Translating Regenerative Biomaterials Into Clinical Practice.

REVIEW ARTICLE

Journal of

Translating Regenerative Biomaterials Into Clinical Practice

Cellular Physiology

EDWARD T. STACE,1,2* STEPHANIE G. DAKIN,1,2 PIERRE-ALEXIS MOUTHUY,1,2 1,2 AND ANDREW J. CARR 1

National Institute of Health Research Musculoskeletal Biomedical Research Unit, Oxford, United Kingdom

2

Botnar Institute of Musculoskeletal Sciences, Nuffield Department of Orthopaedics, Rheumatology and Musculoskeletal Sciences, University of Oxford, Oxford, United Kingdom

Globally health care spending is increasing unsustainably. This is especially true of the treatment of musculoskeletal (MSK) disease where in the United States the MSK disease burden has doubled over the last 15 years. With an aging and increasingly obese population, the surge in MSK related spending is only set to worsen. Despite increased funding, research and attention to this pressing health need, little progress has been made toward novel therapies. Tissue engineering and regenerative medicine (TERM) strategies could provide the solutions required to mitigate this mounting burden. Biomaterial-based treatments in particular present a promising field of potentially cost-effective therapies. However, the translation of a scientific development to a successful treatment is fraught with difficulties. These barriers have so far limited translation of TERM science into clinical treatments. It is crucial for primary researchers to be aware of the barriers currently restricting the progression of science to treatments. Researchers need to act prospectively to ensure the clinical, financial, and regulatory hurdles which seem so far removed from laboratory science do not stall or prevent the subsequent translation of their idea into a treatment. The aim of this review is to explore the development and translation of new treatments. Increasing the understanding of these complexities and barriers among primary researchers could enhance the efficiency of biomaterial translation. J. Cell. Physiol. 231: 36–49, 2016. © 2015 Wiley Periodicals, Inc.

The increasing volume and cost of MSK disease was recognized formally in 1998 when the WHO endorsed the bone and joint decade initiative. The initiative urged collective action from 2000 to 2010 to develop novel, safe and cost-effective MSK treatments and disease prevention strategies (Weinstein, 2000). Much of the hope of this initiative was centred upon tissue engineering and regenerative medicine or TERM research (see Box 1 tissue engineering and regenerative medicine). Unfortunately the significant advances and scientific discoveries were not translated into treatments. Consequently, the Bone and Joint “Decade” Initiative was extended through to 2020 (Woolf et al., 2012). We are now half way through this extended deadline and despite significant volumes of primary research, there have been very few novel treatments developed for MSK disease. The reasons limiting translation are complex and involve preclinical, clinical, commercial, and regulatory barriers. Preclinical barriers include a lack of accurate in vitro/animal models to predict human response to treatment. Clinical factors include clinical trial design, ethical (McLaren, 2001; Beeson and Lippman, 2006; Sandel and McHugh, 2007), and safety concerns (Richards et al., 2004; Swijnenburg et al., 2005; Leeper et al., 2010). Financial barriers include the increased cost and risk of product development (Frantz, 2012). Regulatory issues amount to increasing requirements for demonstration of safety and efficacy and a lack of international agreement on requirements for product approval (Kirouac and Zandstra, 2008; Trautman, 2015). Despite the lack of progress, there is still considerable hope that TERM treatments will emerge. The development of induced pluripotent stem cells (iPSCs) in 2006 was seen as the key to unlocking many of the barriers to TERM treatments listed above (Takahashi and Yamanaka, 2006). No longer were allogenic stem cells with immunological concerns, embryonic stem cells with ethical considerations, or difficult to harvest, culture and differentiate adult stem cells required. Instead abundant and accessible skin fibroblasts could be © 2 0 1 5 W I L E Y P E R I O D I C A L S , I N C .

reprogrammed into stem cells and differentiated into any cell type to reproduce tissue or organs. So pivotal was this work that the 2012 Nobel Prize in Physiology and Medicine was presented for “the discovery that mature cells can be reprogrammed” (Nobel Media, 2014). However, safety concerns with the technology and the associated costs have so far limited clinical translation. Currently only a single human clinical trial using iPSC technology has been commenced; a Japanese trial for patients with age-related macular degeneration (Riken, 2013). In contrast to cell-based treatments, a new generation of biomaterials is poised to seize the power of biophysical epigenetics to provide the much needed MSK treatments (Pashuck and Stevens, 2012; see Box 2 Biophysical Epigenetic Regulation). This new and developing field allows biomaterials to influence cell behavior in a targeted manner, specifically regulating cell biology to promote tissue regeneration. Biomaterial driven biophysical reprogramming is demonstrated through recent discoveries that biophysical clues can replace the exogenous molecular signals currently needed for iPSC generation. Thus biomaterials could potentially be used to reprogram native cells to iPSCs in vivo, eliminating the danger

Contract grant sponsor: Arthritis Research UK; Contract grant number: 20506. *Correspondence to: Edward Thomas Stace, Nuffield Department of Orthopaedics, Rheumatology and Musculoskeletal Sciences, University of Oxford, Nuffield Orthopaedic Centre, Windmill Road, Oxford OX3 7HE, United Kingdom. E-mail: [email protected] Manuscript Received: 30 May 2015 Manuscript Accepted: 5 June 2015 Accepted manuscript online in Wiley Online Library (wileyonlinelibrary.com): 9 June 2015. DOI: 10.1002/jcp.25071

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TRANSLATING BIOMATERIALS TO CLINICAL PRACTICE

Box 1 Tissue engineering and regenerative medicine

Tissue engineering and regenerative medicine (TERM), encompasses research aimed at restoring biological function in pathological conditions. Historically there has been considerable debate as to whether the two fields are distinct, part of the same spectrum or synonymous (Lysaght et al., 2008; Nerem 2010; Jaklenec et al., 2012). Regardless, they are increasingly considered together given the shared aim of regenerating functional tissue. Tissue Engineering emerged over the course of the 20th century with the term first being used in the literature in the early 1980s (Nerem, 2010). The classical definition of Tissue Engineering was provided by Langer and Vacanti (1993) as an “interdisciplinary field that applies the principles of engineering and the life sciences toward the development of biological substitutes that restore, maintain, or improve tissue or whole organ function.” This was subsequently reworded by the multiagency tissue engineering science (MATES) working group to “the use of physical, chemical, biological and engineering processes to direct the aggregate behavior of cells” (Lysaght et al., 2008). Regenerative medicine is a slightly newer term first emerging in the 1990s and was subsequently defined as a field which “replaces or regenerates human cells, tissues, or organs to restore or establish normal function” (Mason and Dunnill, 2008). TERM treatments can be based upon a material, a cellular or a molecular approach (Fig. 1). However with the increasing complexity in cell, matrix, and molecular interaction, there is considerable overlap and combinatorial approaches using two or all three strategies are increasingly common. Successfully harnessing the overlapping areas is the key to unlocking the potential of TERM research in regenerating tissue and developing successful treatment strategies.

Fig. 1. Broad classification of Tissue Engineering and Regenerative Medicine strategies. Increasingly complicated TERM therapies often involve overlap of two or more of these strategies into a combinatorial product. It is important to distinguish the use of a cellular component in a TERM treatment as cell-based therapies or combinational therapies including a cellular component face different regulatory pathways and are much more expensive to develop. These issues are expanded on later in the review (Clinical Trial Design Section).

and expense of current ex vivo reprogramming mechanisms. Biomaterials can also significantly increase reprogramming efficiency when combined with molecular signals (Downing et al., 2013; Kulangara et al., 2014; Yoo et al., 2015). However, the process for clinical adoption of new biomaterials is complex and uncertain involving scientific hurdles, as well as pre-clinical, clinical, regulatory, and commercial challenges (French et al., 2013). An improved understanding of these components of the product development pathway by TERM researchers is crucial to overcoming the factors restraining successful translation. Optimization and international harmonization of these steps will also help to expedite clinical translation of new treatments to minimize patient suffering, as well as product cost. This review aims to inform the scientific reader about; the need for improved MSK therapeutics; the potential advantages of biomaterial based TERM treatments; and the barriers to biomaterial clinical adoption with a focus on regulatory and clinical trial design considerations. While the focus of this article is on biophysically active biomaterials in an MSK context, much of the content holds true for biomaterials in other clinical JOURNAL OF CELLULAR PHYSIOLOGY

areas. We hope an improved understanding of these areas among the scientific research community will facilitate more successful clinical translation of innovative biomaterials. The Increasing Burden of MSK Disease

MSK related disability increased almost fivefold from 1990 to 2010 to make MSK disease the most common cause of severe chronic pain and the second most common cause of long term disability globally (Vos et al., 2012; Woolf et al., 2012; Hoy et al., 2014). Musculoskeletal conditions now account for 15–20% of all GP consultations in the UK (Parsons and Symmons, 2014). The association of MSK disease with age and obesity means that it is likely the disease prevalence will increase further globally (Woolf and Pfleger, 2010; Kohl et al., 2012). This increased volume of treatment is mirrored by an increased cost in individual treatment. The average MSK treatment cost in the USA has risen by 60% from $4832 in 1996–98 to $7768 in 2009–2011 (2011 USD equivalents). This increase is largely driven by inpatient treatment costs which have increased by 207% over this period (Yelin et al., 2014). While treatment costs increased in

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Box 2 Biophysical epigenetic regulation

Until relatively recently the extracellular matrix was viewed as a passive entity existing to support cell function (Guilak et al., 2009; Tsang et al., 2010). However, the interaction between cell and matrix is now accepted as a crucial part of cell biology, impacting on processes from stem cell differentiation (Engler et al., 2006) through to carcinogenesis (Maffini et al., 2004). This interaction occurs in response to both chemical and physical properties of the matrix, with suggestions the physical properties may be more influential than chemical composition (Kumar et al., 2011). In this context, a physical property refers to an aspect of matrix architecture rather than mechanical or physical forces applied through processes such as mechanical loading or shear stress. Advances in nanoscale manufacturing processes have made it possible to specifically manipulate physical features of scaffolds allowing researchers to assess how variation in physical properties influences cell function. Physical properties shown to affect cell behavior so far include, matrix stiffness/elasticity (as shown in Fig. 2), porosity, surface morphology (e.g., grooves or posts) and in the case of fibrous scaffolds; fiber size, fiber density and fiber alignment. Varying these properties has led to effects on cell adhesion, migration, proliferation as well as more complicated cell functioning such as stem cell differentiation (Engler et al., 2006; Kumar et al., 2011) and stem cell self renewal capacity (Nava et al., 2012).

Fig. 2. Biophysical Epigenetic Regulation in action - the effect of scaffold stiffness on stem cell differentiation. When MSCs are seeded on to scaffolds varying solely in stiffness or elasticity, they undergo differentiation down different cell lineages. For example, stiffer matrices promoted osteogenic differentiation. This is one example of scaffold physical parameters being able to direct cell responses. There is mounting evidence that these changes in function are driven by actin-myosin tension in the cytoskeleton leading ultimately to alterations in DNA methylation and acetylation (Downing et al., 2013). However, the exact mechanisms underlying the sensing, communication, and response to different physical properties is an active research area with implications for regenerative biomaterial TERM treatments (Eyckmans et al., 2011). Modified from Cigognini et al. (2013).

part due to climbing hospital-operating costs and expensive adjuncts like advanced imaging modalities, the increased cost is also related to the use of novel treatment strategies. Combining the increased volumes and costs of MSK treatment results in an alarming picture. The 2014 Report on the burden of musculoskeletal disease in the United States calculated that the MSK disease burden had increased by 121% to nearly $900 billion (2011 USD equivalents) over the 15 years from 1996 to 2011 (Fig. 3). This means MSK disease alone accounts for 5% of US GDP JOURNAL OF CELLULAR PHYSIOLOGY

(Yelin et al., 2014). With predicted population demographic changes, this disease burden is expected to reach almost 10% of US GDP by 2025. This level of spending is not sustainable. Further increasing treatment cost are patients expectations for advanced treatments as our scientific knowledge expands (Kim et al., 2001; Ellenberg and Temple, 2000). This is compounded by patients’ increasing ability to access information through the internet. While more informed patients are generally able to make better health


Fig. 3. Annual burden of MSK disease in the United States as a proportion of GDP. The MSK disease burden in the US roughly doubled from $396 billion to $874 billion between 1996 and 2011. It is forecast to continue rising at least as fast over the next decade, meaning the MSK burden will account for nearly 10% of US GDP. This is driven by an aging and increasingly obese population. Modified from Yelin et al. (2014).

choices, it can also result in unrealistic expectations, specifically that particular treatment options should be available regardless of the cost or appropriateness of the treatment (Sullivan et al., 2011). The trend of increasing MSK burden pervades the developed world. However, more worryingly, in the developing world the MSK burden is rising even faster due to occupational and road traffic injury (Woolf et al., 2012). Patients in these settings cannot afford very basic medical care, let alone expensive and technologically demanding treatments emerging through TERM. This underlines the need for novel treatments to be less expensive and deliverable in less advanced and supported operating theaters. TERM Treatments in MSK Disease

Currently, there are cellular, molecular, material, and combinatorial therapies available for use as TERM MSK treatments. Between and within these categories of treatment there is considerable variation in cost, complexity, popularity, and perhaps most importantly, the quality of evidence of clinical benefit. Emerging MSK treatments may supersede the established treatments in efficacy, but also in cost. However, some treatments may supersede in cost, but not clinical benefit. This is possible as products can enter the market through less regulated pathways where proof of clinical superiority or even non-inferiority is not required. Despite these concerns, the field continues to grow quickly. In the United Sates the combined annual growth rate (CAGR) of the TERM MSK treatment market is 7% and 40% higher than the average increase MSK spending (BCC Research, 2010, 2013). This makes TERM treatments one of the fastest growing sectors of MSK treatment. Figure 4 shows that TERM research is a rapidly growing area. However, driven by both the demand for treatment and advances in cell biology, material design, and understanding of pathological mechanisms, MSK TERM research could expand even faster. Unfortunately in comparison to the proliferation of basic and pre-clinical biomedical research, the translation of these discoveries into preventative strategies, diagnostic tools, or JOURNAL OF CELLULAR PHYSIOLOGY

medical treatments is poor. Only a handful of novel TERM treatments have been approved by the FDA over this time; a single cell based therapy (Autologous Chondrocyte Implantation—see Case Study 1); a small number of biologic treatments and a larger number of implants and biomaterials. These biomaterials, however, are largely simple implants or subtle alterations to existing products rather than technological breakthroughs from novel primary research. There is clearly a lag in translating the huge volume of primary research into treatments. With such a huge amount of research why is it so few products emerge on the market? And of the products that do come to market, why are many subsequently removed by regulatory authorities? To answer such questions, one must appreciate that there is much more to creating a clinically translatable treatment than good scientific principle TERM MSK Treatments for the Future Novel treatment requirements

When embarking on the development of a novel biomaterial, researchers must think pragmatically about factors that will determine if the treatment will progress to the market successfully. These criteria are much broader than understanding whether the treatment has efficacy. The criteria to evaluate novel treatments emerge from a range of invested parties including the patient receiving treatment, the doctor administering treatment, the companies, institutions, and investors risking their investment, and society who must often pay for the treatment. Each perspective places different requirements on the treatment. Figure 5 illustrates that the ideal treatment must be cheap, easy to use and have an evidence base to demonstrate its safety and efficacy. For example, when considering financial factors around a novel treatment, the condition must be common enough and severe enough to require treatment. Additionally, if there are already established treatments on the market, the new treatment must either be significantly more effective or significantly less expensive to justify development, regulatory and marketing costs. Investors will not risk money if it is unlikely they will be able to service the costs associated with

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Fig. 4. Graph of publications per year returned in PubMed search for “Tissue Engineering” or “Regenerative Medicine” and orthopaedic” or “musculoskeletal.” This illustrates the nearly exponential rise in MSK TERM research over the last two decades.

development of the treatment. There are also practical considerations to take into account. For example, if the new treatment is impractical to use, more time consuming, requires large volumes of stock to be held on site or needs investment in equipment and training to ensure proper use, then the treatment is less translatable, even if more clinically beneficial. Cell-based treatments

Currently, there is only one cell-based TERM therapy approved for use in MSK disease (see Case Study 1—Autologous Chondrocyte Implantation). This is because cell based treatments fail the considerations set out above in TERM Treatments in MSK Disease Section. There are, however, other treatments in development and mesenchymal stem cells are currently utilized for a variety of conditions despite any sound clinical evidence supporting their use. There is a lack of proven efficacy for cell based therapies. There is also an expensive, technically challenging and time consuming in vitro culture period in producing a cell population

Fig. 5. Considerations in designing an ideal treatment.

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large enough for implantation. This culture period must be individualized and accompanied by stringent safety and sterility testing (quality assurance/quality control [QA/QC]) further adding to treatment cost. Furthermore there are specific considerations that preclude cell based therapies dependent on the stem cell population being considered. Regenerative medical treatments are often required for elderly patients. However, aged tissue has a reduced adult stem cell (ASC) population. ASCs harvested in such cases have a decreased proliferation rate and potentially impaired cell function. Small numbers of slowly dividing ASCs struggle to generate meaningful numbers of cells for treatment in a timely fashion. Furthermore, given a pathological process has arisen in the first place, the harvested cells may be defective and reimplantation could perpetuate or predispose to disease formation after treatment (Leeper et al., 2010). The use of embryonic stem cells in research and TERM treatments is no longer feasible with the ethical pressure placed on scientists and politicians to avoid embryo usage unlikely to dissipate (McLaren, 2001; Beeson and Lippman, 2006; Sandel and McHugh, 2007). Additionally, the freezing and storage of ESCs for autogenic use later in life has raised concerns about long term cell viability and sterility (Richards et al., 2004). iPSCs, even with significant advantages over other stem cell populations, require an additional cellular reprogramming phase involving complicated, expensive, and potentially unsafe molecular mechanisms. These barriers are currently limiting their clinical translation. Admittedly, it is early days in iPSC technology and further research to address the safety concerns around cellular reprogramming may allow iPSC based treatments to flourish (Nishikawa et al., 2008; Okano et al., 2013). One option put forward to reduce the cost and increase the availability of iPSC treatments was the development of a series of cell lines. However, the use of HLA matched allogenic iPSCs still poses patient acceptability and immunological issues (Swijnenburg et al., 2005; Fairchild, 2010). If immunosuppression were needed to control the immune response to allogenic tissue, in the context of immunosuppression, would a potentially self-renewing stem cell population pose malignancy risks? Immunosuppression itself is not without risk. In renal or liver transplantation and other disabling inflammatory conditions, the benefits of immunosuppression outweigh these risks. However, in degenerative conditions where other treatment options


are available, would the risks of immunosuppression outweigh the benefits of the novel treatment over established treatments? Despite concerns and slow clinical translation, in anticipation of iPSC treatments eventuating on the market, there have been attempts to define protocols for quality and safety testing of iPSC processes and suggestions on how such treatments should be regulated (Kirouac and Zandstra, 2008; French and Brindley, 2015; Silva et al., 2015). These processes, however, are immature and not universally accepted necessitating further development to streamline translation in the future. Case study 1—autologous chondrocyte implantation.

Articular cartilage defects arise through injury, joint instability, obesity, and various arthritic conditions resulting in pain and loss of function. Cartilage has a very limited ability to regenerate itself. Autologous chondrocyte implantation is a two-stage procedure used to augment the repair of such defects in the knee to improve function and prevent or delay the need for joint replacement. The initial procedure involves harvesting cartilage tissue from less weight bearing surfaces of the knee. The cartilage matrix is then digested enzymatically leaving the chondrocyte population. This is expanded in vitro before being re-implanted into the cartilage defect in a second procedure. Initially the cell suspension was held in place by a periosteum cap harvested from the patient. Subsequently this cap was replaced with a collagen cap in second generation ACI to prevent the pain associated with periosteal stripping in the patient. In the third generation of treatments, cells were seeded onto a scaffold or membrane in so called matrixassisted chondrocyte implantation. Another step in enhancing ACI was the use of biomarkers to select chondrocytes more likely to produce the desired articular cartilage. Animal studies using concurrent growth factor treatment have also shown promise in improving the quality of the cartilage created through ACI. In the latest generation of ACI chondrocytes are used in conjunction with TERM techniques to produce cartilage tissue in vitro for implantation. ACI is, however, currently not government funded in the United Kingdom and many other countries throughout the world because of the cost involved and the limited clinical benefit currently demonstrated in the literature. This case study highlights the barriers of cost and technical requirements of cell based therapies. It also demonstrates the struggle for regulatory authorities to keep pace with developing technology and the time taken for regulatory approval. ACI also reveals the problems associated with clinical adoption without evidence of clinical benefit. These issues are expanded in Sections Biomaterial Development Pathway, Barriers to Biomaterial Translation, and Clinical Trial Design of the article. Molecular-based therapies

The application of molecules to augment healing of MSK pathology is increasingly common in a growing number of conditions. Autologous platelet rich plasma (PRP) for soft tissue regeneration (Dhillon et al., 2012) is the most common but synthetic cytokines and growth factors are also used, for example, bone morphogenic proteins (BMPs) to augment bone repair (Lissenberg-Thunnissen et al., 2011). Hypothetically these factors may recruit cells to augment the healing process. The evidence in support of these treatments is, however, controversial (see Case Study 2—Infuse1 Bone Graft). PRP despite being widely used following media reports of successful treatment in popular athletes, has a very conflicted evidence base. The latest Cochrane review suggested there is no evidence to support PrP use for soft tissue musculoskeletal JOURNAL OF CELLULAR PHYSIOLOGY

injuries (Vy et al., 2014). This has been supported by other reviews (De Vos et al., 2014) and trials (De Vos et al., 2010; De Jonge et al., 2011). In fact, there are now suggestions it may be acutely harmful in animal models (Beck et al., 2012). Case study 2—Infuse1 bone graft substitute. Degenerative disc disease results in significant morbidity and can require surgical treatment. Traditionally, this involves removing the intervertebral disc and fusing the vertebral bodies together. This fusion is facilitated with the use of bone graft or bone graft substitutes. Autologous bone graft is the gold standard, however, this can be associated with donor site morbidity and is not always possible. As a result a range of bone graft substitutes have been developed. The Infuse1 bone graft and LT-cage device is one example of a bone graft developed to increase rates of fusion. The infuse1 ‘bone graft’ is recombinant human bone morphogenic protein-2 (rhBMP-2) delivered through a bovine collagen sponge implanted inside a metal cage into the intervertebral space. The Infuse1 bone graft was approved by the FDA in 2002 through the PMA pathway for use in lumbar spine fusions based on promising results. Thirteen industry sponsored trials were commenced with infuse1 being used in more complicated spinal surgeries and other anatomical sites. These studies suggested no complications in 780 patients and significant clinical benefit. Complications associated with rhBMP-2 were subsequently reported when in general use, prompting Carragee et al. (2011) to show that the industry sponsored trial publications of Infuse1 suffered from systematic-reporting biases and that the data submitted to the FDA for approval did not include adverse events that had occurred in the trials. Additionally, surgeons involved in the trials had not declared multi-million dollar payments from the owners of Infuse1. This case study underlines the importance of clinical trial design (discussed in detail in Barriers to Biomaterial Translation Section), specifically how open label trials allow bias and the under reporting of complications. The demonstration of considerable financial payments to the doctors involved also shows why doctors and patients are concerned by industry sponsored trials. Despite being reviewed by the FDA as a device through the pre-market approval process (PMA), errors in the methodology and reporting were overlooked emphasising the importance of regulatory funding, training, and expertise. Biomaterial-based treatments

Biomaterials are better poised to satisfy the criteria required of a successful treatment. They are cheaper, available to use off the shelf and can be developed to influence cell biology to promote healing at the implant site through biophysical epigenetic mechanisms (Burdick et al., 2013). This means biophysically active biomaterials could harness the benefits of cell reprogramming and iPSC technology without the drawbacks of cell-based therapies. Biomaterials are likely to be significantly cheaper than cellbased therapies. They can be mass produced in a factory as opposed to autologous cell-based treatments that require an individualized, expensive, technical and time-consuming cell expansion, and differentiation processes in vitro prior to implantation. The mandatory quality control and safety requirements for fabricating scaffolds is also cheaper and faster compare to cell based treatment generation. Biophysically active implants would be specifically tailored to tissue types to promote maximal regeneration in each tissue. These tissue-optimized treatments would be available off the shelf, eliminating the need for special equipment, increasing global accessibility. Additionally, as little or no extra training

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would be required for using these materials, access to such treatment would be increased. Biomaterial based tissue regeneration is likely to be safer. Acting locally through biophysical epigenetic pathways may mitigate safety concerns around insertional mutagenesis and malignancy from ex vivo molecular manipulation techniques. Biomaterials can also be fabricated from biocompatible materials minimizing the chance of foreign body or immunological reactions. Furthermore to elicit better tissue regeneration responses, molecular moieties could be incorporated into the biomaterial to provide a second stimulus to recruit or influence host cells in a favorable fashion to regenerate tissue (Martins et al., 2008). If iPSC technology becomes cheaper, safer, and less technically challenging, a cell population can be added to the biomaterials to further enhance biological capability (Yokoya et al., 2012). Significantly, while biomaterials can be used to influence cell biology, they would likely enter the market through different regulatory pathways to drug or cell based treatments, reducing the cost and time for translation into clinical practice (Pashuck and Stevens, 2012). Case study 3—restore orthobiologic soft tissue implant. Tendon, ligament, soft tissue, and hernia repair are

often facilitated by the use of surgical meshes or patches. These can be synthetic or prepared from xenographic material. Restore is a patch prepared from porcine small intestine which was approved for use by the FDA initially for hernia repairs in 1998 through the 510(k) pathway. Scope was extended in 2000 and 2003 for use in other soft tissue repairs including tendon and ligament repair. As part of the regulatory approval process, no human clinical trials were required to provide efficacy of safety or benefit. Under the 510(k) pathway it sufficed to show biocompatibility in in vitro and animal tests before the product was available on the market. However, a number of clinical trials (Malcarney et al., 2005; Iannotti et al., 2006) and case reports (Walton et al., 2007; Phipatanakul and Petersen, 2009) subsequently showed significant foreign body reactions and the product was discontinued. In vitro studies showed that restore had significant residual porcine cells (Zheng et al., 2005) and DNA material (Gilbert et al., 2009; Chen et al., 2009). Animal studies have also suggested a possible inflammatory response (Chen et al., 2007). This case study underlines the lack of valid pre-clinical models to assess novel therapies, the need for long term safety monitoring and issues with the abbreviated pre-market notification or 510(k) pathway approving devices for widespread use without the need to conclusively demonstrate safety in patients. Biomaterial Development Pathway

After a scientific discovery generates a possible new treatment, the development pathway (Fig. 6) from conception to clinic can be long and uncertain. This pathway is also increasingly expensive and time consuming. Most of this increased cost and time is attributable to the more exhaustive clinical trial testing now required for regulatory approval (Dickson and Gagnon, 2004). While the statistics are not directly translatable to biomaterial innovation, recent studies exploring the increased cost of drug development illustrate the challenges in bringing new treatments to market. Within drug therapy, 5,000 candidate molecules enter the development pathway for a single treatment to emerge on the market (Kraljevic et al., 2014). The cost of development for a novel pharmacological treatment has doubled to nearly $2.6 billion USD over the last JOURNAL OF CELLULAR PHYSIOLOGY

Fig. 6. Overview of the biomaterial development process from conception to clinical treatment.

decade (Tufts Centre For the Study of Drug Development, 2014) and the time to take a treatment from conception to market has also increased by at least 5–13 years (Dickson and Gagnon, 2004). There are barriers throughout the translation pathway contributing to the increasing time and cost. Some are common across all TERM treatments but there are a number of choke points specific to biomaterials. These can occur in the preclinical, clinical, regulatory, or commercial stages of development. The saving grace for biomaterial development is an alternative pathway in the USA that substantially reduces the cost and time for approval, as explained in Clinical Trial Design Section. Barriers to Biomaterial Translation Pre-clinical barriers Lack of accurate pre-clinical models (see case study 3). There is a lack of valid pre-clinical models to accurately

predict the efficacy and safety outcomes of biomaterials (Prestwich et al., 2012). In vitro models are improving but fail to replicate the complexities of in vivo behavior to allow conclusive demonstration of efficacy and safety. This necessitates animal testing despite animal models being biologically, immunologically, and genetically dissimilar to the human condition being studied (Mak et al., 2014). These differences contribute to medical therapies and biomaterials failing the transition from animal to human treatment success. Despite the limitations of invalidated animal models, testing in multiple animal models is often required by regulators to help “prove” safety. This multiplicity can add considerable cost and time to product development while not necessarily providing additional useful data. Improved models and outcome predictors would reduce the risk of subsequent failure in human trials. Improved regulatory guidance on what is required from animal testing would also potentially reduce time and cost spent on poorly predictive animal models. Clinical barriers Clinical trial design (see case study 2). There is a poor understanding of epidemiological and statistical methods required for clinical trial design within the scientific research community (Cook, 2009). A clinical trial of a biomaterial necessitates elements of medical and surgical clinical trials complicating trial design, as discussed in detail in Clinical Trial Design Section. Compared to pharmaceutical products or vaccinations, there is no set format for proving safety and efficacy for biomaterials requiring


individual groups to frequently re-invent the wheel or overcome the same challenges. Clinical trial funding (see case study 2). Clinical trial and product development may be funded by public or private institutions. Medical professionals are more likely to trust results of publically funded clinical trials, believing them less prone to bias (Lu et al., 2015). However, public funding cannot be expected to bank roll the trials required for private commercialization of a product. Efforts need to be made to raise the standards of privately funded, and likely selfinterested, clinical trials to ensure the quality of the trial meets standards that allow medical professionals and patients to trust the data. Commercial barriers Poor communication. There can be an insular approach within the development pathway with academia expecting industry alone to translate a scientific idea to a treatment (Staff et al., 2014). During the development of a product there are often barriers which add time and cost to translation. Overcoming these efficiently requires strong networks between the science, clinical and development arms of a treatment. There is considerable benefit to be had from a “bench to bedside and back again” model with clinical data feeding back to augment future research and treatment development (Lu et al., 2015). Communication and co-ordination between all parts of the product development process from basic scientists to regulators to end user clinicians, is crucial to prevent knowledge sequestration within specific sectors (Bayon et al., 2014). Inter-disciplinary conferences, government initiatives and academic-private industry partnerships are being formed to facilitate this and promote harmonization between international agencies (Bertram et al., 2013; Rietschel et al., 2015). Scalability. Progressing from laboratory level production to large scale good manufacturing processes (GMP) in a clean room environment can be challenging. It is often expensive, may require adoption of alternative or novel techniques or necessitate new production steps impacting upon the ability to translate the product (Staff et al., 2014). Communicating and involving experts in treatment development and production early can help to mitigate against such issues. Intellectual property considerations. A new biomaterial is likely to be the culmination of a number of separate technologies or processes. A company developing such a therapy may need to licence other products or techniques in order to produce its particular innovative product. This is expensive for the company and reduces profit margins. Attracting investors to invest in standalone products is difficult at the best of times, but lack factors such as of ownership of the entire process or intellectual property conflicts are off putting to investors concerned with reduced returns (Prestwich et al., 2012). These considerations seem distantly removed from what a research scientist must consider but illustrates the detail to which researches must be thinking to realize aspirations of commercializing their idea. Patents are a common method to protect intellectual property within biomaterials. However, applying for a patent requires releasing complete methods and all information in support of the patent, potentially releasing trade secrets. Furthermore applying for a patent places strict time frames on further development until a patent can be granted. There is also considerable cost to this process and any subsequent litigation. These reasons may dissuade researchers for applying for patents, preferring to keep knowledge in-house. JOURNAL OF CELLULAR PHYSIOLOGY

Regulatory barriers (discussed further in Clinical Trial Design Section and see case studies 1–3)

Academic researchers have a poor understanding of the regulatory process and requirements (Staff et al., 2014). While distant from more basic research, an awareness of the regulatory process can allow scientists to foresee regulatory issues and plan accordingly to alleviate them. Variations in the product development pathway can hamper translation. The stable route for drug development enables researchers to predict the requisite safety and efficacy data required for regulatory approval (Prestwich et al., 2012). Within biomaterials, because there are multiple routes to market and no accepted consensus on requirements for each different pathway, innovators must decide on the most appropriate actions to take a product from scientific discovery to clinical treatment. Consequently, researchers focused on similar biomaterials re-invent the wheel, obtaining data through a variety of differing methodologies (Prestwich et al., 2012). The resultant heterogeneity in what innovators present to gain approval for their product complicates assessment as comparisons may be less straightforward and the techniques possibly less familiar to the assessors. Improved communication from regulators to innovators and development of accepted product development steps would ensure adequate pre-clinical and clinical testing was undertaken to inform their decision while reducing time and cost spent on superfluous and potentially unnecessary testing (Prestwich et al., 2012; Bertram et al., 2013; Lu et al., 2015). Funding

The efficient translation of scientific advancements to the clinic is one of the most pressing issues in biomedical research. Unfortunately more knowledge does not equate to more treatment. Currently, over 90% of TERM funding is allocated to basic science research with less than 10% going toward clinical translation (Hollister and Murphy, 2011). Well funded primary research is not an effective investment if it fails progression to a treatment that can benefit society. This ratio may be distorted due firstly to expectations that all ground breaking research will evolve into treatments. Secondly, that commercialization is funded by companies and institutions. Thirdly, that basic research is more attractive to funding bodies than translational research. Regardless this ratio needs re-orientating to facilitate successful translation. Attitudes and funding allocations are changing slowly, for example, the NIH set up the National Centre for Advancing Translational Science in 2012 with a $650 million USD budget to “transform and accelerate” science into treatments (National Center for Advancing Translational Sciences, 2015). Changing biomedical research environment Geographical. There are significant changes in where research is being undertaken around the globe. Biomedical research is shifting away from the United States with both public and private research funding falling. The United States provided 57% of total global biomedical funding in 2004 but this had fallen to 44% in 2012 (Moses et al., 2015). Mirroring the decreased funding, US researchers also have a decreased proportion of life science patents (51% in 2011, down from 57% in 1981) and top-cited publications (56% in 2010, down from 63% in 2000; Mullard 2015). In contrast, China, India, South Korea, Singapore, and Japan have invested heavily in biomedical research and consequently have an increasing research output. Shift in innovation away from large biotechnology companies. Public institutions and small biotechnology

companies are becoming increasingly significant within

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biomedical innovation as large biotechnology companies avoid the risks and costs associated with novel product development (Prestwich et al., 2012). For example, within TERM research, publically funded and academic institutions now hold the majority of iPSC patents and patent applications. Additionally within the patents held by private industry, most are held by small biotechnology companies with each company holding only small numbers of patents (Roberts et al., 2014). These changes suggest that novel therapeutics may emerge from institutions with less experience in clinical trial and regulatory approval processes compared to established pharmaceutical companies. Furthermore with the geographic alterations in biomedical research, novel treatments will emerge from countries with different regulatory frameworks and different safety requirements. Efforts to harmonize biomaterial regulatory requirements globally may help to expedite and smooth clinical translation, especially with less experienced institutions likely to drive biomaterial research in the future. Clinical Trial Design Clinical trial design overview

Accurate assessment of the risks and benefits of a new treatment is mandatory. This is usually achieved through a series of different studies as the treatment progresses through the development pathway, as illustrated in Figure 7. These studies culminate in a large multicenter randomized controlled trial or randomized clinical trial (RCT). The RCT is the accepted gold standard for evaluating a new therapy. However, designing and conducting the staple “randomized double blind clinical trial” for devices and surgical interventions is challenging and often not possible. Clinical trial design should involve experts and be developed concurrently through the development process with the appropriate regulatory body in an attempt to counter some of these issues. Because of the additional difficulties in surgical trial design, less than a quarter of established surgical treatments have RCT support in contrast to pharmacological treatments where over half are believed to have RCT support (Cook, 2009). This is significant as low use and poor RCT methodology can allow

new treatments to enter clinical practice without a sound assessment of safety or efficacy (Salzman, 1985). The FDA removed market approval for 79 medical devices and biomaterials for serious or life threatening health risks and a further 2,300 such treatments for less significant safety concerns between 2007 and 2012 alone (Hench, 2012). As illustrated in case studies 2 and 3, it is clear that substandard evaluation persists with treatments being adopted into clinical practice inappropriately. While more RCTs are being performed to evaluate implants and interventions, between 1990 and 2000 only 3.4% of articles in leading surgical journals were based on RCTs with studies lower on the hierarchy of evidence making up the vast majority (Wente et al., 2003). The reasons for low use and poor RCT methodology in interventional settings has been analyzed in an attempt to understand why treatment assessments are sub-optimal and can result in unsafe or ineffective products on the market. These reviews have identified complicated methodological issues in interventional/implant RCTs including blinding issues, randomization concerns, difficulty defining the optimal time to assess treatment effect, surgical learning curves and the optimal trial duration to assess long term safety (Stirrat et al., 1992; Lilford et al., 2004; McCulloch et al., 2013). The IDEAL collaboration was formed to specifically investigate the issues limiting RCT use in interventional settings as well as to formulate strategies which would augment the evidence base for interventional therapies (Ergina et al., 2013; McCulloch et al., 2013; Cook et al., 2013). The resultant IDEAL framework, has been suggested as a strategy to guide biomaterial trial design as no specific biomaterial guidelines currently exist (McCulloch et al., 2013). This framework mirrors the phases of drug development and clinical testing. New biomaterials designed to have biological activity straddle a niche between medical and surgical treatments. Akin to pharmaceuticals where specific factors such as dose, timing and route of administration need assessment, a biologically active biomaterial must undergo similar optimization and testing of the bioactive properties in human participants. While animal and in vitro studies will provide clues to which parameters are likely to be the most efficacious, because of the imperfect correlation between pre-clinical testing and in vivo results, systematic trials of a range of physical parameters may be necessary to optimize the biomaterial for use in humans prior to further clinical testing (Burdick et al., 2013). Thus bioactive (either biophysically or biochemically) biomaterials impose a series of challenges for RCT design. Biomaterial specific clinical trial design considerations

Fig. 7. The phases of clinical trial involved in the testing of a new biomaterial.


Timing of assessment. “It is always too early for rigorous evaluation until suddenly it’s too late” (Cook, 2009). The time at which a novel treatment is assessed in its development is crucial. Early on, refinement of a biomaterial and the method of implantation occurs to optimize the product. If assessment of efficacy is made prior to such optimization, a false negative result may occur and a potentially advantageous treatment incorrectly discarded. If, however, one waits too long, this may erode clinical equipoise precluding an RCT and preventing robust assessment of the novel treatments benefits and risks. This is particularly relevant to bioactive biomaterials that will need to undergo substantial initial human trials to ensure optimization of the bioactive components. The timing of assessment can also be complicated by the time taken to conduct an RCT. This is more relevant to biomaterials that have a long half life and require long term evaluation. Modifications to the design may occur and other competing biomaterials may come to market making the trial redundant.


Tracker trials have been proposed as a way to avoid this (Lilford et al., 2000). Such trials involve patients being randomized to different therapies right from the outset allowing prospective comparisons between groups. This allows comparisons to be made early on in the product testing phase without the need to delay assessment until a stable biomaterial design has been finalized Short-term safety evaluation. Novel pharmaceuticals are initially tested in healthy volunteers to establish short-term safety prior to further clinical trials. This is not possible with biomaterials as a needless operation with inherent potential harm on a healthy volunteer is unethical. This forces initial testing and optimization to be performed in patients with heterogeneous disease and comorbidity states that could potentially cloud comparisons. The lack of short-term safety data can have sequential ramifications. In the case of new pharmaceuticals for cancer or other serious medical diseases, patients have generally failed conventional treatments leaving them desperate for any therapy which may beat the disease regardless of potential harms. However, within regenerative medicine, the conditions being treated generally affect quality of life rather than survival. Consequently when attempting to recruit, patients are less likely to take the risk of the possible benefits of an untested biomaterial in the face of unknown risks. This is particularly true if there are alternatives on the market with a proven longterm safety and efficacy record. Conversely, patients often perceive that any new therapy will be a better treatment regardless. This may help with recruitment and inclusion in clinical trials. It can also be a barrier to recruitment as patients may resist randomization in case they do not receive the novel treatment. Long-term evaluation. Evaluation of the long-term efficacy and safety of a biomaterial is required as demonstrated in case studies 2 and 3. However, some biomaterials are designed to be resorbed over time while others are permanent. The differences in half-life could require a significant period for follow up until definitive safety and benefit assessment can be made, making feedback loops prolonged and expensive. Surgical experience and learning curve. When performing the same operation, there will be inter- and intrasurgeon variation (further influenced by patient anatomical variations). When taking part in a trial, the same surgeon will often perform the procedures in multiple arms of the study. There is no guarantee they will be equally skilled in performing the established procedure as well as implanting and using the new biomaterial potentially biasing results. Patients may be deterred from entering the trial knowing the surgeons may have less experience with the new material and necessary surgical technique. It is also often experienced surgeons who pioneer new treatments. When these treatments are expanded into clinical trials, less experienced surgeons will be administering treatment which depending on the learning curve of the procedure and ability of the surgeon could affect results. Concentrating the new intervention within a small group of trained surgeons to avoid this variation could, however, affect generalizability of the results of the biomaterial to use by the wider surgeon population. Choice of comparison group. New biomaterials can be compared with either a placebo or the best current treatment. Selecting the best currently available biomaterial for comparison is challenging as this may genuinely not be known (e.g., biomaterial implants for shoulder rotator cuff tear repair). In some cases, optimal medical management could be best practice. Trying to then compare an implanted biomaterial would either necessitate sham surgery or prevent blinding which can bias results. While considered ethically questionable JOURNAL OF CELLULAR PHYSIOLOGY

(Wolf and Buckwalter, 2006; Dowrick and Bhandari, 2012), sham surgery has been performed as a comparison group in a number of trials (Cobb et al., 1959; Johnson, 2002) to provide definitive answers on treatment benefit and risk. This is even more important as the power of placebo is increasingly appreciated potentially biasing surgical interventions compared to non-interventional treatments (Beard et al., 2015). Communication. Conveying information about benefits and risks to clinicians and patients in a comprehensible fashion is crucial. This is less important for translation of the treatment but more for ensuring clinical adoption. It is not enough to bring a treatment to market. It must be taken up by the medical profession and patients as an accepted therapy. The consolidated standards of reporting trials (CONSORT) group has published a checklist pertaining to nonpharmacological RCTs of what information should be published with suggestions on format to aid comprehension and communication of RCT results to clinicians (Boutron et al., 2008). Optimal methods and language to communicate risk-benefit information to patients is on going but essential to ensure patients can give informed consent for their treatment decision (Woloshin and Schwartz, 2011; Ahmed et al., 2012). Regulatory Approval Regulation overview

Regulatory approval exists to ensure new treatments are safe and beneficial for patients. While regulatory bodies are often criticized for being overly conservative, considerable harm and even death can result if products are rushed to market without adequate scrutiny (see case studies 1–3). It is worth keeping in mind that regulatory approval does not assess cost effectiveness. A decision on whether to publically fund a treatment is generally made by another institution in a separated process. The specifics of regulatory approval vary with geographical location. However, as North America and Europe form the majority of the biomaterials market, this article will focus on the requirements in these areas. Central to regulatory approval in both these areas is the classification of a new biomaterial. Classifying a new treatment as a drug rather than a medical device has massive implications. It has been estimated that bringing a novel treatment to market under the “device” banner takes around 5 years, costing between $1 and $150 million USD depending on the approval pathway (discussed in Biomaterial Specific Clinical Trial Design Considerations Section). Whereas, approval for a therapeutic product under the “drug” banner takes 5–10 years and costs around $800 million USD (Pashuck and Stevens, 2012). This is likely a dated underestimate with a recent study suggesting development costs for a new drug now exceed $2.5 billion USD (Tufts Centre For the Study of Drug Development, 2014). Regulation through the US food and drug administration (FDA)

The food and drug administration (FDA) is responsible for regulating medical therapies in the United States. Novel treatments are allocated between three Centers for assessment dependent on their primary mode of action. The Centre for Drug Evaluation and Research (CDER) assess treatments which “act through chemical action but are not dependent upon being metabolized for the achievement of their primary intended purpose” (FDA, 2015). These treatments are referred to as drugs. The Centre for Biologic Evaluation and Research (CBER) assess treatments which “act through a virus, therapeutic

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serum, toxin, antitoxin, vaccine, blood, blood component, or derivative, allergenic product or analogous product.” These treatments are referred to as biologics. The Centre for Devices and Radiological Health (CDRH) assess treatments which “have a primarily structural, physical, repair or reconstruction purpose” (FDA, 2015). These treatments are referred to as devices. With increasingly complicated therapies, two supporting offices were created to facilitate the regulatory review process. The office of combination products (OCP) and office of cellular, tissue, and gene therapies (OCTGT). The OCP assigns treatments combining two or more drug, biologic or device elements into a combination treatment to a lead Centre and then liaises between the relevant Centres throughout the review process. It is also responsible for providing guidance and developing the regulatory pathway for combinatorial products. OCTGT exists within CBER and concerns itself specifically with cell, tissue and gene based treatments. The FDA, in accordance with the Food, Drug and Cosmetic Act legislation covering medical devices, separates devices into class I, II, or III medical devices proportional to risk. Class I are low risk and lightly regulated. Class II are moderate risk. Class III are high risk devices which sustain or improve life. Increasing class incurs increased requirements. Depending on class, devices can progress through two regulatory pathways, pre-market approval (PMA) or premarket notification (PMN). The differences between these pathways are outlined in Table 1. Most biomaterials are class II and can generally progress down the PMN pathway. Some biomaterials, however, face the class III pathway. It is likely that bioactive biomaterials designed to influence cell biology be classified as class III devices. Class III devices require PMA assessment. Biomaterials cannot be marketed in the United States without PMA or PMN approval. Any new treatment should be developed with the appropriate regulatory approval process in mind. This can help avoid failing approval or the unnecessary costs and time spent repeating experiments or obtaining the required data to a standard acceptable for PMA approval by CDRH. PMA is the more stringent process to assess devices that “support or sustain health” or “present an unreasonable risk of illness or injury” (FDA, 2015). Only 1% of biomaterials progress through PMA approval. This involves submission of thorough technical, pre-clinical and clinical data to inform reviewers. This more thorough process is essentially the same as the drug approval process. Devices approved through PMA require post-market surveillance (PMS) to monitor safety and benefit. PMN is an abbreviated and less expensive process requiring less supporting documentation for lower risk devices to enter the market. In the PMN/510(k) process a novel device is shown to be substantially equivalent (SE) to a currently approved

product or predicate. This requires the novel device to have the same intended use and technological characteristics, or if different technological characteristics be at least as safe and effective as the predicate and not raise new safety concerns. There is, however, no need to undergo formal clinical testing to prove safety and efficacy. As the number of predicate devices increases, novel biomaterials are more likely to have substantial equivalence to a product already on the market, making it easier for biomaterials to proceed through the PMN pathway. Importantly, the PMN process does not “approve” devices but rather “clears” them for use in the United States. This wording reflects that products entering the market through PMN have a larger degree of uncertainty around their safety and efficacy. These “reduced” standards have invited heavy criticism recently for allowing products to enter the market without adequate investigation. Between 2005 and 2009, 113 devices were removed from the market for serious health risks or risk of death. 71% of these were approved through the 510 (k) pathway and 7% were not subject to any FDA regulation (Zuckerman et al., 2011). To patients, however, PMN clearance suggests product safety and robust assessment. In reality, however, many of these products do not have longterm safety or efficacy data and some may not have undergone any human clinical testing. Despite these concerns, no official mandate requires PMN approved products to undergo post market surveillance testing. Additionally, the predicate device may have not been on the market long enough for robust long-term assessment before SE status is granted to another product. Consequently, a device may be approved and used before the problems associated with the predicate device become apparent. As a device can be granted SE status to a predicate which in turn was cleared based on SE to an early predicate, there could be significant divergence from the originally approved product. With time, this divergence could lead to safety or efficacy concerns. Regulation in Europe through national competent authorities

The process in the European Union (EU) has some similarities to the FDA pathway. There is no centralized approach, however, with each member country reviewing applications for new devices through a National Competent Authority (NCA) against Medical Device Directive (MDD) 93/42/EEC. The application comprises a technical file, which is submitted to show that the device complies with the essential requirements in concordance with the MDD. The file contains similar pre-clinical, clinical and technical documentation as the PMA approval through the FDA. Like the FDA, devices are broken down into class I, II, and III devices proportional to risk. There is no corresponding PMN/510(k) pathway for lower risk

TABLE 1. Comparison of the PMA and PMN pathways for biomaterial regulatory approval by the FDA. PMN can be substantially faster and cheaper. Adapted from Pashuck and Stevens (2012) Pre-market notification (PMN) or 510(k)

Pre-market approval (PMA)

Time (years) Cost (millions, USD) Aims

Post-market surveillance required


Preclinical

Clinical

3–4 $5–50 Concept development In vitro/animal testing to determine safety and efficacy

2–4 $40–400 Device safety and efficacy in patients Prove reliability Determine conditions suitable for device use Yes

Preclinical 3–6 $1–50 Show substantial equivalence to previously approved device No


treatments in Europe; however, provision exists under the MDD to approve products with safe and effective equivalents approved and on the market with less scrutiny. Unlike the FDA approval process, each NCA appoints external standards organizations called Notified Bodies to audit manufacturing systems and processes to ensure compliance with particular standards (ISO13485). These independent bodies are then able to grant CE approval allowing use of the product within the NCA reviewing country only. CE status denotes that the product meets the appropriate regulatory legislation and when used as intended works satisfactorily without undue safety concerns. If successful in receiving CE status though an NCA, a central authorisation procedure application to the European Medicines Authority can be submitted for European Union wide approval. This application is assessed by the Committee for Advanced Therapies under advanced-therapy medicinal product status. At this point, individual countries can veto approval. For example, a product may be given NCA approval in one member state but the NCA of another country may deem that the safety or benefit data is inadequate. At this point, reapplications are possible with improved supporting data or applications can be directed to individual country NCAs to ascertain approval in selected countries only. Given there are more than 30 NCAs, some have questioned if all NCAs implement the regulations in the same manner or if in some countries patients are exposed to more risk or conversely denied potentially beneficial treatments. In Europe, CE marking does not signify the end of product evaluation. Unlike in the USA, PMS is mandatory for all medical devices approved for use within the EU. The design for PMS collection and evaluation are required prospectively as part of the regulatory approval application. Regulation issues for the future Regulatory classification of bioactive biomaterials.

The most important issue regarding biomaterial regulation in the future, is whether biomaterials designed to have a biological effect through biophysical epigenetics will remain under medical device classification for regulatory purposes, and under what class. The FDA designates a therapeutic as a device if, along with other criteria (listed in section 201[h] of the Federal Food Drug and Cosmetic [FD&C] Act), it “does not achieve any of its intended purposes through chemical action within or on the body of man . . . and is not dependent upon being metabolized” to function (FDA, 2015). Under this definition, a biophysically active biomaterial should remain classified as a device. However, this is new technology and currently no biomaterials specifically targeting cell behavior through biophysical parameters have sought regulatory approval to be a test case. Theoretically, biophysically active biomaterials could either be classified as class III devices or face regulation as a drug. However, as outlined in case study 2, Infuse1 (an implant with a biochemical moiety) progressed as a class III device through the PMA process not as a drug. This would suggest biophysically active biomaterials would remain as devices under CDRH governance. Classification as a class III device would, however, require PMA, increasing the cost, the development time and potentially stifling technological advancement in this area as corporations fear inadequate commercial re-imbursement. However, financial considerations should not influence assessment of safety and benefit of novel treatments. Given advancements in this field and biophysically active treatments likely to come to market, regulatory authorities could prospectively provide guidance to allow new bioactive biomaterials to allow development with the appropriate regulatory framework in mind. JOURNAL OF CELLULAR PHYSIOLOGY

Global harmonization of biomaterial regulation.

Given an increasingly inter-connected global supply chain, the vastly different approval processes for biomaterials that exist in different countries creates problems. It would be beneficial if a single system for regulatory approval could be established. International co-operation to harmonize this process would clarify the required steps and data facilitating the process for companies. Companies would also be able to market their product globally in a shorter time period allowing all patients to benefit. The Medical Device Single Audit Program (MDSAP) between Australia, Brazil, Canada, Japan, and the United States is a relatively new example of such an attempt to achieve this (Trautman, 2015). More, however, should be done in concert with this initiative around the world. Conclusions

MSK disease is a significant burden, and with an increasingly old and obese population, is set to continue driving the need for effective and cost effective treatment. This creates a demand for more effective and less expensive treatments. TERM strategies, particularly biomaterials, could provide these treatments. Exciting developments in cell-matrix interaction, biophysical epigenetics, and material science have opened the door to a new wave of biomaterial therapeutics to enhance patient treatment. However, the translation of scientific discoveries and advances in biomaterial science to clinical treatments is hampered by a number of pre-clinical, clinical, and regulatory factors. Improving primary researcher knowledge of these barriers will allow laboratories to proactively design and develop products in ways to mitigate these barriers. Regulatory authorities could provide increased guidance on the requirements that will be imposed on bioactive biomaterials. International harmonization of biomaterial regulatory approval would also allow patients faster access to treatment globally and reduce the costs and time of seeking regulatory approval in multiple geographical jurisdictions. Literature Cited Ahmed H, Naik G, Willoughby H, Edwards AGK. 2012. Communicating risk. BMJ (Clinical research ed.) 344:e3996. Bayon Y, Vertes A a, Ronfard V, Egloff M, Snykers S, Salinas GF, Thomas R, Girling A, Lilford R, Clermont G, Kemp P. 2014. Translating Cell-based regenerative medicines from research to successful products: Challenges and solutions. Tissue Eng Part B Rev 20:246– 256. BCC Research. 2013. Regenerative Medicines: Bone and Joint Applications. June 2013. Available at: http://www.bccresearch.com/market-research/pharmaceuticals/ regenerative-medicines-bone-joint-applications- phm032c.html [Accessed April 24, 2015]. BCC Research. 2010. Therapeutics and Biomaterials for Musculoskeletal Disease: Global Markets. July 2010. Available at: http://www.bccresearch.com/market-research/ healthcare/therapeutics-musculoskeletal-disease-hlc086a.html [Accessed April 24, 2015]. Beard D, Rees J, Rombach I, Cooper C, Cook J, Merritt N, Gray A, Gwilym S, Judge A, Savulescu J, Moser J, Donovan J, Jepson M, Wilson C, Tracey I, Wartolowska K, Dean B, Carr A. 2015. The CSAW study (can shoulder arthroscopy work?) - a placebo-controlled surgical intervention trial assessing the clinical and cost effectiveness of arthroscopic subacromial decompression for shoulder pain: study protocol for a randomised controlled trial. Trials 16. Beck J, Evans D, Tonino PM, Yong S, Callaci JJ. 2012. The biomechanical and histologic effects of platelet-rich plasma on rat rotator cuff repairs. Am J Sports Med 40:2037–2044. Beeson D, Lippman A. 2006. Egg harvesting for stem cell research: medical risks and ethical problems. Reprod Biomed Online 13:573–579. Bertram T, Hellman KB, Bayon Y, Ellison S, Wilburn S. 2013. The regulatory imperative: international perspective. Tissue Eng Part B Rev 19:191–3. Boutron I, Moher D, Altman DG, Schulz KF, Ravaud P. 2008. Extending the CONSORT statement to randomized trials of nonpharmacologic treatment: Explanation and elaboration. Ann Int Med 148:295–309. Burdick Ja, Mauck RL, Gorman JH, Gorman RC. 2013. Acellular biomaterials: an evolving alternative to cell-based therapies. Sci Transl Med 5:176ps 4. Carragee EJ, Hurwitz EL, Weiner BK. 2011. A critical review of recombinant human bone morphogenetic protein-2 trials in spinal surgery: Emerging safety concerns and lessons learned. Spine J 11:471–491. Chen J, Xu J, Wang A, Zheng M. 2009. Scaffolds for tendon and ligament repair: review of the efficacy of commercial products. Expert Rev Med Devices 6:61–73. Chen J.M, Willers C, Xu J, Wang A, Zheng M-H. 2007. Autologous tenocyte therapy using porcine- derived bioscaffolds for massive rotator cuff defect in rabbits. Tissue Eng 13:1479–1491.

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49

Translating Testicular Cancer Epidemiology into Clinical Practice.

Translating Seminoma Genomic Landscapes into Clinical Practice.

Translating evidence into practice.

Translating research into practice.

Translating gerontology into practice.

Translating new developments in eosinophilic esophagitis pathogenesis into clinical practice.

Translating the MDS flow cytometric score into clinical practice.

The process of translating family nursing knowledge into clinical practice.

Translating the molecular diversity of hepatocellular carcinoma into clinical practice.

Challenges and promises for translating computational tools into clinical practice.

Translating the MDS flow cytometric score into clinical practice.

The ethics of translating high-throughput science into clinical practice.

Translating neuroimaging findings into psychiatric practice.

Translating evidence into policy and practice.

Regenerative biomaterials: a review.

Translating research findings to clinical nursing practice.

Biomaterials for Bone Regenerative Engineering.

Immunomodulatory biomaterials and regenerative immunology.

STN vs. GPi Deep Brain Stimulation: Translating the Rematch into Clinical Practice.

Translating Health Services Research into Practice in the Safety Net.

Translating knowledge into practice in critical care settings*.

Hepatocellular Carcinoma From Epidemiology to Prevention: Translating Knowledge into Practice.

Bracing for knee osteoarthritis: translating evidence into practice.

Translating research-based knowledge about infant sleep into practice.