Extract
Orthopaedic surgery has a rich history of introducing new procedures and
new technology into the profession for clinical practice. Orthopaedic surgeons
have become much more innovative and successful in treating a variety of
musculoskeletal diseases and injuries with improved implants and biologics.
This article focuses on the ethics of the introduction of new technology, with
bone morphogenetic proteins (BMP) and platelet concentrations used as primary
examples.With the introduction of any new product or new procedure, ethical concerns
are raised. They include questions about (1) the responsibility of surgeons to
their patients and to medical progress, (2) the responsibility of the product
manufacturer, and (3) the responsibility of a payer to the physician or
medical institution.
Orthopaedic surgery has a rich history of introducing new procedures and
new technology into the profession for clinical practice. Orthopaedic surgeons
have become much more innovative and successful in treating a variety of
musculoskeletal diseases and injuries with improved implants and biologics.
This article focuses on the ethics of the introduction of new technology, with
bone morphogenetic proteins (BMP) and platelet concentrations used as primary
examples.
With the introduction of any new product or new procedure, ethical concerns
are raised. They include questions about (1) the responsibility of surgeons to
their patients and to medical progress, (2) the responsibility of the product
manufacturer, and (3) the responsibility of a payer to the physician or
medical institution.
Orthopaedic practice has introduced into clinical use an abundance of new
procedures and implants that were considered advances in technology. Some have
proven to be beneficial, but others have been deleterious. Some examples of
the latter are carbon-fiber arthroplasty components, thermocapsular shrinkage
in shoulder arthroscopy, and electrical stimulation for scoliosis. The
Hippocratic Oath principle, primum non nocere (first, or above all,
do no harm), is commonly quoted as a guide in these situations. This principle
requires that any new action or change in standard care will be an improvement
upon the natural history of the disease or injury process or upon the current
standard of care.
Clinicians may also be in conflict between two aims: their desire to
provide the best care for an individual patient, whose health and well-being
are their primary concern, and the need for medical progress in research to
improve the overall quality of medical care. The Declaration of
Helsinki1 was one of
the first modern efforts to provide guidance when patient care and the aims of
medical progress coexist and are potentially in conflict.
The Declaration of Helsinki states: (1) "In the treatment of the sick
person, the physician must be free to use a new diagnostic and therapeutic
measure, if in his or her judgment it offers hope of saving life,
re-establishing health, or alleviating suffering," and (2) "The
potential benefits, hazards and discomfort of a new method should be weighed
against the advantages of the best current diagnostic and therapeutic
methods."1
Hence, the Declaration is very clear that there is considerable physician
latitude in innovation, but that all innovations in practice must be judged
primarily by their therapeutic value for the patient.
Many innovations do not constitute research in the official sense. Since
the promulgation of the Federal Regulations in the United States in the 1970s,
it is generally accepted that a new procedure or modification that a surgeon
believes is in the best interest of the patient does not constitute clinical
research unless it is the subject of a systematic data-gathering inquiry
intended to lead to generalizable knowledge. Still, the physician has many of
the same ethical obligations that apply to research, such as the duty to
disclose innovative procedures and to state their risks and benefits to the
patient so that the patient can have a choice among treatment options. It is
the surgeon's responsibility to ensure that the patient has provided informed
consent. If a surgeon is convinced that a new procedure or technology is an
improvement in the current standard of care or in the natural history of an
injury or disease process, the physician has an obligation to demonstrate and
communicate this to his or her peers using scientific methodology.
The relationship of the surgeon to the product company may also raise
ethical questions. Orthopaedic surgeons often have consulting arrangements
with industry, or they are involved in the development of a product and,
therefore, receive royalties or other forms of compensation from its
utilization2-6.
These can produce substantial conflicts of interest that can affect the new
product utilization. The American Academy of Orthopaedic
Surgeons7 and the
American Medical
Association8 have
published codes of medical ethics that address these issues and provide
guidelines. The recent AdvaMed (Advanced Medical Technology Association)
guidelines9 also
provide the view from orthopaedic residents on acceptable behavior. New
technology utilization should be based on scientific principles, biophysical
principles, and a patient's best interest. The orthopaedic industry has the
responsibility to promote the safe and effective use of medical technology.
The claims made regarding a new product should be fair and balanced and should
not be misleading in overstating the product's potential.
The biologic innovations are described below in more detail, together with
costs and the forces driving their use, and then the discussion returns to the
ethical issues to provide a framework for ethical guidance that emphasizes the
primacy of patient benefit over costs or commercial interests.
Any new technology has substantial cost implications. In times of scarce
resources and decreasing reimbursement to physicians and hospitals, one cannot
ignore the considerable increase in cost that is associated with many new
technology introductions. Physicians are often decision makers in new
technology introduction, but they are essentially separated from the cost
implications of the use of new technology and its effects on hospital
profitability or the cost to the patient. Individual patient treatment plans
should be based on surgeon experience and sound clinical evidence. The high
cost of new technology is driven somewhat by the time-consuming and lengthy
processes of research, development, and regulatory approval to bring a new
product to market.
Medical Device Approval
The Medical Device Amendments to the Federal Food, Drug, and Cosmetic Act
in 1976 gave the United States Food and Drug Administration (FDA) the
authority to regulate medical devices. Within the FDA, approval and/or
clearance of devices is handled by the Center for Devices and Radiological
Health (CDRH). New products that are essentially equivalent to those on the
market before May 28, 1976, are cleared through what is known as a 510(k)
premarket notification. Laboratory and animal testing to establish safety and
equivalency is typically all that is needed. Clinical randomized control data
are not required. The majority of devices being sold today are cleared through
the 510(k) process and therefore do not require clinical data that demonstrate
efficacy to receive approval.
The devices that cannot be cleared through the 510(k) process are
considered to be Class-III devices, and the manufacturers are required to
submit a premarket application, which includes clinical data. An
investigational device exemption allows the new device to be used in a
clinical study in order to collect data on safety and effectiveness required
for the premarket application. The investigational device exemption
application contains preclinical testing, animal data, and the proposed plan
for the clinical study. Investigational device exemption studies are usually
conducted in two steps: (1) a pilot study involving a small number of patients
to establish the safety and to monitor for adverse events and (2) a large
randomized pivotal study to prove that the device is safe and effective in the
proposed indication. The investigational device exemption establishes the
indication, the size, the length of follow-up, and the success criteria for
each study. Typically, pivotal studies for premarket application approval
involve hundreds of patients, who are followed for one to three years, and
cost from $10 million to $12 million. Traditionally, the cost of the surgical
procedure in a clinical study of a device has been reimbursed by the insurance
payer. Currently, the experimental group and often the control group must be
paid by the manufacturer conducting the clinical trial, which has greatly
increased the cost of these trials.
In 1996, the FDA added the humanitarian device exemption application for
devices that are "intended to benefit patients by treating or diagnosing
a disease or condition that affects or is manifested in fewer than 4,000
individuals in the United States per
year."10 One
of the criteria that must be satisfied in order for a device to receive a
humanitarian device exemption is that no comparable device is available to
treat the disease or condition. For humanitarian device exemption products,
the manufacturer has to establish safety but does not have to prove clinical
efficacy. The manufacturer does need to establish that there is a probable
benefit for the indicated population. This probable benefit is usually
established by a combination of animal data and a small clinical study. A
humanitarian device cannot make a profit for the manufacturer; the applicant
must submit a report by an independent certified public accountant verifying
that the amount charged for the device does not exceed the cost of research,
development, fabrication, and distribution. Since this is an exemption, the
health-care provider is responsible for ensuring that the device is not
implanted in a patient prior to obtaining institutional review board approval.
The institutional review board does not have to review and approve each
individual use of the device, and institutional review boards should be
cognizant that the use of the device should not exceed the scope of the
FDA-approved
indication10.
Recombinant BMP-7 (OP-1; Stryker, Kalamazoo, Michigan) was approved for use in
recalcitrant nonunions through this process in 2001.
Drug Approval
The approval of new drugs is handled by the FDA Center for Drug Evaluation
and Research (CDER). This process begins with the submission of an
investigational new drug application. The application contains the preclinical
testing data and a plan for clinical testing of the drug. The clinical testing
to gain approval occurs in three parts; Phase-1 studies are conducted on a
small number of volunteers (to determine side effects and drug metabolism),
Phase-2 studies involve a small randomized study in patients to compare the
new drug with a placebo or a different drug (to determine initial safety of
treatment), and Phase-3 studies are used to establish the safety and efficacy
in a large randomized trial of patients treated with the new drug compared
with a standard treatment. Phase-3 studies can involve hundreds to thousands
of patients with typical costs estimated to be between $50 million and $70
million. Submission of a new drug application occurs after the completion of
the Phase-3 study. Table I
provides a comparison of the premarket application and new drug application
approval processes.
Combination Product
A combination product comprises both a drug and a device. Examples of
combination products include antimicrobial-coated catheters, antibiotic
cements, and transdermal drug-eluting patches. Rather than creating a new
approval pathway for combination products, one FDA center (drug or device)
takes the lead with consultation from the other. The assignment of drug or
device is made by the Office of Combination Products (established in 2002) and
is based on the product's "primary mode of
action."11
Prior to 2002, the approval pathway jurisdiction was decided by the FDA on an
individual basis depending on the product description and/or intended use. The
primary mode of action is defined by the FDA as the "most important
therapeutic action of the combination product." For example,
drug-eluting cardiovascular stents are a device because physically maintaining
blood vessel patency provides the most important therapeutic action, while the
drug plays a secondary role in reducing restenosis. Once the designation is
made by the Office of Combination Products, clinical testing and approval
follow either the drug or device pathway (a new drug application or a
premarket application). Since both centers are involved in the review, the
preclinical and clinical protocols often include data relevant to both drugs
and devices. If the combination product contains a tissue or biologic
component, then the Center for Biologics Evaluation and Research may also be
involved in the review.
Industry's Perspective of Approval
For the most part, the approval paths of a premarket application device
containing a biologic and a new drug are very similar. The safety,
preclinical, and preliminary clinical studies would be nearly identical for
the two pathways. The major difference would be in the final clinical study
used to obtain approval. The cost and size of a Phase-3 clinical trial
(investigational new drug application) could be ten to 100 times that of a
pivotal investigational device exemption study. The format of the final
application to the FDA would also differ depending on how each center (CDRH or
CDER) prefers to see the data tables and results. In the case of a combination
product, reviewers from both centers would request data and review the
results. An applicant may be required to submit the same data in different
formats.
In addition to the different approval pathways, drugs and devices also have
slightly different requirements with regard to good manufacturing practice and
postapproval monitoring. A device company has standard procedures in place to
comply with all of the regulations of the CDRH, but these may not fulfill the
exact requirements of the CDER. For example, the CDRH may require a written
response in five days and the CDER may require a response within two days.
Very few companies have the internal systems in place to design, manufacture,
and support both a drug and device. For this reason, a device manufacturer
would prefer that their new combination product be approved and regulated as a
device. That would allow the company to use the same procedures and controls
that are used for all of their other products. If the product were regulated
as a drug, the company would incur a substantial expense to create new
standard procedures, and this could discourage the company from pursuing the
new product. Different rules would apply for different products within the
company, perhaps resulting in confusion. In the future, the increasing
interest in biologics may require that some companies have standard procedures
and support systems in place to handle both device and drug-approved
products.
Bone Morphogenetic Protein
Since bone morphogenetic protein (BMP) was discovered in 1965, several
companies have started different clinical programs with the intent of gaining
FDA approval for a BMP product (see Appendix). Estimates of the combined
expense of these efforts have been at more than $650 million. For each
program, the FDA made a determination on the basis of the product description
and its intended use as to whether the approval would follow a device or a
drug path. During the late 1980s, two companies (Genetics Institute and
Creative BioMolecules) were successful in cloning human BMP to create purified
versions of recombinant human BMP (rhBMP). This recombinant production process
is similar to the method used to manufacture human insulin. The availability
of rhBMP permitted the large-scale testing of carriers and concentrations in
preclinical animal models, prior to starting clinical studies.
Stryker (in collaboration with Creative BioMolecules) was the first to
submit an application to the FDA to start a clinical program on tibial
nonunions treated with an rhBMP-7 (OP-1) product. In 1991, the FDA decided
that the approval pathway for OP-1 would be through the premarket application
(device) route and approval to begin an investigational device exemption
clinical trial was granted. After completing the investigational device
exemption study, Stryker filed a premarket application for an indication in
tibial nonunions. In 2001, the company received a "not approvable"
letter from the FDA that cited the failure of the clinical trial to meet the
study end points. That same year, Stryker filed for and received approval of a
humanitarian device exemption for recalcitrant long-bone nonunions. With that
humanitarian device exemption approval, OP-1 became the first BMP product on
the market and was priced by Stryker at $5000 per kit. One should recall that
the price charged for a humanitarian device exemption product cannot make a
profit for the company selling the device. In 1999, Stryker started an
investigational device exemption clinical program in spine fusions treated
with OP-1, further establishing the device approval pathway for this BMP
product.
In 1994, Genetics Institute applied to the FDA and was granted
investigational device exemption approval for two clinical study programs
utilizing rhBMP-2 (one in open tibial fractures and one in sinus floor
augmentation-alveolar ridge preservation). In granting the investigational
device exemption applications, the FDA established the approval pathway for
these intended uses as that of a medical device. The following year, Medtronic
Sofamor Danek started an investigational device exemption clinical trial using
rhBMP-2 to achieve interbody lumbar spine fusions; once again, the FDA decided
that the intended use of a BMP product would be considered a medical device.
Stryker and Medtronic Sofamor Danek completed separate investigational device
exemption clinical trials in posterolateral spine fusion indications with
their respective BMP products. Medtronic Sofamor Danek has also been granted
investigational device exemption approvals for various other spine fusion
clinical studies involving rhBMP-2. In 2002, Medtronic Sofamor Danek received
premarket application approval for an rhBMP-2 product in interbody spine
fusions. This became the first premarket application-approved BMP product and
was priced at $3500 to $5000 per kit. A second premarket application approval
for rhBMP-2 for the treatment of open tibial fractures followed two years
later.
In conclusion, when companies have submitted clinical study applications
involving BMP products to the FDA, the FDA has decided that the product and
its intended use were that of a device and not a drug. In most of these cases,
the FDA's decision focused on the fact that the intended use of the BMP
product was as an adjunct to a medical device (an intramedullary nail in a
nonunion or fracture, interbody cages in a spine fusion, or a dental implant).
Future approvals of BMP products may be either as a device or a drug, but that
decision will be made by the FDA on a case-by-case basis. It should be noted
that both the rhBMP-7 and rhBMP-2 products were approved as drugs in Europe in
2001 and 2002, respectively. For this reason, their manufacturing procedures
must meet both the FDA device and European drug requirements.
Development of Recombinant Proteins
The introduction of a growth factor into the clinical market has the
inherent conflicts of the desire of industry for financial profit and the
desire of the clinician to improve patient care. Product utilization should be
supported by quality research that proves efficacy and improves health
quality.
The production, testing, and ultimate regulatory approval of a recombinant
protein are not a trivial pursuit. First, the DNA encoding the protein of
interest must be isolated and then transferred into a host (production) cell.
That host cell can be of bacterial or animal origin, but it needs to be one
which can express the desired protein with high efficiency. In the case of
BMP, the host cell is from the Chinese hamster ovary cell line, which is one
that is extremely well studied and understood. The host cells are then placed
in culture media, where they can produce the recombinant protein, and that
protein is recovered from the culture and purified before use. Initial protein
production for preclinical testing can be done in a laboratory-sized
container, but the quantities required for clinical testing and ultimately for
therapeutic use are produced in industrial-size bioreactors. It takes, on the
average, $400 million to $2 billion and three to five years to design, build,
validate, and qualify a bioreactor for recombinant protein production. Once
built and validated, that reactor can only make that single protein. This
investment is usually made after a successful pilot or Phase-2 clinical study
and should be made before the final clinical study. Long-term stability,
package sterility, and production size validations must also be completed for
the regulatory submission. After construction of the bioreactor, the cost of
protein production includes equipment sterilization, cell culture production,
recovery, purification, viral filtration, in-process testing, and aseptic
filling costs. The production of a single batch of recombinant protein can
take up to 100 highly trained personnel working in shifts twenty-four hours
per day, seven days per week for more than a month. Each batch requires
continuous monitoring throughout the production process, and more than 200
analytical tests are conducted to ensure quality. These costs are then
repeated for each batch produced. Even after this investment, the regulatory
approval of a recombinant protein is not guaranteed. A recent analysis of the
recombinant protein market showed that only 35% of proteins in the final stage
of clinical testing between 1990 and 1997 ultimately received FDA
approval12. These
high costs and low approval rates have limited the number of companies willing
to enter the recombinant protein market.
Human insulin (Humulin; Eli Lilly, Indianapolis, Indiana) was the first
recombinant protein to be approved. Since its approval in 1982, dozens of
other recombinant proteins have gained FDA approval. The largest-selling class
of recombinant proteins is the erythropoietins, which have been used in
orthopaedic practice since the 1990s. Even with multiple vendors making and
selling different versions of this protein, the treatment cost of
erythropoietin is between $6000 and $10,000 (see Appendix). This speaks to the
high manufacturing cost of these proteins. With the exception of insulin and
plasma-activated factors, the treatment costs of the BMP products are nearly
equivalent to other recombinant proteins. The cost of the BMP products is
based on the cost of the recombinant protein, the royalty to the inventor of
the recombinant protein, the cost of the carrier, the cost of distribution and
marketing, the cost of continued research to support the products, and (with
the exception of the humanitarian device exemption product) a small profit for
the company. A portion of the profit can be reinvested in further clinical
studies to gain future FDA indications and health economic studies.
The use of recombinant proteins for orthopaedics is expensive, but it is
believed that, when used in the proper patient population, they can be
cost-effective, just as the use of activated protein C in the treatment of
severe sepsis has been shown to be cost-effective in that patient
population13. The
harvest of autogenous bone graft from the iliac crest is not without
complication, and the total estimated cost of this harvest is between $2250
and
$415414,15.
Compared with autograft harvest, the cost of rhBMP-2 has been shown to be
equivalent and eliminates the risks associated with autograft harvest in spine
fusions15,16.
In addition, the clinical outcomes in spine fusion of rhBMP-2 have been shown
to be superior to those of iliac crest
autograft17. An
economic model based on the clinical data used to gain approval of rhBMP-2 in
open tibial
fractures18
suggested that rhBMP-2 could be cost-effective when used in Gustilo type-III
fractures19. In
that analysis, the cost of the rhBMP-2 product was offset by the reduction in
secondary interventions and infections. A prospective study of the
cost-effectiveness of rhBMP-2 in type-III open tibial fractures is currently
under way. BMP products are expensive but when they are used as an autograft
replacement or reserved for the most severe fractures, they have the potential
to be cost-effective. Despite the cost and difficulties of production, BMP-2
has shown efficacy and improved outcomes in open tibial fractures and spine
fusions. Further clinical studies should add support to both the clinical
benefit and cost-effectiveness of the BMP products.
Platelet Concentrators
The formation of a hematoma is involved in the normal bone-healing
response, and platelets provide a source of multiple growth factors that are
involved in blood clot formation. The theory that platelet concentrates (also
known as platelet-rich plasma) could provide an autologous source of growth
factors, which might assist in bone-healing, began in the late
1990s20-23.
For nearly a decade, methods and devices to prepare platelet-rich plasma from
the patient's own blood in the operating room have been strongly promoted by
several companies in the orthopaedic industry. These devices were cleared by
the FDA through the 510(k) process as a means to concentrate platelets and not
as a bone graft "enhancer" (see Appendix). The predicate devices
used to gain an FDA indication were laboratory centrifuges used to process
blood for analysis or dialysis components. Functional testing was performed
with bovine or human blood to confirm that the devices could concentrate
platelets, and biocompatibility testing was conducted to ensure that the
components could safely interact with human blood. Clinical data were not
required, and the early indications did not mention their intended use with
autograft bone. Later syringe-like devices were cleared through the 510(k)
process to assist in mixing the platelet-rich plasma with autograft or
allograft bone; again, no clinical data on the outcome or effectiveness in a
bone-healing environment were submitted to or required by the FDA. These
products have been very profitable for the companies promoting them to
surgeons. In 2003, the combined sales for platelet concentrators were
estimated at $32
million24.
Autologous platelet concentrates contain multiple growth factors, such as
platelet-derived growth factor (PDGF), transforming growth factor beta-1
(TGF-ß1), and insulin-like growth factor. The theory was that mixing
platelet-rich plasma with autograft or allograft could be an inexpensive way
of enhancing the bone graft. No level-I clinical data supporting the use of
platelet-rich plasma were provided; instead animal studies and small case
reviews (level III) were used to market platelet-rich plasma to
surgeons20,22,25.
Most of the investigations were related to comparisons of the different
methods of preparation and how much one system could concentrate growth
factors and/or
platelets26-29.
Studies have shown that there is substantial patient-to-patient variation in
the growth factor content of platelet-rich plasma, regardless of which system
is
used30,31.
Furthermore, the preparation of plateletrich plasma requires the addition of
an anticoagulant (heparin) to the blood during the concentration step and then
the subsequent use of thrombincalcium chloride to make the final platelet gel.
It is unknown what effect the heparin-thrombin-calcium chloride combination
might have on bone-healing. Lieberman et al., in 2002, warned of the lack of
good clinical evidence regarding the growth factors found in platelet-rich
plasma; they noted that "TGF-ß seems to have limited potential as
an agent to enhance bone repair in the clinical setting" and "the
role of PDGF in fracture-healing and bone repair has not been clearly
defined."32
Early preclinical studies showed positive results for platelet-rich
plasma20,22,25.
Others have suggested that the growth factors found in plateletrich plasma are
not osteoinductive and that the concentrates themselves do not enhance
bone-healing. Aspenberg et al., in 1996, showed that high levels of TGF-ß
would inhibit bone formation in a rat bone-healing
model33. High
concentrations of PDGF have also been shown to reduce de novo bone formation
in a dose-dependent
manner34. That same
study also showed that platelet-rich plasma can reduce the activity of
demineralized bone
matrix34. A cell
culture study with use of marrow-derived bone-forming cells showed that high
concentrations of platelet-rich plasma inhibited the osteogenic
differentiation and reduced the alkaline phosphatase activity of those
cells35.
Platelet-rich plasma has also been shown to increase fibroblast growth and
inhibit osteoblast proliferation in
culture36. Choi et
al. found that adding platelet-rich plasma to autograft resulted in less new
bone formation than the autograft control in a canine mandible defect
model37. A rabbit
sinus augmentation study found a similar lack of enhanced bone formation when
platelet-rich plasma was added to
autograft38. A
study by Sarkar et al. showed no effect of platelet-rich plasma on bone
formation in a canine model of a critical-size defect of the
tibia39. These
results raised questions about the efficacy of platelet-rich plasma in
bone-healing but not as many as those raised by the clinical data.
In 2003, Weiner and Walker reported on the detrimental effects of
platelet-rich plasma on autograft in their patients who had posterolateral
spine fusion40.
Radiographs of patients treated with and without platelet-rich plasma were
reviewed by blinded, independent spine surgeons at one and two years
postoperatively. They found a fusion rate of 62% in the patients who received
platelet-rich plasma and autograft compared with a 91% success rate in the
control patients. This was followed by a study that found a higher incidence
of pseudarthrosis when platelet-rich plasma was added to autograft compared
with the use of autograft alone in patients with an interbody spine
fusion41. A third
spine study also found a lower rate of fusion success when platelet-rich
plasma was added to autograft
bone42. In that
study, a group of seventy-six patients treated with autograft mixed with
platelet-rich plasma was compared with a similar, matched historical group of
patients' treated with autograft alone. The nonunion rate was 25% in the
platelet-rich-plasma group compared with only 17% in the control group.
Although not significant, these results led the authors to conclude that the
use of platelet-rich plasma should not be recommended in spine fusion. The FDA
now requires manufacturers of platelet-rich plasma to add text to the warnings
section of the device label such as: "The safety and effectiveness of
this device for bone healing and hemostasis have not been
established"43
and the "Efficacy of the biologic product of this device has not been
established in any clinical
trial."44
These warnings from the FDA, the highly variable nature of the platelet
concentrate produced, the negative preclinical evidence, and the presence of
negative level-III clinical evidence should lead surgeons to question the use
of platelet-rich plasma in their patients. These products were introduced and
marketed without substantial preclinical and clinical supporting data. The
best clinical data available indicated no improvement in outcome and possibly
decreased rates of spinal fusions. The way these products were introduced is
not a model of new technology introduction that should be followed.
The duty of physicians to benefit their patients first and foremost is the
defining professional obligation of medicine. The Hippocratic Oath states,
quite simply, that the physician's actions are "for the benefit of the
sick."45
While much of the Hippocratic Oath is no longer relevant, the duty of
beneficence persists as the central feature of twenty-first century medical
ethics46. This
obligation is what distinguishes professional actions, motivated by the
well-being of the patient, from trade or commercial practices, which privilege
economic self-interest and profit motives. Hence, ethical questions about the
growing presence of orthobiologics should take this general form: "For
whose benefit are policies being written and decisions being made?"
The obligation to patient
beneficence47,
understood broadly as protecting patients from harm as well as actively
promoting their good, provides the basic framework for posing the particular
questions that arise regarding orthobiologics. Whether they are best approved
as devices or drugs can be addressed through the lens of patient benefit. Does
the shortened and less rigorous 510(k) device approval route yield an
advantage for the well-being of patients, or does it present risks to patients
that could be avoided? This does not imply that orthopaedic surgeons have
control over the FDA approval processes or over biologics manufacturers. It
simply means that attending to how differences in standards of evidence for
different FDA approval routes impact patient care is part of a larger duty of
beneficence.
The obligation to benefit patients then, as the centerpiece of medical
ethics, implies a second set of duties. Among these duties are competence in
assessing the available evidence about biologics and vigilance about the
inevitable temptation to displace patients' well-being with other goals, such
as professional advancement, surgical innovation, or greater remuneration.
Each of these goals is desirable, but none is a substitute for the fundamental
commitment to patient care. Surgeons should require industry to provide sound
scientific evidence of the efficacy and benefit of a product for their
patient.
Conflicts of Interest, Transparency, and Patient Autonomy
Several major publications concerning conflicts of interest have appeared
recently48,49,
and the questions they raised apply directly to orthopaedic surgery. Generally
speaking, conflicts of interest are a test of the beneficence principle,
arising when obligations to other persons or groups clash with the best
interests of the patient. In academic medicine, this frequently takes the form
of a pharmaceutical or device manufacturer's influence over patient-care
decisions or the way research is
conducted50. This
influence can easily become problematic, potentially violating the canons of
good patient care or good science, or both.
The aim of ethical probes into conflicts of interest is not to eliminate
them. Conflicts are ubiquitous and inevitable. They arise precisely because
patient well-being, while being the primary value, is not the only value, and
they sometimes compete with legitimate physician self-interest, obligations to
improve future patient care through research, or stewardship of scarce
resources. The aim of ethics is to reduce conflicts of interest when possible,
eliminate the ones that are pernicious to patient care, and provide
transparency and independent oversight for the rest.
Transparency for patients is achieved through informed consent. The modern
practice of consent is grounded in the right of individuals to control their
lives and to make healthcare decisions on the basis of their own values,
rather than medical, commercial, or social values. Beneficence comes into play
in a derivative but important way, since respecting the autonomy of patients
honors their sense of what is best for them, as they see it. For example,
disclosure that an orthopaedic surgeon receives a royalty payment for the use
of a particular device, or a recruitment fee for enrolling patients in a
clinical trial, is a necessary part of a valid consent process, since it
provides patients an opportunity to consider all of the relevant information
about their options. Likewise, knowing that a recommended device is being used
"off-label" (or outside the current indication) but is, in the
physician's judgment, the best choice is also a prerequisite for a valid
consent, for precisely the same reason. The disclosure that the physician has
a potential conflict or may be deviating from established practices enhances
the patient's self-determination and provides a way for the patient to weigh
the significance of that potential conflict or variation along with the
physician's recommendation. Peer review mechanisms and oversight committees
serve the same goal of transparency, and they provide additional benchmarks of
acceptable peer practice and public accountability, both of which are
important in achieving high ethical
standards3.
Biologics: Innovative Practice or Research?
United States federal policy governing research with human subjects evolved
over the two decades between 1962 and
198151. In 1991,
the policies of most federal agencies were harmonized into "The Common
Rule,"52
which applies to all research conducted or supported by any federal agency or
department. A great deal of privately sponsored research also follows the
federal guidelines. The ethical basis of the federal regulations is the
Belmont Report53,
issued in 1979. This report identifies three principles as fundamental to
research with human subjects: respect for persons, which largely applies to
informed consent; beneficence, which relates to risk-benefit assessment; and
justice, which concerns the selection of subjects and distribution of the
benefits and burdens of research.
The Belmont Report also provides a distinction between clinical research
and medical practice, in order to differentiate the activities that would fall
under the federal regulations from those that would not. Medical practice is
defined as "interventions that are designed solely to enhance the
well-being of an individual patient... that have a reasonable expectation of
success."53
By contrast, "`research' designates an activity designed to test an
hypothesis... and... contribute to generalizable
knowledge."53
Procedures that are "experimental" in the sense of not being
well-established or being innovative in some way are not considered to be
research, and they would not fall under the jurisdiction of an institutional
review board. The Belmont Report does suggest, however, that substantial
departures from established practice need to be set forth in a formal protocol
and systematically evaluated for safety and effectiveness.
On the basis of the definitions of the Belmont Report, it seems clear that
off-label use of biologics is not officially considered research unless it is
part of a project designed to lead to generalizable knowledge. Perhaps of
greater importance is whether such innovative use would pass ordinary medical
ethics standards for safety and efficacy and would fulfill the standard
ethical requirement for beneficence discussed above. To make this judgment,
peer review and full patient disclosure are essential. The use of the ethical
norms for routine practice, as opposed to the norms for research regulation,
would mean that there is less formal oversight, but the principles of respect
for patient autonomy through full disclosure and protection of patient safety
and well-being are still strict requirements. Orthopaedic surgeons engaged in
novel uses of devices or the use of non-FDA-regulated biologics will also want
to weigh their obligation to the profession and the public that would require
them to submit innovative therapies to the scrutiny of a clinical trial in
order to learn as much as possible about these new procedures. Whenever
surgeons are considering the enrollment of their patients in research
protocols, they can consult—in addition to the Federal
Regulations—the guidelines of the Declaration of
Helsinki1, which
stress the psychological and relational aspects of physician-patient
interactions at the boundaries between clinical research and routine medical
care.
The introduction of any new technology into medical practice carries with
it potential conflicts in quality medical care, research, cost, and business
relations. As decision makers in medical care, physicians have the ultimate
responsibility to keep the principle of beneficence for patients foremost in
mind and to ensure transparency of potential conflicts.
Tables showing the BMP commercialization timeline, the treatment costs of
various recombinant proteins, and examples of platelet concentration systems
are available with the electronic versions of this article, on our web site at
(go to
the article citation and click on "Supplementary Material") and on
our quarterly CD-ROM (call our subscription department, at 781-449-9780, to
order the CD-ROM).
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