The history of the Drug Utilization Research Group in Europe

Following the recommendations from a World Health Organization (WHO)/Euro symposium Consumption of drugs in 1969, a common classification system for drugs was developed, the Anatomical Therapeutic Chemical (ATC), and a technical unit of comparison, the Defined Daily Dose (DDD), as a comparative unit of drug use. This was found to be robust across therapeutic classifications, dosing forms and diverse populations. To maintain and develop the ATC/DDD system a WHO-Collaborating Centre was established in Oslo. As this was found to be of global interest the centre now reports to the WHO headquarters in Geneva.An informal WHO Drug Utilization Research Group (WHO-DURG), later the EuroDURG, has by now met 28 times in Europe. Since 1994 in Stockholm all these meetings have been with ISPE (International Society for Pharmacoepidemiology) when meeting in Europe.The main focus was initially to improve drug utilization through cross-national drug utilization studies based on the ATC/DDD methodology as they revealed large differences between and within countries that could not easily be explained by morbidity differences alone. These observed differences have led to the expansion of the area to include social, economic and qualitative methods with a more generalized public health focus. One of the most recent contributions was the development of drug use quality indicators.     

Advancing toxicology in RiskMAPP: Setting ADEs based on the subsequent drug substance

Cleaning validation programs are developed to demonstrate acceptable carryover of drug substances/products when multiple drug substances are manufactured in shared process equipment. The International Society of Pharmaceutical Engineers (ISPE) developed a guidance document in 2010 describing the Risk-Based Manufacture of Pharmaceutical Products (referred to as RiskMAPP) (ISPE, 2010). This guidance document developed the concept of an acceptable daily exposure (ADE), which is the toxicologically acceptable daily dose for the first drug substance used in processing drug equipment (DS_A) without prior knowledge of the subsequent drug substance (DS_B). This paper discusses an extension of the ADE methodology called the product-specific ADE (PSADE) which is derived when DS_B is known. Four case studies demonstrate examples in which the PSADE can be scientifically supported in lieu of the ADE and highlight some limitations in its application. The PSADE approach can be used to justify higher acceptance limits for cleaning validation when the ADE based acceptance limits are below the process capability limit of the cleaning process or limit of quantitation of the analytical method.     

Guidelines for submitting adverse event reports for publication.

Publication of case reports describing suspected adverse effects of drugs and medical products that include herbal and complementary medicines, vaccines, and other biologicals and devices is important for postmarketing surveillance. Publication lends credence to important signals raised in these adverse event reports. Unfortunately, deficiencies in vital information in published cases can often limit the value of such reports by failing to provide enough details for either (i) a differential diagnosis or provisional assessment of cause-effect association, or (ii) a reasonable pharmacological or biological explanation. Properly described, a published report of one or more adverse events can provide a useful signal of possible risks associated with the use of a drug or medical product which might warrant further exploration. A review conducted by the Task Force authors found that many major journals have minimal requirements for publishing adverse event reports, and some have none at all. Based on a literature review and our collective experience in reviewing adverse event case reports in regulatory, academic, and industry settings, we have identified information that we propose should always be considered for inclusion in a report submitted for publication. These guidelines have been endorsed by the International Society for Pharmacoepidemiology (ISPE) and the International Society of Pharmacovigilance (ISoP) and are freely available on the societies' websites. Their widespread distribution is encouraged. ISPE and ISoP urge biomedical journals to adopt these guidelines and apply them to case reports submitted for publication. They also encourage schools of medicine, pharmacy, and nursing to incorporate them into the relevant curricula that address the detection, evaluation, and reporting of suspected drug or other medical product adverse events.     

AACR -91st meeting. Interview with Dr Lars Breimer

A number of novel compounds generated much interest and discussion at the AACR Meeting in San Francisco. Among these was a novel cell cycle inhibitor from F Hoffmann-La Roche Ltd, Ro-31-7453. The synthesis and preclinical investigations conducted with this compound had not been discussed in public before the AACR meeting. Roche has quite clearly been keeping developments relating to this compound very confidential since the compound progressed as far as phase I trials before any public disclosures were made. In an interview, Dr Lars Breimer (Roche Products Ltd, Welwyn Garden City, UK), explained why Ro-31- 7453 should be generating so much interest at the AACR, and how cell cycle inhibition is proving to be an attractive target for drug development.     

Guidelines for submitting adverse event reports for publication

Publication of case reports describing suspected adverse effects of drugs and medical products that include herbal and complementary medicines, vaccines, and other biologicals and devices is important for postmarketing surveillance. Publication lends credence to important signals raised in these adverse event reports. Unfortunately, deficiencies in vital information in published cases can often limit the value of such reports by failing to provide sufficient details for either (i) a differential diagnosis or provisional assessment of cause-effect association, or (ii) a reasonable pharmacological or biological explanation. Properly described, a published report of one or more adverse events can provide a useful signal of possible risks associated with the use of a drug or medical product which might warrant further exploration. A review conducted by the Task Force authors found that many major journals have minimal requirements for publishing adverse event reports, and some have none at all. Based on a literature review and our collective experience in reviewing adverse event case reports in regulatory, academic, and industry settings, we have identified information that we propose should always be considered for inclusion in a report submitted for publication. These guidelines have been endorsed by the International Society for Pharmacoepidemiology (ISPE) and the International Society of Pharmacovigilance (ISoP) and are freely available on the societies' web sites. Their widespread distribution is encouraged. ISPE and ISoP urge biomedical journals to adopt these guidelines and apply them to case reports submitted for publication. They also encourage schools of medicine, pharmacy, and nursing to incorporate them into the relevant curricula that address the detection, evaluation, and reporting of suspected drug or other medical product adverse events.     

In silico prediction of ADMET properties: how far have we come?

There have been considerable advances in the last few years in both the quantity and the quality of in silico ADMET property predictions. Most ADMET properties are now computable, and the accuracy of some of the software predictions for physicochemical properties in particular is close to that of measured data. There is, however, universal agreement that more good experimental ADMET data are needed for use in in silico model development, for models are only as good as the data on which they are based. Many data remain confidential but it is to be hoped that, with projects such as the Vitic toxicity database, being developed by Lhasa Limited, pharmaceutical companies will be prepared to release data to an 'honest broker' on a confidential basis, so that better in silico models can be developed. Incorporation of calculated ADMET properties into drug discovery and development is a multi-factorial problem and really needs a multi-factorial solution. Some progress is being made in this direction and it is hoped that within the foreseeable future software will be available for this purpose.     

Application of the threshold of toxicological concern concept when applied to pharmaceutical manufacturing operations intended for short-term clinical trials

In the manufacture of pharmaceuticals, if a multiproduct facility shares equipment amongst drug substances/products it is incumbent upon the manufacturer to demonstrate removal of the pharmaceutical through a robust cleaning validation/verification program. Removal must be to below limits considered acceptable from a quality and toxicological perspective. In order to address the toxicological concerns, an acceptable daily exposure (ADE) was developed which is the “dose that is unlikely to cause an adverse effect if … exposed, by any route … at or below this dose every day for a lifetime” (ISPE, 2010). For compounds in development, defaulted ADEs were proposed by Dolan et al. (2005) and adopted by the International Society of Pharmaceutical Engineers (ISPE) as conservative cutoffs for compounds with limited data. In Phase 1 clinical trials, exposure is typically short-term (single dose or repeated doses for $\le$30 days) compared to the chronic doses used to derive ADE and defaulted ADEs. An analysis of publicly available databases for toxicological and pharmacological effects supports the use of 10-fold higher defaulted values when the residual drug substance is in a developmental pharmaceutical intended for Phase 1 clinical trials (exposure $\le$30 days).     

An organizational analysis of service patterns in outpatient drug abuse treatment units

The effectiveness of drug abuse treatment depends in part on meeting clients' medical and social needs related to drug abuse. Yet, we know little about the type and amount of medical and social services that clients receive in outpatient drug abuse treatment units. This article addresses this issue, drawing from conceptual perspectives in organizational theory and using data from a national random sample of 481 outpatient treatment units that participated in a phone survey in both 1988 and 1990. We examine the extent to which clients in these units receive: physical (medical) and mental health care; special treatment for multiple drug abuse; and employment, financial, and legal counseling. Results from a multivariate analysis of variance (MANOVA) indicate that there was a significant decrease from 1988 to 1990 in all of the services we examined. Regression analyses were conducted to identify organizational and client characteristics related to these decrease. Results show that changes in both client characteristics and key organizational factors (e.g., resources, staffing) are significantly related to decreases in the services clients receive. Implications for meeting the medical and social service needs of drug abuse clients are discussed.     

We are all in this together (ISPE Presidential Address, 15th Annual Conference on Pharmacoepidemiology,Boston, 27 August 1999)

(1) The scientific study of drug safety is a relatively new discipline. (2) The public may find it difficult to evaluate the risks and benefits of drug therapy. (3) Pursuit of drug safety must be a multidisciplinary exercise, and the International Society for Pharmacoepidemiology (ISPE) provides a valuable focal point. Copyright © 2000 John Wiley & Sons, Ltd.     

Successes in drug discovery and design

The Society for Medicines Research (SMR) held a one-day meeting on case histories in drug discovery on December 4, 2003, at the National Heart and Lung Institute in London. These meetings have been organized by the SMR biannually for many years, and this latest meeting proved extremely popular, attracting a capacity audience of more than 130 registrants. The purpose of these meetings is educational; they allow those interested in drug discovery to hear key learnings from recent successful drug discovery programs. There was no overall linking theme between the talks, other than each success story has led to the introduction of a new and improved product of therapeutic use. The drug discovery stories covered in the meeting were extremely varied and, put together, they emphasized that each successful story is unique and special. This meeting is also special for the SMR because it presents the "SMR Award for Drug Discovery" in recognition of outstanding achievement and contribution in the area. It should be remembered that drug discovery is an extremely risky business and an extremely costly and complicated process in which the success rate is, at best, low.     

The emerging role of lawyers as addiction ‘quasi-experts’

This paper examines a discrete set of issues pertaining to the constitution of addiction in law. Based on qualitative interviews undertaken with lawyers in Australia and Canada, I examine how addiction figures in lawyers’ daily practice. Drawing on ideas from science and technology studies scholars Sheila Jasanoff, Michael Lynch and Bruno Latour, and building on recent research I undertook on legal addiction veridiction, I explore the constitution of addiction ‘facts’ in law. I examine how and when lawyers claim to make decisions about addiction in the course of their legal practice. Lawyers report playing a central role in the making of decisions about addiction, at multiple stages of the legal process including: before taking cases on, while running cases in court, and while negotiating and/or settling cases. I argue that these decisions can be properly described as ‘quasi-expert’ determinations with important parallels to scientific, technological and medical claims often made in legal settings by more conventional ‘expert witnesses’. I call these ‘quasi-expert’ decisions because they are decisions of the kind that might be assumed to be the purview of scientific or medical experts and because they have tangible implications for clients. Lawyers uniquely constitute addiction in unique ways, drawing on a combination of factors, including their own experience with and observations about addiction, the experiences of family members who have experienced alcohol and other drug problems, relevant legal concepts and frameworks, popular and scientific claims about addiction, emotions and values, including the gender politics of alcohol and other drug addiction. These addiction ‘facts’ can have a range of material and discursive effects, including potentially adverse implications for people characterised as ‘addicts’. I conclude the paper with a discussion of some implications of these practices, and with reflections on how we might address these issues in future research.     

Cambridge Healthtech Institute's 2nd Annual Conference on Pharmacogenomics Europe: presaging profits

Pharmacogenomics promises to offer distinct strategic advantages to pharmaceutical companies, physicians, providers and patients. Cambridge Healthtech Institute's 2nd Annual Conference on 'Pharmacogenomics Europe: Presaging Profits' covered all aspects of pharmacogenomics and gave scientists from both academia and from pharmaceutical and biotech companies a great opportunity to discuss the latest progress in pharmacogenomic research. The meeting considered technologies for single nucleotide polymorphism (SNP) screening and expression profiling, bioinformatic tools for data evaluation and gave an overview on the state of affairs and novel approaches to implement pharmacogenomics and pharmacogenetics into drug development and medical treatment. The major strength of the meeting was the merging of scientists from many different disciplines, such as clinicians, pharmacologists, molecular biologists, engineers and bioinformatics experts, into one meeting.     

Using serum creatinine concentrations to screen for inappropriate dosage of renally eliminated drugs

The impact on drug therapy and costs of a program to identify and correct unadjusted dosage in renally impaired patients is described. The program was instituted in May 1988 by the clinical pharmacy staff at a 272-bed hospital. Each day the clinical pharmacist uses laboratory data to list patients with serum creatinine concentrations greater than 1.5 mg/dL. The pharmacist screens the pharmacy profiles of listed patients and calculates creatinine clearance for patients receiving renally eliminated drugs. If, after reviewing the patient's medical record, the pharmacist judges that a dosage adjustment may be appropriate, he writes a confidential note to the physician. From May 1988 through June 1989, 2341 patients with elevated serum creatinine were monitored. During that period, 162 notes were left; recommendations from 142 (88%) of the notes were accepted by physicians. Most of the notes were written for patients receiving antimicrobials or histamine H2-receptor antagonists. The program, which requires 20-30 minutes of pharmacist time per day, avoided $5003 in drug acquisition costs and cost $2700 to administer during the one-year period. When the costs associated with drug preparation and administration are considered, net cost avoidance was $5040. An intervention program in which notes to physicians are written when patients with abnormal serum creatinine values are receiving drugs for which a dosage adjustment appears indicated (1) has medical staff acceptance, (2) helps to satisfy standards of the Joint Commission on Accreditation of Healthcare Organizations, and (3) saves money.     

Application of Micro- and Nano-Electromechanical Devices to Drug Delivery

Micro- and nano-electromechanical systems (MEMS and NEMS)-based drug delivery devices have become commercially-feasible due to converging technologies and regulatory accommodation. The FDA Office of Combination Products coordinates review of innovative medical therapies that join elements from multiple established categories: drugs, devices, and biologics. Combination products constructed using MEMS or NEMS technology offer revolutionary opportunities to address unmet medical needs related to dosing. These products have the potential to completely control drug release, meeting requirements for on-demand pulsatile or adjustable continuous administration for extended periods. MEMS or NEMS technologies, materials science, data management, and biological science have all significantly developed in recent years, providing a multidisciplinary foundation for developing integrated therapeutic systems. If small-scale biosensor and drug reservoir units are combined and implanted, a wireless integrated system can regulate drug release, receive sensor feedback, and transmit updates. For example, an “artificial pancreas” implementation of an integrated therapeutic system would improve diabetes management. The tools of microfabrication technology, information science, and systems biology are being combined to design increasingly sophisticated drug delivery systems that promise to significantly improve medical care.     

National Trends in Adolescent Substance Use Disorders and Treatment Availability: 2003–2010

This study examines trends in adolescent substance use disorders (SUDs) and treatment utilization in the United States using data from the National Household Survey on Drug Use and Health (NSDUH) and data from the National Survey of Substance Abuse Treatment Services (N-SSATS). Results indicate an overall decrease in the percentage of adolescents meeting past-year criteria for an alcohol or illicit drug disorder between 2003 and 2010, but the percentage of adolescents meeting criteria who had not received any treatment in the past year was substantial and has remained stable since 2003. In 2010, fewer than 30% of facilities participating in the N-SSATS indicated that they offered special programming for adolescents, reflecting an overall decrease since 2003.     

Therapeutic oligonucleotides: the state-of-the-art in purification technologies

Currently, there are over 40 oligonucleotide-based pharmaceutical products in various stages of clinical development for the treatment of an assortment of life-threatening diseases. As a result, the production of synthetic oligonucleotides has become increasingly important, with applications in antisense-, aptamer-, ribozyme-, immunostimulatory CpG molecule- and RNAi-related therapeutics. Due to the enormous commercial interest in these technologies, the manufacturing and purification processes for oligonucleotide production have been furtive and practiced in a confidential environment. As a result, limited information on large-scale processing is available in the scientific literature. The purpose of this article is to review the current state-of-the-art in oligonucleotide purification technologies, which have resulted in drug products meeting stringent therapeutic specifications. An indication of new and emerging purification technologies, including simulated moving bed- and membrane-based separation, is given.     

PQLI Key Topics - Criticality, Design Space, and Control Strategy

This paper gives an overview of progress made by the ISPE PQLI initiative - a global industry-led initiative aimed at facilitating the implementation of ICH Q8, Q9, and ultimately Q10 guidance. Through this initiative ISPE is spearheading the effort to help industry begin to define areas where they will be able to provide the technical framework for the implementation of key elements of Quality by Design (QbD) - a systematic approach to development that begins with predefined objectives and emphasizes product and process understanding based on sound science and quality risk management. Three topic areas, Design Space, Criticality, and Control Strategy were selected for specific focus and discussion, and this paper gives an overview of progress in these three areas.

Survey nonresponse bias among young adults: the role of alcohol, tobacco, and drugs

The purpose of this study is to determine the role of alcohol, tobacco, and drug use as predictors of survey panel attrition among an occupational cohort of young adults in the U.S. military. Baseline data on substance use and sociodemographic factors were obtained from 2838 men and women through confidential, self-administered questionnaires while they attended Navy basic training or Officer Candidate School in 1998. Longitudinal follow-up using mailed self-administered questionnaires was begun in 2000. Multivariate logistic regression models were developed to estimate the odds of attrition in relation to baseline substance use. Results revealed that tobacco use was a significant predictor of attrition [Odds ratio (OR) = 1.63; 95% Confidence Interval (CI): 1.37, 1.95]. A significant interaction between level of education and drug use indicated that respondents with less than a college education who were also drug users were at elevated risk for attrition (OR = 2.39; 95% CI 1.09, 5.28). Other significant predictors of panel attrition were male gender and younger age. Alcohol use was not significantly associated with attrition. The findings suggest that tobacco users and drug users with less than a college education may be an important source of nonresponse bias in longitudinal surveys of employed young adults.     

Optimizing the preclinical/clinical interface: an Informa Life Sciences conference 12-13 December, 2006, London, UK

The primary goal of this meeting was to propose strategies for expediting the Phase 0 drug research process for valuable drug candidate identification by taking full advantage of innovative technologies and cost-effective decision-making procedures. A theme that recurred throughout the meeting was the identification, validation and full exploitation of specific integrated biomarkers, which serve as quantifiable indicators of normal biologic processes, pathophysiological states and responses to therapeutics. These are indispensable tools for generating reliable data from proof-of-mechanism, proof-of-principle and proof-of-concept investigations. Real-life biomarkers can also be obtained from modeling and simulating preclinical and early clinical findings. The successful migration of these and other pertinent data into predictive models of efficacy, toxicity and diseases is a sine qua non for translation medicine to become a discipline that realistically predicts clinical outcomes. Indeed, the discovery of novel, efficacious drug treatments for neurological and psychiatric diseases is intrinsically dependent on reliable translation medicine approaches. Novel microdosing technologies that enable Phase 0 pharmacokinetic profiling of drug candidates in humans improve the success rate of the drug development process. In addition, the clear identification of risk, the calculation of its probability, the assessment of its severity in relation to medical need and the availability of a management strategy can help to establish realistic safety goals. Performing in vitro and in vivo cardiac safety evaluation earlier in Phase 0 research can substantially reduce the number of drug candidates that eventually fail on the basis of unacceptable cardiac harm. Emerging 'omics' technologies allow the identification of species-specific toxicity and the reliable extrapolation of non-clinical observations to humans. Regulatory perspectives on the use of non-clinical information to gain approval for Phase I studies were given special consideration. In particular, key recommendations for preventing tragic events, such as those that resulted from a cytokine storm caused by the CD28 tumour antibody, TGN-1412, in healthy volunteers, were the subject of detailed scrutiny. Interestingly, the bispecific CD9/CD3 tumour antibody MT-103 produces target antigen-redirected lysis without causing notable adverse effects. In conclusion, this conference provided participants with state-of-the-art approaches for improving the present low predictive power of non-clinical information regarding clinical outcome.     

Desiring assemblages: A case for desire over pleasure in critical drug studies

While critical drug researchers have long pushed for an acknowledgement of pleasure in discourses of drug use, few have explored the alternative possibilities offered by Deleuze and Guattari’s concept of desire. In this paper I map out some of the conceptual differences between pleasure and desire and explore the opportunities opened up by attending more closely to desire in critical drug studies. I suggest that while discourses of pleasure do make an important intervention into and against dominant narratives of risk, harm, and addiction, they may inadvertently be working to keep in place the very binaries and forms of neoliberal western subjectivity that support those narratives. I argue that a Deleuzo–Guattarian ontology of desire is a better tool with which to make sense of the complex relations that form between drugs and bodies, challenge medical and criminal responses to drug use, and bring forth assemblages that enhance, rather than diminish, bodily capacities.