The Spine Journal - (2013) -

Review Article

Ethical implications of regenerative medicine in orthopedics: an empiricalstudy with surgeons and scientists in the field

Sophie L. Niemansburg, MDa,*, Johannes J.M. van Delden, MD, PhDa,F. Cumhur €Oner, MD, PhDb, Wouter J.A. Dhert, MD, PhDb, Annelien L. Bredenoord, PhDa

aDepartment of Medical Humanities, Julius Center, University Medical Center Utrecht, Heidelberglaan 100, 3584 CG, Utrecht, The NetherlandsbDepartment of Orthopedics, University Medical Center Utrecht, Heidelberglaan 100, 3584 CX, Utrecht, The Netherlands

Received 25 January 2013; revised 23 September 2013; accepted 17 October 2013

Abstract BACKGROUND CONTEXT: Regenerative

FDA device/drug

Author disclosure

(BMM) (F, Paid dire

FC €O: Consulting: Sy

(B, Paid directly to

Speaking and/or Teac

stitution), Medtronic (

vestigator Salary, S

institution); Grants: S

Support: Synthes (E,

ical Materials Public

1529-9430/$ - see fro

http://dx.doi.org/10.10

medicine (RM) interventions, such as (stem) celltransplantation, scaffolds, gene transfer, and tissue engineering, are likely to change the field of or-thopedics considerably. These strategies will significantly differ from treatments in current ortho-pedic practice, as they treat the underlying cause of disease and intervene at a biological level,preferably in an earlier stage. Whereas most of the RM interventions for orthopedics are still inthe preclinical phase of research, the number of clinical studies is expected to increase rapidly inthe future. The debate about the challenging scientific and ethical issues of translating these inno-vative interventions into (early) clinical studies is developing. However, no empirical studies thathave systematically described the attitudes, opinions, and experiences of experts in the field of or-thopedic RM concerning these challenges exist.PURPOSE: The aim of this study was to identify ethical issues that experts in the area of RM formusculoskeletal disorders consider to be relevant to address so as to properly translate RM inter-ventions into (early) clinical studies.STUDY DESIGN/SETTING: In-depth qualitative interviews were conducted with 36 expertsin the field, mainly spine surgeons and musculoskeletal scientists from The Netherlands and theUnited Kingdom.METHODS: A topic list of open questions, based on existing literature and pilot interviews, wasused to guide the interviews. Data analysis was based on the constant comparative method, whichmeans going back and forth from the data to develop codes, concepts, and themes.RESULTS: Four ethical themes emerged from the interview data. First, the risks to study partici-pants. Second, the appropriate selection of study participants. Third, setting relevant goal(s) for meas-uring outcome, varying from regenerating tissue to improvingwell-being of patients. Finally, the needfor evidence-based medicine and scientific integrity, which is considered challenging in orthopedics.DISCUSSION: The overall attitude toward the development of RM was positive, especially be-cause current surgical treatments for spine disorders lack satisfactory effectiveness. However, ef-forts should be taken to adequately address the ethical and scientific issues in the translation ofRM interventions into clinical research. This is required to prevent unnecessary risks to study par-ticipants, to prevent exposure of future patients to useless clinical applications, as well as to preventthis young field from developing a negative reputation. Not only will the orthopedic RM field ben-efit from ethically and scientifically sound clinical studies, but the rise of RM also provides an

status: Not applicable.

s: SLN: Grant: BioMedical Materials Program

ctly to institution). JJMvD: Nothing to disclose.

nthes (B, Paid directly to institution), Medtronic

institution), NLT (B, Paid directly to institution);

hing Arrangements: AOSpine (B, Paid directly to in-

B, Paid directly to institution); Research Support (In-

taff/Materials): AOSpine (C, Paid directly to

ynthes (E, Paid directly to institution); Fellowship

Paid directly to institution). WJAD: Grant: BioMed-

Private Consortium Grant (F, Paid directly to

institution); Scientific Advisory Board/Other Office: DSM BioMedical

(B). ALB: Grants: BioMedical Materials Program (BMM) (F, Paid directly

to institution), ZonMw VENI grant (F, Paid directly to institution), ZonMw

Program Priority Medicines for Children (F, Paid directly to institution).

The disclosure key can be found on the Table of Contents and at www.

TheSpineJournalOnline.com.

* Corresponding author. Department of Medical Humanities, Julius

Center, University Medical Center Utrecht, Heidelberglaan 100, 3584 CG,

Utrecht, The Netherlands. Tel.: (31) (0)88-75-68530, (31) (0)6-13-85-27-

06; fax: (31) (0)88-75-68099.

E-mail address: S.L.Niemansburg-2@umcutrecht.nl (S.L. Niemansburg)

nt matter � 2013 Elsevier Inc. All rights reserved.

16/j.spinee.2013.10.016

2 S.L. Niemansburg et al. / The Spine Journal - (2013) -

opportunity to stimulate evidence-based practice in orthopedics and address hype- and profit-drivenpractices in orthopedics. � 2013 Elsevier Inc. All rights reserved.

Keywords: Empirical research; Regenerative medicine; Stem cells; Translation; Orthopedics; Musculoskeletal disorders

Introduction individuals in a specific context or practice [15,16]. Data

Regenerative medicine (RM) is a new, interdisciplinary,innovative field of complex interventions focused on biolog-ically repairing, replacing, or regenerating damaged or dis-eased tissues [1]. Potential orthopedic RM approachesinvolve, among others, (stem) cell transplantation, scaffolds,gene transfer, and tissue engineering [2]. These approachescould be used for treating degenerative disorders, such asintervertebral disc disease, or for improving surgical treat-ments, such as spinal fusion [2]. Most of the RM interven-tions for orthopedics are still in the preclinical phase,although some early clinical (including first-in-human)studies have commenced and several have been completed[3–9]. Today only one orthopedic RM treatment, specifi-cally the treatment for focal knee cartilage defects, is ap-proved for market use [10,11].

As the amount of (early) clinical studies in this field is ex-pected to rapidly expand in the near future, it is time to pro-actively discuss the scientific and ethical issues involved inthe translation of preclinical research into clinical studies.For innovative technologies, like RM, the traditional ethicalbenchmarks for conducting clinical research proposed byEmanuel et al. [12] require refinement. In particular, the de-cision of when translation into first-in-human studies is jus-tified is challenging, because these complex novelapproaches have never been applied in humans before. Ad-ditionally, the combination of the specific characteristics ofRM with the characteristics of orthopedic patients impliesthat new challenges will arise [13]. Specific characteristicsof RM include complexity, new aims (compared with drugsand devices), and early-stage effectiveness, whereas ortho-pedic patients are characterized by their relatively healthystatus (in the sense of having a nonlethal disorder) and thestrong influence of psychosocial factors.

Empirical ethics research provides factual informationabout the state of affairs in a specific practice and identifiesthe attitudes, opinions, and experiences of relevant actors.By combining experts’ attitudes, opinions, and experienceswith ethical theories and principles, a coherent view on theethical issues in orthopedic RM research can be formed[14]. The aim of this study was to identify the ethical issuesexperts consider necessary to address before translating RMinterventions into clinical research, and to combine thementioned issues with our own ethical analysis.

Materials and methods

Design

Qualitative research aims to generate rich, in-depthunderstanding of attitudes, opinions, and experiences of

are primarily gathered from an interview design, and dataanalysis is largely inductive, which allows meaning toemerge from the data rather than the more deductive,hypothesis-centered approach of quantitative research[15]. Therefore, the attitudes, opinions, and experiences(when available) of experts regarding the ethical issues intranslational clinical RM research for musculoskeletal dis-orders were examined by means of qualitative interview de-sign [16,17]. This study was conducted as part of the DutchBioMedical Materials–funded consortium IDiDAS (NewEarly Therapies for Intervertebral Disc Diseases. Drug De-livery and Augmentation through Smart Polymeric Bioma-terials). IDiDAS involves four academic medical centers,one technical university, and industrial partners and is inthe preclinical phase of developing RM interventions forthe treatment of intervertebral disc disease. In our work-package ethics, IDiDAS is used as an example to identifyethical issues that will arise in translating RM interventionsfor orthopedic disorders from bench to bedside.

Respondents

Respondents were recruited using the network of theIDiDAS consortium and by following recommendationsfrom the interviewees (so-called snowball sampling) [18].Inclusion criteria were that the respondent is involved in(pre)clinical orthopedic RM research, and/or has experi-ence with conducting clinical research or practice in degen-erative musculoskeletal disorders. These latter respondentswere included to provide insight in the general challengesin conducting orthopedic research. One-on-one, in-depthinterviews were mainly held with scientists working atthe bench in orthopedic RM and with surgeons in differentareas of orthopedic surgery (primarily spine) who were in-volved in the field of RM or orthopedic research (Table).We aimed to collect a range of attitudes, opinions, and ex-periences as wide as possible, termed contrast maximiza-tion, by selecting respondents of different professions,specializations, and nationalities [16].

In total, 36 interviews were conducted; 12 people did notrespond and 4 rejected the invitation. Recruitment wasended when saturation was reached (ie, when no new the-matic content was found) [19].

Interview strategy

The interviews were conducted by S.N. between Apriland November 2012. The interviews lasted between 30and 75 minutes and most interviews took place at the work-place of the respondent. Five interviews were done bytelephone.

Table

Respondents’ characteristics

Respondents N536

Sex

Male 31

Female 5

Nationality

Dutch 23

English 11

German 1

Swiss 1

Profession

Surgeon 20

Basic scientist 14

Research funder 2

Specialization of surgeons

Spine surgery 10

Knee surgery 2

General surgery 6

Hand surgery 1

Veterinary surgeon 1

RM research experience

Preclinical research 26

Clinical study 13

No RM experience, but experience in orthopedic research 9

RM, regenerative medicine.

3S.L. Niemansburg et al. / The Spine Journal - (2013) -

A topic list, based on existing literature and pilot inter-views, was used to guide the interviews but respondentswere able to add other aspects (Supplemental file: TopicList). Questions about the translation from preclinical re-search to first-in-human studies, and from clinical studiesto society, were incorporated. Typically, for qualitative in-terview design, the topics evolved during the interviews.Hence, not all topics were systematically discussed in allrespondents in the same way. In this article, we report theresults about the issues raised in the translation into earlyclinical studies. The description of three possible futureRM interventions for different types and stages of orthope-dic disorders (depending on the specialization of the re-spondent) were often used as a tool during the interviews(Supplemental File: Topic List). Although only a smallnumber of early clinical studies and applications exist,many respondents (n513) had experience with clinical re-search or applications in orthopedic RM. These respondentswere also asked about their experience with conductingclinical studies in this field.

Data analysis

The interviews were audiotaped, transcribed verbatim,and stored anonymously, after permission was given by re-spondents. Data analysis was based on the constant compa-rative method, which involves going back and forth from thedata to develop codes, concepts, and themes [16]. S.N. inde-pendently coded the full transcripts by labeling units of textsthat referred to one or more topics relevant to the study pur-pose. Coding was done with NVivo 8 software [20]. Onemember of the research team, A.B., read the full transcripts

with coding and J.v.D. and A.B. checked the codes for con-sistency. The codes were adjusted by comparison acrosstranscripts and by discussion with all authors. After consen-sus on coding was reached, the codes were developed intohigher-order concepts and themes to provide a frameworkfor coding subsequent transcripts. Subsequently, the themesfor discussion were discussed with all authors. We did notshow which percentage or number of respondents expresseda certain opinion, as quantification does not correspond withthe aim and method of qualitative research [15].

Results

We identify four main themes emerging from the inter-views regarding the translation of RM interventions intoearly clinical research.

Theme 1. Keep risks of RM interventions low

Many respondents expressed concerns about RM technol-ogy because it exposes study participants to possible harms.Most experts highly favor the ‘‘first do no harm’’ principle,especially because orthopedic disorders are mainly quality-of-life disorders, whereas the risks of RM are often un-known. Experts were concerned about potential seriousadverse events of RM approaches, especially the increasedrisk of cancer. They pointed to evidence on bone morphoge-netic proteins (BMPs) for spinal fusions, aimed at regenera-tion, which showed tumor formation could be a possible sideeffect. Risk-averse attitudes were especially displayed forexperimental interventions in the intervertebral disc, be-cause both the magnitude and the probability of harm wereregarded to be higher than for interventions in synovialjoints, among others, due to the anatomy of the spine andthe location near the spinal cord.

Theme 2. Consider carefully which participants are mostappropriate

Many respondents brought up two issues related to thechoice of the most appropriate participants for (early) clin-ical studies in orthopedic RM: the uncertainty around therelationship of degeneration and symptoms, and the appro-priate stage of intervening.

Uncertainty around relationship of degeneration andsymptoms

Many emphasized that for research to be relevant, aclear diagnosis and natural history are needed to draw accu-rate conclusions about the effect of the intervention. In al-most every interview, the point was raised that injectingregenerative compounds in patients with a degenerative or-thopedic disorder is currently doubtful to recommend, ascontroversy exists on the relationship between degenerativechanges and patients’ clinical symptoms. Many surgeonsmentioned that this correlation is disputable, because the

4 S.L. Niemansburg et al. / The Spine Journal - (2013) -

exact origin of pain is unclear and psychosocial factorshave a considerable influence. Many mentioned that the di-agnosis of osteoarthritis in peripheral joints, compared withdisc degeneration, is less controversial because more diag-nostic instruments, such as arthroscopy, are available.

Appropriate stage of interveningFurthermore, most respondents speculated about the

most appropriate stage of a degenerative musculoskeletaldisorder for enrolling patients in a clinical study. For degen-erative disorders, experts mentioned several groups thatcould be eligible for intervening with RM: asymptomaticpersons with high risk of degeneration, symptomatic pa-tients with minor degeneration (early-stage patients), andsymptomatic patients with severe degeneration (advanced-stage patients). Some respondents favored includingearly-stage patients because these belong to the group inwhich highest efficacy could be achieved. However, the in-clusion of this group of patients is also complicated becauseof higher risks involved.

Theme 3. Setting the goal(s) for measuring outcome:tissue regeneration versus improving patients’well-being

Most experts noticed that the choice of outcome meas-ures in clinical studies for RM interventions is challenging.Actually, setting the goals of a clinical RM study is closelyrelated to setting the goal of RM. Many experts noticed thatthe field should deliberate about what RM should ulti-mately strive for: tissue regeneration or improving symp-toms and well-being of patients.

Most respondents expressed that it is most important thatoutcome measures reflect well-being of participants, be-cause this should be the goal of medical research. Somewarned that a narrow focus on regeneration of tissues prob-ably will not benefit patients, because of the difficulty ofcorrelating radiological signs of degeneration with experi-enced pain (Theme 2). Especially scientists, however, wereconvinced that regeneration also should be used as an out-come measure in the design of clinical studies, to gain sci-entific knowledge about the working mechanism of theinterventions.

Theme 4. Conduct evidence-based medicine andstimulate (scientific) integrity

The experts expressed concerns about a lack of bothevidence-based medicine (EBM) and of (scientific) integ-rity in orthopedic surgery. These aspects could also nega-tively affect a proper research climate for researching RMinterventions.

Evidence-based medicine in surgeryTo avoid a lack of evidence-based practice when RM in-

terventions are introduced in health care, the experts rec-ommended RM research to be developed carefully, with

adequate basic science, preclinical research, pilot studiesand, preferably, randomized controlled trials (RCTs). Themost mentioned reasons that hamper EBM practice in sur-gery were related to the (traditional) culture and nature oforthopedic surgery.

Some experts mention that the lack of EBM is partiallycaused by the culture of a ‘‘trial-and-error’’ approach in sur-gery. In addition, the attitude of orthopedic surgeons wasthought to be, at least partly, causal to hampering the devel-opment of an EBM practice: the eagerness to operate (‘‘find-ing a quick fix’’) and experiment with new interventionswhile no proper evidence is available. Some UK respondentsmentioned that the attitude of easily performing surgery ismore widespread there, compared with The Netherlands.Furthermore, the free market system in some Western coun-tries, as well as the preference of many patients to be oper-ated, would also make surgeons more willing to operate.Others, however, mentioned that EBM is lacking as surgicaltrials are more difficult to perform than drug trials, for exam-ple, as a surgical trial is more expensive and logisticallymore challenging. For RM specifically, the different ‘‘lan-guages’’ of scientists and surgeons could hamper the devel-opment of proper clinical studies.

(Scientific) integrity in orthopedic researchThe experts worried about the hype of RM, which is par-

tially caused by the drive for profit of industries and by thehigh expectations of researchers for providing a definitecure for diseases that are now intractable. They were wor-ried that these secondary interests cause a lack of scientificintegrity in RM research. One of the consequences could bethat it leads to improper design of clinical studies. Manyobserved that a consequence of the hype and profit drivein orthopedic surgery is that interventions are commercial-ized too soon without proper research beforehand.

Discussion

It is expected that the use of RM interventions in ortho-pedics will rapidly increase in the near future. Although ex-perts in the orthopedic RM field welcomed the increasing(preclinical) research into RM interventions for orthopedicdisorders, they addressed four challenges in the translationto clinical research, especially for degenerative musculos-keletal disorders [13].

It was not surprising that the issues of acceptability ofrisks and participant selection were mentioned by the re-spondents, as we have earlier identified these aspects asbeing challenging in orthopedic RM [13]. Especially chal-lenging is the uncertainty of risks owing to the relative nov-el and complex character of RM, while orthopedic patientsare relatively healthy. Furthermore, in the early trial phases,the choice for the appropriate participant group will mainlydepend on the acceptability of risks and uncertainty in rela-tion to the expected scientific knowledge (as individual

5S.L. Niemansburg et al. / The Spine Journal - (2013) -

benefits are hardly expected). In the end, advanced-stagepatients are probably most eligible, because these patientshave least functionality to lose when harms occur, and alsodiagnosis in these participants is easier [21–23].

The mentioned aspect of the need to discuss the aim ofRM research is interesting, as this issue has hardly been ex-pressed in the ethical debate before. The responses show thatsome favor clinical studies that aim at outcome measurescapturing well-being so as to inform clinical practice, where-as others favor gaining scientific knowledge about the mech-anism of action of RM. In a developing a field like RM it isimportant to combine both aims, as is also proposed in the‘‘translational model of value.’’ Whereas especially in latertrial phases a focus can be placed on clinical outcome meas-ures (progressive value), the value of a study should be en-hanced by also collecting information to promote further(pre)clinical studies; for example, by collecting tissue ortracking cells to understand the working mechanism (alsocalled iterative, collateral, or reciprocal value) [24]. This lastaspect also ensures that negative findings on clinical out-comes, which can be expected in these first-in-human stud-ies due to its novelty and complexity, are valuable [25,26].

Next to the challenge of establishing valuable goals forRM research, a pertinent issue is how to obtain valid andreliable research results in the current context in which or-thopedic surgery lacks a strong tradition of EBM practice[27–29].

As also mentioned by the respondents, the lack of evi-dence-based practice in orthopedic surgery complicatesthe achievement of an evidence-based culture in RM. Insurgery, pathophysiological theories, mechanism of dis-ease, and reliance on clinical experience have historicallydominated the basis for treatment of individual patients[27]. This paradigm still remains, although the need formore rigorous evaluation, such as RCTs, for surgical inter-ventions is increasingly being acknowledged [29–31].Many reasons for the current reliance on theory and indi-vidual experience instead of on large empirical studies ex-ist, ranging from the surgical ‘‘culture’’ (eg, the importanceof personal prestige) to methodological and practical issuesthat complicate RCTs in surgery [27,29]. The methodolog-ical and practical issues are, for example, the learning curveand variability in experience between surgeons of a newsurgical technique, high efforts required for recruitmentand treatment of patients, difficulties of blinding the sur-geon and the patient, and the problems of crossover whenone of the alternatives is available elsewhere as a standardcare [27,29–33]. These difficulties in designing RCTs forsurgical interventions are valid, but not all are applicableto RM. It is likely that under certain circumstances, RCTsfor RM approaches are required and feasible.

Furthermore, it is interesting that the stakeholders areworried that in their field the role of commerce in surgicalresearch and clinical practice causes conflicts of interestthat could negatively affect the integrity of researchersand the scientific validity of clinical studies [34–36]. The

BMP turmoil has shown that conflicts of interest can bothlead to adverse events being underreported and the designbeing methodologically flawed [37,38]. Additionally,profit-driven research may result in novel interventionsbeing introduced, although there is relatively scarce evi-dence and later shown to be less promising than expected[39]. This hype cycle is not only caused by industry, butalso by various other parties, such as universities,valorization-driven government bodies, and funding bodies[40]. Especially RM interventions are at risk of beingpushed onto the market too early because they are often de-veloped by small companies and sponsored by venture cap-italists, who need a quick return on investments [38,41,42].

To promote a research climate that facilitates the gain ofrobust, valid, and ethically obtained results, several meas-ures could be taken, such as the disclosure of conflicts of in-terest in reported studies, and improving the review ofresearch protocols and editorial review of manuscripts[34,42,43]. Furthermore, incorporation of education aboutRM, surgical clinical studies, and ethics in the specializationtrajectory to orthopedic surgeon is important. Additionally,research programs should stimulate collaborations betweenscientists (eg, biologists, engineers) and orthopedic surgeonsto promote translational research.

Our study has some limitations. Aweakness of this studymay be that many of the clinicians interviewed were notconducting RM research. These clinicians might not be suf-ficiently aware of the latest developments and characteristicsof the different types of RM to be able to representativelyconvey current facts and knowledge, such as concerningrisks. However, assessing risks cannot be objective, as theanalysis and evaluation depend also on subjective elementsand have social and cultural dimensions [44]. Another poten-tial weakness is that this study is limited to mainly two na-tionalities of respondents, and that mainly spine surgeonswere interviewed. However, as the experts varied highlywith regard to profession, a diversity of attitudes, opinions,and experiences was expected.

Another limitation is that financial and other conflicts ofinterest could have influenced the responses of interview-ees, and that these were not explicitly described in thisstudy. However, these respondents are at the same time alsothe ones who have the most experience with the topics inthis study. General characteristics of the respondents areprovided in the Table, but conflicts of interest were not de-scribed explicitly so as to ensure the anonymity ofrespondents.

Concluding remarks

Regenerative medicine is a new, innovative field of com-plex, biologically based interventions that is expected tochange the orthopedic field considerably in the future. Itis necessary to ensure that these interventions are, in theend, aimed at patients’ well-being, while at the same timeadding to biological knowledge. Regenerative medicine

6 S.L. Niemansburg et al. / The Spine Journal - (2013) -

could form an impetus to address and improve evidence-based practice in orthopedics, and to stimulate responsibleinnovation and collaboration among industry, researchers,surgeons, and other partners. Not only the orthopedic RMfield alone will benefit from proper efforts to promote ethi-cally and scientifically sound translation into clinical re-search, but also the orthopedic field as a whole.

Acknowledgments

The authors thank all the respondents who participatedin this study.

This research forms part of the Project P2.01 IDiDAS ofthe research program of the BioMedical Materials institute,cofunded by the Dutch Ministry of Economic Affairs. Thefinancial contribution of the Dutch Arthritis Foundation isgratefully acknowledged.

Supplementary data

Supplementary data related to this article can be found athttp://dx.doi.org/10.1016/j.spinee.2013.10.016.

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