"Threshold-crossing": A Useful Way to Establish the Counterfactual in Clinical Trials?

A central question in the assessment of benefit/harm of new treatments is: how does the average outcome on the new treatment (the factual) compare to the average outcome had patients received no treatment or a different treatment known to be effective (the counterfactual)? Randomized controlled trials (RCTs) are the standard for comparing the factual with the counterfactual. Recent developments necessitate and enable a new way of determining the counterfactual for some new medicines. For select situations, we propose a new framework for evidence generation, which we call "threshold-crossing." This framework leverages the wealth of information that is becoming available from completed RCTs and from real world data sources. Relying on formalized procedures, information gleaned from these data is used to estimate the counterfactual, enabling efficacy assessment of new drugs. We propose future (research) activities to enable "threshold-crossing" for carefully selected products and indications in which RCTs are not feasible.

Advancing the science of medicines regulation: the role of the 21st-century medicines regulator.

The history of medicines regulation is punctuated with sudden swings in focus mandated by a public injured by medicines and skeptical of regulators' abilities to protect them. As stakeholder communities and the science that undergirds medicines have both grown more sophisticated, seemingly conflicting mission equities, such as public health protection vs. promotion or population vs. individual patient product development focus, have created new challenges to defining the mission and role of twenty-first-century medicines regulators. The role of medicines regulators as a nationally focused, retrospective assessor of data is rapidly shifting to that of a prospective generator of public data and tools to help drive what has now become a global product development and regulatory enterprise that is fast gaining recognition as an integral part of any truly effective twenty-first-century health-care system. This article discusses this evolution and describes how regulatory science will help to both drive and define it.

Adaptive licensing: taking the next step in the evolution of drug approval.

Traditional drug licensing approaches are based on binary decisions. At the moment of licensing, an experimental therapy is presumptively transformed into a fully vetted, safe, efficacious therapy. By contrast, adaptive licensing (AL) approaches are based on stepwise learning under conditions of acknowledged uncertainty, with iterative phases of data gathering and regulatory evaluation. This approach allows approval to align more closely with patient needs for timely access to new technologies and for data to inform medical decisions. The concept of AL embraces a range of perspectives. Some see AL as an evolutionary step, extending elements that are now in place. Others envision a transformative framework that may require legislative action before implementation. This article summarizes recent AL proposals; discusses how proposals might be translated into practice, with illustrations in different therapeutic areas; and identifies unresolved issues to inform decisions on the design and implementation of AL.

International pharmacovigilance: developing cooperation to meet the challenges of the 21st century.

Much has been accomplished internationally in the past decade to harmonise the much of the process of post-marketing drug risk detection. However, formidable challenges exist in harmonising analytical approaches to such data and in leveraging international database resources to improve the quality of such data. In addition, international challenges continue in the arena of drug risk management once a specific risk has been detected. Especially problematic are the questions of appropriate methodology and metrics to assess the public health impact of our risk management techniques. Finally, international challenges remain in the world of drug risk communication to practitioners, dispensers, and patients. The primary challenge confronting us is that of providing easily accessible, understandable, unbiased information on drug risk to these communities so that truly informed decisions about medicines can be made at the individual patient level. Only by meeting internationally these challenges in drug risk detection, management, and communication can our citizens know how to best use these wonderful pharmacological gifts to which we now have access.

The safety of newly approved medicines: do recent market removals mean there is a problem?

The removal of 5 pharmaceuticals from the market in a 12-month period because of unexpected adverse events raised concerns about the adequacy of the drug review process at the US Food and Drug Administration (FDA). Specifically, concerns were raised about improvements in drug review efficiency that significantly reduced FDA review times. We have reviewed the circumstances of the 5 removals to determine whether there was any relationship to the increased efficiencies in the drug review process. When the removed drugs were analyzed by date of approval, no increase in the number of drugs taken off the market was seen, demonstrating that reduced review processing time was not the reason for the cluster of removals. We conclude that the agency's drug review procedures and postmarketing surveillance system after a drug has been marketed are currently adequate but must continually adjust to future challenges.

Ureaplasma urealyticum in semen for artificial insemination: its effect on conception and semen analysis parameters.

Semen specimens from 24 donors in an artificial insemination program--selected for women whose infertile status was determined to be male factor-related and for whom no female factor could be determined--were cultured for the presence of Ureaplasma urealyticum. A life table statistical analysis indicated that conception did not occur sooner in the U. urealyticum-negative group (n = 14) compared with those women inseminated with the U. urealyticum-containing semen (n = 10). In addition, no significant differences were detected in semen analysis count, grade, or motility between semen with or without U. urealyticum. We found no differences in the occurrence of fetal morbidity or mortality in ten conceptions between the women impregnated with Ureaplasma-positive (n = 14) and Ureaplasma-negative (n = 6) semen. Thus, our study does not support the role of U. urealyticum as a cause of male factor-related infertility or early pregnancy loss.