Showing papers in "International Journal of Pharmaceutical Medicine in 2007"
TL;DR: The concepts of gastric emptying and absorption windows, and current technological developments in gastroretentive drug delivery systems are discussed, including their advantages and disadvantages, along with various evaluation techniques and marketed products for gastro Retention.
Abstract: Recent technological advancements have been made in controlled oral drug delivery systems by overcoming physiological difficulties, such as short gastric residence time and highly variable gastric emptying time. Gastroretentive dosage forms have been designed over the past three decades to overcome these difficulties. Several technical approaches are currently utilised in the prolongation of gastric residence time, including high-density, swelling and expanding, polymeric mucoadhesive, ion-exchange, raft forming, magnetic and floating drug delivery systems, as well as other delayed gastric emptying devices. Gastroretentive drug delivery systems have been shown to have better efficacy in controlling the release rate for drugs with site-specific absorption. In this review, the concepts of gastric emptying and absorption windows, and current technological developments in gastroretentive drug delivery systems are discussed, including their advantages and disadvantages, along with various evaluation techniques and marketed products for gastroretentive drug delivery. Bioadhesive, superporous hydrogel, floating and expanding systems show the most promising potential for achieving the goal of gastroretention. A superporous hydrogel drug delivery system is currently the most reliable, convenient and advantageous technique available that assures prolonged gastric residence time.
47 citations
TL;DR: The impact of research regulation on the duty of doctors to help to resolve uncertainties about the effects of treatments; in particular, treatments already in use within ‘normal’ or ‘usual’ clinical practice is considered.
Abstract: In this paper, I consider the impact of research regulation on the duty of doctors to help to resolve uncertainties about the effects of treatments; in particular, treatments already in use within ‘normal’ or ‘usual’ clinical practice. After providing examples of ways in which current research regulation is obstructing this professional duty, I consider the influence of “a confused ethical analysis”, the double-standard in informed consent to treatment within and outside of controlled trials, and the failure of research regulators to use their powers to reduce unnecessary research and promote full publication of necessary research. I suggest that these problems should be addressed by more thoughtful ethical analyses, more effective protection of the interests of patients by research regulators and empirical research to inform the future development of research regulation. Because ethicists and research regulators have paid insufficient attention to these issues, I conclude that they have contributed to the avoidable suffering and deaths of millions of people, the vast majority of whom have not been participants in clinical research.
39 citations
TL;DR: This article focuses on time-to-event composite endpoints that combine fatal and nonfatal events and aim to demonstrate efficacy of a treatment in long-term trials.
Abstract: Composite endpoints are commonly used in randomised controlled clinical trials because they offer potential advantages, such as smaller sample sizes, shorter completion times and the summary measure for a treatment effect if more than one outcome is important. However, they are also associated with risks and pitfalls, particularly if basic clinical and statistical requirements are not adequately respected. This article focuses on time-to-event composite endpoints that combine fatal and nonfatal events and aim to demonstrate efficacy of a treatment in long-term trials. The most important issues with the selection of individual endpoint components — the trial conduct, data analysis, interpretation and reporting — are discussed. Composite endpoints should be clinically meaningful and the expected effects on each component should be similar, based on biological plausibility. Surrogates as endpoint components must have been validated, i.e. a correlation to a hard clinical outcome must have been confirmed. Patients need to be followed up on assigned treatment (clinical status permitting) until death or end of planned follow-up in the absence of events, and must not be regarded as ‘a trial completer’ after occurrence of the first component event. Difficulties in interpretation arise when the results on single components of the composite endpoint go in opposite directions, and when hard clinical outcomes are combined with soft endpoints, particularly if the latter occur much more frequently but are of inferior relevance. Accordingly, all individual components of the composite need to be analysed separately. In this review, several examples from recently published trials are used to illustrate both the principal needs and the inherent problems of using a composite endpoint. More specific regulatory guidelines and better reporting standards are needed. The ultimate goals of a trial with a composite endpoint should be to solve a medical problem and to support clinical decision making, rather than just to provide statistical convenience.
24 citations
TL;DR: As a postgraduate medical discipline, pharmaceutical medicine has a recognised international syllabus, training courses with examinations and qualifications, its own research methodologies, professional bodies and academic societies, journals and texts, and embraces new technologies and regulations in pursuit of proof of efficacy, safety and effectiveness of medicines.
Abstract: For over 30 years pharmaceutical medicine has developed as a medical scientific discipline for the discovery, development, evaluation, registration, monitoring and medical marketing of medicines for the benefit of patients and community health. Pharmaceutical medicine occupies common ground between the clinical and healthcare professions, pharmaceutical industry and government. While the boundaries of pharmaceutical medicine are indistinct, at its centre is the clinical testing of medicines, translation of drugs into new medicines, safety and well-being of research subjects in clinical trials, and understanding the safety profile of medicines and their benefit-risk balance. Pharmaceutical medicine is a discipline that takes its place alongside other medical specialties; it has developed its own professional ethos; it has established a distinct body of knowledge based primarily on clinical science; and its practitioners represent a cohesive group of specialists with common goals and aspirations. Pharmaceutical physicians work in industry, drug regulatory authorities and clinical research organisations, but have a close affinity with their medical colleagues in primary and secondary healthcare and at universities.As a postgraduate medical discipline, pharmaceutical medicine has a recognised international syllabus, training courses with examinations and qualifications, its own research methodologies, professional bodies and academic societies, journals and texts, and embraces new technologies and regulations in pursuit of proof of efficacy, safety and effectiveness of medicines. Pharmaceutical medicine is a listed medical specialty in the UK, Ireland, Switzerland and Mexico. This official recognition is underlined by the availability of accredited education and training of specialist pharmaceutical physicians and the establishment and maintenance of standards of practice and professionalism in the competency, care and conduct applied to their work and of growing public recognition and accountability.
18 citations
TL;DR: Patient recruitment is a complex process and successful strategies are likely to require several complementary approaches in order to achieve the goal of improved enrolment rates, and the integration of EHRs into clinical trials has major potential to increase recruitment rates.
Abstract: The recruitment rate of adult patients into clinical trials continues to be low. There are a number of barriers to recruitment and, for the most part, these can be classified as patient-, physician-, organisation- or protocolrelated. For practical reasons the process of trial recruitment can be divided into three steps: awareness of the trial, assessment of patient eligibility and the decision to participate. Two key strategies to improve patient recruitment are related to (i) knowledge, information and data management, and (ii) changing the behaviour of physicians and patients. Patient recruitment strategies cover individual services (e.g. call centre, web-based outreach campaigns) or integrated services (e.g. provided by recruitment companies). Unfortunately, there is only limited and inconclusive evidence from randomised or quasi-randomised trials comparing different recruitment strategies. The integration of electronic health records (EHRs) into clinical trials has major potential to increase recruitment rates, as demonstrated by a small number of recent studies. However, there are prerequisites for the successful application of EHR systems in clinical trials, including the provision of adequate patient data, availability of technical solutions from vendors and dual operability between the worlds of medical care and clinical research; changes in the attitudes of physicians and patients are also required. Nevertheless it should be borne in mind that patient recruitment is a complex process and successful strategies are likely to require several complementary approaches in order to achieve the goal of improved enrolment rates.
16 citations
TL;DR: The fundamental concepts of noninferiority and equivalence of bioequivalence trials applied in some specific drug products and how they are extended in the application for the interpretation for ‘test treatment is superior to placebo’ assessment are discussed.
Abstract: Clinical trials designed with the objective of demonstrating that a test treatment is noninferior or equivalent to an active control treatment have long been used in drug development. In general, in order to fulfil the requirement of a New Drug Application, a sponsor needs to conduct randomised clinical trials to demonstrate that the test treatment is effective. With placebo control in the clinical trial, efficacy of the test treatment is demonstrated by showing that the test treatment is statistically and clinically superior to placebo. However, because of the ethical concerns of exposing patients to placebo when there is a proven therapeutic method available, many clinical trials can only be designed with the approved active control treatment. Because of the lack of placebo exposure in the current clinical trial, neither the sponsor nor the regulatory reviewer can assess whether the test treatment is superior to placebo directly. When the concept of noninferiority and equivalence of bioequivalence trials is applied to this type of trial, it complicates the efficacy assessment of the test treatment (superior to placebo) because of the indirectness of the comparison. This article discusses the fundamental concepts of noninferiority and equivalence testing applied in some specific drug products and how they are extended in the application for the interpretation for ‘test treatment is superior to placebo’ assessment. It also discusses why such an application makes the drug evaluation so complicated. The limitations and recommendations for the use of noninferiority or equivalence testing will also be considered.
8 citations
TL;DR: The characterisation of that immune response, including concentration, isotype(s), affinity and neutralising capability can be very informative, and the clinical relevance of antibodies against therapeutic proteins can be determined by monitoring the effect of the antibodies in patients.
Abstract: Immunogenicity is an important factor in determining the success of human therapeutic proteins and may not be adequately predicted based on the currently available animal models. There are many variables that affect a protein’s immunogenicity, including oxidation, aggregation, purification, storage, route and frequency of administration, and the immune status of the patient population.
8 citations
TL;DR: Examples of the applications of metabolomics in the characterisation of phenotype, determining the mode of action of compounds and detection of drug toxicity are presented.
Abstract: In the post-genomic era, increasing our understanding of genotype-phenotypic correlation and its changes in diseases is of the highest priority in drug development. The phenotype of an organism consists of its physical/chemical attributes and its functional attributes. Metabolomics is a promising research tool for the phenotypic characterisation of an organism providing physical and functional assessment of a cellular metabolic network. Metabolomics has evolved from analytical biochemistry. With advances in nuclear magnetic resonance spectroscopy and mass spectrometry, metabolomics provides comprehensive analyses that detect and measure a wide range of small molecules (metabolites) in bodily fluid or tissue extracts. With automation, metabolomics analysis has the potential of a high throughput screening tool for measuring the effects of drugs in cells or in whole organisms, including humans. There are two major forms of metabolomics: metabolite profiling, which includes ‘fingerprinting’, and metabolic profiling, which includes tracer-based metabolomics. In this review, techniques and concepts for each of these modalities is reviewed. Examples of the applications of metabolomics in the characterisation of phenotype, determining the mode of action of compounds and detection of drug toxicity are presented.
6 citations
TL;DR: This research presents a novel, scalable, scalable and scalable approaches that can be scaled up and scaled up for rapid and efficient implementation in the rapidly changing environment.
Abstract: 1 Risk Management Strategy, Pfizer Inc., New York, New York, USA 2 Department of Medicine, New York University School of Medicine, New York, New York, USA 3 Department of Community and Preventive Medicine, Department of Pharmacology, New York Medical College, Valhalla, New York, USA 4 School of Information Systems, Computing and Mathematics, Brunel University, London, England 5 Department of Statistics, Rutgers University, Piscataway, New Jersey, USA 6 ProSanos Corporation, Harrisburg, Pennsylvania, USA
6 citations
TL;DR: The introduction of changes to regulations regarding generic substitution was followed by a decrease in price for the two most commonly dispensed antidepressant drugs in Finland, and high price elasticity was observed within but not between active ingredients.
Abstract: Background: Spending on pharmaceuticals is increasing faster than the gross national product in western European countries. The use of generic drugs may result in direct drug cost-savings for patients, governments and insurers. Objective: The objective of this study was to examine the drug cost development of the two most commonly dispensed antidepressant drugs in Finland following the introduction of regulatory changes to mandate generic substitution by pharmacists in April 2003. Methods: The prescription claims database of the Social Insurance Institution of Finland was used to calculate the quarterly cost of reimbursements per user for citalopram and fluoxetine from January 2003 to June 2004. Price data for the originator brand of citalopram, market incumbent brand of fluoxetine, and generic versions of both citalopram and fluoxetine were extracted from the registry of the Association of Finnish Pharmacies for April 2003 to April 2004. Results: The quarterly drug cost of citalopram and fluoxetine per user to the Social Insurance Institution of Finland decreased by 45% and 48%, respectively, 1 year following the changes to the regulations regarding generic substitution. The companies that marketed the originator brand of citalopram and the market incumbent brand of fluoxetine adopted two contrasting pricing policies in response to changes in the regulations regarding generic substitution. A ‘pseudo-generic’ version of citalopram, but not fluoxetine, was available throughout the study period. Regardless of the pricing policy, equivalent drug cost-savings were realised for both patients and government. These cost reductions did not lead to a corresponding increase in the use of citalopram or fluoxetine. Conclusions: The introduction of changes to regulations regarding generic substitution was followed by a decrease in price for the two most commonly dispensed antidepressant drugs in Finland. High price elasticity was observed within but not between active ingredients. Price did not appear to be an important factor guiding antidepressant prescribing by physicians.
6 citations
TL;DR: With this increased scrutiny, significant improvements in regulatory process, clinical trial costs and site performance are anticipated over the next few years and it is hoped that these positive trends will revitalise Japan as a leading global player in pharmaceutical R&D in the Asian region and beyond.
Abstract: As Japan becomes more integrated into the global market, pharmaceutical research and development (R&D) in the country faces considerable challenges. While global simultaneous drug development including Asian countries has become a common feature for multinational pharmaceutical companies, Japan has also been frequently set aside because of its unique regulatory requirements and provincial clinical trial infrastructure. To counter this, pharmaceutical companies operating in Japan have been working to improve their efficiency. As a result, a gradual but measurable improvement in the clinical trial environment has been witnessed over the past several years — including a reduction in average study duration. Meanwhile, a tremendous number of improvement programmes focussed on the biopharmaceutical industry have been initiated in conjunction with Prime Minister Shinzo Abe’s vision of innovation for Japan. With this increased scrutiny, significant improvements in regulatory process, clinical trial costs and site performance are anticipated over the next few years. At the same time, efforts to promote the field of pharmaceutical medicine in Japan are ongoing. A number of academic institutions have established education and training programmes in drug development and regulatory science. In addition, collaborative initiatives between academia and industry to set standards and establish qualification for the specialists in drug development are continuing with the hope that the number of experts in drug development in Japan will increase. It is hoped that, together, these positive trends will revitalise Japan as a leading global player in pharmaceutical R&D in the Asian region and beyond.
TL;DR: Biomarkers discovered with the aid of molecular profiling may have particular utility in approaching complex diseases with poorly characterised pathophysiology, as in type 2 diabetes mellitus and may have broader utility in both a regulatory context and in clinical practice.
Abstract: Biomarkers are measurable properties that reflect the pathophysiology of disease, mechanism of action of a molecule or the interaction between the two. The early implementation of a biomarker strategy within drug development offers a great opportunity to enhance the efficiency of drug development. More specifically, biomarkers may be used to aid in lead compound selection, dose focusing, patient stratification and defining the mechanism of action of novel therapeutics. Validated biomarkers, especially surrogate endpoints, may have broader utility in both a regulatory context and in clinical practice. Biomarkers may be used to evaluate both the safety and efficacy of new drugs. Biomarker identification is enhanced with a clear understanding of the steps involved in a pathophysiology cascade. Biomarkers discovered with the aid of molecular profiling may have particular utility in approaching complex diseases with poorly characterised pathophysiology, as in type 2 diabetes mellitus. For example, expression profiling experiments enabled the discovery of the 30kD protein adiponectin — a specific biomarker for in vivo activation of peroxisome proliferator-activator receptor gamma (PPARψ) activity. Adiponectin offers great utility in short-term clinical studies in healthy volunteers or patients with type 2 diabetes to assess whether new potential PPAR? agonists are efficacious in humans. In addition to enlightening key underlying pathophysiology, biomarkers such as adiponectin allow for improved decision-making earlier in development. Ultimately biomarkers can be used to optimise development efficiency from discovery through to registration.
TL;DR: The ethical hurdles of paediatric research are reviewed, the basic principles of medical ethics are described, and some strategies to overcome these challenges are offered.
Abstract: Ethical concerns and paediatric clinical trials go hand in hand. Without knowledge on how to overcome ethical challenges, companies will struggle to develop drugs for the paediatric population. This article reviews the ethical hurdles of paediatric research and offers some strategies to overcome these challenges. It also describes the basic principles of medical ethics, discusses ethical issues unique to children, the benefit-risk balance of research in children, off-label uses and US and EU legislations regarding paediatric research.References
TL;DR: This article addresses the practical aspects that need to be considered when deciding when to conduct formal safety pharmacology studies and harmonising the requirements for good laboratory practice (GLP) compliance in safety Pharmacology studies for regulatory purposes.
Abstract: Safety pharmacology assessments of new drug candidates have recently been described in regulatory guidances (International Conference on Harmonisation [ICH] S7A and ICH S7B) in which the objectives of such studies have been laid out and experimental approaches recommended. It is also clearly stated that when these studies support clinical development, they should be conducted prior to ‘first in man’ studies, in order to protect volunteers and patients from possible inadvertent effects on important physiological functions. Otherwise, the guidelines are flexible on when to conduct safety pharmacology studies.
TL;DR: Three major conclusions emerge from the analysis: first, better performing sites begin enrolling quickly, providing more time to enrol patients, and these sites continue to enrol and complete patients over that extended period of time, and second, investigators with overall clinical experience, especially with the sponsor company, are usually the better performers.
Abstract: This paper explores the impact of various factors on completion times in phase III clinical trials; specifically, why some sites are able to complete more patients during the course of the clinical trial than other sites, including those within the same trial. Seven companies provided research data for inclusion in this analysis. The study sample inclusion criteria were the indications of asthma, chronic obstructive pulmonary disease, depression, schizophrenia, bipolar disorder, hypertension, type 2 diabetes mellitus or menopausal syndrome; phase III; study completion between 2002 and 2005; a New Chemical Entity for an initial (primary) indication and formulation; adult outpatient subjects; and multinational design, with sites in the US, at least one Western European country, and at least one Eastern or Central European country. The analysis assessed both study-level and site-level variables. This paper analyses the results from 262 phase III studies, involving 2047 sites, meeting the stated inclusion criteria. Unsurprisingly, the number of enrolled patients is a clear predictor of the number of completed patients (standardised beta coefficient 0.877; p=0.001). Better performing sites started enrolling patients earlier than other sites and continued to enrol patients over a longer period of time. The time between when a site enrols its first patient and the time the first site in that study enrols its first patient, is a specific predictor of how well a given site will perform; indeed the relationship is inverse so that the greater the time difference, the poorer the performance. Sites involved in studies using competitive enrolment and milestone payments generally complete a higher number of patients. The same holds for sites in clinical trials using upfront, nonrefundable start-up payments, although the relationship is weaker. Interestingly, higher grant payment levels do not translate into better site performance. Site level variables were consistent with study level variables. In addition, investigators with more recent clinical research experience with that sponsor company perform better and sites using a central institutional review board (IRB) outperform sites using local IRBs or a combination of central and local IRBs. Three major conclusions emerge from the analysis. First, better performing sites begin enrolling quickly, providing more time to enrol patients, and these sites continue to enrol and complete patients over that extended period of time. Second, investigators with overall clinical experience, especially with the sponsor company, are usually the better performers. Third, how much an investigator is paid seems less important than how that investigator is paid. Higher payment levels are not associated with improved site performance. In contrast, the use of competitive enrolment and milestone payments does seem to positively affect performance.
TL;DR: Some of the current key industry strategic trends and themes that may govern whether the current business model succeeds and continues to be the engine house of delivery for new medicines for society, or whether key changes are required to maximise R&D efficiency and to deliver regulatory approvable and medically required new drugs are analyzed.
Abstract: factor in the transformation of the course and treatment of disease over the past half century. It is estimated that over 90% of the medicines in use today have been discovered or developed by the industry. Successful medicines bring revenues to the companies who research and develop them through long-term at-risk investment; the ensuing returns through medicine sales are a key element in sustaining a virtuous circle in the traditional drug research and development (R&D) model. However, late-stage attrition, along with increasing development costs, are now challenging companies and the current R&D model. As a consequence, biopharmaceutical companies are under ever increasing pressure to develop new R&D models. This article describes the current status of large pharma R&D and how it goes about developing new drugs. It analyses some of the current key industry strategic trends and themes that may govern whether the current business model succeeds and continues to be the engine house of delivery for new medicines for society, or whether key changes are required to maximise R&D efficiency and to deliver regulatory approvable and medically required new drugs.
TL;DR: In providing product-specific plans, pharmaceutical companies need to supplement careful labelling with a proposal for a suitable package of additional data collection and risk minimisation measures, chosen to be appropriate to the risks posed by the product.
Abstract: Patient safety is a key concern for pharmaceutical companies. The external environment and regulatory requirements have changed considerably over recent years. Risk management planning is becoming increasingly important, partly because of a number of high profile safety issues that have led to the withdrawal of marketed products. Openness, accountability and attribution of responsibility have become the norm. Previous practices were that product labelling would describe the recognised undesirable effects and list contraindications, warnings and precautions; additional measures were only used in exceptional circumstances. However, merely identifying and communicating risks is no longer considered sufficient, and active risk management processes that minimise risk and avoid the likely consequences are now required to support the optimal use of products. Formal Risk Management Plans now need to be prepared and submitted to regulatory authorities prior to marketing authorisation in Europe, and similar legislation has recently been implemented in the US. In providing product-specific plans, pharmaceutical companies need to supplement careful labelling with a proposal for a suitable package of additional data collection and risk minimisation measures, chosen to be appropriate to the risks posed by the product. Companies should monitor the effectiveness of their Plans and revise them if necessary. The regulatory authorities will be checking to ensure that public health is better protected. The aim is to ensure that the risks associated with medicines are actively minimised rather than just communicated.
TL;DR: Data from in vitro studies, including the recently introduced human ether-a-go-Go-related gene (hERG) potassium channel inhibition test to predict QT interval prolongation and the in vitro 3T3 neutral red uptake (3T3 NRU) phototoxicity test to Predict photot toxicity, should be used with great care for decision-making.
Abstract: The importance of in vitro methods for decision-making in drug development is shown for four important areas of pharmaceutical safety evaluations: genetic toxicology, safety pharmacology, phototoxicity and organ toxicity. Since in vitro screening and mechanistic in vitro investigations provide early information on toxicity, the safety of patients in clinical studies has been significantly improved by the performance of in vitro studies. In addition, the high throughput of in vitro technologies allows the pharmaceutical industry to eliminate toxic structures long before ‘first dose in human’ studies. In vitro organ toxicity models provide important mechanistic information. However, a comprehensive analysis of the predictivity of genetic toxicity tests for rodent carcinogenicity has revealed a major problem with the specificity of the in vitro mammalian cell assays, leading to a risk that the development of efficacious drug candidates might have been stopped because of false-positive in vitro results. Therefore, data from in vitro studies, including the recently introduced human ether-a-go-go-related gene (hERG) potassium channel inhibition test to predict QT interval prolongation and the in vitro 3T3 neutral red uptake (3T3 NRU) phototoxicity test to predict phototoxicity, should be used with great care for decision-making. All areas of in vitro safety assessments require significant refinements. Stem cell-derived cell lines and the use of ‘omics’ technologies are expected to make a major contribution to an improved future generation of in vitro screening assays.
TL;DR: The big political event for the FDA in 2007 was always going approval process under close pharmacovigilance, the reviewing to be re-authorisation of the Prescription Drug Users Fee Act divisions within the FDA might be more confident in their deci(PDUFA).
Abstract: As the world’s pre-eminent regulatory authority, what has of reviewers and that orphan drugs were exempt. The Act would happened at the US Food and Drug Administration (FDA) each have expired in September 2007 without re-authorisation, and it year always deserves review. There have, however, been a few went right down to the wire (technically, 7 days after the FDA things both in Europe and outside the Agency that are impacting should have been issuing lay-off notices). However, in lieu of US pharmaceutical medicine. delaying the legislation any longer, the House of Representatives and the Senate ultimately agreed to disagree. Fee scales were First, the US now has a Democrat-lead congress. While the increased, and the review of an ordinary NDA will now attract a FDA is a rather smaller object than many others on the national, fee well in excess of $US1 million (score one for the FDA). There political radar screen, it nonetheless finds itself in the middle of the had been a proposal to reduce the incentives for paediatric recontentious relationship that now exists between the Republicansearch, but this was also dropped in the final legislation (score one lead Executive (headed by the President and his staff in the White for large pharma). Follow-on biologics (i.e. quasi-generic biotechHouse) and the elected members of Congress. nology products) do not exist in the US, and a proposal to The FDA’s new Commissioner, Dr Andrew von Eschenbach, authorise these was deferred (score one for BIO). However, large was confirmed in his post by the US Senate (7 December 2006), pharma lost out when its efforts to get some protection from lightand only after the approval of Plan B® 1 had been assured.[1] Thus, weight lawsuits in State courts failed. Doubtless, in some quarters, the Agency is now led by someone who is a urological surgeon, this re-authorisation will be interpreted as bolstering a position oncologist and former Director of the National Cancer Institute. that the FDA is in the pocket of industry (an opinion that is The appointment of someone who is a rare combination of clinigenerally not shared by those who have had the experience of cian, academic, and Washington insider was warmly welcomed trying to get an NDA approved). by, among others, the Biotechnology Industry Organisation (BIO), One important change that will result from the PDUFA rethe Senate and the White House. But that warm welcome did not authorisation is that there will be more emphasis on, and funding last for long and, for almost a year now, Dr Von Eschenbach has for, pharmacovigilance, although we await the precise mechancompetently withstood regular bashings by the politicians at Senisms, regulations and staffing of this function within the FDA. ate committee hearings. There is nonetheless every hope that This is all highly consistent with many of the recommendations in desperately needed stability to the leadership of the FDA has now the Institute of Medicine’s report on drug safety, issued in 2006.[2] arrived. It is possible that with the advent of some sort of provisional The big political event for the FDA in 2007 was always going approval process under close pharmacovigilance, the reviewing to be re-authorisation of the Prescription Drug Users Fee Act divisions within the FDA might be more confident in their deci(PDUFA). This is the legislation that authorises the FDA to collect sion-making. For once, a good report seems not to have been fees from industry, for New Drug Application (NDA) reviews and buried. some other types of work; PDUFA fees form a significant part of the FDA budget. The major trade-offs when first enacted were that That brings us to this year’s pharmacovigilance cause célèbre, a routine 180-day clock would operate for NDA reviews (with with often remarkable performances from some of the actors, provisions to extend it if new data were submitted during the reaching new heights of hysteria and, frankly, perversion of the review), that the additional budget was devoted to the actual hiring scientific process. The title might have been: ‘Said rosiglitazone to
TL;DR: Why a signature on a consent form does not in itself mean that consent has been obtained, and why the concept of minimal risk that is used by some ethics committees is seriously flawed are shown.
Abstract: Informed consent is a cornerstone of contemporary healthcare as well as of contemporary healthcare research. However, what counts as informed consent differs significantly from one setting to the other. This review begins with a brief discussion of the notion of informed consent itself and then applies it to the research setting. It gives a brief sketch of how the requirement for informed consent in research evolved from the Prussian Directive of 1900 to the current national and international guidelines and regulations, and outlines the various requirements that must be met for such consent to be valid. In research, the complete standard of disclosure is mandatory whereas in therapy an ‘objective reasonable person standard of disclosure’ is generally considered sufficient. In therapy, the discussion of expectations for a positive outcome and of hope for a cure form part of the consent process; in research, this must be handled differently so as to avoid unduly enticing potential research participants. For similar reasons, rewards for participating in the research must be kept to a minimum. Venue-shopping is also considered unethical. Since potential research participants who lack decision-making capacity cannot give consent, substitute decision-makers must take over the decision-making role. In considering whether to enrol incompetent persons in research, substitute decision-makers must follow either the previous competently expressed wishes of the now-incompetent persons or use what is known as the objective reasonable person standard. However, an incompetent person’s refusal to give assent is considered binding in nontherapeutic research and overrules even the duly empowered substitute decision-maker’s decision, and the wishes that have previously been expressed by the now-incompetent person in an advance directive are considered binding even if that may exclude the individual from participating in potentially life-saving trials. The article also distinguishes between deferred consent, presumed consent, prospective consent and substituted consent, and evaluates their acceptability in light of current ethical and legal considerations. The right of research participants to withdraw from any project is explained and the current standards for data management in the case of such a withdrawal are discussed. A separate section deals with consent to research in the emergency setting. It is shown why a signature on a consent form does not in itself mean that consent has been obtained, and why the concept of minimal risk that is used by some ethics committees is seriously flawed. Since legal standards of informed consent differ from jurisdiction to jurisdiction, the discussion highlights some of these differences and suggests ways to minimise any difficulties that might arise for multicentred trials involving distinct jurisdictions.
TL;DR: The EMEA realises that it must improve the operating efficienfacturing and thus, the exhibit provided participants with easy access to the centralised approval procedure without compromising to many potential suppliers and partners.
Abstract: cated to the global exchange of information across the full range of EMEA must help to stimulate innovation, research and developdrug development and lifecycle management issues. There were ment in the EU. approximately 2500 attendees from Europe and many corners of The EMEA and the Heads of the National Medicines Agencies the globe, including South America, North America, the Middle in the EU collaborated to develop the European Risk-Management East, India, Southeast Asia and China. Strategy (ERMS).[3] Currently, the EMEA and the National ComThe programme included more than 130 session topics and over petent Authorities are undertaking further work in context of the 400 speakers, including representatives from the European ERMS, in order to develop additional activities and implement the Medicines Agency (EMEA), the US Food and Drug Administraalready agreed initiatives, which will lead to a more efficient tion (FDA), the Japanese Pharmaceuticals and Medical Devices system for supervising the safety of medicines. One of the main Agency (PMDA), and the Austrian Agency for Medicinal Prodpillars of the ERMS is the EudraVigilance database and the ucts and Medical Devices (AGES PharmMed). submission of individual case safety reports (ICSRs). EMEA is The 230 exhibitors included regulatory agencies and service currently organising the EU Network of Centers for companies offering a wide range of services, such as transport of Pharmacoepidemiology and Pharmacovigilance (ENCePP) to clinical trial materials and biological samples, recruitment, biologmonitor targeted medicines. ical and chemical analysis, statistical analysis and contract manuThe EMEA realises that it must improve the operating efficienfacturing. Thus, the exhibit provided participants with easy access cy of the centralised approval procedure without compromising to many potential suppliers and partners. the quality of the assessment process that assures the safety of
TL;DR: The issues associated with interpretation of data from OLEs and the potential sources of bias associated with these types of studies are described.
Abstract: Open-label extension studies (OLEs) create a number of challenges for data analysis and interpretation. These challenges include bias in outcomes and adverse clinical events that may exist because of subject selection and participation. OLEs are usually performed following the successful completion of a randomised, controlled clinical trial (RCT) and, thus, the characteristics of the study participants who chose to continue to be enrolled are likely to differ significantly from the individuals who dropped out of the RCT. Bias may also exist for outcome and adverse clinical events because of unmasking. The effect that treatment knowledge may exert on participant behaviour may be profound and, in addition, leads to an inability to distinguish temporal trends from differences due to administration of the treatment. Statistical issues that must be considered in OLEs include the introduction of both type I and type II errors into the analysis. There may be an increased type I error rate for outcome assessment because of multiple looks at the data set and a lack of rigour in the selection of variables for analysis of outcomes. There may be type II errors in the detection of uncommon adverse clinical outcomes and type I errors for those adverse events that do appear to occur. Finally, statistical procedures to describe effect sizes for outcomes offer challenges for interpretation. This paper will describe the issues associated with interpretation of data from OLEs and the potential sources of bias associated with these types of studies.
TL;DR: Toxicogenomics is being integrated at different stages of the drug research and development process to provide value-added and critical data that may, ultimately, make the difference between the advancement of a compound or its demise.
Abstract: The advent of genome-based technologies held a lot of promise for drug discovery and development, as it was envisioned that they would impact multiple stages of the discovery and development pipeline. The area of toxicology and drug safety assessments has also invested heavily in these technologies either to predict toxicological outcomes or determine the underlying molecular basis for toxicological observations. This has led to the emergence of the field of toxicogenomics, defined as the application of genomic-based technologies to toxicology evaluations. It is not surprising that such investments of time and resources have been allocated to toxicogenomics, considering that safety studies are time consuming and expensive, and that safety data are arguably the most critical part of a first-in-man regulatory dossier. However, due to the challenges associated with integrating these novel approaches in traditional toxicological evaluations and the fact that a lot of the expectations have not been met, there is some scepticism as to the value of toxicogenomics, with some companies now scaling back their investments in the field. Nevertheless, toxicogenomics is being integrated at different stages of the drug research and development process to provide value-added and critical data that may, ultimately, make the difference between the advancement of a compound or its demise. The purpose of this review is to discuss the current applications of these technologies in drug toxicity profiling during preclinical and clinical development, and how different companies are adopting different approaches.
TL;DR: An overview of spontaneous reporting systems and signal detection and evaluation is presented and regulatory issues and risk management with an emphasis on the new European Community system is discussed.
Abstract: Worldwide, drug regulation safety requirements in the past can be seen as responses to major drug disasters, such as thalidomide or diethylstilbestrol. In the light of the more recent drug disasters, the public is less willing to accept risk associated with drug therapy. Increased emphasis has to be placed on the proactive identification of potential safety issues with new drugs at the earliest possible occasion, and before large populations have already been exposed to the drug. The concept of balance between potential benefit and risk also has to be communicated more strongly. This article presents an overview of spontaneous reporting systems and signal detection and evaluation. It also discusses regulatory issues and risk management with an emphasis on the new European Community system. A number of new initiatives and obligations are introduced that are handled by the European regulatory agencies.
TL;DR: In this article, the authors provide an explanation of the driving forces of consolidation involving genomics-based biotechnology and small pharma companies with large pharma with the aim of providing a new form of governance of technological change.
Abstract: This article aims to provide an explanation of the driving forces of consolidation involving genomics-based biotechnology and small pharma companies with large pharma. The factors that lead firms to choose acquisitions over alliances have set forth the foundation for a new form of governance of technological change. The synergies resulting from internally coherent and mutually supportive resources along the drug discovery value chain totally justifies much of the mergers and acquisitions (M&A) activity. As such, M&A can help firms become more competitive through the reconfiguration of their resources, skills and capabilities in the face of changing business environments. There is clearly an awareness that finding a gene or protein target does not automatically lead to a new therapeutic drug. As such, many of the genomics companies have gone through a reality check and realised that they do not have the necessary expertise, intellectual property and resources for securing their long-term survival. Consequently, acquisitions have multiplied over the last years, mainly fuelled by such requirements as managing product portfolios, accessing critical capabilities, entering new markets, building critical mass, accelerating research and development, and reducing costs.
TL;DR: The MedEd team has delivered over 80 programmes on four continents to over 4500 participants in AstraZeneca’s research and development organisation and subsidiary marketing companies, as well as through web-based distance learning programmes.
Abstract: In 1999 a global medical education function (later called ‘MedEd’) was established with the goal of delivering high quality learning opportunities to AstraZeneca’s physicians and scientists in the form of inhouse courses and seminars, as well as through web-based distance learning programmes. To maximise the sharing of internal competence and experience, the courses and seminars are directed, staffed and taught primarily by our own professionals. This ‘peer-to-peer’ learning model allows AstraZeneca employees to focus on the most company-specific and relevant information. Participation of our professionals as both faculty and students also encourages informal networking among functions and across the global organisation. The MedEd team has delivered over 80 programmes on four continents to over 4500 participants in AstraZeneca’s research and development organisation and subsidiary marketing companies. In our experience, the teachers, who are usually senior specialists or managers, find the activities as rewarding as the students.
TL;DR: There is a remarkable chain of events involving the intilocked that they can actually be considered as a single enterprise, and can these two parties help each other in this single enterprise?
Abstract: Medicines regulation and the health of the patient are so interHere then, is a remarkable chain of events involving the intilocked that they can actually be considered as a single enterprise. mate relationship between patients and regulators. The product Thus, there are two fundamental aspects to the title of this lecture, was approved on the basis of clinical trials involving them both. which can, perhaps, be put in an unfamiliar order: what can the Adverse event reporting led to the withdrawal of the product. patient do for the regulator? and, perhaps less surprisingly, what Advocacy on the part of one group and revision of the benefit-risk can the regulator do for the patient? analysis by both parties (in particular, the patients wanting to accept the risk) then led to the product’s reintroduction. How then The purpose of this lecture is to look at these two questions with can these two parties help each other in this single enterprise? some practical and topical examples drawn from the recent regulatory and clinical environments. However, before dissecting these 1. Adverse Event Reporting: a sine qua non for questions let us consider the recent case of natalizumab Benefit-Risk Analysis (Tysabri® 2) because it evokes many of the complexities and dilemmas that we must resolve. One way that patients help the regulator is by reporting adverse An abridged history of this humanised monoclonal antibody to events. We may quickly rehearse the obvious benefits: identificaα integrin, which has been investigated in patients with Crohn’s tion of rare or idiosyncratic adverse event types (e.g., occurring in disease and disseminated (multiple) sclerosis (MS) is: less than 1 per 5000 patients), increasing the generalisability of • Prior to late 2004: more than 5000 patients studied in clinical clinical trial findings, improving labelling post-launch and learntrials with one disease or the other; ing about over-the-counter (OTC) medications, including ‘herbal’ • November 2004: approval by the US Food and Drug Adminispreparations, that may be used when patients are unobserved by tration (FDA) for treatment of relapsing MS; clinicians. Yet, some still raise arguments against adverse event • February 2005: three patients exposed to the drug were reported reporting by patients: sorting the signal from the noise is never with progressive multifocal leukodystrophy, resulting in two easy, large human and computational expenditures are needed for fatalities; what is essentially a high-volume, low-yield scientific exercise, • February 2005: US marketing authorisation suspended; and which may have more cost-effective alternatives, and the • March 2005–February 2006: patient activist groups lobbied the capability of advocacy groups (and, whisper it softly, even comUS FDA and the pharmaceutical company to reverse the decipeting pharmaceutical companies) to create false signals by stimusion to withdraw the product; lated, selective reporting. • March 2006: natalizumab was reintroduced into the US market Those arguments being what they may, from 2005–2006 the with a tight risk management plan; Medicines and Healthcare Products Regulatory Agency (MHRA) • May 2006: approval in Europe with a similar risk management received 3500 adverse event reports from patients, compared with plan. 28 000 from healthcare professionals. Thus, the resources devoted
TL;DR: Since the inception of the Internet and the World Wide Web, the way these standards have revolutionised the world is comparable to the industrial revolution, but all this activity and technological innovation has, in some ways, not been fully utilised within the clinical trials industry, where the adoption of technology has been markedly slow.
Abstract: Since the inception of the Internet and the World Wide Web in adopted at sites and the use of various forms of technology. The the 1970s and 80s, the world has changed. Websites and e-mail survey results indicated that only 30% of trials run by pharmaceuhave become central to the way enterprises conduct their business; tical companies and 11% of those run by contract research orindeed, it would be hard to imagine any company not using ganisations (CROs) were employing electronic data capture electronic communications to run their day-to-day operations. (EDC) technology in 2004, even though the development of the VeriSign Inc. reported that, as a conservative estimate, there are first systems used for the capture of clinical trial data appeared 2.25 billion e-mails sent every day,[1] while a 2003 report from the around 20 years ago (see figure 1).[5-7] While these early systems International Data Corporation put the number at approximately were not web systems, the CDISC research from 2004 indicates 31 billion.[2] Companies like Amazon and Google exist only that 66% of trials were still using paper. It is evident that the because of the web. Amazon.com was formed in 1994, launched clinical trials world has not embraced technology to its fullest its first international site in October 1998 and in 2005 made a gross extent; however, as shown in the figure for electronic case report profit of $US2039 million on a turnover of $US8490 million.[3] form (eCRF) and electronic patient reported outcome (ePRO) Google, founded in 1998, was handling 4.1 billion searches in July systems, adoption is on the rise. 2007 from within the US alone.[4] These two companies illustrate the impact of the web and the underlying technology that allows 1. Why Not in Clinical Trials? the web to function, technology that must surely be a consideration for the future of clinical trials. The financial sector is often used as an example of the successUnsurprisingly, powering websites such as Amazon and Googful adoption of technology, with Automated Teller Machines le are standards. The standards that are now maintained by the (ATMs) cited as an example of successful implementation of both World Wide Web Consortium (W3C) – the Hyper Text Protocol standards and technology. As we started to move more freely Standard (HTTP), the Transmission Control Protocol (TCP) and around the world, the financial services market recognised the the Internet Protocol (IP) – sit at the very core of the web and came advantages of being able to put a bank card into an ATM anywhere together in the early 1990s to form what we understand today as the Internet and the World Wide Web. Combined with the standards for e-mail, Post Office Protocol 3 (POP3) and Simple Mail Transfer Protocol (SMTP), the way these standards have revolutionised the world is comparable to the industrial revolution. However, all this activity and technological innovation has, in some ways, not been fully utilised within the clinical trials industry, where the adoption of technology has been markedly slow. In 2002, 2003 and, most recently, in 2004, the Clinical Data Interchange Standards Consortium (CDISC) conducted surveys to ascertain the uptake of technology within clinical trials. In particular, the 2004 survey tried to establish how far technology had been 30