Fast track: The practice of drug development and regulatory innovation in the late Twentieth Century U.S

This thesis examines the laws and regulations created in the 1980s and 1990s in the U.S. to hasten development, evaluation, and approval of drugs to treat serious and lifethreatening diseases, and to allow access of seriously ill patients to investigational drugs on a pre-market approval basis. Using detailed historical exposition in tandem with the social-theoretic tools of the sociology of scientific knowledge (SSK), and particularly Barnes’s account of meaning finitism, this thesis examines the social origin, definition, and case-by-case application of conceptual categories in the regulatory oversight of drug development and approval. With this approach, rules and standards for drug approval are shown not to be fossilised machinery for decision-making, but rather living, socially produced and maintained, inherently revisable resources for action. Key conclusions from this study are that: the regulatory actions taken to confront AIDS in the 1980s, often considered to be a radical break with previous practice, had their conceptual origins in the 1960s and 1970s; rule-making is often constitutionally related to a creative process of rule-‘breaking’; tacit processes of consensus outside of, and prior to, formal consensus mechanisms for rule-making are often fundamental to the rule-making process, resulting in de facto ‘rules’ on which later, formal rule-writing can be based; as predicted by finitism, newly created categories of action in drug development and approval require reinterpretation of underlying concepts in related existing categories. The thesis also demonstrates the flexibility and revisable nature of existing conceptual resources for application to current circumstances, consistent with a finitist view of knowledge. While the conclusions of this research are based on only one area of regulation, they are suggestive for more general descriptions of regulatory action. Contemporary theories of regulation are typically designed as economic models or are viewed through traditional categories of law and political science. As a result, they tend to abstract reality, ignoring day-to-day administrative practice, idealizing the nature of rule-following and rulemaking, and ignoring tacit processes of consensus. This thesis brings an interdisciplinary perspective to the theory of regulation, suggesting the outlines of a ‘social’ theory of regulation more fully sensitive to the empirical reality of the social process of rule-making and rule-breaking in contemporary regulation

Barriers to clinical adoption of next generation sequencing: Perspectives of a policy Delphi panel

AbstractThis research aims to inform policymakers by engaging expert stakeholders to identify, prioritize, and deliberate the most important and tractable policy barriers to the clinical adoption of next generation sequencing (NGS). A 4-round Delphi policy study was done with a multi-stakeholder panel of 48 experts. The first 2 rounds of online questionnaires (reported here) assessed the importance and tractability of 28 potential barriers to clinical adoption of NGS across 3 major policy domains: intellectual property, coverage and reimbursement, and FDA regulation. We found that: 1) proprietary variant databases are seen as a key challenge, and a potentially intractable one; 2) payer policies were seen as a frequent barrier, especially a perceived inconsistency in standards for coverage; 3) relative to other challenges considered, FDA regulation was not strongly perceived as a barrier to clinical use of NGS. Overall the results indicate a perceived need for policies to promote data-sharing, and a desire for consistent payer coverage policies that maintain reasonably high standards of evidence for clinical utility, limit testing to that needed for clinical care decisions, and yet also flexibly allow for clinician discretion to use genomic testing in uncertain circumstances of high medical need

Understanding practice-based research participation: The differing motivations of engaged vs. non-engaged clinicians in pragmatic clinical trials

Background/Aims: Pragmatic clinical trials (PCTs) represent an increasingly used strategy for “real-world” trials. Successful PCTs typically require participation of community-based practices. However, community clinicians often have limited interest or experience in clinical research. Many barriers to practice-based research have been described, but possible motivations to participate among community practices not active in research have not been well explored. The tendency is for researchers to assume similar motivations and priorities across all candidate practices. This is not necessarily the case. A better understanding of the range of reasons clinicians might see for participating in pragmatic trials could be key to promoting this type of practice-based research. Methods: Semi-structured interviews were conducted with 30 clinicians and staff members. Half of the interviewees had experience doing practice-based clinical trials and half did not. Individuals in these two groups were also diversified in terms of their practice size and location. Participants were asked about motivations and barriers to doing practice-based research in the context of a planned osteoporosis pragmatic clinical trial. Interviews were transcribed, coded, and analyzed. Results: Barriers identified for both experienced and not-experienced clinicians and staff members included: a lack of time, increased paperwork, disruption to work flows, and concern over practice finances. Similar findings have been reported in the US, UK, Europe, and Australia. However, regarding positive motivations of practices to participate, we found systematic differences in attitude between research-engaged and research-naïve practices that have not been previously reported. The research-experienced group offered a greater number and variety of reasons to take part than the not-experienced group. While both groups expressed motivations related to patient care, clinicians and staff members experienced in practice-based clinical trials were much more likely to cite intellectual, professional, and societal benefits not envisioned by the other group. Conclusions: We conclude that clinicians not already participating in practice-based trials may have a narrower range of motivations than those already participating. The lack of a broader view of possible benefits to participation may also translate into more obdurate recruiting challenges. These results point to the need for recruitment, engagement, and messaging approaches differentially tailored to the needs and interests of non-participating practices

Parenteral Delivery of HPβCD: Effects on Drug-HSA Binding

It is thought that cyclodextrins, such as 2-hydroxypropyl-β-cyclodextrin (HPβCD), will at high concentration affect pharmacokinetics of drugs through competitive binding with plasma proteins. Albumin is the major component of plasma proteins responsible for plasma protein binding. The purpose of this study was to evaluate in vitro the competitive binding of drugs between human serum albumin (HSA) and HPβCD in isotonic pH 7.4 phosphate buffer saline solution (PBS) at ambient temperature. Eight model drugs were selected based on their physicochemical properties and ability to form complexes with HSA and HPβCD. The drug/HPβCD stability constants (K1:1) were determined by the phase-solubility method and HSA/HPβCD competitive binding determined by an equilibrium dialysis method. Protein binding of drugs that are both strongly protein bound and have high affinity to HPβCD (i.e., have high K1:1 value) is most likely to be affected by parenterally administered HPβCD. However, this in vitro study indicates that even for those drugs single parenteral dose of HPβCD has to be as high as 70 g to have detectable effect on their protein binding. Weakly protein bound drugs and drugs with low affinity towards HPβCD are insensitive to the cyclodextrin presence regardless their lipophilic properties