based on the book chapter by Mariano Sanz and Fabio Vignoletti Summary Selection of endpoints, or outcome measures, can be daunting for researchers because of the huge variation in disease processes and outcomes relating to implants, surgery and tissue regeneration, and factors such as the research question and study design. This chapter advises investigators on the selection of valid, patient-applicable, sensitive, specific, ethical endpoints, that do not damage tissue integrity. It defines the terms, and distinguishes between true and surrogate and primary and secondary endpoints. It explains about different types biological, clinical, psychological and economic -- and summarizes their limitations and value, such as biological measures for disease etiology and progress, and clinical measures for assessing survival and function. The authors focus on common parameters relating to periodontal probing, bone radiography and patient-related outcomes, and describe the relevance of numerous specific endpoints in studies of localized gingival recession, soft tissue augmentation and mandibular furcation regeneration. They also review endpoint selection in implant therapy, for evaluating bone regenerative therapies, protocols for socket preservation and immediate implantation, lateral and vertical bone augmentation, and implant-supported restorations. Throughout the chapter, the chosen endpoints are related to the wider aspects of patient selection, randomization and compliance, data collection and observer variation, error proneness and reporting of results. Open full-text PDF (2.3 MB)

based on the book chapter by William V. Giannobile Summary This chapter describes how the volume of published research papers has risen over the last fifty years. The reasons it gives include not only dissemination of the findings and adding to the body of evidence but also the fulfilment of professional requirements -- for sponsors, for promotion and tenure. The author points to the valuable resources provided by the ICMJE (International Committee of Medical Journal Editors) and COPE (Committee on Publication Ethics), and lists what must be done when preparing a manuscript for submission. The tendency to include more authors is seen in all areas of research, including orodental, particularly with respect to dental practice-based research networks. Consequently, it is very important to be consistent and fair when assigning authorship, as distinct from contributorship. Here, the two roles are clearly distinguished, with a list of four ICJME criteria that must be met by authors. Reference is made to the publishing standards for common types of studies, such as CONSORT for randomized controlled clinical trials, which addresses how trials are designed, analyzed and interpreted; and STROBE for non-randomized clinical investigations, such as case reports, case series and cohort studies. The chapter also addresses issues such as over-citation, intellectual rights, gift authorships, redundancy, plagiarism, scientific misconduct and transparency, and points out the requirement by most peer-reviewed journals for international trial registration. Open full-text PDF (0.9 MB)

based on the book chapter by Jeanie Suvan Summary The focus of this chapter is on the appointment of a study manager to maximize the success of a clinical investigation. It explains the role of study managers (as distinct from principal investigators) in clinical trials, from initiation to study closure, applying project management principles from chairside to site facility. They use tailored planning strategies and tools including checklists, agendas, schedules, databases and spreadsheets, to deal with administrative and financial matters, standard operating procedures, timelines, logistics and auditing. Their involvement begins with translation of the protocol into reality and meeting regulatory requirements, through to data collection, adverse event recording and collation of documents in site files. The authors point out how good study managers identify limiting factors and barriers, prevent serious errors from occurring, and ensure all phases of the study flow smoothly. Their invaluable contributions include budgeting and tracking systems, devising formulae for calculating resources and clinic time, and contingency plans for coping with equipment failures and sickness absence. They contribute to team training, motivation and communication, and collaborate externally with ethics committee, funders, sponsors and report writers. They also help with patient recruitment, gaining informed consent, monitoring and retaining patients, and ensuring compliance. This information provides a compelling case for engaging a study manager. Open full-text PDF (1.1 MB)

based on the book chapter by Maurizio S. Tonetti Summary Clinical investigations that fail to provide clear and relevant answers are a waste of valuable resources. This chapter describes how to avoid common pitfalls at the proposal stage, such as rejection by an ethics committee, or producing meaningless study results. With reference to ISO-14155-2011 throughout, the authors offer guidance on writing robust clinical protocols, formulating clinically relevant questions, and designing experiments that align directly with the clinical question. In the context of equipoise and ethical soundness, the practical aspects of patient selection, bias, sample size, trial arms and control groups, are addressed, as well as blinding and randomization, data collection and analysis, and obtaining meaningful outcome measures. Among these are patient-related outcomes (PROMs), which are increasingly important for identifying therapies that produce relatively less discomfort and better esthetics. When it comes to protocol design, prevention rather than cure is clearly preferable; among the issues raised are identifying potential errors and taking corrective action at the protocol stage; collaborating with all stakeholders including statisticians and administrators during the development stage; using the peer review process to improve chances of ethical approval; and allowing public and academic access to the protocol via trial registries, in order to aid recruitment, enhance collaboration, identify gaps in the research, and prevent duplication of studies. Open full-text PDF (1.1 MB)

based on the book chapter by Klaus Peter Rippe Summary This chapter deals with the moral and ethical minefield faced by all investigators conducting clinical experiments in patients. Obtaining histological material for studies of tissue regeneration can be ethically compromising, and any intervention may lead to burdens as well as benefits for patients, even after robust studies in animal models. In the absence of a clear concensus on morality or a simple philosophical stance, the authors focus on the principals of proportionality and equipoise, the potential for risk, international justice, and protecting patients from exploitation due to geographical or socioeconomic factors. They stress the importance of obtaining voluntarily consent from every participant, or surrogate decisions for vulnerable patients, and highlight the need for leaving no doubt about what might happen during the trial and the potential for harm. The obligation to help all patients poses unique issues: some are simply fixed, for example by comparing a new therapy with the current best one (rather than no therapy or placebo); and others are complex. However, it is acknowledged that when a particular trial arm offers more potential than one or more other arms of the study, any patient who gains a benefit also provides a means to benefit others. The doctorpatient relationship is also examined in this chapter, particularly clinicians who must recruit their own trial participants, for example when conducting preventive oral health trials among school-children. Open full-text PDF (1 MB)

based on the book chapter by Gudrun Denke Summary It is critical for researchers conducting patient-oriented research to attend to the regulatory aspects of their studies and employ good clinical practice (GCP) throughout. This chapter provides an overview of GCP in both Europe and the USA, with valuable summaries of the many processes involved when preparing to conduct trials on medical devices, drugs and biologics in regenerative surgery, with a particular focus on the content and scope of ISO 14155:2011. The regulatory documentation is described, such as investigator brochures, case report forms, and clinical investigation plans. They authors go into detail about meeting ethical, quality and national standards through appropriate clinical investigation planning and monitoring. They draw attention to the roles and functions of sponsors and principal investigators, as well as CE marking and trial termination. The importance of assigning risk to medical devices and products is also discussed, whereby absorbable materials, bone morphogenic proteins, dental lasers and subperiosteal implants are deemed to carry significant risks, while caries-removal solutions, fillers and traditional cushions pads are considered insignificant. The four phases of trials for drugs and biologics are also outlined, together with the need for a separate classification scheme for medical devices that comprises exploratory (first-in-human), confirmatory (safety and efficacy) and post-marketing follow-up (improvement) phases. Open full-text PDF (1.1 MB)

Inserting implants immediately after tooth extraction reduces clinic appointments, but some patients experience breakdown of their gum and bone tissues; this early exposure of the implant inhibits bone regeneration and implant success. Increasing numbers of people have implants nowadays, more of which contain titanium, which is good for osseointegration, but tends to harbor bacteria if the surrounding bone shrinks away. Preclinical research is therefore important for investigating the nature of implantitis and its relations to bacterial plaque formation. Flap procedures need to be optimized to ensure adequate wound closure and prevent wound breakdown. To this end, inflammation resembling that encountered by dentists is induced in animals by allowing plaque to accumulate or placing cotton ligatures on the gum. It is difficult to create standardized defects, but valuable observations can be made on the timings of extraction and implantation, healing periods and plaque control. The efficacy of treatments for preventing tissue loss can be assessed, as well as options for antimicrobial decontamination. Investigators can rely on the clinical relevance of the endpoints described here, which involve assessment by probing of peri-implant pockets, determining the level of the alveolar bone crest, the amount of bone–implant contact and the extent of inflammatory cell infiltrates. This remains a rich area for research in a growing area of practice.

Technological advances in engineering materials and biological agents continue to provide new potential therapies for patients whose quality of life and physical well-being are affected by severe orofacial defects, tooth loss or the consequences of gum disease. However, getting new therapies into everyday use by dental surgeons is not simple. Currently, only one in every thousand newly developed materials reaches patients, in a process that can take decades, and incurs enormous costs. To ensure that all suitable therapies developed in the laboratory become available to dentists, preclinical studies in animals must streamline neatly with clinical trials in humans, which can only happen if approval is gained by the regulatory authorities. This chapter provides guidance on the many practical issues that must be addressed before, during and after conducting animal experiments, in order to achieve the rigorous safety, efficacy and quality standards that must be met for human use. The emphasis is on effective planning and design, and choosing the most suitable animal models and techniques. The authors also outline ways to optimize and standardize experimental approaches, and set meaningful endpoints that translate directly into the clinical arena.