Ethics of bioengineering organs and tissues

Abstract

Tissue-engineered medical products are now entering the clinical testing phase of development. Therefore, an open discussion is warranted regarding ethical issues that may arise as these novel ‘combination’ products move forward, such as when to conduct clinical trials, how to regulate such trials, when and how to responsibly introduce these strategies into clinical practice and how to maintain a positive public perception of the tissue-engineering field as a whole. These issues are discussed, and recommendations are provided for conducting first-in-human clinical studies.

Keywords::

• bioethics
• clinical trials
• tissue engineering

1. Introduction

The field of tissue engineering is evolving rapidly and some engineered tissues are now ready for clinical testing [1,2]. This makes it important to have an open and candid discussion regarding the ethical dilemmas faced by professionals and patients in this burgeoning field. Initially, the primary ethical concern as tissues/organs were being developed was the sources of cells and scaffolds, especially the use of human embryonic stem cells and xenogeneic new cell source-generated tissues [3]. However, as cell therapy has evolved and nanotechnology has emerged, these concerns have given way to additional questions, including when to conduct the clinical trials, how to regulate such trials, when and how to responsibly introduce these strategies into clinical practice and how to maintain a positive public perception of the tissue-engineering field as a whole. Here, we explore some of these issues and suggest guidelines for conducting first-in-human clinical studies.

2. Clinical translation of tissue-engineered products will likely be different from that of other therapeutics

Several aspects of tissue-engineered products make these therapeutic options more ethically complex than drugs or biologics. First, the approval pathway for clinical translation of these products is not clearly delineated. These therapeutics include a combination of novel pharmaceuticals, medical devices, biologics, and surgical procedures – each of which, in most nations, is governed by different sets of regulations and government agencies. Further, varying degrees of autonomy exist regarding whether or not and when to put each element into clinical practice. For example, in the USA, new surgical procedures are not regulated by the FDA and can be used on an ‘as needed’ basis at the discretion of the surgeon performing the operation, and organ transplants are regulated by Health and Human Services not the FDA. But surgically implanted engineered organs or tissues fall under FDA purview either as devices or biologics depending on their makeup. New medical devices, on the other hand, are federally regulated, meaning that a device must be tested in clinical trials before a surgeon is allowed to use it in clinical practice. Where engineered products fit in this schema remains a challenge in the field. Second, due to the regenerative nature of engineered products, many become integrated into the body after implantation, making it extremely difficult, if not impossible, to remove the product or reverse its effects once the procedure has been completed. Finally, the target population for tissue-engineered products primarily comprises patients with serious end-stage diseases, for whom there is rarely any conventional therapy available. These patients are particularly vulnerable to the ‘therapeutic misconception’ and are more likely to consent to participate in research studies without fully understanding all the potential outcomes [4,5].

It is, therefore, incumbent on the tissue engineering community to educate the public, patients and the regulatory agencies about the pros and cons of specific therapeutics. Above all, fostering autonomous decision making and practicing beneficence are critical. The placing of tissue-engineered products on the market is regulated in the EU under the Regulation 1394/2007 on advanced therapy medicinal products (ATMPs) and the Directive 2001/83/EC on the Community code relating to medicinal products for human use. However, in its article 3.7, the directive excludes from the scope of its application any ATMP ‘which is prepared on a non-routine basis according to specific quality standards, and used within the same Member State in a hospital under the exclusive professional responsibility of a medical practitioner, in order to comply with an individual medical prescription for a custom-made product for an individual patient’. Such products may then be subject to specific national requirements, which may vary from one country to another.

3. Preclinical testing of tissue-engineered products

Due to the complex nature of tissue-engineered products, each element must be tested, both individually and in combination, before clinical safety testing can begin. Although in vitro assays and small animal in vivo testing can provide significant information, these tests are not likely to fully elucidate the biochemical and physiological interactions that occur in humans. Thus, clinically relevant large animal studies, potentially even in nonhuman primates, are essential with novel organs/tissues before clinical trials are begun, and both positive and negative results from these preclinical studies should be published in peer-reviewed journals and made available to potential patients.

4. Clinical testing of tissue-engineered products

As tissue-engineered products enter the clinical testing phase, the growing cost of conducting clinical trials becomes an issue. Traditionally, countries with highly regulated medical industries, such as the USA, have been considered the most appropriate sites for conducting clinical studies. However, as the cost of healthcare in these countries continues to increase, it may be more morally sound to conduct clinical trials in countries that have relatively lower costs, provided that scientific rigor can be maintained. For this approach to be an option, these clinical trials would need to be conducted in accordance with the standards set by agencies such as the US FDA, World Health Organization and European Medicines Agency.

Another challenging issue is sponsorship for clinical trials. As funding of the US National Institutes of Health has flattened, controversy has emerged regarding whether dwindling resources should be allocated to basic research or to clinical studies. Although clinical trials should be conducted with the same degree of rigor and impartiality whether sponsored by industry or government, a survey conducted by Kesselheim et al. [6] indicates that physicians have less trust in the results of industry-sponsored clinical trials and are less willing to apply the treatments from such trials. In light of these findings, government-sponsored clinical trials remain the best option to avoid the perception of bias.

Finally, due to the complexity of tissue-engineered products, clinical teams conducting these studies should have experience with other regenerative medicine strategies (e.g., stem cell transplantation, gene therapy and bone marrow transplantation) and with post-treatment care and follow up. Those conducting trials should also be willing and able to publish the results.

5. Use of new tissue-engineered products for compassionate-use cases

In some situations, approval may be obtained to treat a patient with a life-threatening illness with a new tissue-engineered product that has not completed the full regulatory approval process. Because the possible outcomes and side effects have not been thoroughly evaluated and documented, it is imperative that a full risk–benefit analysis be disclosed to the patient before informed consent is obtained [4]. Further, these procedures should be conducted only in countries that require thorough, independent review (by the institutional ethics committee and governmental bodies) for compassionate-use cases. When agreeing to perform such procedures, clinicians must realize and accept the moral obligation to document and publish the results of such cases, regardless of the outcome, so that short-term efficacy and safety can be assessed. Conversely, observers should recognize that these patients have a very short life expectancy with conventional treatments and a high number of comorbidities, which may contribute to lower than expected efficacy of the tissue-engineered product. Thus, for such early clinical-use cases, success should be judged according to the knowledge gained from the experience.

6. Trial design issues

6.1 Safety studies

As complex products are developed that contain components previously tested for safety in other applications, a critical issue will be defining what constitutes sufficient evidence that the new product or its components are safe and do not require additional safety testing. In a study by Lalu et al. [7], the authors performed a meta-analysis of clinical trials involving intravascularly delivered mesenchymal stem cells (MSCs), regardless of the clinical application, to determine whether MSCs are likely to cause adverse effects when used in treating pulmonary diseases. This study included data from > 1000 patients. In situations such as these, in which the therapeutic product has already undergone numerous safety tests and shown no adverse effects, investigators must work with research review committees to determine when it becomes ethically more acceptable to combine safety and efficacy studies to reduce costs and decrease the number of patients who receive potentially less-than-optimal care than it does to delay trials and to randomly assign patients to the placebo group of a clinical trial.

6.2 Control groups

When a tissue-engineered product is ready to undergo more advanced clinical trials, the study design will need to be tailored to the specific type of product. This raises another set of ethical considerations, such as what types of controls to use. Recently, the FDA began advocating the use of sham surgical procedures in clinical trials assessing medical devices [8]. In these trials, patients in the control group undergo potentially harmful surgical procedures that are unlikely to provide any benefit, which appears to violate the bioethical principle ‘first, do no harm’. Nonetheless, advocates for this practice remain [9]. Because some elements of tissue-engineered products could be considered similar to medical devices, this type of control group may be suggested. Before these products reach clinical testing, it would be prudent for researchers and clinicians in this field to determine whether this is an ethical means of obtaining control data and, if not, to develop scientifically accurate alternatives for determining the efficacy of tissue-engineered products.

6.3 Patient selection

One of the most important steps in conducting a clinical trial is the patient selection process. First, clinicians will need to decide whether to include patients with the least number of comorbidities (i.e., the healthiest patients) or those with the highest number of comorbidities (i.e., the sickest patients), as each of these populations will likely provide different information. Next, researchers will need to screen the potential participants to ensure that they are capable of giving competent and informed consent, have adequate social support, have appropriate psychological health and are willing to lose some degree of personal privacy. Patient consent forms should include full details regarding the composition of the tissue-engineered product, the process for implantation, all conflicts of interest and all potential outcomes and adverse effects. These details should be provided in such a way that the patient can fully comprehend this information. Because some aspects of these products and procedures can be complex, the use of unbiased patient advocates should be considered. This would allow the patient to consult with an expert and to ask questions before signing the consent form.

6.4 Outcomes

A further consideration is to determine what outcomes to assess. Should all tissue-engineered devices be expected to ‘cure’ the target disease, or should the efficacy of a product be judged according to other benefits, such as increased quality of life? Because these products are designed to become fully integrated with the natural tissue over time, the follow-up period should be an appropriate length not only to assess immediate outcomes but also to determine any long-term beneficial or adverse effects associated with this integration process. Finally, strategies must be determined ahead of time to address potential product failure and to assist patients who experience adverse effects as the result of participation in a study.

6.5 Registries

Once a tissue-engineered product has gone through initial clinical studies, it will be necessary to set criteria to determine when the product is no longer considered experimental. As part of this process, detailed registries should be developed for all uses of tissue-engineered products so that complete statistics can be easily obtained regarding these cases on an ongoing basis. A related issue involves determining whether or not a new product has efficacy and safety comparable to that of a similar product already on the market. For this to be assessed, producers of these products should be required to allow head-to-head testing of their products to confirm equivalency.

7. Public perception of tissue engineering

The development, testing and eventual marketing of tissue-engineered products will often involve the same community of experts within this field; therefore, it is important to address conflicts of interest so that physicians, patients and the public at large know that the patient's best interest is always the top priority. One important question to consider is whether all individuals with a financial interest in a tissue-engineered product should be excluded from the testing process or whether they can maintain a non-leadership role in these studies. In the latter case, full disclosure should be provided regarding all conflicts of interests, including financial, personal and those related to intellectual property. In general, those with financial interests or the leader of clinical studies should not be the sole decision makers in the evaluation of clinical results. Further, to ensure full transparency, all conflict of interest information regarding the development, testing and clinical use of a product should be disclosed, and the techniques used, cell sources and costs should be made available on request so that the product can be fully evaluated.

8. Conclusion

Tissue engineering could provide new therapeutic options for countless people with life-threatening conditions, such as severe congenital defects and end-stage organ disease. Therefore, there is a desire to quickly translate research findings in this field into viable clinical options. However, in this fast-paced environment, all research and testing must be conducted in a manner that protects the safety of the patients and builds trust in the field as a whole. When deciding the best course of action, we should examine the histories of other innovative technologies, such as cell and gene therapies, and learn from the successes, setbacks and roadblocks encountered as these therapies made their way from the research stage to clinical application. Future discussions of clinical trials should include all parties involved in the translation process, including researchers, clinicians, regulatory agencies, industry representatives, ethics committees, patient coalitions and professional organizations dedicated to the care of patients and the development of new technologies.

Declaration of interest

DA Taylor holds a financial interest in Miromatrix, Inc. and is entitled to sales royalty through the University of Minnesota for products related to the research described in this article. This relationship has been reviewed and managed by the university in accordance with its conflict of interest policies.

Acknowledgment

The authors thank Heather Leibrecht from the Texas Heart Institute for editorial assistance.