Showing papers in "International Journal of Pharmaceutical Medicine in 2004"

Medical Dictionary for Regulatory Activities (MedDRA)

Abstract: Medical Dictionary for Regulatory Activities (MedDRA), as the ICH approved standard terminology for all drug regulatory activities, is in many aspects different from previously used terminologies, mainly in size, specificity, structure, rules and conventions. All these aspects impact on retrieval strategies, analysis and presentation of the coded data. After shortly describing the key features of MedDRA and their theoretically anticipated impact on data analysis and presentation, two examples for display of MedDRA coded data are described, one from a clinical study project and one from spontaneous reporting. The first example compares the adverse drug reaction (ADR) profile of the same data coded in WHO Adverse Reaction Terminology (WHO-ART) and recorded in MedDRA; the second example demonstrates different ways of presenting the ADR profile of an antibacterial, using different elements in MedDRA with the aim of presenting the ADR profile in a way that best transports the medical concepts reported with this drug. Based on some results obtained from these examples and based on analysis of the content of MedDRA version 6.0, the following limitations of MedDRA for data analysis have been identified: (i) the Preferred Term level is generally too granular, bearing the danger of underestimating risks, and the midlevels are currently not a robust, consistent and non-ambiguous level for data aggregation; and (ii) the rules relating to multiaxiality add complexity for data aggregation because related medical concepts may be split into different System Organ Classes, which may mislead frequency analysis. In the absence of guidance from regulatory agencies and with the growing need for analysis of MedDRAencoded data, there is a risk of diminishing the benefits of MedDRA as a standard terminology through the use of user-specific and non-standardised data analysis and presentation strategies. MedDRA would benefit from a redesign of the group terms (High Level Group Terms/High Level Terms) to become a robust, consistent and non-ambiguous level for data analysis and aggregation. This should be done in an interdisciplinary effort coordinated by the MedDRA Maintenance Supply and Support Organisation (MSSO).

Price and Market-Share Competition of Anti-Ulcer Gastric Medications in the Ohio Medicaid Market

Abstract: Objectives: Our objectives are (i) to determine whether an increase in competition among companies selling prescription anti-ulcer pharmaceuticals has an impact on drug costs for Ohio Medicaid; (ii) to separate competition’s impact into its effect on generic drugs and its effect on branded drugs; and (iii) to distinguish between inter-drug (market) and intra-drug (generic) competition in their effects on drug-prescription reimbursements and utilisation

Medical Dictionary for Regulatory Activities (MedDRA): Data retrieval and presentation

Abstract: Medical Dictionary for Regulatory Activities (MedDRA), as the ICH approved standard terminology for all drug regulatory activities, is in many aspects different from previously used terminologies, mainly in size, specificity, structure, rules and conventions. All these aspects impact on retrieval strategies, analysis and presentation of the coded data. After shortly describing the key features of MedDRA and their theoretically anticipated impact on data analysis and presentation, two examples for display of MedDRA coded data are described, one from a clinical study project and one from spontaneous reporting. The first example compares the adverse drug reaction (ADR) profile of the same data coded in WHO Adverse Reaction Terminology (WHO-ART) and recorded in MedDRA; the second example demonstrates different ways of presenting the ADR profile of an antibacterial, using different elements in MedDRA with the aim of presenting the ADR profile in a way that best transports the medical concepts reported with this drug. Based on some results obtained from these examples and based on analysis of the content of MedDRA version 6.0, the following limitations of MedDRA for data analysis have been identified: (i) the Preferred Term level is generally too granular, bearing the danger of underestimating risks, and the midlevels are currently not a robust, consistent and non-ambiguous level for data aggregation; and (ii) the rules relating to multiaxiality add complexity for data aggregation because related medical concepts may be split into different System Organ Classes, which may mislead frequency analysis. In the absence of guidance from regulatory agencies and with the growing need for analysis of MedDRA-encoded data, there is a risk of diminishing the benefits of MedDRA as a standard terminology through the use of user-specific and non-standardised data analysis and presentation strategies. MedDRA would benefit from a redesign of the group terms (High Level Group Terms/High Level Terms) to become a robust, consistent and non-ambiguous level for data analysis and aggregation. This should be done in an interdisciplinary effort coordinated by the MedDRA Maintenance Supply and Support Organisation (MSSO).

Setting limits for genotoxic impurities in drug substances: Threshold-based and pragmatic approaches

Abstract: In December 2002, the Safety Working Party (SWP) of the European Committee for Proprietary Medicinal Products (CPMP) published a Position paper on the limits of genotoxic impurities. The European Union intended to supplement a gap in the International Conference on Harmonisation (ICH) guidelines on qualification of impurities, as it was deemed that impurities with genotoxic potential were a special case not specifically covered in terms of qualification by the Q3A and Q3B guidelines. In fact, the SWP's proposed approach follows a safety factor-based risk assessment process similar to that in ICH Guideline Q3C on limits for residual solvents, rather than a qualification process as described in ICH Q3A and B. The need to provide particular advice for the control of drug substance impurities that bear the risk of non-reversible toxicity (e.g. genotoxic impurities) is widely acknowledged. If such impurities can be shown to exert their genotoxicity via a mechanism with a threshold, then control of the impurity according to calculated permitted daily exposures (PDEs) should not pose major problems. However, in most cases, threshold mechanisms for such genotoxic impurities will not have been demonstrated. Employing conservative uncertainty factors to calculate PDEs in such cases may lead to limits that could be out of proportion to the impurity qualification limits (as per ICH quality guidelines), normally 1500 parts per million (≡ 1.5mg/1g substance), and orders of magnitude lower than exposures to genotoxins via other sources, such as diet and the environment. Alternative approaches based on the calculation of a lifetime cancer risk of 1/10 5 or 1/10 6 , which have been recommended for control of carcinogens in other circumstances, should be considered. This could lead to more realistic limits for genotoxic impurities, e.g. an intake of up to 1.5 μg/day for most genotoxic impurities without evidence of a threshold is considered to be toxicologically insignificant. Control of 'suspect' or 'known' potentially genotoxic impurities at such a level is important when one considers that many genotoxins present in drug substance at much higher concentrations would escape detection during standard genotoxicity testing of drug substance. Whilst a generic limit of 1.5 μg/day of an identified genotoxin may be suitable for chronic use drugs in a wide patient population, higher levels may be acceptable for shorter duration use, and in circumstances involving closely-defined patient populations, for example, where a case-specific assessment is appropriate.

Quantitative Drug Activity Prediction for Inhibitors of Human Breast Carcinoma

Abstract: There are sufficient data on a series of N−aryl−N-(2-chloroethyl) ureas tested as inhibitors of human breast carcinoma of the MDA-MB-231 cancer line to allow us to apply the so-called electron-conformational (EC) method in order to predict the drug activity of other molecular systems. The EC method reveals the pharmacophore and predicts the activity quantitatively based on conformational analysis and electronic structure calculations for a set of molecules that were tested for the activity under consideration (the training set). To reveal the pharmacophore of inhibitors of the human breast carcinoma MDA-MB-231 and to determine the parameters of molecular structure that enhance or diminish the activity, thus providing a tool for further increasing the inhibitor activity. Details of the EC method are described elsewhere. For the training set of the tested molecules, the electronic structure of the lowest conformations is calculated and presented in matrices, which are then processed in comparison with the activity. This reveals the pharmacophore: the special features of the drug molecules that are common for all active compounds and absent in the inactive ones. No arbitrary descriptors are used in the identification of the pharmacophore. The out-of-pharmacophore groups are then analysed and parameterised in an error-minimisation scheme that allows for calculation of the quantitative activity of any molecular system that has the pharmacophore. The pharmacophore of human breast carcinoma inhibitors is given by ten numbers with certain limits of flexibility. They represent four atoms (reactivity positions) with certain interatomic distances within the defined tolerances. Typical out-of-pharmacophore groups in the drug molecule serve as either antipharmacophore shields that diminish the activity or as other factors that may enhance the lipophilicity. A formula is obtained in which the roles of pharmacophore tolerances and out-of-pharmacophore group influences are presented by numerical coefficients, allowing the calculation of the expected activity quantitatively. The formula liability is estimated to be ≈97%. A cross-validation is performed showing that the prediction power is 92%. The pharmacophore evaluation is ≈100% correct, within the accuracy of the experimental data in the training set. An additional simple formula allows for the discrimination of the most active out-of-pharmacophore groups and the most influential pharmacophore tolerance parameters. The pharmacophore of the inhibitors of human breast carcinoma MDA-MB-231 is revealed and allows for high-accuracy data mining for potential drugs. A formula is derived for quantitative prediction of the activity of untested molecules with an expected accuracy of 92%.

Is Attention-Deficit Hyperactivity Disorder (ADHD) Diagnosed in Adults?

Abstract: Objective: To evaluate whether the trend in adults seeking medical care for the treatment of attention-deficit hyperactivity disorder (ADHD) reflects the upward pattern seen among children

Risk Management for Biological Products

Abstract: The risks of biotechnology-derived products and other biologicals are different from the risks of small chemical entities and, thus, their risk management will have special features For many biological products, the safety is mainly dependent on the starting materials and the manufacturing process Therefore, their risk management must be focused accordingly In certain issues, such as immunogenicity of recombinant DNA products, a proper risk management plan can only be built during the pre-licensing studies Application of special epidemiological methods for investigation of very rare safety signals is crucial for some biologicals, eg vaccines Genetically modified viruses used as vaccines and vectors for gene transfer, as well as xenogeneic cells, carry major public health risks Therefore, the use of such products is possible only with extensive risk management programmes Some elements of these programmes may be difficult to enforce because of legal, ethical and practical obstacles The main special risk of biologicals is the transmission of infectious agents The mitigation of this risk is complicated by the ever-changing epidemiological situation and the long latency of some infections The impact of any measure for risk reduction of essential products, such as vaccines and plasma-derived medicinal products, must be considered carefully from the overall benefit/risk point of view The risk must be reduced to the lowest level that is reasonably achievable without unduly putting the availability of essential products at risk Adequate expertise and consultations with special experts are important in the risk management of the new advanced therapies in order to ensure the full understanding of the risks and to avoid creating unnecessary barriers for innovation Due to the sensitive issues linked with biotechnology-derived products and other biologicals, risk communication is of critical importance From the regulatory point of view, the risk management of biologicals is far from optimal, especially in the EU where legislation lags behind the progress in the field, and where the concerted actions of the national regulatory agencies need improvement From the industry point of view, the risk management plans for biologicals should be designed in multidisciplinary teams

The Migraine Disability Assessment (MIDAS) Questionnaire in the Primary-Care Setting

Abstract: Migraine is a remarkably disabling condition, although unpredictable and heterogeneous in frequency, duration and severity. It can be difficult to manage in primary care where it is under-recognised, underdiagnosed and undertreated. Proposals have been made that migraine care could be improved by incorporating assessments of migraine impact into management strategies, and measuring headache-related disability can be used to assess the impact of migraine on people’s lives and society. The Migraine Disability Assessment (MIDAS) questionnaire was developed from this research. MIDAS is a scientifically reliable and valid measure of migraine disability that can improve communication between patients and physicians, assess migraine severity and act as an outcome measure to monitor treatment efficacy. Perhaps the most important use of MIDAS is as an aid to public health initiatives on headache. MIDAS can be used to screen populations for headache-related disabilities and medical needs and be part of generalised migraine management guidelines in primary care in order to produce an individualised treatment plan for each patient. MIDAS can be used by physicians, pharmacists, nurses and patients.

Acceptability of Low Levels of Genotoxic Impurities in New Drug Substances: Case Reports

Abstract: The Safety Working Party (SWP) of the European Committee for Proprietary Medicinal Products (CPMP) published a draft Position paper on the limits for genotoxic impurities in December 2002. Genotoxic impurities was a topic selected for the joint Drug Information Association (DIA)/European Medicines Agency (EMEA) meeting that was organised in London on October 27-28, 2003, to facilitate the exchange of opinion and perspective between industry and regulatory scientists. Scientific and regulatory updates were presented and discussed in the light of case studies, which are described in this article. The four cases span a range of different scenarios that can be encountered in development: (i) candidate for life-threatening indication - an alkylating reagent used in synthesis is an impurity in the active substance; (ii) late-stage candidate for non-life-threatening chronic indication - a route change leads to a new intermediate becoming a potential impurity - as it is an isolated intermediate, worker safety data is generated and needs to be risk managed; (iii) late-stage candidate for non-life-threatening chronic indication - a mutagenic and structural-alerting starting material - the commercial route confers excellent purging; and (iv) early-stage candidate for non-life-threatening chronic indication - considers strategic approaches for impurities with structural-alerting functionality under different scenarios (dependent upon toxicological data available, daily dosing regimen, route of delivery etc.). The outcomes of the discussions of the cases at the DIA/EMEA Workshop are presented in a separate article in this issue of the journal.

Utilisation of Foreign Clinical Data in Japanese New Drug Approval Review On What Basis Did the Regulatory Agency Accept Them

Abstract: Objective: Foreign clinical evidence for efficacy and safety of new pharmaceutical drugs was utilised in decisions for marketing approval in Japan without specific regulatory guidelines until a new internationally harmonised guidance for bridging strategy was introduced in 1998. We examined how foreign clinical studies were used in recent marketing approval decisions and also how the new guidelines affected the trends of foreign data acceptance. Methods: New drug applications (NDAs) approved between 1999 and 2003 with review reports issued by the regulatory authority available on the official website were scrutinised. Focusing on critical clinical trials including dose response studies in phase II and confirmatory studies in phase III, we classified the type of utilisation of foreign clinical data into several groups. Results: Of the 171 NDAs approved during this period, 55 (32%) contained foreign studies as formally submitted data. Twenty NDAs (12%) were approved based on the bridging strategy. In 24 NDAs (14%) important foreign data were used as references, but not as formally submitted materials. NDAs that were given orphan drug status or priority review status were more likely to be submitted and approved on the basis of foreign clinical data. The number of bridging-based NDAs successfully approved increased from three in 2000 to ten in 2002, although confusion about the application of the new guidelines was observed after the guidelines’

Assessment and acceptance of thresholds of genotoxic Impurities in New Drug substances: A regulatory perspective

Abstract: Impurities in drug substances can arise from a variety of sources during the manufacturing process, and include residues from starting materials, by-products, intermediates, reagents, ligands and catalysts, as well as degradation products arising during storage. The Safety Working Party of the European Committee for Medicinal Products for Human Use (CHMP) is currently in a process of preparing a position paper intended to provide guidance on how to define acceptable limits of those impurities in new drug substances and novel excipients which have been found to be genotoxic. According to the existing International Conference on Harmonisation (ICH) Q3A(R) Guideline on Impurities in New Drug Substances, impurity acceptance criteria should be set no higher than the level that can be justified by safety data, and should be consistent with the level achievable by the manufacturing process and the analytical capability. How can these demands be applied to impurities with genotoxic properties? In current regulatory practice, genotoxic compounds are usually considered to operate by a non-threshold mode of action and, thus, any level of exposure carries - at least theoretically - a risk. This precautious view implies that pharmaceutical measurements should be guided by the so-called 'ALARA' principle, i.e. where avoidance is not possible, genotoxic impurities must be kept to a level 'As Low As Reasonably Achievable'. From a toxicological point of view, different approaches for assessing acceptable limits are suggested depending on the availability of data. For known genotoxic carcinogens, where a full genotoxicity and carcinogenicity set of data is available, risk assessment can be carried out either by applying quantitative risk assessment based on mathematical modelling or using no effect levels of the carcinogenic response modified by uncertainty factors. For in vivo genotoxins of unknown carcinogenicity, use of a 'no-effect-level-uncertainty-factor approach' is justified in those (probably rare) cases where adequate data for demonstrating a threshold for genotoxic effects are available. Whether such an approach is also applicable to in vivo genotoxins with no evidence of a threshold is currently a controversial issue. For most impurities, where there may only be limited in vitro data available, a pragmatic approach is needed, which recognises that the presence of very low levels of genotoxic impurities might be without appreciable risk. The application of a target level for an acceptable daily intake of 1.5 μg/day for most genotoxic impurities, based on the concept of threshold of toxicological concern (TTC), is currently under discussion for this purpose. From this threshold value, a permitted level in the drug substance can be calculated based on the expected dose to the patient. A higher threshold may be justified taking into consideration duration of treatment, as well as therapeutic indication and exposed populations. On the other hand, unusually potent genotoxic and/or carcinogenic impurities may have to be excluded from the TTC approach and may need individual risk assessment.

Non-clinical development of fixed combinations: A European regulatory perspective

Abstract: The concomitant use of medicinal products may trigger the development of a fixed combination product with the intention to facilitate for the user and improve compliance. At present, there is a lack of detailed regulatory guidance on the strategies for the non-clinical development of a fixed combination, and companies often seek scientific advice at the European Medicines Agency (EMEA) and its scientific committee, the Committee for Medicinal Products for Human Use (CHMP). Four main scenarios can be identified: combination of well known compounds already approved/used in combination; combination of approved/well known compounds not previously approved in combination; combination of one or more new chemical entity(ies) [NCE] with one or more well known compound(s); and combination of two or more NCEs. The level of knowledge and experience in these scenarios will differ markedly and, therefore, different strategies for the non-clinical development programme are justified. The current paper discusses these different scenarios and addresses specific issues in relation to the need of non-clinical studies to support the development of a fixed combination.

Do Acetylcholinesterase Inhibitors Have a Role in Improving Cognitive Impairment in Patients with Schizophrenia

Abstract: At present, there are no really efficacious tools available to counteract cognitive deficits in patients with schizophrenia: even though new atypical antipsychotic drugs represent an advance compared with typical antipsychotic drugs, the results obtained with this class of drugs are actually partial. Acetylcholinesterase inhibitors (AChEIs) that have been proven to be effective on psychiatric symptoms, behavioural abnormalities and cognitive dysfunction of patients with dementia may be effective on cognitive deficit in patients with schizophrenia, and may also improve their psychopathology and behaviour. In the present paper we review the use of AChEIs in the treatment of schizophrenia. Although these AChEIs have different action mechanisms (donepezil only inhibits acetylcholinesterase; rivastigmine also inhibits butyryl-cholinesterase; galantamine also interacts with nicotinic acetylcholine receptors), they have similar clinical effects. We have observed no or mild effects on cognitive deficits and symptoms in double-blind studies, a dramatic effect on a patient’s subjective well-being and ability to cope and subjective judgement of psychiatrists in the case reports and open studies. The question remains as to how we can accurately measure a patient’s capacity to feel, to cope and his/her desire to live with other people — aspects very different from intelligence and cognitive function. Further double-blind placebo studies are required to determine the role of AChEIs in the improvement of quality of life for patients affected by schizophrenia.

Impact of the Clinical Trials Directive on the Research-Based Pharmaceutical Industry

Abstract: The clinical trial directive was first proposed in order to implement the requirements of the International Conference on Harmonisation (ICH) E6 on Good Clinical Practice (GCP)[1] into the European Legislation as a white paper in the early 1990s. It had a long and troublesome gestation before it appeared as final legal text in May 2001.[2] The scope was greater than originally envisaged and covered all aspects of the initiation and management of clinical research in the European Union (EU). There were many compromises required to reach consensus in the relevant bodies of the European systems. The directive text makes reference to many supporting guidelines and these have been delayed repeatedly. Due to delay in issuing the final guidelines, all Member State (MS) were unable to transpose the Directive’s schedule of May 2003 and, indeed, are still struggling to meet the final deadline for implementation of 1 May 2004. It has proved difficult both to plan and to manage at an operational level the changes required to cope with the new legislative requirements. There is concern that each MS may define elements of the Directive text differently and include or exclude different types of study e.g. non-interventional studies1 [1] (excluded from the Directive) in different ways; however, in principle, most studies will have to be performed under a Clinical Trial Authorisation (CTA). The primary aim of the Directive is to safeguard subjects taking part in clinical research and, therefore, applies not just to the pharmaceutical industry but also to academia. Anyone performing a clinical trial with an Investigational Medicinal Product (IMP) in Europe must comply with its regulations. In developing the Clinical Trials Directive and its guidelines, it would have been possible fundamentally to change the way in which Europe manages clinical research. Advances in the efficiency of regulatory and ethical review of clinical research can still be achieved. These potential opportunities are not being taken and it seems that the focus of elaborating procedural guidance has been on administrative control and bureaucracy rather than facilitating clinical research and thereby improving the competitiveness of clinical research in Europe. There will be no single decision across Europe for a multinational, multicentre study, but each involved MS will assess the application and reach its own decision, potentially creating conflict as well as duplication. A single, positive opinion per involved MS Ethics Committee (EC) must be received and ‘no grounds for non-acceptance’ communicated from the Competent Authority (CA). Concern remains that both the CA and EC will be looking at the same dossier and that no clear remit of each is yet published – again there is potential for ambiguity and conflict. This was delegated as a MS responsibility and is anticipated to differ as the national legislation and guidance evolves. The guidance and Directive introduces new terms and concepts into Clinical Trial Management as outlined in table I.

Releasing the human spirit in developing drugs: Increasing clinical pharmacokinetics productivity

Abstract: A common problem in drug development is that highly trained people become trapped in doing the work of their respective discipline without taking individual responsibility for the most important questions. ‘Getting the dosage regimen right’ is a fundamental problem in drug development that is often not well performed. The experience described here transformed a department from completing required clinical pharmacokinetic studies to focusing on the most important questions in dosage regimen design that did not have a unique solution. Elements of the story include vision, quality, best practice, automation, transformation and impact. Productivity was increased by 81% within 2 years by one measure and there was a substantial positive financial impact.

The European Clinical Trials Directive: Will it Promote Clinical Research in Europe?

Abstract: The European Clinical Trials Directive (2001/20/EC) is due for implementation in all 25 Member States of the European Union on 1 May 2004. In an article by Moira Daniels in this issue of the International Journal of Pharmaceutical Medicine, she outlines very accurately what the potential impact of the Directive will be on the research-based pharmaceutical industry. Her message is clear, it is not going to provide the benefits that were hoped for when the Directive was first published in April 2001. Why is this? Well, quite simply, Europe consisted of 15 Member States when the Directive was finalised and there are ten new entrants on 1 May 2004. The majority of these Member States have particular individual and cultural opinions on the process of clinical research and these have come through in the detailed guidance documents that support the Directive. Reading those guidance documents that have been published so far indicates where compromise and debate have taken place with the Commission’s Council Working Party but have been flavoured by national opinion. This has led to differences in what Member States will require in information to accompany applications to the competent authorities and ethics committees. Inevitably, this will lead to problems for companies involved in multinational multicentre trials in Europe. However, I believe that there is good news for the UK as part of Europe. Even though phase I trials will require competent authority approval for the first time in the UK, the Medicines and Healthcare products Regulatory Agency (MHRA) will be working to a 14-day average time for phase I approvals. In addition, 80% of phase II trials and beyond will be approved 14% faster by the MHRA, with a 30-day timeline compared with the current 35 days for the majority of Clinical Trial Exemptions. Daniels highlights the fact that the requirements of the competent authorities and ethics committees have not been clearly defined. In the UK, it will be very clear what documentation each authority will require, and duplication will be kept to a minimum, i.e. essentially the protocol. The MHRA are also working on a series of algorithms that will aid applicants as to whether an application is appropriate. The algorithms will cover: what is a clinical trial under the Directive, what is manufacture and what is a substantial amendment? At the time of writing (4 February 2004) it is not clear when the UK legislation will finally be in place. The delay is due to the failure of the Commission to finalise the technical Directive on good clinical practice (GCP) and GCP inspection. The British Government and MHRA, concerned about the continuing delay, are investigating ways in which the legislation can be produced prior to 1 May to enable the UK to comply and allow sponsors to get started. One other major issue is around investigator-led studies. Academics around Europe have been signing a petition to call for repeal of the Directive. So far, 1500–2000 people have signed the petition but it is far too late for this activity. It is my belief that in the UK, the legislation will support and probably increase the opportunity for investigator-led trials leading to greater and more open collaboration between industry and academia. Potentially, industry will be able to provide significant resource to investigatorled trials of interest without becoming the sponsor and this must enhance the tradition of clinical research in the UK and therefore benefit patients. We live in a competitive world; one of the purposes of the EU Directive was to enhance Europe as a competitive location for clinical research. There is no doubt that Daniels’ paper brings that premise into question but I believe that the UK will be a major player in clinical research in Europe and will be attractive to sponsors. Already UK cancer trials have doubled their accrual rate to 8% over the last 3 years and there is no reason why this initiative could not be duplicated in other disease areas. The UK is and will remain a major centre for clinical research. EDITORIAL Int J Pharm Med 2004; 18 (1): 3 1364-9027/04/0001-0003/$31.00/0

Pharmaceutical Pricing and Reimbursement Strategies Over the Whole Product Life Cycle

Abstract: Despite the significant increase in spending on pharmaceutical research and development that we have seen in real terms over the past 20 years, this has not been matched by an increase in new chemical entities (NCEs). Therefore, each NCE has to produce ever-increasing financial returns to the company in order to fund further research to maintain the viability of the industry. However, the payers in the marketplace have limited pharmaceutical budgets and have introduced various cost containment strategies to limit access to all new pharmaceuticals until they are proven to be a cost-effective replacement to the current treatments. The impact of these cost containment strategies is seen at the national, regional and/or local (formulary) approval level. Therefore, for companies to ensure rapid market access with an NCE that will be reimbursed at a suitable level, and take market share from a current market leader, they must have proof of comparative cost effectiveness at launch. To achieve this goal, companies need to address the pricing and reimbursement strategy at each stage of development to ensure that they have the critical data collected to prove comparative value in use. In reality, however, not all potential NCEs will have the ability to deliver the comparative level of improvement over available treatments needed to achieve the required price, at the necessary level of reimbursement and at sufficient volume to satisfy the financial targets. Therefore, companies need to invest in collecting and analysing market data at each stage of development, from project selection through to phase III, to ensure that they can make informed decisions. This market place data will help to determine the returns that can be achieved from different product profiles, thereby enabling ‘go/no go’ decisions to be put in place. The indication, subpopulation and launch sequencing are other critical factors that need to be addressed by the company.

The New World of Global Drug Development

Abstract: The world of drug development is changing. That ‘world’ includes co-workers, suppliers, contractors, alliance partners and other contributors from all corners of the globe, trying to work as a team to achieve project deliverables. ‘Drug development’ has increasingly come to mean new biological information and processes, which are subject to various degrees of readiness and acceptance from workforces, regulatory agencies and consumers, around the world. This paper addresses the global challenges life science managers face in developing biotechnologies for pharmaceutical applications. A global project management framework to help managers handle these project challenges is proposed. The framework advocates that managers dynamically analyse a project’s language, culture, communication channel and cash flow profiles throughout the development and marketing cycles, adjusting project plans accordingly. Each step of the global management framework is described in detail with examples relevant to the drug development process. The author also shares a checklist of specific factors for managers to consider, organised by their likely impact on various cash flow elements. This review highlights current trends in biotechnology science, finance and markets in the context of the proposed framework, and explores implications for successful global development of biopharmaceutical products. Guidance is given towards specific measures managers can undertake to respond to these trends.

The Changing European Regulatory Landscape Present and Future Challenges to the Development of Biotechnological and Emerging Technology Products

Abstract: Whilst the US has traditionally been considered the Agency that sets the gold standard for medicines regulation, with the increasing demand for global cooperation and harmonisation of technical conformity and regulatory control, consideration should be given to regulatory requirements in jurisdictions other than the US. The European Union is becoming an important region for global product development. This review sets out scientific and public policy aspects that underpin the European legislative framework for certain healthcare products, including those derived from novel technological platforms. This review attempts to highlight some of the current and new challenges to the development of biotechnological and emerging technology products. There seems little doubt that the whole area of regulatory laws and policy will present new challenges to companies and their advisors in the coming years. It should be recognised that the development of high technology products is more costly and carries higher business risks compared with conventional pharmaceutical products. A successful product development should therefore be underpinned by not only good science, but a thorough understanding of the regulatory environment, which is increasingly complex. The development programme should integrate regulatory strategy at the early stages. This will help identify, address and manage potential regulatory risks that will greatly facilitate the progress of research and development, and the timeliness of the commercial launch of a product.

The New World of Global Drug Development What Pharma Managers Need to Know

Abstract: The world of drug development is changing. That 'world' includes co-workers, suppliers, contractors, alliance partners and other contributors from all corners of the globe, trying to work as a team to achieve project deliverables. 'Drug development' has increasingly come to mean new biological information and processes, which are subject to various degrees of readiness and acceptance from workforces, regulatory agencies and consumers, around the world. This paper addresses the global challenges life science managers face in developing biotechnologies for pharmaceutical applications. A global project management framework to help managers handle these project challenges is proposed. The framework advocates that managers dynamically analyse a project's language, culture, communication channel and cash flow profiles throughout the development and marketing cycles, adjusting project plans accordingly. Each step of the global management framework is described in detail with examples relevant to the drug development process. The author also shares a checklist of specific factors for managers to consider, organised by their likely impact on various cash flow elements. This review highlights current trends in biotechnology science, finance and markets in the context of the proposed framework, and explores implications for successful global development of biopharmaceutical products. Guidance is given towards specific measures managers can undertake to respond to these trends.