Registration Dossier Research Articles

Assembling International Regulatory Submissions: A Simplified Approach

This paper provides a process for developing and assembling worldwide regulatory dossiers. It is based on having a regulatory filing strategy and an infrastructure in place in advance to create, review, file, and find documents. The benefits of keeping it simple will be explained.

A framework establishing clear decision criteria for the assessment of drug efficacy.

Much has been published on various aspects of data analysis and reporting from clinical trials within the biopharmaceutical environment. This ranges from regulatory guidelines on the format and content of registration dossiers to recommendations on data presentation and the statistical methodologies that are appropriate for the diverse types of data one observes in clinical trials. Little has been written about designing a clinical trial analysis and reporting package that focuses on the decisions that must be made throughout the drug development process. Pharmaceutical companies today are under enormous pressure to develop drugs quickly and (cost-) efficiently. Because of this, drugs often move into the later phases of drug development before evidence from prior phases is completely understood. This provides a challenge to clinical trialists to design and execute a clinical trial programme which can expedite drug development. The statistician, as a clinical trialist, must strive to determine the optimum analytical methodology that facilitates decision making for this clinical trial programme. This paper proposes a new framework for the assessment of efficacy in drug development called the 'one programme, one p-value' framework. This framework will accelerate drug development by providing clear criteria for the decisions which must be made along the way. The 'one programme, one p-value' framework is based on the notion that the clinical trial programme comprises exploratory and confirmatory phases. The use of the likelihood function in the exploratory phase facilitates the decision whether (or when) to move into the confirmatory phase. The confirmatory phase consists of one confirmatory trial with a single hypothesis test of the drug's efficacy; hence 'one p-value'. Sponsor interaction with regulatory agencies is necessary at each decision point. Finally, the paper considers how analysis and reporting of efficacy data can be accomplished from a clinical trial programme as described.

A framework establishing clear decision criteria for the assessment of drug efficacy

Much has been published on various aspects of data analysis and reporting from clinical trials within the biopharmaceutical environment. This ranges from regulatory guidelines on the format and content of registration dossiers to recommendations on data presentation and the statistical methodologies that are appropriate for the diverse types of data one observes in clinical trials. Little has been written about designing a clinical trial analysis and reporting package that focuses on the decisions that must be made throughout the drug development process. Pharmaceutical companies today are under enormous pressure to develop drugs quickly and (cost-) efficiently. Because of this, drugs often move into the later phases of drug development before evidence from prior phases is completely understood. This provides a challenge to clinical trialists to design and execute a clinical trial programme which can expedite drug development. The statistician, as a clinical trialist, must strive to determine the optimum analytical methodology that facilitates decision making for this clinical trial programme. This paper proposes a new framework for the assessment of efficacy in drug development called the ‘one programme, one p-value’ framework. This framework will accelerate drug development by providing clear criteria for the decisions which must be made along the way. The ‘one programme, one p-value’ framework is based on the notion that the clinical trial programme comprises exploratory and confirmatory phases. The use of the likelihood function in the exploratory phase facilitates the decision whether (or when) to move into the confirmatory phase. The confirmatory phase consists of one confirmatory trial with a single hypothesis test of the drug's efficacy; hence ‘one p-value’ Sponsor interaction with regulatory agencies is necessary at each decision point. Finally, the paper considers how analysis and reporting of efficacy data can be accomplished from a clinical trial programme as described. © 1998 John Wiley & Sons, Ltd.

Population Pharmacokinetics and Pharmacodynamics: An Underutilized Resource

A meeting was convened in Canberra, Australia, at the request of the Australian Drug Evaluation Committee (ADEC), on December 3-4, 1997 to discuss the role of population pharmacokinetics and pharmacodynamics in drug evaluation and development. The ADEC was particularly concerned about registration of drugs in the pediatric age group. The population approach could be used more often than is currently the case in pharmacokinetic and pharmacodynamic studies to provide valuable information for the safe and effective use of drugs in neonates, infants, and children. The meeting ultimately broadened to include discussion about other subgroups. The main conclusions of the meeting were: 1. The population approach, pharmacokinetic and pharmacodynamic analysis, is a valuable tool both for drug registration purposes and for optimal dosing of drugs in specific groups of patients, 2. Population pharmacokinetic and pharmacodynamic studies are able to fill in the gaps' in registration of drugs, for example, to provide information on optimal pediatric dosing. Such studies provide a basis for enhancing product information to improve rational prescribing, 3. Expertise is required to perform the population studies and expertise, with a clinical perspective, is also required to evaluate such studies if they are to be submitted as part of a drug registration dossier Such expertise is available in the Australasian region and is increasing. Centers of excellence with the appropriate expertise to advise and assist should be encouraged to develop and grow in the region, 4. The use of the population approach by the pharmaceutical industry needs to be encouraged to provide valuable information not obtainable by other techniques. The acceptance of population pharmacokinetic and pharmacodynamic analyses by regulatory agencies also needs to be encouraged, and 5. Development of the population approach to pharmacokinetics and pharmacodynamics is needed from a public health perspective to ensure that all available information is collected and used to improve the way drugs are used. This important endeavor needs funding and support at the local and international levels.

Quality and quantity of data

When collecting data, deciding what type and how much to obtain will depend in large measure on how the data will be used and the group(s) that will be given the data, as well as the risk-taking or risk-averse position adopted. Among the most important issues involving the quality of data are knowing what plans and activities will lead to obtaining high-quality data and recognizing whether the data obtained achieve one's goals. Factors to consider in deciding on the quality and quantity of data to collect include the following: robustness of data required for extrapolatability; potential use of the data; degree of bias that is acceptable; the quantity of data that must be collected in a study or trial which must be considered separately from the quantity to be submitted in a regulatory dossier; practicality of the study; cost of the study; and time available and necessary to complete the study. In preclinical experiments involving discovery research, the protocols prepared are generally loose and can be readily modified during the study in order to take advantage of serendipitous observations or sudden ideas of the experimenter; this is not generally the case with well-controlled clinical trials, although in some circumstances feedback loops can be established to monitor data collection during a trial. A feedback loop of adjusting the amount of data to collect during a study has both advantages and disadvantages (described in the text) when compared with creating a relatively inflexible plan in advance of starting a study, as required for most clinical trials.

Field Evaluation of a Commercial Formulation of the Spodoptera exigua (Lepidoptera: Noctuidae) Nuclear Polyhedrosis Virus for Control of Beet Armyworm on Vegetable Crops in Thailand

Small - scale field trials were conducted in the Kanchanaburi and Ratchaburi provinces of Thailand between December 1994 and March 1996 to gather efficacy data to support a registration dossier for a commercial formulation of a nuclear polyhedrois virus of beet armyworm , Spodoptera exigua, under the tradename Spod - X . A liquid concentrate formula tion of Spod - X was compared with two commercial standards , Bacillus thuringiensis subsp . aizawai (CenTuri 3 . 5 WDG) and the insect growth regulator tebufenozide (Mimic 20F , a benzoylhydrazine ecdysone agonist) , for control of beet armyworm on garden pea , Chinese kale , shallot and table grape . Spod - X applied at 4 - day intervals at 3 . 1 - 12 . 5 1011 occlusion bodies (OBs) ha 1 in a spray volume of 625 - 1000 l ha 1 provided excellent control of beet armyworm on garden pea and grape (75 - 100 % reductions) after the second application . On Chinese kale and shallot , rates of Spod - X in the rate 5 - 60 1011 OBs ha 1 sprayed every 4 days in a spray volume of 1000 l ha 1 provided significant protection from infestation of beet armyworm over the growing season; however , efficacy was poor to moderate . Tank - mixing Spod - X with the pyrethroid , deltamethrin (Decis3EC) , did not improveefficacy on shallot;however , combinations of virus and B. thuringiensis or tebufenozide achieved commercially acceptable levels of crop protection on Chinese kale compared with virus alone . Lower levels of control and crop pro tection observed with all materials on Chinese kale and shallot reflect , in part , the tendency of S. exigua larvae to feed within sheltered sites and directly damage marketable plant parts . In general , all rates of Spod - X performed as well as , or better than , the B. thuringiensis standard (56 . 3 - 105 g ha 1 a.i.) on all crops tested . In general , reductions of beet armyworm larval populations and plant damage provided by all labeled rates of the chemical standard , tebufenozide (125 - 250 g ha 1 a . i .), were marginally greater than all rates of Spod - X tested . On crops such as pea and grape , where beet armyworm predominately feed on exposed leaf surfaces , our data unequivocally support the use of Spod - X for cost - effective , season - long pest management . Strategies to improve the efficacy of virus on shallot and kale are discussed .

Quality Education: Regulatory Aspects in the Pharmaceutical Industry

Quality education in the regulatory field depends on the capacity to communicate not only the rules and the standards but also the principles underlying their rationales. It is, therefore, necessary to have assimilated rules and principles to examine how quality is generated, produced, and controlled, bearing in mind that total quality corresponds to the quality of the process through which the result is obtained.The characteristics of the processes leading to final products in chemistry, manufacture, control (CMC), pharmacotoxicology, and the clinical part of the registration dossier are examined and considered in a context of total quality management. The educational approach in the regulatory field must be characterized by interdisciplinarity and the capacity to highlight the interactions of diverse and highly specialized contributions.

The Industry View of International Standardization of Regulatory Dossiers

Ideally, it should be possible to use an identical submission file for the European Union, Japan, and the United States. With respect to chemical entities and the manufacturing and controls section of the dossier some questions remain to be answered. Is harmonization still required? What is the present status of the harmonization process? Which developments may be expected in the future?

Experience of International Data Management for Drug Development in a Local Operating Company

Success in the pharmaceutical industry is dependent on many factors. Among them, the efficient management of clinical data is increasingly important. Glaxo Group Research (GGR), to accelerate the preparation of international registration dossiers (IRDs), has devolved the data management of international multicenter studies to the local operating companies (LOCs). The mother company has set up a standalone package that enables LOCs to process data according to central standards.The Italian subsidiary was recently involved in international development. This paper attempts to provide an overview of this experience, with special reference to data management activities in the context of international development—the issues encountered, the acquisition of knowledge (methodologies, computer tools), and the advantages of this working method.

Interspecies Extrapolation in Safety Evaluation of Human Medicines in the Netherlands (1990-1992): Practical Considerations

Doses used in animal toxicity studies can be extrapolated to therapeutic doses in man on the basis of body weight equivalence, metabolism equivalence, or toxicokinetics. The validity of extrapolation rules is a matter of debate. However, extrapolation on the basis of toxicokinetics is often preferred for human medicines, provided that adequate data are available. In registration dossiers on human medicines, often insufficient data are available to extrapolate on toxicokinetics only. This prompted us to study whether extrapolation on the basis of body weight equivalents or metabolism equivalents resembles the toxicokinetic way of extrapolation best. A survey was made of new chemical entities that have been applied for registration to the Medicines Evaluation Board in The Netherlands (College ter Beoordeling van Geneesmiddelen) between 1990 and 1992. In the majority of cases, larger margins of safety were achieved by extrapolation on the basis of body weight equivalents as compared to toxicokinetic data. Extrapolation on the basis of metabolism equivalents resembled toxicokinetic extrapolation factors better. The method of extrapolation using metabolism equivalents was rarely encountered in the registration dossiers on human medicines submitted to the Board.

Responsible use of antimicrobials in veterinary medicine: perspectives in France

In France a survey of the use of antimicrobials in veterinary medicine was set up in connection with the Committee for the Marketing Authorization of Veterinary Medicinal Products. This survey has emphasized the importance of antimicrobials in veterinary medicine and the reality of antibiotic resistance in both man and animals. Certain epidemiological data tend to demonstrate that the use of antibiotics in animals increases the risk of antibiotic resistance in man, through selection in animals of resistant pathogenic bacteria or of a non-pathogenic resistant bacteria carrying resistance plasmids. Four proposals are put forward for the control of these different risks: reserve certain antibiotics (life-saving antibiotics) for human medicine, conform to a code of good practices for antibiotic use in animals, strengthen and connect up existing networks for the epidemiosurveillance of antibiotic resistance, provide for studies on the ecological impact of antibiotics in the registration dossiers for veterinary medicinal products. These evolutive measures, based on scientific progress in microbiology, epidemiology and clinical studies should respond satisfactorily to the expectations of all concerned.

Call for socioeconomic drug evaluation grows worldwide

Drug registration in the future is almost certain to require socioeconomic evaluations as part of the registration dossier. Already, many countries around the world are beginning to request socioeconomic analyses for reimbursement and pricing negotiations. Progress in this area was discussed at a Management Forum conference, Cost-Containment Initiatives, in London, UK, last month, giving pharmaceutical companies an idea of what will soon be expected.

Phytomedicines in Korea: Regulatory Affairs

Korea uses two medical systems: Western medicine and Oriental medicine. This paper concentrates on herbal medicines, which are part of Oriental medicine. Herbal medicines are regulated by the Ministry of Health and Social Affairs. A registration dossier is required for new herbal medicines; requirements of that dossier are covered here. Also covered are herbs as raw materials, definitions of herbal medicine versus health foods, distribution channels, advertising, and pricing systems.

A Module System for the Preparation of International Dossiers, Manufacturing, and Controls (New Chemical Entities)

A system of modules is described for the preparation of core dossiers (manufacturing and controls section). It consists of individual monographs of the narrowest subject scope, such that the information required for any local drug registration dossier may be selected from the whole.

A practical approach to method validation in pharmaceutical analysis

Guidelines issued by Regulatory Authorities make it clear that validation of analytical methodology is now widely required in support of registration dossiers. Although some attempts are made at defining terms and some vague indications are sometimes provided within these guidelines, no clear advice is provided on how validations should be conducted and what results should be expected. In this paper it is attempted to suggest some practical approaches to conducting validation and in particular to the determination of accuracy, linearity and limit of detection/quantitation.

TMO: The Trial Management Organization—A New System for Reducing the Time for Clinical Trials

Commercial clinical drug development requires formulating the clinical development plan, executing the plan, compiling the regulatory dossier, and regulatory review and approval of the dossier. Streamlining the development plan with fewer but larger studies, executing the plan using a trial management organization (TMO) approach, taking a proactive, standardized approach to compiling the regulatory dossier, and requiring total quality may shorten the total time required to approval.

Cost-Benefit Analysis and Pricing Considerations in the Regulatory Arena

The objectives of a well-integrated regulatory affairs department should include a drug development strategy that assures a competitive dossier capable of receiving expeditious review and approval. Except for the United States. Canada, and Germany, price controls on new pharmaceuticals are a fact of life. Among the competitive factors that determine price are cost-effectiveness of the new therapy, therapeutic advantages and time of approval. Earliest possible approval is determined by quality of the data, quality of the presentation, and interest of the reviewer . . . all competitive factors that can be either controlled or influenced. Obtaining approval to market a new drug is a significant challenge. To get there early and with a competitive data package is a major achievement. Ten percent to 5070 of the time-course to market a new medicine is consumed in regulatory review. The increase in present value of the asset is significant for each month saved in the review process. Strategies should be developed to effect a more rapid review, to assure a more favorable pricing or reimbursement, and to position the new medicine for its optimal competitive opportunity. Strategic considerations will be identified to fulfill the regulatory objective of developing a regulatory dossier capable of receiving expeditious approval for a competitive product in major markets.

The Pyramid Concept

Clinical Study Reports (CSR) have been organized into five levels of detail which form a pyramid. The peak is a one-page synopsis (Level 1) and the base is composed of case reports (Level 5). The second level is a brief summary written in the form of a manuscript as for publication, while the fourth level is composed of computer listings, study documentation, special analyses, and so on. The core, or third level, is a comprehensive summary which can stand alone without Levels 4 and 5. This organization permits us to meet the needs of regulatory agencies on a worldwide basis and allows reviewers to select the level of detail necessary for their specific requirements. The concept also has been applied to the preparation of a Marketing Authorization Application (MAA). This registration dossier is divided into ten sections. Each section contains a synopsis, a summary, and references, which in the case of the clinical section are CSRs.

Format, organization, and processing of registration dossiers in the European Economic Community (EEC).

The free circulation of drugs among the European Economic Community (EEC) member states ensues from the principles stated by the Treaty of Rome. This is possible thanks to a series of legal and technical directives stating the criteria with which the national authorities--who are sovereign in this matter--must comply. These directives are briefly explained. In particular, the procedure by which the initial authorization, granted by one member state, can be extended to at least five others is presented. The content and order of the registration dossier is presented in detail.

The mechanics of assembling an international drug dossier.

An international registration dossier is a comprehensive scientific document used to obtain worldwide licensing approval of a drug by diverse health authorities. Its creation, processing, compilation, and dispatch to the field by a regulatory affairs department of a major, US-based, multinational pharmaceutical company is dependent upon many interrelated activities beginning years prior to its physical assembly. The following activities are briefly discussed to show the magnitude of the task and the type of activities encountered: planning and scheduling; creating, organizing, and formatting; typing; copying and collating; working with extramural suppliers and services; and finally, shipping the document to the field. Suggestions for making the process more efficient are offered.