ENQUIRY TO
MEDICAL DEVICE COMPETENT AUTHORITIES
Helsinki Procedure 2013
Problem :
Status and classification of a bone void filler composed of -tricalcium
phosphate granules, polyethylene glycol, glycerol, stearic acid and
reindeer bone extract
Originating CA: Swissmedic, Swiss Agency for Therapeutic Products
Contact Point:
Saskia Dunkel-de Raad
E-mail :
medical.devices@swissmedic.ch
Circulated:
22.04.2015
Deadline:
22.05.2015
Date Summary issued: 22.06.2015
Extended deadline:
SUMMARY
Description of the problem
A Swiss clinical trial centre has notified the Swiss Agency a clinical trial with an investigational bone
void filler (IBVF). The sponsor has categorized the IBVF as a medical device and intends to use the
results of the clinical trial for the purpose of a conformity assessment procedure in order to affix the CE
marking (cf. art. 11 of directive 93/42/EEC).
Composition of the IBVF: -tricalcium phosphate granules (-TCP, 46 w-%), polyethylene glycol (PEG,
20 w-%), glycerol (31 w-%), stearic acid (1.8 w-%) and reindeer bone extract (extracellular matrix of
cortical diaphyseal reindeer bone; 1.3 w-%).
Clinical use: The IBVF is indicated for the filling of non-load bearing defects of the extremities and
pelvis. These defects may be osseous defects created by surgery or due to traumatic injury of the
bone. The IBVF is a resorbable bone graft substitute which is replaced with new bone during the
healing process.
Mechanism of action of the IBVF: The sponsor of the clinical trial claims that the resorbable
-TCP granules provide an osteoconductive scaffold in the bone void for new bone formation. The
reindeer bone extract stimulates bone growth and enhances the resorption of the -TCP granules.
-TCP in the form of porous granules (i.e. without any additives) is an established, widely used
osteoconductive substitute for bone grafts in orthopaedics and maxillofacial surgery. The IBVF
combines the -TCP granules together with the PEG/glycerol/stearic acid matrix with a reindeer bone
extract. This extract contains, among other constituents, Bone Morphogenetic Proteins (BMP). BMPs
belong to the Transforming Growth Factor-β (TGF-β) superfamily, a large group of various growth and
differentiation factors, and are osteoinductive (i.e. they induce the formation of bone and cartilage).
Pre-clinical evidence shows that the osteoinductive action of the reindeer bone extract is more than
ancillary to the osteoconductive action of the -TCP granules together with the PEG/glycerol/stearic
acid matrix. Indeed, markedly more new bone formation, bone unions and resorption of the -TCP
component of the IBVF in the defect area were shown in groups treated with the IBVF in comparison
to groups treated with the matrix only (-TCP granules together with the PEG/glycerol/stearic matrix,
without reindeer bone extract).
The IBVF has been classified by the sponsor of the clinical trial as a class III device according to rule
17 of Annex IX of Directive 93/42/EEC, concerning devices manufactured utilising animal tissue which
is rendered non-viable or non-viable products derived from animal tissue. Regulation EU 722/2012
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lays down particular requirements in relation to the placing on the market and/or putting into service of
such medical devices. The TSE risk has been assessed according to EN ISO 22442.
With reference to the facts presented, the Swiss Agency considers that
(1) the osteoinductive nature of the reindeer bone extract cannot be clearly established as merely
ancillary to the osteoconductive -TCP granules. Therefore it suggests that the IBVF should
fall within the definition of a medicinal product (MEDDEV 2.1/3 rev 3 chapter B.4.1 1 and
MEDDEV 2.1/3 rev 3 chapter B.2.12). Indeed, it is stated in Directive 2001/83/EC (MPD) that
in cases of doubt, where a product may fall within the definition of a “medicinal product” and
within the definition of a product covered by other Community legislation, the provisions of the
MPD will apply (art. 2 par. 2 MPD).
(2) the pharmacological properties of the growth factors present in the reindeer bone extract are
more relevant than its animal origin. Consequently, if the IBVF is considered as a medical
device and not a medicinal product, rule 13 of Annex IX of Directive 93/42/EEC ― concerning
devices incorporating a substance considered to be a medicinal product and liable to act on
the human body with action ancillary to that of the device ― and not rule 17 should be
enforced. Accordingly, a consultation procedure on devices incorporating, as an integral part,
an ancillary medicinal substance should be considered by the sponsor of the clinical trial (cf.
part C of MEDDEV 2. 1/3 rev 3.).
For further information on osteoconduction (without addition of exogenous growth factors), please
refer to the following youtube-movie. Please note that the product shown in the movie and its
manufacturer are not subject to this enquiry: https://www.youtube.com/watch?v=9L1PbVx0cSA.
Enquiry result
16/32 CA have replied to this enquiry.
Summary of responses:
Question
Answer
Do you consider the IBVF as a medicinal product?
Do you consider the IBVF as a medical device?
If you consider the IBVF as a medical device, which
classification rule should prevail:
- Rule 13 (devices incorporating, as an integral
part, a medicinal product) ?
- Rule 17 (devices manufactured utilizing animal
tissues or derivatives rendered non-viable) ?
Yes
No
Depends
Yes
No
Depends
N/A
Rule 13
Rule 17
Rules 13&17
6/16
7/16
3/16
7/16
6/16
3/16
3/16
8/16
0/16
5/16
1
MEDDEV 2.1/3 rev 3 chapter B.4.1 Examples of medical devices incorporating, as an integral
part, an ancillary medicinal substance: Bone void filler intended for the repair of bone defects
where the primary action of the device is a physical means or matrix, which provides a volume and a
scaffold for osteoconduction and where an additional medicinal substance is incorporated to assist
and complement the action of the matrix by enhancing the growth of bone cells. In such cases, the
ancillary nature would be determined by the performance of the matrix on its own and the extent of the
enhancement of growth due to the presence of the substance. With reference to the overall purpose of
the product, where the medicinal substance has such an effect that its ancillary nature cannot
be clearly established, then the product should be considered in accordance with the concept
of a drug delivery system.
2 MEDDEV 2.1/3 rev 3 chapter B.2.1 Examples of drug-delivery products regulated as medicinal
products: Implants containing medicinal products in a polymer matrix whose primary purpose is to
release the medicinal product, for example plastic beads containing antibiotic for treating bone
infections, or a matrix to release osteoinductive proteins into the surrounding bone.
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Question addressing the regulatory route of the IBVF:
The responses to the CA enquiry on the regulatory route of the IBVF are split: 6/16 in favour of a
medicinal product and 7/16 in favour of a medical device. As long as the manufacturer does not clearly
demonstrate
- that the principal intended action of the IBVF is achieved by the osteoconductive -TCP and is
only assisted in its function by the osteoinductive action of the reindeer bone extract, or
- that the principal intended action of the IBVF is significantly achieved by the osteoinductive
action of the reindeer bone extract and is only assisted in its function by the osteoconductive
-TCP,
the regulatory route of the IBVF will be unclear. The manufacturer should therefore present studies in
order to evaluate the osteoconduction of the matrix on its own and the extent of the osteoinduction.
The use of the -TCP bone void filler (-TCP granules together with the PEG/glycerol/stearic acid
matrix) with and without reindeer bone protein extract as well as pertinent controls (e.g. empty defect,
autogenous control, -TCP with rhBMP-2) in a defect model may be suitable to distinguish between
osteoinduction and osteoconduction.
However, it should be emphasized that the majority of the examples of bone void fillers cited in
MEDDEV 2.1/3 rev 3 chapter B.2.12 and B.4.11 are in favour of medicinal products.
Question addressing the classification rule considering that the IBVF is a medical device:
No CA (0/16) considers that the IBVF should be classified according to rule 17 only. All CA consider
that the BVF should be classified either to rule 13 only (8/16) or both to rules 13 and 17 (5/16).
Further course of action:
No majority view concerning the regulatory route of the IBVF can be reached as long as the
manufacturer does not clearly demonstrate which of the osteoconduction and of the osteoinduction
has a major contribution to the intended purpose.
In cases where the IBVF falls within the definition of a medical device, both rules 13 and 17 attribute it
to class III. Consequently, the IBVF should undergo both the consultation procedure for
medicinal products (Annex I, Section 7.4) and the procedures referred to in Regulation No 722/2012
(New Regulation regarding medical devices utilizing tissues of animal origin; Annex I, Section 8.2),
since it incorporates a substance of animal origin considered to be a medicinal substance.
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Proposed draft entry for the Manual
Background:
A bone void filler (BVF) is indicated for the filling of non-load bearing defects of the extremities and
pelvis. These defects may be osseous defects created by surgery or due to traumatic injury of the
bone. The BVF is a resorbable bone graft substitute which is replaced with new bone during the
healing process. It is made of -tricalcium phosphate granules (-TCP), polyethylene glycol,
glycerol, stearic acid and reindeer bone extract (extracellular matrix of cortical diaphyseal reindeer
bone.)
The manufacturer has categorized the BVF as a medical device and attributed it to class III
according to rule 17 of Annex IX of Directive 93/42/EEC concerning devices manufactured with nonviable products derived from animal tissue. Regulation EU 722/2012 lays down particular
requirements in relation to the placing on the market and/or putting into service of such medical
devices. The TSE risk has been assessed according to EN ISO 22442.
The pharmacological properties of the growth factors present in the reindeer bone extract may yet
not be ignored. Depending on the contribution of the osteoinduction and the osteoconduction to the
intended purpose, the regulatory route could differ:
(i)
MEDDEV 2.1/3 chapter B.4.1: Medical devices incorporating, as an integral part, an
ancillary medicinal substance
Bone void filler intended for the repair of bone defects where the primary action of the
device is a physical means or matrix, which provides a volume and a scaffold for
osteoconduction and where an additional medicinal substance is incorporated to assist and
complement the action of the matrix by enhancing the growth of bone cells. In such cases,
the ancillary nature would be determined by the performance of the matrix on its own and
the extent of the enhancement of growth due to the presence of the substance. With
reference to the overall purpose of the product, where the medicinal substance has such
an effect that its ancillary nature cannot be clearly established, then the product
should be considered in accordance with the concept of a drug delivery system.
(ii)
MEDDEV 2.1/3 chapter B.2.1: Drug-delivery products regulated as medicinal products
Implants containing medicinal products in a polymer matrix whose primary purpose is to
release the medicinal product, for example plastic beads containing antibiotic for treating
bone infections, or a matrix to release osteoinductive proteins into the surrounding
bone
Outcome:
The regulatory route of the BVF cannot be defined as long as the manufacturer does not clearly
demonstrate which of the osteoconduction and of the osteoinduction has a major contribution to the
intended purpose.
Where the medicinal substance has such an effect that its ancillary nature cannot be clearly
established, then the product should be considered in accordance with the concept of a drug delivery
system (MEDDEV 2.1/3 chapter B.4.1)
In cases where the BVF falls within the definition of a medical device, both rules 13 and 17 attribute it
to class III. Consequently, the IBVF should undergo both the consultation procedure for
medicinal products (Annex I, Section 7.4) and the procedures referred to in Regulation No
722/2012 (New Regulation regarding medical devices utilizing tissues of animal origin; Annex I,
Section 8.2), since it incorporates a substance of animal origin considered to be a medicinal product.
Best regards,
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Competent Authority
Question 1
Question 2
Do you consider the IBVF as a medicinal product? Do you consider the IBVF as a
medical device?
1
2
3
4
5
6
Question 3
No. Since -TCP is an established, widely used
medical device for bone grafts in orthopaedics
and maxillofacial surgery, we consider that the TCP in combination with the reindeer bone
extracellular matrix (which contains BMPs) has to
be seen as a medical device with a medicinal
product in ancillary effect. In our understanding
the extracellular bone matrix improves the
performance of the already existing medical
device based on your description.
No.
Yes
If you consider the IBVF as a medical
device, which classification rule should
prevail:
- Rule 13 (devices incorporating, as an
integral part, a medicinal product) ?
- Rule 17 (devices manufactured
utilizing animal tissues or derivatives
rendered non-viable) ?
Rule 13
Yes.
Rule 13
Yes, since the osteoinductive action of the
reindeer bone extract cannot be clearly
demonstrated as ancillary to osteoconductive TCP granules, we consider IBVF as a medicinal
product.
Yes
No
N/A
No
Depends. The principal intended use seems to fill
osseous defects even if an osteo-induction can be
proved.
The results of the clinical trial particularly of the
group treated with the matrix only, should be
considered to conclude on the status of this
product.
Yes. If the ancillary action cannot be clearly
demonstrated, then the product would be
considered as a medicinal product.
Possibly, yes. If, on the basis of
scientific demonstration, clinical
demonstration, the principal
intended use is to fill osseous
defects.
Rule 13 (devices incorporating, as an
integral part, a medicinal product). We
consider that this product fulfils the
definition of a medicinal product. The
product has the main effect of the
pharmacological action. For this reason will
not be classified this product as medical
device.
Rule 13. If a substance has a
pharmacological action, the rule 13
applies. The aspects linked to the animal
origin will be included in the quality
documentation of the substance.
No.
In our opinion manufacturer can’t
demonstrate the ancillary action.
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N/A
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Competent Authority
Question 1
Question 2
Do you consider the IBVF as a medicinal product? Do you consider the IBVF as a
medical device?
Question 3
7
No.
Yes.
8
Yes. The product has the main effect of the
pharmacological action.
No.
No.
If you consider the IBVF as a medical
device, which classification rule should
prevail:
- Rule 13 (devices incorporating, as an
integral part, a medicinal product) ?
- Rule 17 (devices manufactured
utilizing animal tissues or derivatives
rendered non-viable) ?
Rule 13 and rule 17.
Both rules 13 and 17 should apply, leading
to class III. The device should undergo:
- the consultation procedure for the
medicinal substance in compliance with
MDD Annex I 7.4 and
- the procedure in compliance with
Regulation (UE) 722/2012 for the animal
tissues or derivatives
N/A
Yes
Rule 13.
Possible.
Considering that -TCP granules alone is a
synthetic bone regeneration material and already
on the market as medical device, the added
osteoinductive reindeer bone extract (medicinal
product) is ancillary.
When the reindeer bone extract is considered as
the main mode of action and the -TCP is merely
the way of administering the medicinal product,
this product has to be considered as a medicinal
product
Possible.
-TCP granules alone is a
synthetic bone regeneration
material. -TCP will accomplish
regeneration without reindeer bone
extract. Consequently, the
intended use is in accordance with
the definition of a medical device.
By adding an osteoinductive
substance the regeneration will be
enhanced. This activity is ancillary
to the -TCP.
Rule 13 and rule 17 (both special rules).
Both rules classify the product as class III
medical product. Notified body and
manufacturer have to comply with both
Sections 7.4 and 8.2 of Chapter II of Annex
I of the MDD.
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10
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Competent Authority
Question 1
Question 2
Do you consider the IBVF as a medicinal product? Do you consider the IBVF as a
medical device?
Yes.
There are several β-TCP- based
products on the market, which are
considered to be medical devices.
All these products are used as
bone fillers in orthopaedics and
maxillofacial surgery. Because the
process of bone tissue response
performs with or without reindeer
bone extract, its mode of action
seems to be ancillary to the
osteoconductive action of the βTCP and whole product should be
considered as a medical device
containing medicinal product.
Depends. It would be a medical
device, if the manufacturer can in
fact demonstrate that the
osteoinductive action of the
reindeer bone extract is ancillary to
the osteoconductive action of the
β-TCP granules together with the
PEG/glycerol matrix.
Question 3
If you consider the IBVF as a medical
device, which classification rule should
prevail:
- Rule 13 (devices incorporating, as an
integral part, a medicinal product) ?
- Rule 17 (devices manufactured
utilizing animal tissues or derivatives
rendered non-viable) ?
Both rules 13 and 17 should be applied.
11
No.
12
Yes, possibly. Considering the provided
information we would tend to agree with the
presented rational. If the ancillary action cannot
be clearly demonstrated, then the product would
be considered as a medicinal product.
13
Yes.
No.
N/A. If considered as a medical device, we
understand the reasoning presented by the
CH CA, but this is an unusual situation
where 2 special rules may apply, and
associated to 2 distinct conformity
assessment procedures.
We believe that this would be an important
topic to discuss at an upcoming meeting,
so as to ensure that all MSs have a similar
approach to the application of 2 special
rules.
Rule 13
14
No.
Yes.
Rule 13
15
Yes.
No.
Rule 13.
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Competent Authority
Question 1
Question 2
Do you consider the IBVF as a medicinal product? Do you consider the IBVF as a
medical device?
16
No.
Yes.
Based on the provided information, pre-clinical
experiments have shown that the osteo-inductive
effects of the reindeer bone extract are not
ancillary to the osteo-conductive effects of -TCP.
Therefore, based on this, according to the current
regulations and guidance, the product should
probably be considered as a medicinal product.
However, taking into account that
 -TCP in the form of granules is an
established, widely used osteoconductive
substitute for bone grafts in orthopaedics
and maxillofacial surgery and are as
medical devices
 there is a clear physical/replacement
mode of action
 there is also an inherent, passive osteoinduction effect (according to the video)
 understanding of how these products are
used by physicians and possible effects
of the bone extract on performance of the
-TCP granules is important for success
of the treatment
 expertise with assessment of such bone
fillers lies with notified bodies,
it is considered more appropriate that this product
is regulated as a medical device.
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Question 3
If you consider the IBVF as a medical
device, which classification rule should
prevail:
- Rule 13 (devices incorporating, as an
integral part, a medicinal product) ?
- Rule 17 (devices manufactured
utilizing animal tissues or derivatives
rendered non-viable) ?
Rule 13.
Because a consultation with a medicines
authority will be required, however as rule
17 also applies the requirements for animal
derivatives must also be complied with.
See additional remarks.
MHRA agrees that Rule 13 should prevail
to take into consideration the intended
effect of the growth factors which are a
component of the reindeer bone extract.
Full consideration of the relevant quality,
safety and benefit/risk profile aspects of
the inclusion of the reindeer bone extract is
necessary.
This should include consideration of
appropriate post-marketing surveillance /
post-marketing clinical follow up
requirements.
Regarding the application of Rule 17,
relating to animal tissue concerns, the
requirements of EN ISO 22422 may be
taken into account in assessment of the
quality, safety and clinical benefit/risk
profile of the reindeer bone extract.
This is a similar situation to the MHRA
approach to heparin coated device
products, where Rule 13 is the
predominant Rule, but animal tissue risks
are taken into account during the
consultation, since the concerns are similar
for both medicinal products and medical
devices.
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Additional rationale and remarks
Note: please remove individual competent authority names prior to circulation to the whole of the borderline and classification working group.
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