseline serum testosterone. Subgroup analysis and visual inspection of linear spline fit of these data suggested an approximate serum testosterone cutoff for normal of 300 ng/dl for percent change in hematocrit, and 200 ng/dl for baseline prostate specific antigen and percent change in prostate specific antigen. CONCLUSIONS: This exploratory study revealed considerable variation among individuals and target tissues in individuals. Further study should be performed using standardized assays in a broader population.

Benign prostate glands at the bladder neck margin in robotic vs open radical prostatectomy.

OBJECTIVE: To compare the prevalence and extent of benign glands at the bladder neck (BN) margin in a large population undergoing open retropubic radical prostatectomy (RRP) and robotic-assisted laparoscopic RP (RALP), as RALP was previously suggested to be associated with a higher rate of benign glands at the surgical margin than RRP. PATIENTS AND METHODS: From 2005 to 2008, 137 RRP and 152 RALP were performed by one surgeon. Pathology slides were re-reviewed while unaware of origin to examine the extent of benign glands at the BN margin (minimal, moderate, or extensive). Statistical analysis was used to assess the prevalence and extent of benign glands in the two procedures. RESULTS: Benign prostatic glands were present at the margins in 89 (58.2%) RALP and 57 (41.6%) RRP specimens (P= 0.005). There were also a significantly greater extent of benign glands in RALP vs RRP (P= 0.031). After multivariate adjustment for prostate-specific antigen (PSA) level, clinical stage, and biopsy Gleason score, RALP maintained a significant association with both the presence (P= 0.019) and extent (P= 0.018) of benign glands at the BN. Two patients with organ-confined disease (no cancerous margins) with benign glands at the BN margin had an initially high postoperative PSA level. CONCLUSIONS: Benign prostate glands were present at the BN margin in a greater proportion of RALP than RRP specimens, possibly due to differences in the surgical approach to BN dissection. Additional study is necessary to determine the long-term biological significance, if any, of these histological differences.

Noninvasive laser vasectomy: preliminary ex vivo tissue studies.

BACKGROUND AND OBJECTIVES: Male sterilization (vasectomy) is more successful, safer, less expensive, and easier to perform than female sterilization (tubal ligation). However, female sterilization is more popular, primarily due to male fear of vasectomy complications (incision, bleeding, infection, and scrotal pain). The development of a completely noninvasive vasectomy technique may eliminate these concerns. MATERIALS AND METHODS: Ytterbium fiber laser radiation with a wavelength of 1,075 nm, average power of 11.7 W, 1-second pulse duration, 0.5 Hz pulse rate, and 3-mm-diameter spot was synchronized with cryogen cooling of the scrotal skin surface in canine tissue for a treatment time of 60 seconds. RESULTS: Vas thermal lesion dimensions measured 2.0+/-0.3 mm diameter by 3.0+/-0.9 mm length, without evidence of skin damage. The coagulated vas bursting pressure measured 295+/-72 mm Hg, significantly higher than typical vas ejaculation pressures of 136+/- 29 mm Hg. CONCLUSIONS: Noninvasive thermal coagulation and occlusion of the vas was produced in an ex vivo canine tissue model. However, chronic in vivo animal studies will be necessary to optimize the laser/cooling treatment parameters and confirm long-term vas occlusion with absence of sperm in the ejaculate, before clinical application.

Personalized reproductive medicine: regulatory considerations.

Personalized medicine has many definitions. This term is often used synonymously with precision medicine, which is defined as the classifying patients with a disease or condition based on their phenotypic findings, such as biomarkers or genomics, into subpopulations that differ in their response to a specific treatment. Personalized medicine, however, can also mean the treatment of individual patients based on many contextual factors, such as response to therapy and patient preferences, in addition to predefined phenotypic findings. Regulatory approval for the marketing of a new drug or a new indication for a marketed drug requires a positive benefit risk profile and substantial evidence of effectiveness. The indication is based on the eligibility criteria and outcomes of the clinical trial(s) underpinning the regulatory approval. For precision medicine, drugs are often developed with companion diagnostics that are necessary for selection of the subgroup of patients, in contrast to personalized medicine which may be directed at a single patient. Most drugs are approved with a fixed dosage regimen for the approved population, but some drugs and biologics are approved with instructions to tailor therapy for individual patients, whether it be dosing, combination with other therapies, or selection among a class of medications. Hence, more often than not, personalized medicine directed at individual patients is achieved through the practice of medicine rather than regulatory action.

Regional Approaches to Expedited Drug Development and Review: Can Regulatory Harmonization Improve Outcomes?

Drug regulatory agencies around the world have implemented programs to expedite drug development and review for promising new products for serious diseases. These programs are all intended to minimize delays in patient access to innovative medicines, and have used broadly similar strategies to shorten drug development and review timelines. However, they differ in many key respects, and some stakeholders have suggested that these differences create unnecessary barriers in the development and approval process, possibly leading to delays in access. In collaboration with FDA, the Duke-Margolis Center for Health Policy convened an expert workshop to elicit feedback from a broad range of stakeholders as to whether a lack of harmonization across expedited programs is interfering with the efficient development of new products and, if so, to explore strategies for addressing these challenges. This report provides a summary of key themes and major findings from that discussion.

Diagnostic approach to the infertile male patient.

There are several objectives to be achieved during the diagnostic evaluation of a male partner of an infertile partnership. The first is to identify whether or not there is a male factor present and, if so, whether this is attributable to an underlying medical illness. The second is to identify the cause of reduced male fertility and whether or not it is amenable to therapeutic intervention.

Impact of Expanded Access on FDA Regulatory Action and Product Labeling.

Background: The purpose of this study is to address concerns that expanded access may negatively impact the ultimate regulatory action and product labeling for new drugs. Methods: We performed queries of FDA's Center for Drug Evaluation and Research (CDER) document tracking system to determine the effect of expanded access on FDA's regulatory decision making from 2010 through 2016. We also examined product labeling to determine whether safety events occurring under expanded access had an adverse effect on the approved product labeling. Results: There were 321 regulatory decisions made by FDA, with 28% of the drugs having prior expanded access. The approval rate for drugs with expanded access (84%) was higher than those that did not (76%). None of the negative regulatory marketing decisions were based on the adverse experiences reported under expanded access. The vast majority of deaths and serious adverse events that occurred under expanded access were not interpreted by FDA to be due to the investigational drug and did not affect product labeling. There was only 1 instance, a drug-drug interaction, for which safety events occurring during expanded access alone lead to potentially adverse product labeling. Conclusions: There was no instance in which expanded access lead to a negative regulatory decision regarding a drug application, and there was only 1 instance that safety events under expanded access had a potentially negative effect on product labeling. Concern that expanded access will have a negative impact on drug development and review is not based on the evidence and is unwarranted.

Ten-Year Experience for the Center for Drug Evaluation and Research, Part 2: FDA's Role in Ensuring Patient Safety.

BACKGROUND: The purpose of this study was to describe the role of the US Food and Drug Administration (FDA) in ensuring the safety of patients receiving investigational drugs under expanded access. METHODS: To better define FDA's role in the review of requests for expanded access, multiple queries of FDA's Center for Drug Evaluation and Research (CDER) document tracking system were performed. The queries identified reasons for, and outcomes of, expanded access requests for investigational drugs that were either not allowed to proceed or denied over a 10-year time period. An in-depth review of a random sample of single-patient, non-emergency investigational new drug (IND) applications that were allowed to proceed was also conducted. RESULTS: Overall, 99.3% of the applications for almost 9000 expanded access of an investigational drug were allowed to proceed. There were 62 requests that were either denied (38 emergency INDs) or not allowed to proceed (24 non-emergency INDs). The most common reasons for denying emergency INDs was that the patient was stable on current therapy and that it was not deemed an emergency. The most common reasons for not allowing non-emergency expanded access INDs to proceed were incomplete application, unsafe dosing, demonstrated lack of efficacy for intended use, availability of adequate alternative therapies, and inadequate information provided in the application on which to base a decision. A review of a random sample of 150 single-patient, non-emergency INDs revealed that FDA recommended changes to dosing, safety monitoring, or informed consent in 11%. CONCLUSIONS: FDA plays a significant role in the protection of patients who receive investigational drugs under expanded access. An extremely small percentage of applications received are not allowed to proceed; however, FDA provides significant input based on information that may not be available to treating physicians in order to ensure patient safety under the applications that do proceed.

Overview of FDA's Expanded Access Program for Investigational Drugs.

Expanded access, also called "compassionate use," provides a pathway for patients to gain access to investigational drugs, biologics, and medical devices used to diagnose, monitor, or treat patients with serious diseases or conditions for which there are no comparable or satisfactory therapy options available outside of clinical trials. The US Food and Drug Administration (FDA) facilitates the expanded access process; however, access to investigational treatments requires not only FDA's review and authorization but also the active involvement and cooperation of other parties, including drug companies and health care providers, in order to be successful.

Precision medicine and the changing role of regulatory agencies.

The growth of precision medicine presents challenges for the regulators of medicines, related to aspects that include the basis of evidence generation, patient involvement in the regulatory process, cost of new medicines and the need for new regulatory models. It also raises questions about the tolerance of risk, especially with early interventions for life-threatening diseases.

Expanded Access of Investigational Drugs: The Experience of the Center of Drug Evaluation and Research Over a 10-Year Period.

BACKGROUND: The purpose of this study was to describe the experience of the Center of Drug Evaluation and Research (CDER) with expanded access of investigational drugs. METHODS: Multiple searches of CDER's document tracking system were performed to identify the number, type, and indication for all expanded access requests over the 10-year time period of January 2005 through December 2014. An additional search was performed to identify all active commercial investigational drug development programs during that time period and whether or not the clinical program was placed on hold. The two searches were then cross-referenced to identify those commercial investigational drug development programs placed on clinical hold due to serious adverse events occurring within expanded access programs. RESULTS: CDER receives over 1000 applications for expanded access each year. The majority are for single patients, roughly evenly split between emergency and nonemergency use. The vast majority, 99.7%, are allowed to proceed. The incidence of clinical holds for all commercial investigational drug development programs is 7.9%, as compared to only 0.2% related to adverse events observed in patients receiving drug treatments under expanded access. CONCLUSIONS: The expanded access program is viewed as a success from FDA's perspective based on the large number of applications processed and allowed to proceed each year. However, the actual number of patients and their health care providers that desire drug treatments available under expanded access is not known. It is exceedingly rare for a serious adverse event under expanded access to affect the development program for that drug.

The Majority of Expedited Investigational New Drug Safety Reports Are Uninformative.

Sponsors of human drug and biologic products subject to an investigational new drug (IND) application are required to distribute expedited safety reports of serious and unexpected suspected adverse reactions to participating investigators and the FDA to assure the protection of human subjects participating in clinical trials. On September 29, 2010, the FDA issued a final rule amending its regulations governing expedited IND safety reporting requirements that revised the definitions used for reporting and clarified when to submit relevant and useful information to reduce the number of uninformative reports distributed by sponsors. From January 1, 2006, to December 31, 2014, the FDA's Office of Hematology and Oncology Products received an average of 17,686 expedited safety reports per year. An analysis of FDA submissions by commercial sponsors covering this time period suggested a slight increase in the number of expedited safety reports per IND per year after publication of the final rule. An audit of 160 randomly selected expedited safety reports submitted to the FDA's Office of Hematology and Oncology Products in 2015 revealed that only 22 (14%) were informative. The submission of uninformative expedited safety reports by commercial sponsors of INDs continues to be a significant problem that can compromise detection of valid safety signals. Clin Cancer Res; 22(9); 2111-3. ©2016 AACR.

Partial Gland Ablation for Prostate Cancer: Report of a Food and Drug Administration, American Urological Association, and Society of Urologic Oncology Public Workshop.

OBJECTIVE: To summarize the discussion that took place at a public workshop, co-sponsored by the U.S. Food and Drug Administration, the American Urological Association, and Society of Urologic Oncology reviewing the current state of the art for partial gland ablation (PGA) for the management of patients with prostate cancer. The purpose of this workshop was to discuss potential indications, current available evidence, and designs for future trials to provide the evidence needed by patients and providers to decide how and when to use PGA. METHODS: A workshop evaluating PGA for prostate cancer was held in New Orleans, Louisiana, in May 2015. Invited experts representing all stakeholders and attendees discussed the regulatory development of medical products, technology available, potential indications, and designs of trials to evaluate this modality of therapy. RESULTS: The panel presented the current information on the technologies available to perform PGA, the potential indications, and results of prior consensus conferences. Use of magnetic resonance imaging for patient selection, guide therapy, and follow-up was discussed. Designs of trials to assess PGA outcomes were discussed. CONCLUSION: The general consensus was that currently available technologies are capable of selective ablation with reasonable accuracy, but that criteria for patient selection remain debatable, and long-term cancer control remains to be established in properly designed and well-performed prospective clinical trials. Concerns include the potential for excessive, unnecessary use in patients with low-risk cancer and, conversely, that current diagnostic techniques may underestimate the extent and aggressiveness of some cancers, leading to inadequate treatment.

Low-dose human chorionic gonadotropin maintains intratesticular testosterone in normal men with testosterone-induced gonadotropin suppression.

In previous studies of testicular biopsy tissue from healthy men, intratesticular testosterone (ITT) has been shown to be much higher than serum testosterone (T), suggesting that high ITT is needed relative to serum T for normal spermatogenesis in men. However, the quantitative relationship between ITT and spermatogenesis is not known. To begin to address this issue experimentally, we determined the dose-response relationship between human chorionic gonadotropin (hCG) and ITT to ascertain the minimum dose needed to maintain ITT in the normal range. Twenty-nine men with normal reproductive physiology were randomized to receive 200 mg T enanthate weekly in combination with either saline placebo or 125, 250, or 500 IU hCG every other day for 3 wk. ITT was assessed in testicular fluid obtained by percutaneous fine needle aspiration at baseline and at the end of treatment. Baseline serum T (14.1 nmol/liter) was 1.2% of ITT (1174 nmol/liter). LH and FSH were profoundly suppressed to 5% and 3% of baseline, respectively, and ITT was suppressed by 94% (1234 to 72 nmol/liter) in the T enanthate/placebo group. ITT increased linearly with increasing hCG dose (P < 0.001). Posttreatment ITT was 25% less than baseline in the 125 IU hCG group, 7% less than baseline in the 250 IU hCG group, and 26% greater than baseline in the 500 IU hCG group. These results demonstrate that relatively low dose hCG maintains ITT within the normal range in healthy men with gonadotropin suppression. Extensions of this study will allow determination of the ITT concentration threshold required to maintain spermatogenesis in man.

The androgen microenvironment of the human testis and hormonal control of spermatogenesis.

It is well established for both rat and man that the total testosterone concentration within the testis is far higher than that in serum. We know for the rat that intratesticular testosterone can be reduced by 50-60% without an adverse effect on spermatogenesis but that the required intratesticular testosterone concentration is still 10-fold greater than serum testosterone concentration. This kind of information, if available for the human, could prove invaluable for understanding and treating select men with infertility and in the development of male hormonal contraceptives. Unfortunately, we know little about the androgen content of intratesticular fluid within the human testis and nothing about the relationship between intratesticular androgens and human spermatogenesis. Using a newly developed minimally invasive technique for repetitive testicular sampling, our recent studies of the human have demonstrated that, as in the rat, there is a gradient between the concentration of testosterone in serum and within the testis; intratesticular testosterone levels were found to be 100-fold higher than serum testosterone levels in normal men. Using liquid chromatography tandem mass spectroscopy, we have shown that intratesticular 5alpha-dihydrotestosterone (DHT) levels are only 2% that of testosterone and, thus, despite greater affinity for the androgen receptor, intratesticular DHT is not significant in normal men. In order to assess how much of the testosterone within the human testis is bioactive, we adapted a highly sensitive recombinant protein mammalian cell-based bioassay to measure androgen bioactivity. The androgen bioactivity in the normal human testis is roughly two-thirds that of the total testosterone measurable by radioimmunoassay, despite the fact that the concentrations of the major androgen-binding proteins (sex hormone-binding globulin- and androgen-binding protein) are insufficient to account for this difference. This finding suggests that androgens may bind to other, as-yet-unknown molecules in the human testis. How, or if, this relates to spermatogenesis in the rat, or to man-to-man differences in the response to hormonal contraceptives, is not clear. We do not yet know how much testosterone is required within the human testis to either maintain or restore quantitatively normal spermatogenesis because, as yet, experimental studies comparable to those performed in the rat have not been feasible for the human.

Bioactivity of androgens within the testes and serum of normal men.

Little is known about how human spermatogenesis is regulated, so it is not surprising that there have been few breakthroughs in the treatment of male infertility resulting from abnormalities of spermatogenesis. Testosterone is the predominant intratesticular steroid in both the rat and man. Previous studies have shown that the testosterone concentration within the rat testis that is required for the quantitative maintenance of spermatogenesis is far higher than the total testosterone concentration in rat blood, indicating that much of the testosterone within the testis might be biologically inactive. In contrast to the rat, little is known about the androgen requirements for human spermatogenesis, in part because, until recently, a minimally invasive method suitable for obtaining intratesticular fluids from the human testis has not been available. Percutaneous aspiration now makes it feasible to do so. A major objective of the present study was to assay the bioactive androgen concentration within the testes of normal, fertile men. Percutaneous aspiration was used to obtain intratesticular fluid from such men, and we adapted a highly sensitive recombinant protein mammalian cell-based bioassay to measure androgen bioactivity. Total intratesticular testosterone concentration, which we define as immunoreactive testosterone as measured by radioimmunoassay, was well in excess of that in serum (1236 +/- 86 nM vs 11.7 +/- 0.7 nM). The concentration of bioactive androgens within the normal human testis was found to be about two thirds that of the total testosterone concentration. Interestingly, the concentration of the major, known binding proteins for testosterone within the testis, serum hormone-binding globulin (SHBG)/ABP (52.4 +/- 9.7 nM), was insufficient to account for the difference between total testosterone and bioactive androgens. This indicates that, in addition to its binding to SHBG/ABP, androgens may also be bound by unknown molecules, and that this contributes to reducing androgen bioactivity. These observations could have relevance for understanding the relationship between spermatogenesis and intratesticular androgens in normal men and in men diagnosed with infertility.

Medical devices: US medical device regulation.

Medical devices are regulated by the US Food and Drug Administration (FDA) within the Center for Devices and Radiological Health. Center for Devices and Radiological Health is responsible for protecting and promoting the public health by ensuring the safety, effectiveness, and quality of medical devices, ensuring the safety of radiation-emitting products, fostering innovation, and providing the public with accurate, science-based information about the products we oversee, throughout the total product life cycle. The FDA was granted the authority to regulate the manufacturing and marketing of medical devices in 1976. It does not regulate the practice of medicine. Devices are classified based on complexity and level of risk, and "pre-1976" devices were allowed to remain on the market after being classified without FDA review. Post-1976 devices of lower complexity and risk that are substantially equivalent to a marketed "predicate" device may be cleared through the 510(k) premarket notification process. Clinical data are typically not needed for 510(k) clearance. In contrast, higher-risk devices typically require premarket approval. Premarket approval applications must contain data demonstrating reasonable assurance of safety and efficacy, and this information typically includes clinical data. For novel devices that are not high risk, the de novo process allows FDA to simultaneously review and classify new devices. Devices that are not legally marketed are permitted to be used for clinical investigation purposes in the United States under the Investigational Device Exemptions regulation.