1

Introduction

The process of moving bench-top research to clinical practice is often called research “translation” . Several authors have reported that it takes 17 years for scientific knowledge (“evidence” in this context) to be translated and incorporated into clinical practice; however, Morris et al. point out that the convergence on 17 years may be a coincidence, one that hides the complexities of the translation process. There is no common set of standard measurement points or even agreement of the process model itself to definitively answer how long it takes for bench-top research to be applied clinically.

It can be agreed, however, that it takes a long time to implement research in practice, and in the last decade, it may even be taking longer. In 2004, the Food and Drug Administration (FDA) published a report stating that the medical product development process was “increasingly challenging, inefficient, and costly. During the past several years, the number of new drug and biologic applications submitted to FDA has declined significantly; the number of innovative medical device applications has also decreased…(and) the path to market even for successful candidates is long, costly, and inefficient” . To counter this trend, the FDA has launched the Critical Path Initiative , which is “…FDA’s strategy to drive innovation in the scientific processes through which medical products are developed, evaluated, and manufactured”.

Fig. 1 presents the major steps in the research translation process, which is adapted from several sources . There is a gap in the process of translating bench-top research to human clinical research, which is often called “T1”.

Simplified process of translating bench-top research to clinical practice, which involves several steps. T1 is the translation of bench-top research to human clinical trials. The human clinical research is synthesized into systematic reviews. T2 is the translation of clinical knowledge into everyday practice. Research synthesis is often incorporated in clinical guidance, but need not be. Research synthesis does not imply clinical implementation. Outcomes of implementation into clinical practice ideally include improvements in patient health and, if there is widespread implementation, population health. Note that this process is bidirectional, with clinical practice also feeding in the opposite direction and informing clinical and bench-top research .

As will be described in more detail later in the manuscript, research synthesis into SRs is not the end of the process , and it does not mean that the bench-top research has made it chair-side. At this point the research has been translated into clinical knowledge, but it has not been translated into clinical guidance nor implemented into clinical practice. A gap exists at this stage in the process, often labeled “T2”.

When it is determined that a particular topic needs to be summarized, the human clinical research is synthesized into systematic reviews (SRs).

This paper describes the challenges in moving from bench-top to human clinical research, addresses the process of the generation of clinical knowledge and guidance, discusses challenges in implementation into clinical practice, and touches on shared decision making with patients.

2

Translating bench-top research to human clinical research (T1)

Sung et al. defined T1 as “the transfer of new understandings of disease mechanisms gained in the laboratory into the development of new methods for diagnosis, therapy, and prevention and their first testing in humans.”

Bridging this gap is not unique to the field of dental materials. Since, to the author’s knowledge, there has not been an assessment of the barriers to negotiating the T1 gap for dental materials researchers, some general advice for bridging the gap for medical research in general includes: (1) educating researchers and clinicians about the translation process; (2) standardizing translation across institutions; (3) facilitating interdisciplinary research teams, academic-industry partnerships, and researcher–clinician connections; (4) improving infrastructure including shared facilities; and (5) funding positions that provide program/project management, institutional review board (IRB) process management, intellectual property management, informatics support, and facilitation of industry-academic liaisons .

To facilitate dental materials researchers in bridging the T1 gap, it is useful to think about dental materials and their place in the larger system of biomaterials, medical devices, and finally medical products as illustrated in Fig. 2 . This categorization helps bench-top dental materials researchers to navigate the appropriate regulatory guidance and requirements that are needed when developing a new material for clinical application. Note that this overview is not an exhaustive review of the guidance that is necessary, but is intended to provide a starting point for further investigation.

Dental materials in context as a subset of larger categories of medical products from a regulatory point of view.

Fig. 3 illustrates the complex nature of bench-top research, the successful negotiation of which will close the T1 gap. The FDA has identified three dimensions of bench-top research (also called preclinical testing) which are: medical/dental utility, safety, and industrialization.

Closing the T1 gap involves successfully navigating the requirements for medical/dental utility, safety, and industrialization. Test development and validation between the laboratory and clinic are crucial to improve the research translation process.

For a material to be viable for further development in dental applications, medical/dental utility needs to be shown by, for example, material property testing to show the product performs as required in the environment of use. Standard test methods that are available from ANSI/ADA and the International Standards Organization (ISO) for different material/application combinations, and should be considered when comparability of results is important.

Safety can be assessed by biocompatibility testing. Several standards give guidance on what types of tests should be performed as well as how to conduct the tests. Preclinical evaluation of dental materials’ biocompatibility is described in ANSI/ADA Specification No. 41 and other relevant documents and based on the type and duration of exposure to tissues. In addition, the FDA publishes guidance documents intended to help disseminate information about what is required to receive FDA approval .

Because of the critical role that processing has on materials properties, research related to industrialization is key to improve performance. Collaborations between researchers, manufacturers, and dental laboratories would help ensure this type of research is directly utilized in dental product manufacturing.

If academic researchers discover new or novel materials and/or properties, they should also be aware that there are grants available for translational research to help them develop the inventions for commercial use . More efforts are needed to educate researchers on patenting and licensing procedures if applicable.

The last element involved in closing the T1 gap is the need for improved testing procedures, safety and efficacy predictive models, and validation of laboratory testing with clinical performance. By enabling new products to be developed and moved to the market faster, cheaper, and with more certainty, the trend in stagnation of medical product innovation should reverse .

Materials researchers need to provide meaningful outcomes to the broader community to enable the results to be translated to the clinic. It may be helpful to consider the context of dental materials research to design studies that provide these meaningful results. Ultimately, the purpose of dental materials research is to help patients be healthier and live better lives.

2

Translating bench-top research to human clinical research (T1)

Sung et al. defined T1 as “the transfer of new understandings of disease mechanisms gained in the laboratory into the development of new methods for diagnosis, therapy, and prevention and their first testing in humans.”

Bridging this gap is not unique to the field of dental materials. Since, to the author’s knowledge, there has not been an assessment of the barriers to negotiating the T1 gap for dental materials researchers, some general advice for bridging the gap for medical research in general includes: (1) educating researchers and clinicians about the translation process; (2) standardizing translation across institutions; (3) facilitating interdisciplinary research teams, academic-industry partnerships, and researcher–clinician connections; (4) improving infrastructure including shared facilities; and (5) funding positions that provide program/project management, institutional review board (IRB) process management, intellectual property management, informatics support, and facilitation of industry-academic liaisons .

To facilitate dental materials researchers in bridging the T1 gap, it is useful to think about dental materials and their place in the larger system of biomaterials, medical devices, and finally medical products as illustrated in Fig. 2 . This categorization helps bench-top dental materials researchers to navigate the appropriate regulatory guidance and requirements that are needed when developing a new material for clinical application. Note that this overview is not an exhaustive review of the guidance that is necessary, but is intended to provide a starting point for further investigation.

Dental materials in context as a subset of larger categories of medical products from a regulatory point of view.

Fig. 3 illustrates the complex nature of bench-top research, the successful negotiation of which will close the T1 gap. The FDA has identified three dimensions of bench-top research (also called preclinical testing) which are: medical/dental utility, safety, and industrialization.

Closing the T1 gap involves successfully navigating the requirements for medical/dental utility, safety, and industrialization. Test development and validation between the laboratory and clinic are crucial to improve the research translation process.

For a material to be viable for further development in dental applications, medical/dental utility needs to be shown by, for example, material property testing to show the product performs as required in the environment of use. Standard test methods that are available from ANSI/ADA and the International Standards Organization (ISO) for different material/application combinations, and should be considered when comparability of results is important.

Safety can be assessed by biocompatibility testing. Several standards give guidance on what types of tests should be performed as well as how to conduct the tests. Preclinical evaluation of dental materials’ biocompatibility is described in ANSI/ADA Specification No. 41 and other relevant documents and based on the type and duration of exposure to tissues. In addition, the FDA publishes guidance documents intended to help disseminate information about what is required to receive FDA approval .

Because of the critical role that processing has on materials properties, research related to industrialization is key to improve performance. Collaborations between researchers, manufacturers, and dental laboratories would help ensure this type of research is directly utilized in dental product manufacturing.

If academic researchers discover new or novel materials and/or properties, they should also be aware that there are grants available for translational research to help them develop the inventions for commercial use . More efforts are needed to educate researchers on patenting and licensing procedures if applicable.

The last element involved in closing the T1 gap is the need for improved testing procedures, safety and efficacy predictive models, and validation of laboratory testing with clinical performance. By enabling new products to be developed and moved to the market faster, cheaper, and with more certainty, the trend in stagnation of medical product innovation should reverse .

Materials researchers need to provide meaningful outcomes to the broader community to enable the results to be translated to the clinic. It may be helpful to consider the context of dental materials research to design studies that provide these meaningful results. Ultimately, the purpose of dental materials research is to help patients be healthier and live better lives.

3

Translating clinical research to clinical knowledge: generating a systematic review

Those dental materials or other medical products that have successfully navigated the T1 gap move on to the next step, which is testing in human clinical trials. If approved by the FDA, new products can be marketed and are available for clinical use. However, publications on the results of trials conducted for FDA approval are only a fraction of clinical trials that are published. When an individual or group determines that the evidence on a specific topic needs to be systematically gathered and synthesized, a systematic review (SR) is developed. Conducting an SR entails developing specific question(s); identifying, collecting, and screening potentially eligible citations; evaluating (appraising) the publications; summarizing the totality of the evidence; and discovering gaps in knowledge for further research. Note that in evidence-based medicine (EBM) and dentistry (EBD) the highest level of evidence is SRs of preferably randomized controlled trials of human clinical research; and accordingly, bench-top studies are the lowest level of evidence and not typically included in SRs. The following section provides more details of the steps involved in generating an SR.

4

Translating clinical knowledge to clinical guidance

There is a small step in the T2 gap bridging research synthesis (in the form of SRs) and implementation. This step is the generation of specific clinical guidance intended for the clinician to apply to practice ( Fig. 1 ). Not all SRs go through this step, but all evidence-based clinical guidance is grounded in SRs.