European Medicines Agency

EMEA/H/C/0408
COMMITTEE FOR MEDICINAL PRODUCTS FOR HUMAN USE
EUROPEAN PUBLIC ASSESSMENT REPORT (EPAR)
INDUCTOSInternational Nonproprietary Name (INN): Dibotermin alfa
Abstract
Active substance:

Dibotermin alfa

Pharmaco-therapeutic group(ATC Code):

Bone morphogenetic protein
M05BC01

Currently approved therapeutic indication:

Single-level (L4 - S1) anterior lumbar spine fusion asa substitute for autogenous bone graft in adults withdegenerative disc disease who have had at least 6months of non-operative treatment for this condition.
Treatment of acute tibia fractures in adults, as an
adjunct to standard care using open fracture reduction
and intramedullary nail fixation.

Authorised presentations:

See the Module ”All authorised presentations”

Marketing Authorisation Holder:

Wyeth Europa Ltd
Huntercombe Lane South
Taplow, Maidenhead
Berkshire
SL6 0PH
United Kingdom

Date of issue of Marketing Authorisation
valid throughout the European Union:

9 September 2002

Orphan medicinal product designationdate:

Not applicable

The active substance of InductOs is dibotermin alfa, a bone morphogenetic protein, which is an
osteoinductive protein that results in the induction of new bone tissue at the site of implantation bybinding to receptors on the surface of mesenchymal cells and causing cells to differentiate into
cartilage-and bone-forming cells.
Inductos is approved for the treatment of acute tibia fractures in adults, as an adjunct to standard careusing open fracture reduction and intramedullary nail fixation. The effect of dibotermin alfa in patientswas demonstrated in a multinational, randomized, controlled, single-blind study of patients with open
tibial shaft fractures requiring surgical management. Patients with all fracture severity levels were
included, excluding only patients at high risk of amputation. Patients received standard care (control
group) consisting of intramedullary (IM) nail fixation and routine soft tissue management or standard
care plus InductOs. This study showed that InductOs increased the probability of fracture healing;
patients treated with InductOs had a reduced risk of treatment failure (where secondary intervention to
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promote fracture healing was required) compared with patients in the standard-care group. In thesubgroup of patients who received reamed IM nail fixation, InductOs was not observed to reduce therate of secondary intervention.
The efficacy and safety of InductOs were subsequently demonstrated in a randomised, controlled,
multicenter, non-inferiority study in patients undergoing an open anterior lumbar interbody fusion
procedure. These patients had received at least six months of non-operative treatment prior totreatment with InductOs for anterior lumbar spine fusion. Therefore on 29 March 2005 the European
Commission amended the Marketing Authorisation to include that InductOs is indicated for singlelevel (L4 - S1) anterior lumbar spine fusion as a substitute for autogenous bone graft in adults withdegenerative disc disease who have had at least 6 months of non-operative treatment for thiscondition. For this new indication InductOs should not be used alone, but must be used with the LTCAGE Lumbar Tapered Fusion Device.
The most common adverse events observed during treatment for acute tibia fractures were generally
representative of the morbidity associated with either orthopaedic trauma or the surgical procedure.
However, increased amylasaemia, headache, tachycardia and hypomagnesaemia were observed more
frequently in the InductOs treatment group.
The undesirable effects observed in anterior lumbar spine fusion patients were generally representativeof the morbidity associated with spine fusion using autogenous bone graft taken from the iliac crest.
Very common undesirable effects were accidental injury, neuralgia, back pain and bone disorder:these undesirable effects were similar in both control and InductOs treatment groups.
The CHMP, on the basis of efficacy and safety data submitted, considered that InductOs showedadequate evidence of efficacy for the approved indication, as well as a satisfactory risk/benefit profileand therefore recommended that the Marketing Authorisation should be granted.
For detailed conditions for the use of this product, scientific information or procedural aspects pleaserefer to the relevant modules.

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SCIENTIFIC DISCUSSION
This module reflects the initial scientific discussion for the approval of Inductos. This scientificdiscussion has been updated until 1 January 2004. For information on changes after
1 January 2004 please refer to module 8B.
Introduction
InductOs (dibotermin alfa/ACS) is a surgically implantable medicinal product, consisting of a solutionof recombinant human Bone Morphogenetic Protein-2 (rhBMP-2 or dibotermin alfa) applied to amatrix, an Absorbable Collagen Sponge (ACS). When administered locally, dibotermin alfa /ACS
results in the induction of new bone at the site of implantation.
Human BMP-2 is a member of the TGF-beta superfamily of growth and differentiation factors and is a
glycosylated, disulfide-bonded, dimeric protein with two major subunit species of 114 and 131 aminoacids. dibotermin alfa is expressed and secreted in a Chinese hamster ovary (CHO) cell culture
process.
Recombinant hBMP-2 binds to receptors on the surface of mesenchymal cells and causes cells todifferentiate into cartilage- and bone-forming cells. dibotermin alfa is combined with a matrix tofacilitate surgical implantation and dibotermin alfa retention at the treatment site.
The indication sought for InductOs is the treatment of acute tibia fractures in adults, as an adjunct tostandard care using open fracture reduction and intramedullary nail fixation.
1.

Part II: Chemical, pharmaceutical and biological aspects

Composition
InductOs 12 mg kit for implant comprises a 20 ml vial containing 12 mg of dibotermin alfa (rhBMP2), a 10 ml vial with solvent (water for injection), a 7.5 x 10 cm matrix (Absorbable Collagen
Sponge), two 10 ml syringes, and two 20G needles. After reconstitution the solution is applied to thematrix.
Active substance
The active substance, dibotermin alfa, is recombinant human Bone Morphogenetic Protein-2 (rhBMP2) produced in a CHO cell culture. It is a dimeric glycosylated protein with an apparent molecularweight of approx. 30 kDA.
Development genetics and cell banks
The cDNA for dibotermin alfa was cloned from a human osteosarcoma cell line using as a probe abovine genomic BMP-2 fragment. Through multiple subcloning procedures, the human BMP-2 cDNA
was ligated into a mammalian expression vector. The resulting expression construct was used totransfect the CHO cells. The strain was adapted for growth in serum-free, antibiotic free suspension
culture to prepare the MCB and WCB.
The stability of the expression system during inoculum preparation and full scale fermentation has
been extensively verified. The preparation of the MCB and WCB is well described. MCB, WCB and
End of production cells underwent extensive microbial/viral testing.
Fermentation
The cell culture process is a suspension culture in which cells replicate constantly and constitutively
secrete dibotermin alfa. Appropriate in-process controls have been implemented. Mycoplasma and invitro adventitious virus testing is performed.
Purification
The purification process consists of validated chromatographic and ultrafiltration steps and viral
filtration. Appropriate in-process controls have been implemented.

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Column resin cleaning and regeneration procedures and storage conditions of the columns are welldescribed. Maximum lifetimes for the columns have been set. The storage time and temperature of thedifferent intermediate products have been extensively validated. Viral validation studies of thepurification process demonstrated that the process effectively removes enveloped and some nonenveloped viruses. The purification process, together with the viral testing after fermentation assure
the viral safety of the product.
Characterisation of dibotermin alfa
The active substance has been characterized using a combination of traditional and state-of-the-art
techniques. dibotermin alfa has also been characterized in combination with the matrix (ACS).
Analytical methods used during dibotermin alfa development and current test methods for release ofactive substance and the dibotermin alfa vialed protein have been qualified or validated inconcordance with guidelines in force.
Specifications and routine tests
The active substance is adequately controlled by a combination of physico-chemical, biological andimmunological methods. All analytical methods have been appropriately validated. Batch analysis
demonstrates consistent manufacture of active substance. All tests for release of the active substanceand the dibotermin alfa vialed protein have been extensively described and thoroughly validated.
Other ingredients
Excipients
All excipients (sucrose, glycine, polysorbate 80, sodium chloride, L-glutamic acid, water for
injections) comply with the European Pharmacopoeia.
Matrix: Absorbable collagen sponge (ACS).
Genetics Institute uses an Absorbable Collagen Sponge, manufactured by Integra LifeSciences
Corporation, as a matrix for dibotermin alfa . ACS consists of purified bovine type I collagen crosslinked and sterilised by chemical means.
The specifications of the ACS have been statistically justified. The preparation of the type I collagenfor ACS involves an alkaline treatment step. A virus validation study was performed to assess theability of this step to inactivate relevant and model viruses. It can be concluded that this alkaline step
has a sufficient capacity to inactive a broad range of viruses.
A TSE Certificate of Suitability of the European Pharmacopoeia for the ACS has been granted by the
EDQM. The ACS matrix showed stability for 36 months at room temperature.
Packaging material
The protein vial and the solvent vial are made of type I glass, closed by bromobutyl stoppers and flipoff plastic caps. The ACS sponge is packaged in 20 ml trays formed from polyvinyl chloride (PVC)and sealed with Tyvek lids. The packages are double blisters.
Product development and finished product
The manufacturing of the vialed protein takes place at Abbott Laboratories, Kansas, USA. Labellingand packaging of dibotermin alfa /ACS is performed at Wyeth Laboratories, New Lane, Havant, UK.
This site is also responsible for EU batch release.
The specifications and test methods for the vialed protein were selected to ensure identity, purity,
potency, quality and safety. Specifications and release criteria have also been set for dibotermin alfa
in combination with the ACS matrix.
Stability of the Product
The vialed protein is stable for 24 months at 2-30°C. The reconstituted protein is stable for 3 hours atroom temperature.
Based on the stability data provided for storage of the kit (vialed protein, solvent and matrix) at room
temperature, a shelf life as indicated in the SPC is acceptable.
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2.

Part III: Toxico-pharmacological aspects

Considering the nature (biotechnology product) and intended use of the product, the applicant has
carried out a fairly extensive preclinical pharmacology and safety study programme. Appropriate
statements regarding GLP compliance have been attached to the study reports.
Pharmacodynamics
The proposed concentration of dibotermin alfa /ACS to be used in clinical practice is 1.5 mg/ml.
•
In vitro studies
The submitted in vitro data describe several bone forming related effects of dibotermin alfa.
It has been demonstrated that the effect of dibotermin alfa is local and that no systemic effects havebeen found. The local effect of dibotermin alfa is likely to be due to a combination of its specificity
and its rapid systemic clearance. A comparison of the affinity of dibotermin alfa and natural BMP-2
for the receptor(s) was not feasible due to the difficulty in obtaining individual purified BMP proteins.
The signal transduction role of the type I and type II serine/threonine kinase receptor subunits ofdibotermin alfa receptors has been closely examined and a comparison of iodinated dibotermin alfa
with “native” dibotermin alfa showed no differences. It has also been shown that dibotermin alfa
does not bind to any other receptor component of the TGF-β superfamily.
In vivo studies•
A number of preclinical studies support the ability of dibotermin alfa /ACS to induce the formation of
new bone at the site of implantation in diaphyseal defect models (critical size bone defects),
metaphyseal defects, augmentation of fracture repair, and extraosseous sites. Altogether, these studies
suggest that the relationship between dose and osteogenic response is complex and remarkably
different depending on the animal model and species.
Numerous pharmacodynamic studies in several models in rats, dogs, rabbits, sheeps, goats andnonhuman primates were conducted to show the safe and efficacious use of dibotermin alfa /ACS.
Healing of critical size diaphyseal defects was demonstrated with dibotermin alfa /ACS in the rat
femoral defect model, canine radial defect model and nonhuman primate radial and ulnar defectmodels.
The best results in the canine radius defect model were obtained at a very low concentration comparedto that proposed for clinical use (0.05 vs. 1.5 mg/ml). At concentrations clearly below those intended
for clinical use, formation of voids in the bone, heterotopic bone formation and potentially inferiorbiomechanical strength and radiographic density of the defect area were observed compared toautologous bone graft. It has been observed in each of the studied species, that the bone formation in
response to dibotermin alfa , both in quantitative and qualitative terms, depends on the concentrationof dibotermin alfa . At the low end of the concentration range, inadequate bone formation is observed.
At the high end, excessive bone formation and/or generation of fluid-filled voids within the inducedbone are observed. The applicant claims that fluid-filled voids in the newly formed bone seen in thisanimal model have not been observed in man. Nevertheless it is reassuring that the newly formed bonewith voids was not biomechanically inferior to bone autograft group.
However, it must be noted that in the set of similar experiments using the canine radial defect model,
results were not quite uniform from one experiment to another. Equal or event trendwise superiorbiomechanical strength compared to autograft were observed in some experiments.
The nonhuman primate critical size radial defect model has a lower sensitivity compared to the canineradial defect model. In the monkey, concentrations of dibotermin alfa /ACS approximately equal to, oreven double those intended for clinical use did not lead to significant bone formation. The lack ofconsistent efficacy to bridge critical-sized defects in primates does not appear to be related to impairedbone formation at increasing concentrations of dibotermin alfa or changes in the dibotermin alfa
manufacturing process. Rather, it is more likely that the dibotermin alfa /ACS implant was unable toresist soft tissue compression during bone induction, resulting in insufficient bone to repair the defect.
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Soft tissue compression has a more pronounced effect in nonhuman primate models than in models of
lower animal species due to a slower rate of dibotermin alfa -induced bone formation. This conclusion
is supported by the random distribution of successful bridging in individual animals in the radiusdefect studies, and the histologic observation of soft tissue compression into the defect observed in theaccompanying time series studies. Additionally, successful bridging was demonstrated in the positive
control animals implanted with dibotermin alfa added to autogenous bone graft; a material much moreresistant to soft tissue compression than ACS.
Two studies in sheep evaluated the ability of dibotermin alfa /ACS to induce bone formation when
implants were placed into trabecular bone in the metaphyseal region (femoral head core defect).
These two studies reveal an important property of dibotermin alfa /ACS: when used to fill trabecularbone defects, resorption of surrounding trabecular bone is observed in the initial phase of healing.
This appears to have taken place mostly during the first two weeks. Histology revealed the presence ofmultinucleated giant cells degrading the peripheral region of the implant. This phenomenon has been
described in the the SPC and for the time being use in metaphyseal fractures and endoprosthetic
applications are discouraged.
Several studies have evaluated the ability of dibotermin alfa /ACS to facilitate fracture repair(acceleration of repair and/or assurance of healing) in rabbits and goats when used as an onlay.
These models are relevant in view of the proposed therapeutic indication. However, this effect has notbeen investigated in monkeys, where the osteoinductive capacity was shown to be relatively poor.
The rabbit ulnar diaphysis fracture onlay model provides evidence of a significant acceleration ofhealing in response to dibotermin alfa /ACS. The variable and modest effect of ACS alone(with buffer) in this model suggests that dibotermin alfa has more than an ancillary role in theefficacy of the product that resembles the intended clinical use. However, no dose response
relationship could be observed with regard to concentration of dibotermin alfa .
As regards the goat tibial fracture model, a decreased consolidation and internal callus in dibotermin
alfa /ACS treated fractures compared to untreated controls has been observed. The rapid rate ofhealing with extensive periosteal new bone formation highlights one of the major weaknesses of using
closed tibia fracture in goats as a model for closed fractures in human. Periosteal stripping was notfound to be effective in slowing down the healing response of closed fractures in this model.
Due to these limitations, the goat model was not studied further.
•Pharmacodynamic drug interactions
No traditional in vitro product interaction studies have been conducted which is considered acceptablefor biopharmaceutical agents. In in vivo studies glucocorticoids reduced dibotermin alfa /ACS-inducedbone formation in rats and rabbits.
•
General and safety pharmacology programme
In rabbits, healing of osteotomies in bone previously induced by dibotermin alfa /ACS wascomparable in nature and kinetics to that of native bone.
Repair of rabbit distal radial defects by dibotermin alfa /ACS and evaluation of the potential effects on
the radiocarpal joint has been studied. When dibotermin alfa /ACS was placed in a bone defectcommunicating with a joint, no pathological changes in the joints or its capsules were observed.
However trabecular bone resorption, periarticular bone formation and joint damage remain potential
risks despite the results of this study. For the time being, the product should not be used in thetreatment of fractures that involve joint space.
Treatment of ulnar osteotomies with dibotermin alfa /ACS was studied in juvenile rabbits.
The purpose of this study was to evaluate the effect of treating unilateral mid-diaphyseal ulna
osteotomies with the product in growing juvenile rabbits with open growth plates. In growing juvenile
dibotermin alfa /ACS accelerated osteotomy bridging and healing were observed without clinically
relevant effects (< 1.5 %) on total limb length. Although the difference in total length between
dibotermin alfa /ACS treated and control limbs was small and the effect of treatment of growth plate

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thickness was not statistically significant, the differences were of such magnitude that a true effect islikely and biologically plausible. The product must not be used in skeletally immature patients.
A series of conventional safety pharmacology studies were conducted in accordance with GLP
regulations to examine the potential extraneous pharmacological effects of dibotermin alfa .
These experiments showed that dibotermin alfa had no effects on locomotion, the central nervous
system, locomotor activity, respiration and cardiovascular systems, gastrointestinal systems, urinary
system and blood coagulation at the doses tested. Therefore, it is concluded that the potential ofdibotermin alfa exerting extraneous pharmacological effects - if there were to be inadvertent systemic
exposure, is minimal.
Pharmacokinetics- Pharmacokinetics after a single dose/repeated administration
The pharmacokinetic data are limited. Pharmacokinetic single dose IV studies were perfomed in rats
and monkeys and showed minimal systemic exposure of dibotermin alfa . However, only plasma
levels (CMax) are available of these studies. AUC data were not present in the dossier. A single dose IV
injection in rats (juvenile) of 3mg/kg resulted in a CMax of 21 µg/ml, 5.3 mg/kg in a CMax of 30µg/ml
and a dose of 0.86 mg/kg in a CMax of 18µg/ml.
The PK of dibotermin alfa following bolus IV administration was examined also in the rat and incynomolgus monkeys. The clearance of dibotermin alfa from the circulation is high. Although theuptake of dibotermin alfa by highly perfused tissues and organs is rapid, residence of the protein inthese tissues is short. As a result of these pharmacokinetic characteristics, systemic presence ofdibotermin alfa in the circulation is minimal after IV dosing. The CMax and AUC values are shown
below in the table.
Table

Species
Rat

Blood Cmax and AUC of dibotermin alfa After Intravenous Administration in
Rats and Monkeys (Mean±SD)
AUC
Dose
Cmaxa
(ng•min/ml)(ng/ml)(mg/kg)Report No.
0.00043
4.0b
4.0
PB-034-91
0.0043122±1666.2±21.4
0.043
892±110955.6±424.7
0.86
7811±492
39,091±5331
PS-010-94
5.3
28,662±2916
172,391±43,339

MonkeyPB-024-92
0.0049161.09±74.51
a: Determined at the first sampling time (0.5 min post doing).
b:136.1±71.8

n=2

The pharmacokinetic studies in rats show that the clearance of 125I dibotermin alfa from blood was
biexponential with mean half-lives of 0.8 and 15.3 minutes (increase with dose). Rapid metabolism of125
I dibotermin alfa was suggested by the increase in trichloroacetic acid (TCA) soluble counts in the
blood as early as 5 min after dosing. It is considered to be likely that the early increase in TCAprecipitable radioactivity reflects the rapid metabolism of dibotermin alfa , but it is also bourne inmind that the systemic exposure to dibotermin alfa may be overestimated by measuring TCAprecipitable radioactivity.
The pharmacokinetics of IV bolus dose of dibotermin alfa in the cynomolgus monkey are in line withthose obtained in rats.
Following implantation of dibotermin alfa /ACS, 125I-dibotermin alfa was slowly released from theimplant site with a mean residence time of approximately 8 days. The peak amount of radiolabeled
dibotermin alfa detected in the blood was small; 0.1% of the implanted dose, and consistent with therapid systemic clearance described above. Studies evaluating retention of dibotermin alfa when
implanted SC in rats showed an initial recovery at the site of implantation of 70–75% of thedibotermin alfa , and a mean residence time of 4.6 to 5.6 days. The pharmacokinetic data obtained in
the implant studies correlate with a bi-exponential model in which the initial half live is very short
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(0.1 to 0.04 days) and the second half life is 3 to 4 days. After 2 weeks 1.2 to 4 % of the implanted
radioactivity is still present in the implant. Systemic exposure appears to be low and to decline rapidly.
Cmax values were generally less than 10 ng/ml and, hence, reliable AUC values for dibotermin alfa
could not be calculated.
Release of dibotermin alfa in vitro and in vivo from ACS was studied in the rabbit ulna osteotomy
model. The results of this study show that the incorporation of dibotermin alfa in ACS, when the
sponge is soaked with dibotermin alfa at the concentration intended for clinical use, varies
substantially from as low as 54% to virtually complete incorporation. Although the % incorporation in
the sponge did not affect the pharmacokinetic behaviour of the dibotermin alfa /ACS device, thepossibility of the total dose and the efficacy being affected has been examined since it has been argued
that the ACS has the capacity to absorb more fluid than what is administered in the soaking process.
The worst possible case scenario has been examined (where up to 70% of the fluid administeredwould be lost from the ACS) and it is agreed that a loss of this magnitude is unlikely to affect theefficacy of the product.
Different buffers have been used in the dibotermin alfa formulations during development of the
product. The pharmacokinetic parameters following intravenous administration of dibotermin alfa in
Arg/His or MFR 00842 are similar after adjusting for the doses administered in each study.
The original formulation of dibotermin alfa used with ACS was MFR 00842. Very minor
modifications to the MFR 00842 buffer were made to minimize the potential for precipitation of theprotein in the presence of ACS. These modifications have had no impact on the efficacy of thedibotermin alfa /ACS product.
- Distribution in normal and pregnant animals used in reproduction studies
The distribution of rhBMP-s is restricted to the blood volume in monkeys and to the extracellularvolume in rats. dibotermin alfa is transiently observed in the liver kidney and spleen in rats.
Preclinical studies evaluating the PK of dibotermin alfa during pregnancy, placental transfer and milk
excretions have not been performed.
- Biotransformation & Excretion
Dibotermin alfa is an endogenous protein that is rapidly degraded in the liver and excreted via thekidneys. The renal excretion was found to consist mainly of trichloroacetic acid (TCA)-soluble
radioactivity, reflecting dibotermin alfa metabolism.
Toxicology
The toxicity studies that were performed conform to GLP.
Dose extrapolation
Dose extrapolation is complex for this product, it has been difficult to identify an effective dose.
Species variances for this local implant application are unknown, which makes dose extrapolation
complex. Based on the highest single IV dose (5.3 mg/kg), the CMax values in the toxicity studies are a
multiple (10 to 103) of the anticipated human CMax (2.3 µg/ml- 2.3 ng/ml). In rats the highest IV doseused in the repeated toxicity studies was 0.16 mg/kg.
- Single dose toxicity
In Sprague-Dawley rats the intravenous no-toxic-effect level was 0.533 mg/kg, the highest dose tested.
A second single-dose intravenous toxicity study of dibotermin alfa using doses up to 5.33 mg/kg inSprague-Dawley rats showed no toxicity. Single-dose i.v. administration in beagle dogs resulted in ano-toxic-effect dose of 5.33 mg/kg, the highest dose tested.
- Repeated dose toxicity
In rats and dogs receiving i.v. injections of dibotermin alfa for 28 days, there were no treatmentrelated haematology, clinical chemistry, urinalysis, or organ weight findings. In rats discoloration wasnoted at the injection site of some rats. Treatment and dose-related histopathology findings at the
injection site included soft tissue thickening and cartilage and bone formation. In dogs histologically,
dose-related perivascular fibroplasia was observed at the injection site in all dibotermin alfa -treated
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groups. Slight-to-severe osseous metaplasia of the fibrous tissue surrounding the injection site wasobserved in some dogs from the mid- and high-dose groups after 28 days and in all of the high-dose
dogs after the 28-day recovery period. All injection-site-related changes were a result of the expectedpharmacologic activity of dibotermin alfa and were not considered toxicologically significant.
The no-toxic-effect level was 0.16 mg/kg/day in rats and dogs, the highest dose tested. No remote site
effects on bony tissues were observed macroscopically or microscopically.
The safety of implanted dibotermin alfa /ACS was evaluated in a mandibular/maxillofacial inlay study
in beagle dogs and a femoral onlay study in Sprague-Dawley rats.
In both studies there were no treatment-related adverse systemic effects and dose-related increases in
the incidence of post-surgical swelling was observed. In dogs, histologic examinations of the implantsites demonstrated dose-related fibrocellular tissue and/or new bone formation within and around theimplant sites in the dibotermin alfa -treated groups. There were also fluid-filled tissue cysts andoccasional strands of residual ACS material at some implant sites with apparent
regression/remodeling, but not complete resolution of these changes between 3 and 6 months.
The implant site tissue responses were the expected pharmacologic response to dibotermin alfa /ACS
and were not toxicologically adverse. There was no systemic toxicity at any dose level, and the notoxic-effect dose was 0.78 mg/kg.
In rats hard, raised areas or masses at the implant sites of dibotermin alfa -treated animals wereobserved in a dose related fashion. Microscopically, the implant sites were characterized by doserelated periosteal new bone formation with occasional fibrocellular tissue proliferation within thecenter of the newly formed bone. The presence and persistence of slight to moderate new boneformation along the lateral aspect of the femur resulted in remodeling over time with cancellation(increased porosity) of the pre-existing cortex and integration of the new bone into the cortex.
These changes were considered to result from normal remodeling due to altered biomechanical forceson the cortex as a result of the new bone formation.
The administration of dibotermin alfa /ACS as a femoral orthotopic implant in the rat at doses up to
1.6 mg/kg did not result in toxicity during the 12-month duration of this study. There was an expectedpharmacologic response of dose-related increased incidence and/or severity of post-surgical soft tissueswelling, which was associated with the expected bone formation at the implant site. The no-toxiceffect dose observed was 1.6 mg/kg (4.0 mg/ml).
Antibodies to rh-BMP-2 were only detected in the dog implant study.
- Reproduction studies
In all the studies animals received the dibotermin alfa via intravenous injection. In fertility and early
embryonic development studies dibotermin alfa treatment at dosages up to 0.16 mg/kg/day had noeffect on reproduction and fertility in male and female rats.
Embryo-fetal development studies in gravid rabbits treated with dibotermin alfa did not result insystemic maternal toxicity, embryo lethality or gross fetal abnormalities at dosages up to
1.6 mg/kg/day. Measurement of dibotermin alfa transfer across the placenta at doses comparable tothose used clinically cannot be performed because the ELISA (sensitivity limit of 0.9 ng/ml in rat
serum) will not detect the dibotermin alfa in the serum of the dam or the fetus.
Treatment of rats with high intravenous doses of rhBMP (1.6 or 0.5 mg/kg/day) during organogenesis
resulted in increased foetal weight in 2/3 experiments. Additionally, some skeletal variations wereobserved indicating a more advanced foetal development. These differences were attributed to thevariance in time to cesarean section. An effect of BMP-2 can not be ruled out. The product should
therefore not be used in pregnant women and is contraindicated as such in the SPC.
The route, level and frequency of exposure of the effects can be considered to be of limited relevancefor the clinical situation.

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- Mutagenic potential
The mutagenic potential was not investigated. This is acceptable according to the (ICH) guidance on
Preclinical Safety Evaluation of Biotechnology-Derived Pharmaceuticals.
- Oncogenic/carcinogenic potential
In vitro studies to assess the potential effects of dibotermin alfa on tumor cell growth using various
tumor cell lines and primary tumor isolates have shown minimal evidence of growth potentiation,
including studies of osteosarcoma cell lines.
Additionally, the literature review of the role of BMP-2 on growth regulation and tumor biology
provided indicates that BMP-2 and its role in growth regulation and tumor biology does not warrantcause for concern about the carcinogenic potential of dibotermin alfa /ACS in relation to its surgicalapplication. The product is intended for single local use and there is almost no systemic exposure; thelocal exposure is transient.
A panel of human tumor cell lines were assayed for their ability to respond to dibotermin alfa.
The tumor cell types were chosen for their relationship to bone (osteosarcomas) and by the increased
incidence of certain tumor types to metastasize to bone (prostate, breast, lung). dibotermin alfa had no
statistically significant effect on thymidine uptake in the presence or absence of serum in TE-85,
SaOS-2 or U-2 OS osteosarcoma cell lines. MG-63 osteosarcoma cells were slightly inhibited(not significantly).
The applicant proposes that further studies be carried out to investigate the effects of dibotermin alfa
on tumor cell growth. BMP-2 receptor expression will be assessed. Post-authorisation studies havebeen proposed and the tumor types/cell lines outlined by the applicant are considered to be sufficient.
dibotermin alfa did not change basal alkaline phosphatase activity in MG-63, U2 OS or TE-85 cells,
but slight to moderate increases were observed in the SaOS-2 cells. This suggests inhibition of
proliferation and increased differentiation of this osteosarcoma cell line. However the changes inalkaline phosphatase are also quite modest relative to the response to dibotermin alfa in other celllines and it has been concluded that dibotermin alfa has minimal effects on SaOS-2 cells.
A more careful evaluation of the effects of dibotermin alfa on tumor cell growth is warranted, and aseries of in vitro and in vivo experiments are underway as mentioned above.
Standard in vivo carcinogenicity testing has not been carried out with dibotermin alfa /ACS.
Considering the product profile, the arguments against requiring standard carcinogenicity testing are:•
The product is intended for single dose administration and biologically active dibotermin alfa isexpected to be present locally for a limited period of time. dibotermin alfa released into blood
circulation is rapidly eliminated in all studied animal species.
•
The availability of a relevant animal model is questionable.
•
Considering experience with other products containing recombinant bone morphogenetic factor
and collagen matrix, the finding that no neoplasia was induced by dibotermin alfa /ACS in thelong-term observation studies is reassuring.
- Local tolerance
Due to the nature of the product, local tolerance assessment was part of the general toxicity studies.
In the 6-month toxicity study of dibotermin alfa /ACS in dogs using the mandibular/maxillofacial
inlay model, gum lesions adjacent to implant were observed. The histologic findings observed in thegingival (gum) lesions adjacent to the implant site did not correlate with the induction of detectableanti-dibotermin alfa antibodies. Furthermore, soft tissue cyst formation was noted in the same study.
Two types of cystic lesions were observed: reversible soft tissue cysts and less readily reversible bony
cysts. The development of these lesions is likely to be a reflection of the pharmacodynamic activity ofthe product. Histological analysis and immunohistochemistry did not suggest that the lesions were
inflammatory or of vascular (endothelial) origin.
- Immunogenicity
The immunogenicity of dibotermin alfa and bovine collagen was not assessed in most of the
preclinical studies nor were the antibodies detected evaluated for neutralising activity. This is not ideal
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because the potential impact of immune responses either on the presence or absence of toxicologicalfindings or variability in efficacy in the animal models cannot be assessed. Immunogenicity in the rat
cannot be excluded due to very sparse sampling. Dibotermin alfa was clearly immunogenic in dogs
and rhesus monkeys. Anti-dibotermin alfa antibody responses were more frequent than anti-bovine
type I antibody responses. Indeed, the possibility of neutralising antibodies cannot be excluded basedon the available preclinical data. However, at least the limited available data do not suggest that
antibody response to dibotermin alfa was associated with lack of osteogenic efficacy.
- Special toxicity studies
This section contains studies for medical devices. The studies were performed according toInternational Standard ISO-10993 “Biological Evaluation of Medical Devices Part 1: Evaluation andTesting”. They revealed no adverse effects.
- Ecotoxicity/Environmental risk assessment
The applicant’s evaluation of environmental risk was reviewed. The manufacture and use of the
medicinal product is not expected to lead to any adverse environmental consequences.
3.

Part IV: Clinical aspects

Appropriate statements regarding GCP compliance have been attached to the clinical study reports.
Clinical pharmacology
Pharmacodynamics
The osteoinductive effect of dibotermin alfa /ACS has been evaluated in three dental-craniofacialstudies where the product was used for alveolar ridge preservation/augmentation (study C9514-11)
and maxillary sinus floor augmentation (studies C9409/10-11 and C9531-11). Bone formation wasassessed by measurement of the change in alveolar ridge height and width and bone density using
quantitative computed tomography (QTC) and histology.
Three concentrations of dibotermin alfa /ACS applied to the matrix have been studied in these trials:
0.43, 0.75, and 1.5 mg/ml. Osteoinduction was demonstrated at all 3 concentrations in a majority ofpatients (80% to 100%). The lowest concentration was found to be suboptimal (C9409/10-11) and thehighest was the most effective for bone induction (C9531-11 and C9514-11). A concentrationdependent response was observed between 0.75 and 1.5 mg/ml in 2 dental-craniofacial studies(C9514-11 and C9531-11).
In a study in which a matrix-only control was feasible to use, dibotermin alfa /ACS was more effective
than the matrix alone; both the matrix alone and no treatment were not significantly osteoinductive(C9514-11). Comparisons made to ACS alone, clearly demonstrate that dibotermin alfa has a morethan ancillary role in the product.
Pharmacokinetics- General:
The applicant has not performed formal pharmacokinetic trials in healthy subjects since such trials
were not feasible in view of the nature and intended use of the product.
The applicant has collected a limited set of blood samples in two exploratory clinical trials (C9414-11
and C9109-11). Dibotermin alfa was measured using ELISA method (limit of detection 10 ng/ml).
Dibotermin alfa (max. dose 12 mg) implanted in patients with bone fractures, revealed no concrete
data with regard to the pharmacokinetics, as only predose and 1 day post-dose samples were analysed.
In the 1 day post-dose samples no dibotermin alfa could be detected (detection limit 10 ng/ml and4 ng/ml).
According to preclinical pharmacokinetic data in rats and monkeys, rapid elimination of dibotermin
alfa from blood is expected. However, this cannot be verified in man with the currently available
methods.
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In preclinical studies, the mean local residence time of dibotermin alfa when implanted with ACS wasapproximately 5 to 8 days (using radiolabeled dibotermin alfa ). Similar studies are not feasible inman.
Altogether, the pharmacokinetic characteristics of dibotermin alfa in man are unknown. However,preclinical data suggest that any dibotermin alfa escaping the implant to circulation would be rapidly
eliminated.
The influence of renal function on the pharmacokinetics of dibotermin alfa is not studied.
This is agreed, as renal elimination of dibotermin alfa is considered to be a minor pathway for
dibotermin alfa clearance.
The influence of hepatic function on the pharmacokinetics of dibotermin alfa is not studied. As it isexpected that the metabolic pathway of dibotermin alfa will follow the pathways of other proteins(peptide hydrolysis), an impaired liver function is not expected to affect the pharmacokinetics ofdibotermin alfa in a clinically significant way.
In this particular case, considering the nature and intended clinical use of the product, the lack ofhuman pharmacokinetic data is not considered an obstacle for marketing authorisation.
- Interaction studies:
In vitro interaction studies have not been carried out and no specific in vivo clinical drug interaction
studies have been performed. It is argued that s dibotermin alfa is a protein, it is: 1) not expected tobind to proteins, 2) expected that metabolic degradation will follow the pathways of other proteins, i.e.
peptide hydrolysis, and therefore unlikely to be a candidate for pharmacokinetic drug-druginteractions.
Clinical efficacy
Clinical documentation of the efficacy and safety of dibotermin alfa /ACS consists of one pivotal trial
in open tibial shaft fractures requiring surgical management (Study report C9530-11) and a dosefinding study in open tibial shaft fractures (C9612-11). In addition to these two studies, the applicant
has conducted two small-scale pilot studies (C9414-11 and C9320-11) where the emphasis is on safetyof the product. Several small-scale studies have evaluated the rationale for methodology, endpoints
and choice of patient population for the pivotal trial.
The maximum feasible concentration of dibotermin alfa
is noted to be 1.5 mg/ml.
Higher concentrations have been found to lead to precipitation when the active substance is added tothe collagen sponge. This is important, since the clinical trial results cannot conclude that 1.5 mg/ml is
the optimal concentration, although it has shown to be superior to the 0.75 mg/ml concentration.
Dose response study
Study report C9612-11: A dose finding study of dibotermin alfa /ACS in open tibial shaft fractures
requiring surgical management and intramedullary (IM) nailing. This was a multicentre (n=10)
randomised, single-masked, dose-finding, stratified controlled study. The objectives were to evaluate
the safety of dibotermin alfa /ACS, to identify the optimal dibotermin alfa dose that will prevent adelayed union of open tibial shaft fractures, to assess the time to radiographic fracture union, and toevaluate the potential economic benefit of treatment. Patients were randomised to standard surgicaltreatment or standard treatment plus one of two dibotermin alfa doses (0.75 mg/ml or 1.5 mg/ml) at
the time of definitive wound closure. Patients were followed for 12 months after definitive woundclosure.
Sixty patients were planned, 59 were assessed for efficacy and 60 were evaluated for safety.
There were 19 patients evaluable for efficacy in the control group, 20 in the 0.75 mg/ml group and
20 in the 1.5 mg/ml group.
Based on current knowledge, it appears that the assumptions behind sample size determination for thisdose-finding study were unrealistic and the study was underpowered to detect differences between thestandard and standard plus dibotermin alfa /ACS treatment groups.
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Main study C9530-11
1.

Description of the study

This is a multinational, multicentre, prospective, single-blind, stratified, randomised, controlled Phase
III study of the efficacy and safety of dibotermin alfa /ACS in open tibial shaft fractures requiring
surgical management (treatment with intramedullary nailing - IM - nailing).
An appropriate statement regarding GCP compliance has been attached to the final study report.
The primary objectives of the study were to demonstrate that in at least one of the two treatmentgroups in which dibotermin alfa /ACS (0.75 mg/ml or 1.5 mg/ml) was added to the standard of care
(SOC) at the time of Definitive Wound Closure (DWC):•
An increased assurance of fracture healing in patients treated with dibotermin alfa /ACS•The safety of dibotermin alfa /ACSThe secondary objectives were as follows:•
To demonstrate that the rate of fracture healing at 6 months is higher among patients who
receive dibotermin alfa /ACS as compared to SOC•
To demonstrate that the independent radiographic assessment of fracture union is observed
earlier among patients who receive dibotermin alfa /ACS as compared to SOC•
To evaluate the potential economic benefit compared to SOC•

The primary efficacy variable was the proportion of patients who require a secondaryintervention to promote fracture healing within 12 months of DWC. All surgical procedures
performed to promote fracture healing after DWC were considered secondary interventions(such procedures included augmentation bone grafting with autograft or allograft, or bone graft
substitutes, IM nail dynamisation, exchange nailing, or exchange to external fixation).
In addition, noninvasive treatments (ultrasound, magnetic field or electrical stimulation) wereconsidered secondary interventions. Patients with hardware failure resulting in dynamisation
were counted as treatment failures

To check for potential bias in the assessment of fracture union, the investigator's assessment was to becompared with the independent radiographic assessment. A combined clinical and radiographic
endpoint (CCRE) analysis was performed, incorporating both the investigator's and the independentradiology panel's assessments. This endpoint combines 2 independent sets of outcomes:
1.
••

Investigator's assessment:no secondary intervention recommended and/or performed (success)secondary intervention recommended and/or performed (failure)2.
••

Independent radiographic assessment:
fracture united (success)not united (failure)

The secondary efficacy variables were as follows:•
Clinical - rate of fracture healing at 6 months: The proportion of patients healed without
secondary intervention. This variable was based on investigator's clinical and radiologicalassessment: radiographic fracture union as assessed by investigator, full weight bearing,no tenderness at the fracture site upon palpation.
•
Independent radiographic assessment - time to fracture union: Three radiologists blinded totreatment assignment.
Pharmacoeconomic•
Patient treatment assignments were stratified by Gustilo fracture classification at the time ofrandomisation. Stratum A consisted of Gustilo Grade I, II and IIIA. Stratum B consisted of Gustilo
Grade IIIB fractures. This prospective stratification was justified on the basis of study C9402-11
where the rate of secondary interventions was substantially higher in Gustilo IIIB fractures compared
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to less severe grades. Only patients with high risk of amputation (Gustilo IIIC) were excluded.
Patients were followed up for 12 months after DWC.
IM nails are used more frequently and were the standard treatment for patients in this study. Use of alarger diameter nail requires enlargement of the intramedullary canal (IM reaming). The effect ofreaming is uncertain, but benefit in terms of fracture healing has been described. As there is no clear
consensus about the use of reaming in open tibial shaft fractures, both reamed and unreamed nailinsertion techniques were included in the study.
The total dose of dibotermin alfa was 6 mg or 12 mg. In line with the experience from the pilot
studies, the use of dibotermin alfa /ACS in the treatment of open tibial shaft fractures is limited to one
unit. The choice of control group (standard of care) is acceptable. Since ACS alone has not been foundto possess osteoinductive properties in preclinical experiments, the omission of a "placebo" (ACS
matrix plus buffer) is acceptable. Had a "placebo" group been included, the SOC control group would
still have been necessary, effectively preventing the conduct of the study under double-blindconditions.
The method of implantation, the amount of ACS used, the location of ACS relative to tibia and bone
circumference covered by ACS were well balanced in the 0.75 mg/ml and 1.5 mg/ml dibotermin alfa
/ACS treatment groups.
The study evaluations occurred at 7 postoperative time points at 6, 10, 14, 20, 26, 39, and 50 weeks.
Treatment was administered within 24 hours of randomisation.
2.

Statistical analysis

For the purpose of sample size estimation, a conservative rate of recommendation for secondaryinterventions (35%) was projected for the SOC group (based on study C9402-11). Under these
conditions, a sample of 120 patients per treatment group would give >80% power to detect an 18%
difference in the rate of recommendation for secondary interventions using a two-sided Fisher's exact
test. The primary analysis was based on the ITT population. A second analysis was performed on theevaluable patient population (patients who underwent the assigned treatment within 14 days of theinitial injury, had no major protocol violations, and had a verifiable study outcome).
Two analyses of the CCRE endpoint were performed. In the first analysis, patients with no secondaryintervention and united (category 1) and patients with no secondary intervention and not united(category 2) were considered successes. In the second, more conservative analysis, only category
1 patients was considered a success.
3.

Study populations/accountability of patients

Altogether 49 investigators from 11 countries participated in the study, and 450 patients wererandomised. Of the 450 patients, 150 were randomized to the standard of care (SOC) group, 151 wererandomized to the 0.75 mg/ml dibotermin alfa /ACS group, and 149 were randomized to the 1.50
dibotermin alfa /ACS group. A total of 421 of the 450 randomized patients (94%) completed the final
study visit. Nineteen of the 29 patients (66%) who did not complete the study were lost to follow-up.
Seven patients withdrew at the patient’s or investigator’s request and 3 patients died during the study.
A total of 437 (97%) patients received their randomized treatment: 149 patients in the SOC group, 147patients in the 0.75 mg/ml dibotermin alfa /ACS group, and 141 patients in the 1.50 dibotermin alfa
/ACS group. At the time of randomisation, 85% of the patients were in Stratum A and 15% in Stratum
B. The ITT population consisted of 437 patients, and the evaluable population of 404 patients.
Although there was a statistically significant difference among treatment groups for patient age, withyounger patients in the 1.50 mg/ml dibotermin alfa /ACS group as compared with the SOC and0.75 mg/ml dibotermin alfa /ACS groups (P = 0.0243 and P = 0.0202, respectively), the difference was
not clinically meaningful. It appears likely that 1) there were very few postmenopausal female patientsand 2) there were few elderly patients, male or female (actually only 14 patients were at least 65 yearsof age). A great majority (>70%) of the patients were Caucasian. There was a slightly higher
proportion of patients with smoking history in the dibotermin alfa /ACS groups compared to controls,
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but this is unlikely to be of clinical significance. Less than 3% of the patient population had diabetes.
Approximately 58% of the population had isolated tibia fractures. Most injuries were caused by a highenergy trauma and 61% were motor-vehicle accidents. Most fractures (85%) were classified as
Gustilo Grade I, II, or IIIA (stratum A). There were more Gustilo IIIB fractures in the dibotermin alfa
/ACS groups, but the difference among groups was not statistically significant. The distribution of
fractures by AO classification also was similar among treatment groups. Most fractures in all
3 treatment groups were between the middle and distal third of the tibia and the fracture location was
similarly distributed across treatment groups.
4.
Efficacy results
Primary efficacy endpoint: Rate of secondary interventions within 12 months after Definitive
Wound Closure: The primary efficacy endpoint was evaluated for the ITT and evaluable patient
populations. Patients in the SOC group had a higher rate of secondary intervention (46%) than patientsin the dibotermin alfa /ACS treatment groups (37% and 26% for the 0.75 and 1.50 mg/ml groups,
respectively); the difference among treatment groups reflects a dose-dependent effect and wasstatistically significant (P = 0.0017, chi-square test). Pairwise comparison of the difference between
the SOC and 1.50 mg/ml dibotermin alfa /ACS groups was highly significant (P = 0.0005, Fisher’s
exact test). The rate of secondary interventions in the 0.75 mg/ml dibotermin alfa /ACS group was
lower than that in the SOC group; however, the difference between groups was not statisticallysignificant (P = 0.1162, Fisher’s exact test). Patients treated with 1.50 mg/ml dibotermin alfa /ACS
had a 44% reduced risk for secondary intervention to promote fracture healing compared with patientsin the SOC group (RR = 0.56; 95% CI = 0.40 to 0.78).
Results for the primary efficacy endpoint analysis in the evaluable patient population were similar to
those for the ITT population.
The rate of secondary interventions in the standard of care control group is somewhat higher than the
expected 35%. Although dose-dependence of clinical effect cannot be deduced from two points, theresults do suggest a trend of increasing efficacy towards the higher 1.5 mg/ml concentration.
According to the applicant, 1.5 mg/ml is the highest feasible concentration since precipitation has beenfound to occur above this.
Examination of subgroups for primary endpoint: Demographic and baseline comorbidity: To
establish whether demographic characteristics influenced treatment outcomes, the rate of secondaryinterventions by age, sex, race and smoking history were examined. Within each of these subgroups,
the results of the primary efficacy analysis were similar to the entire ITT population.
The nails were inserted using a reaming procedure in 33% of all patients. The percentage of patientswith reamed nails was lowest in the SOC group (27%) and highest in the 1.50 mg/ml dibotermin alfa
/ACS group (41%); the difference between these 2 groups was statistically significant (P = 0.0131).
This imbalance appears to be attributable to an imbalance at some centers in patients randomized to
the SOC, 0.75 mg/ml dibotermin alfa / ACS, and 1.50 mg/ml dibotermin alfa /ACS groups, whichcoincided with those centers’ preferred use of reamed nails in a majority of their patients, independentof treatment group. More patients randomized to 1.50 mg/ml dibotermin alfa /ACS were entered incenters using primarily reamed nails. In contrast, an evaluation of the distribution by center of SOC
patients reveals that more were recruited at centers using unreamed nails. This baseline imbalanceseen in the ITT population was not statistically significant for the randomized and evaluable patient
populations. In each of the 3 treatment groups, the median IM nail diameter was 9 mm. Over all
treatment groups, 88% of the IM nails were statically locked; this proportion was consistent acrosstreatment groups.
Primary efficacy variable: analysis according to nail type (reamed vs unreamed)
As noted previously, the proportion of subjects receiving reamed IM nails was higher in the
1.50 mg/ml dibotermin alfa /ACS group compared to control group (standard of care). According to
the pivotal study report, dibotermin alfa /ACS was more effective than SOC only in the subgroup ofpatients who received an unreamed IM nail. Overall, the results were better in the subgroup of patients
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who received reamed nails, but dibotermin alfa /ACS did not provide improvement over SOC in thissubgroup.
The applicant confirms in the response that dibotermin alfa /ACS was not better than SOC in thesubgroup of patients who received reamed IM nail. The rate of secondary intervention (primary
efficacy endpoint) was the same in the SOC and dibotermin alfa groups (24%). Furthermore, although
not statistically significant, there was a trend (p=0.08) in the post hoc logistic regression analysis
suggesting nail type and dibotermin alfa /ACS treatment interaction with respect to the primary
efficacy endpoint. The odds ratio of secondary intervention for delayed union was significantly lower
in patients who received reamed IM nails compared to unreamed nails (0.55, 95% CI 0.35-0.86).
Both the protocol defined and post hoc analyses (requested by the CPMP) suggest that the clinicalbenefit is mainly observed in patients who receive unreamed IM nail. However, it is recognised thatthe study was not powered for subgroup analyses. Furthermore, although the primary efficacy
endpoint analysis does not confirm efficacy in the important subgroup of patients who received
reamed IM nails, several secondary efficacy variables (acceleration of fracture healing, reduction in
the rate of hardware failure, acceleration of soft tissue healing) are favourable. In conclusion, the data
do not suggest that the indication should be limited to tibia fractures treated with unreamed IM nails.
The SPC states that the rate of secondary intervention was not reduced by dibotermin alfa /ACS
compared to standard of care in patients who received reamed IM nail.
Secondary efficacy endpoint: Clinical - rate of fracture healing at 6 months: Fracture healing
status at 6 months (Visit 7) for each patient was determined based on clinical and radiographic
assessments performed by the investigator. There was a dose-dependent increase in the rate of fracture
healing. The higher rate of fracture healing observed in the 1.50 mg/ml dibotermin alfa /ACS group(58.2%) compared with the other 2 treatment groups (0.75 mg/ml 41.9%, SOC 37.6% healed) was
statistically significant (P = 0.0013). Pairwise comparisons revealed statistically significant
differences between the 1.50 mg/ml dibotermin alfa /ACS group compared with the SOC (P = 0.0008)
and 0.75 mg/ml dibotermin alfa /ACS groups (P = 0.0082). For the purpose of this analysis, patients
who were not yet healed at 6 months comprised those who already required a secondary intervention
and those who were recommended follow-up care with no intervention.
Combined clinical and radiographic endpoint (CCRE): This secondary endpoint was developed toassess outcomes by taking into consideration both the investigators' and independent radiology panel's
assessments. The CCRE analysis was performed in an expanded patient data set comprising the ITT
population and the non-ITT patients who were treated. The four different outcome categories analysed
are shown in Table 11.4.1.5.2-1.

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Two analyses of the CCRE were performed, comparing successes with failures. In the first analysis,
patients in the first and second categories (no secondary intervention and united, no secondaryintervention and not united) were scored as treatment successes and all other patients as treatment
failures. In this analysis, the difference in success rates among treatment groups was statisticallysignificant (P = 0.0027, chi-square test). Pairwise comparison of the difference between the 73%
success rate for the 1.50 mg/ml dibotermin alfa /ACS group and the 54% success rate for the SOC
group was statistically significant (P = 0.0009, Fisher’s exact test).
In the second, more conservative analysis only patients in the first category (no secondary intervention

and united) were scored as treatment successes and all other patients were scored as treatment failures.
In this analysis, the difference in success rates among treatment groups also was statisticallysignificant (P = 0.0114, chi-square test), as was the pairwise comparison between the
1.50 mg/ml dibotermin alfa /ACS and SOC groups (success rates of 64% and 47%, respectively;
P = 0.0042, Fisher’s exact test).
Internal validity of the study has also been examined to address the issue of presence or absence ofbias in the study and the evidence points to consistent results supporting the conclusion that study
conduct and primary outcome determination were not biased. The most important findings are as
follows:•
A centralised, automated block randomisation procedure was used•
An independent radiology panel, blinded to treatment assignment reviewed the radiographs.
High concordance was found between clinical diagnosis and blinded independent radiology
review. Patients without recommendations for secondary intervention were consistently
considered united by the radiology panel. Similarly, patients with recommendations forsecondary intervention were consistently considered not united by the radiology panel at thetime the recommendation was made. Atlhough these analyses were secondary, they support the
primary efficacy variable analysis.
The imbalance observed in the rate of outpatient rehabilitation (clearly more frequently•
prescribed in the 1.50 mg/ml dibotermin alfa /ACS group compared to control group) could be achance finding. Although the latter cannot be verified, it is important to note that no significant
interaction was found between the prescription of outpatient rehabilitation and efficacy of the
product with respect to the primary efficacy endpoint (Breslow-Day test) and the overall
treatment effect was confirmed in the Cochran-Mantel-Haenszel test identifying patients withand without outpatient rehabilitation.

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•

•
•

The imbalance observed in the distribution of reaming procedure (reamed vs. non-reamed
intramedullary nailing) in the treatment groups (more frequent in the dibotermin alfa /ACS 1.50
mg/ml group than in the control group) appears to be the result of the central randomisation
system. Centres that enrolled a higher proportion of patients in the 1.50 mg/ml group were also
centres that primarily used reamed IM nails. However, within those centres which usedpredominantly reamed IM nails, there was no noticeable imbalance between the treatmentgroups, suggesting that the choice of fixation method was not affected by treatment group
allocation. Hence, the likelihood of bias caused by knowledge of treatment allocation appears
small. The possible impact of this imbalance as a confounding factor on efficacy results is
discussed below.
The fact that the time to recommendation for secondary intervention was similar acrosstreatment group and that there was good concordance between prescription and performance of
secondary interventions suggest absence of meaningful bias.
The treatment effect was dose-dependent and consistent across a number of subgroup analyses,
including analysis by geographical region and risk factors (smoking and Gustilo-Andersentype).

Secondary efficacy endpoint: Independent radiographic assessment - time from definitive
fracture fixation to fracture union: There were no statistically significant differences between thetreatment groups in the time to independent radiographic assessment of fracture union. The mediantime to fracture union was 275, 271, and 271 days for the SOC, 0.75 mg/ml and 1.5 mg/ml groups.
Secondary efficacy endpoints: Pharmacoeconomic: Initial hospitalisations were evaluated toestablish comparability between treatment groups. The incidence and duration was similar across thegroups. The proportion of patients with inpatient rehabilitation prescribed after the initial
hospitalisation was similar across groups. However, a statistically significant number of patients in 1.5
mg/ml group (37%) had outpatient rehabilitation prescribed as compared with the SOC group (22%).
This imbalance appears to be driven by differences in prescribed rehabilitation at specific centres, but
could bias the results in favour of dibotermin alfa /ACS.
Rate of secondary and subsequent interventions to promote healing: This measure of health resource
consumption was expected to closely relate to the primary efficacy measure. It differs, however, in
two respects: it captures only interventions actually performed and considers overall procedures. In the
ITT population, there was a dose-dependent trend towards a decrease in the overall number ofprocedures that was caused by a decrease in the number of most invasive interventions(Table 11.4.1.4.2-1). Some of the procedures required hospitalisation. This resulted in 317 hospitaldays for patients in the SOC group compared to 185 days in the 1.5 mg/ml group.

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These data are important in showing that 1) the rate of both invasive and less invasive procedures was
lower in the dibotermin alfa /ACS groups compared to SOC, although the difference was notstatistically significant with regard to less invasive procedures, and 2) the division of interventions into
invasive and less invasive within the threatment groups is similar.
Secondary endpoint: Time from definitive fracture fixation to fracture healing: There were
statistically significant, and clinically meaningful, differences between treatment groups in the time tofracture healing, with earlier healing in the 1.50 mg/ml dibotermin alfa /ACS group compared with the
SOC group (P = 0.0022 [Wilcoxon]; P = 0.0595 [log rank]) and 0.75 mg/ml dibotermin alfa /ACS
group (P = 0.0127 [Wilcoxon]; P = 0.0407 [log rank]). A 50% probability of fracture healing wasobserved at 184, 187, and 145 days in SOC, 0.75 mg/ml dibotermin alfa /ACS, and 1.50 mg/ml
dibotermin alfa /ACS groups, respectively. However, the median time to clinical decision of healing
was 138 days in the 1.5 mg/ml group, 157 days in the 0.75 mg/ml group, and 155 days in the SOC
group. Here the clinical relevance of the difference is less obvious.
It is agreed that there is medical need to improve treatment results in long bone fractures requiring
open surgical reduction and IM nail fixation and also that tibia fractures are the most demanding
model for new treatments. However, tibia fractures tend to heal more slowly and delayed union or
non-union are more frequent in fractures of the tibia compared to other long bone fracture. Therefore,
the question is left open whether use of this medicinal product would offer any clinically relevant
advantage over standard of care in fractures which heal more rapidly. The claim for a broader
indication would have to be substantiated with data. The indication is therefore restricted to thefollowing:“InductOs is indicated in the treatment of acute tibia fractures in adults, as an adjunct to standard careusing open fracture reduction and IM nail fixation.”
Clinical studies in special populations
There is very limited experience with the use of dibotermin alfa /ACS in children and elderly patients.
Sections 4.2 (Posology) and 4.3 (Contraindications; for children) of the SPC have been revised toreflect this.
Experience with the use of dibotermin alfa /ACS in diabetic patients is limited. Results up to now do
not indicate an increased risk for retinopathy in diabetic patients.
The use of dibotermin alfa /ACS in patients with osteoporosis or age-related osteopenia should be safe
because dibotermin alfa /ACS, when applied to long-bone diaphyseal fractures, does not increase therisk of bone resorption. However a statement in the warning section of the SPC that the product should
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not be used for direct applications to trabecular when bone resorption may create a risk of bone
fragility has been added.
Subgroup analyses and exploratory analysis performed across trials
Fracture and wound characteristics: Subgroup analyses of the primary endpoint were also done by
Gustilo strata and AO classification, and the presence of gap following fracture reduction. In theanalysis of patients in stratum A (Gustilo I-IIIA), the rate of secondary intervention was statisticallysignificantly lower in the 1.50 mg/ml dibotermin alfa /ACS group (23%) compared with the SOC(41%) and 0.75 mg/ml dibotermin alfa /ACS (35%) groups (P = 0.0026 and 0.0438, respectively;
Fisher’s exact test). For patients with more severe fractures (stratum B; Gustilo IIIB), the rates ofsecondary intervention were also statistically significantly lower in the 1.50 mg/ml dibotermin alfa
/ACS group (42%) and the 0.75 mg/ml dibotermin alfa /ACS group (45%) compared with the SOC
group (88%) (P = 0.0074 and P = 0.0157, respectively; Fisher’s exact test). AO classification did notappear to be a strong predictor of outcome. The failure rate in SOC patients with type A, B or C
fractures did not show a progression from less to more severe. Overall, the presence of a post fracture
reduction gap was associated with an increased risk of secondary intervention. In the SOC group,
patients who were left after fracture reduction with a gap >2mm had twice as many secondaryinterventions to promote fracture healing as compared with SOC patients with no gap (P = 0.0129).
However, dibotermin alfa /ACS appears to affect healing and decrease the rate of secondaryinterventions irrespective of the presence of a post reduction gap.
The results of primary efficacy variable analysis according to nail type (reamed, nonreamed) has
already been discussed above.
Time from definitive fracture fixation to clinical decision of secondary intervention was similar in
the three treatment groups (105 to 107 days). This is suggested to show that no bias was introduced inassessment of patient status and recommending secondary interventions.
The number of secondary interventions that were recommended but not performed was low andsimilarly distributed among the groups. There were no patients with a clinical outcome of secondaryintervention who met the criteria of a healed patient at the time of the decision.
An analysis of investigator treatment interaction has been subsequently presented and. the results do
not suggest that the treatment effect was different across countries/centres.
A total of 11 patients had diabetes, 10 of these had a clinical outcome. The rate of outcomes was 75%
in the SOC group and 50% in the 1.5 mg/ml group.
The rate of secondary interventions has been analysed according to NSAID and corticosteroid use.
Only 16 patients used corticosteroids and the results do not allow a clear conclusion (20-33% rate ofsecondary interventions, no dose-related trend). Altogether 151 patients used NSAIDs. The rate ofsecondary interventions in these patients decreased with increasing dibotermin alfa /ACS dose: 60%(SOC), 45% (0.75 mg/ml), and 39% (1.5 mg/ml). The relatively high rate of secondary interventions
in patients who used NSAIDs regardless of treatment group is noteworthy. NSAIDs may impair
fracture healing.
Clinical safety
The safety of dibotermin alfa /ACS has been evaluated in altogether 13 studies. For the Integrated
Summary of Safety (ISS), two separate data sets were generated. The first includes the orthopaedic
trauma studies (long-bone fracture data set). The second includes all GI sponsored studies (all-studies
data set). The five studies included in the long-bone data set are C9320-11, C9414-11, C9530-11(pivotal phase III trial), C9612-11, and C9828-11, all evaluating the safety of the medicinal product inpatients with open tibial shaft fractures.

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Patient exposure
The long-bone fracture data set comprises 588 patients. A total of 202 patients were treated withstandard of care (SOC), 12 with 0.43 mg/ml dibotermin alfa /ACS, 172 with 0.75 mg/ml and 202 with
1.50 mg/ml.
The all-studies data set comprises 1000 patients, and includes 348 patients who received 1.50 mg/ml
dibotermin alfa /ACS, 239 patients treated with 0.75 mg/ml, and 48 patients treated with 0.43 mg/ml.
The proposed dibotermin alfa /ACS concentration for clinical use is 1.50 mg/ml.
Long-bone fracture data set
No patients were withdrawn from studies due to dibotermin alfa /ACS complications. The averagefollow-up was 45 weeks. The patients were predominantly under 65 years of age (97%), male (81%)
and Caucasian (67%).
The most frequently reported adverse events (reported by at least 10%) are representative of themorbidity observed in the trauma setting (pain, oedema, anaemia) (Table 4.3.1-1). The frequency ofthese AEs was similar across treatment groups with the exception of pain (more frequent in the SOC
group compared to dibotermin alfa /ACS groups).

Adverse events reported in <10%, but more than 10 patients (>1.7%) also were consistent with themorbidity associated with trauma setting. The frequency of AEs in this category was similar acrossgroups with two exceptions: tachycardia and increased serum amylase occurred more frequently in the
dibotermin alfa /ACS compared to controls. A total of 4, 11, and 11 patients in the SOC, 0.75 mg/ml,
and 1.50 mg/ml groups, respectively, reported tachycardia (overall in 2% of patients in the SOC group
and 6% in the combined dibotermin alfa /ACS groups). The events were graded mild to moderate andresolved without sequelae. The tachycardia was correlated to concurrent anaemia and/or fever
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secondary to trauma. Patients who experienced increased amylasaemia did not show overt signs ofpancreatitis. A total of 6, 21, and 10 patients in the SOC, 0.75 mg/ml, and 1.50 mg/ml groups,
respectively, experienced increased amylasaemia. Two additional patients (1 in the SOC and 1 in
0.75 mg/ml group) were identified in the all-studies data set. This finding has been attributed to thetrauma setting. The overall frequency of increased amylasaemia was 3% in the SOC group and 8% in
the combined dibotermin alfa /ACS groups. No dose- response effect was observed. This issue, as wellas cases of pancreatitis, will remain under close surveillance.
The updated data with regard to cardiovascular reactions, including tachycardia, do not suggest thatthese reactions are related to the use of dibotermin alfa /ACS.
Twenty-eight Grade 4 (life-threatening) adverse events were reported. The most frequent Grade 4 AE
was anaemia.
The frequency of serious AEs was similar in the SOC (42%) and dibotermin alfa /ACS groups (38%).
Five deaths were reported in this data set, one patient randomised to SOC and 4 patients randomised todibotermin alfa /ACS. All cases were considered unrelated to administration of dibotermin alfa /ACS.
Six patients underwent amputation of the limb under study. Three of these patients received
dibotermin alfa /ACS before amputation. Five of the cases were considered unrelated to treatment. In
one case, the relationship to dibotermin alfa /ACS was reported as unknown.
Overall, the patients treated with dibotermin alfa /ACS had fewer instances of hardware failure whencompared to SOC, and fewer patients experienced delayed union or nonunion. Hypertrophic callus orsoft tissue calcification was reported in 3% of patients. The ISS data set does not suggest an increased
risk of hypertrophic callus or soft tissue calcification compared to SOC.
In contrast, the pivotal efficacy and safety study showed, quite expectedly, that hypertrophic callus or
local heterotopic ossification was more frequent following dibotermin alfa /ACS implantation.
The frequency in the SOC group was 2.7% and in the 1.50 mg/ml group it was 5.5%. Furthermore, it
should be noted that patients with a history of heterotopic ossification were excluded from clinicalstudies.
Twenty-five percent of patients evaluated in this data set for the region under study developed
infections. Of these, 20% required administration of antibiotics and 8% required surgery. There wasno difference in the frequency of infection across treatment groups.
Soft tissue healing complications (e.g. delayed wound healing, discharge, erythema, necrosis,
inflammation) were equally distributed in the SOC and dibotermin alfa /ACS treatment groups.
In the long bone fracture studies dataset, the frequency of soft tissue healing complications(e.g. delayed healing, discharge, erythema, necrosis, inflammation) were equally distributed in thetreatment groups. The higher incidence of ”healing abnormal”, wound draining and oozing in one of
the studies is a cause of some concern. However, this could be related to pharmacological activity ofdibotermin alfa with resulting oedema and extravasation of fluid.
Compartment syndrome was not reported, but one patient treated with dibotermin alfa /ACS
underwent fasciotomy after definitive wound closure.
The updated integrated summary of safety shows that the frequency of hypesthesia is not significantly
higher in dibotermin alfa /ACS treated patients compared to controls. However, the frequency remains
slightly higher (10.7% vs. 7.1%). The severity of trauma (and differences in the severity between
treatment groups) and resulting oedema/compression is thought to be the most likely explanation.
No clear association was found between hypesthesia and inflammation, heterotopic ossification or
antibody response.

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All-studies data set
The average follow-up was 54 weeks. The majority of patients were under 65 years of age (94%),
male (69%) and Caucasian (72%).
The most frequently reported AEs (at least 10% of patients) were pain, oedema, anaemia, andhyperglycaemia. With the exception of pain, oedema, and rash (erythema) which were observed more
frequently in SOC patients, the frequency of AEs was similar across treatment groups.
The incidence of tachycardia and increased amylasaemia was not significantly different acrosstreatment groups in this larger data set. The increased amylasaemia is thought to reflect the patients’trauma status. The high incidence of hyperglycemia is largely a result of postoperative fluid
replacement.
With regard to AEs reported in <10% of patients, but in more than 10 patients (>1%), headache wasreported by a statistically significant higher percentage of patients treated with dibotermin alfa /ACS
when compared to SOC. By treatment group, 7% of SOC patients, 12% of 0.75 mg/ml patients and
10% of 1.50 mg/ml dibotermin alfa /ACS treated patients reported headache.
All deaths and Grade 4 AEs were reported in the long-bone fracture data set. Serious adverse eventswere evenly distributed cross treatment groups.
Malignancies
An updated review of all reported cases of cancer or other malignancies in all patients enrolled indibotermin alfa /ACS studies sponsored by Genetics Institute up to 15 September 2001.
This evaluation includes 1250 patients, with a cumulative follow-up of 1744 years. A total of
517 patients were enrolled in control groups, 28 received only the ACS matrix, and 705 patients wereenrolled in dibotermin alfa treatment groups.
Of the 517 patients enrolled in control groups, 6 patients (1%) reported 6 cases of malignancy.
Of 705 patients enrolled in dibotermin alfa -treatment groups, 7 patients (1%) reported 9 cases ofmalignancy. No case was reported in any of the 28 patients who received the ACS alone.
Of the 9 cases reported by dibotermin alfa -treated patients, 3 occurred either before treatment or atshort intervals after exposure to dibotermin alfa (<52 weeks). This makes drug-related
carcinogenicity unlikely. No reports of malignancy have been received for patients in the pivotal
study, C9530-11.
Thirteen (13) of 15 cases reported were found in patients enrolled in dental craniofacial or in
orthopedic nontrauma studies. This observation is consistent with the older patient population
enrolled in these studies and the longer follow-up required by these studies. There are various types ofmalignancies reported, which are generally representative of those observed in this older patient
population: 6 skin cancers (including 1 melanoma), 4 breast cancers, 2 prostate cancers, 1 cancer ofabdominal lining cells, 1 multiple myeloma, and 1 brain tumor. None of the cancers appeared at thesite of product implantation, and there is no indication that their development was unusual. The low
number of cases observed does not allow for an accurate calculation of the incidence index for any oneof them.
Data on the occurrence of malignancies seem to be reassuring, with no indication of an increased riskof cancer in patients exposed to dibotermin alfa /ACS. However, total follow-up is still relatively shortfor most patients. Therefore postmarketing periodic safety updates will specially address this issue ofthe occurrence malignancies.
Due to the pharmacodynamic properties of dibotermin alfa , use of the product must be
contraindicated in the vicinity of any tumor or metastasis. The limited data available so far (including
tumor incidence in control and dibotermin alfa /ACS groups and tumor types) does not suggest an
increased incidence relative to general population. However, the available database is too small to beconclusive. The concerns with regard to oncogenic potential of dibotermin alfa have been outlined in
the preclinical assessment report.
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Quality of bone
Bone biopsies were obtained systematically only in patients enrolled in the oral surgery studies, andoccasionally in a subset of patients treated for long-bone fractures. These samples indicated that
osteoinduction was observed without signs of excessive inflammation or excepssive or abnormal boneformation. No residual ACS was found 16 weeks following implantation. Unfortunately, in thepivotal efficacy and safety trial, only a limited number of bone biopsies were performed and only at
the time of secondary intervention. Therefore, it is not unexpected that the findings were consistent
with fibrous nonunion.
The “radiolucent voids” that were reported in dental-craniofacial studies were actually hypodenseareas of nonmineralized bone rather than radiolucent voids. The findings of hypodense areas werereported as “radiolucent void” in the clinical studies because the reporting form did not include otheroptions such as “hypodense area.” Furthermore this radiographic finding is quite different from theradiographic findings observed in the preclinical program where, unlike in the human radiograph,a distinct shell of bone is present at the dibotermin alfa /ACS implantation site.
The occurrence of adjacent bone resorption (trabecular or cortical) clearly appears to exceed the
expected resorption taking place during remodelling. This finding has been observed in bothpreclinical and clinical trials (c.f. C9524-11) and has been reflected in the SPC: it has been mentionedthat dibotermin alfa /ACS should not be used in the treatment of metaphyseal fractures and should not
be used to facilitate attachment of endoprosthetic devices.
Safety in special populations
Safety of dibotermin alfa /ACS was also analysed in subsets of the population (age, gender, and race).
No conclusion could be drawn for patients over 65 years of age due to low numbers. In addition, no
conclusion could be drawn when examining the data by gender since women were more numerous in
the oral surgery studies and males were more numerous in the long-bone fracture studies. The Black
population was found to have no increased risks. Administration of dibotermin alfa /ACS in pregnant
or nursing women and in children has not been systematically studied. Three patients in the clinical
trials became pregnant 10-582 days after administration of dibotermin alfa /ACS. In one case thepregnancy was diagnosed 10 days after administration. The patient delivered a full-term healthy baby.
One of the patients had an elective abortion and the third had 2 uncomplicated pregnancies carried toterm.
The very limited experience in elderly patients has been stated in the SPC. The use of the medicinal
product has been contraindicated during pregnancy.
Interactions
The concomitant use of glucocorticoids or non-steroidal anti-inflammatory drugs (NSAIDs) was notfound to increase overall safety risks. However, patients taking NSAIDs for more than 14 days andwho received dibotermin alfa /ACS concomitantly, experienced an increased frequency of mild tomoderate healing abnormal AEs when compared with patients receiving dibotermin alfa /ACS without
concomitant NSAIDs.
NSAIDs may impair normal healing process. An interaction between NSAIDs and dibotermin alfa
/ACS leading to impaired efficacy/safety of the medicinal product cannot be excluded. The above data
are consistent with the efficacy results of the pivotal long-bone fracture trial. In the pivotal trial, arelatively high rate of secondary interventions (to promote fracture healing) in patients who used
NSAIDs is noted regardless of the treatment group.
Immunogenicity
In all studies combined, 3% of patients had an immune response to dibotermin alfa . Almost all
patients presenting with an immune response were exposed to dibotermin alfa /ACS. Twenty-three of582 (4%) patients who received dibotermin alfa /ACS developed antibodies to dibotermin alfa
compared with 2/296 (0.7%) patients in the SOC group. This difference was significant (p=0.0045).
The incidence in the group receiving 1.50 mg/ml dibotermin alfa was 6%.

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In the pivotal phase III trial, a dose-dependent immune response to dibotermin alfa was observed.
The number of patients who developed antibodies against dibotermin alfa in the SOC, 0.75 mg/ml
dibotermin alfa /ACS, and 1.50 mg/ml dibotermin alfa /ACS groups, respectively, were 1 (1%),
3 (2%), and 9 (6%). The immune response was characterized by low titers mostly present 6 weeks
after definitive fracture fixation and of a transient nature (titers were negative in 10/10 patients withsamples available for follow-up). However, based on the small data set, there appears to be no
relationship between antibody responses and secondary interventions (efficacy) or incidence ofspecific adverse events. However, a larger database would be needed to rule out an impact.
Anti-bovine Type I collagen antibody responses: For all protocols combined, 14% of patients had
antibody responses to bovine Type I collagen. Increased levels of circulating antibodies were observedin 11% of patients in the SOC group, 7% of the patients treated with buffer/ACS alone, and 15% of all
patients in the BMP-2/ACS group. The difference in the incidence of anti-bovine Type I collagenantibodies in patients receiving dibotermin alfa /ACS compared with SOC approached significance(p=0.0610). To evaluate this trend, 2 analyses were performed: 1) comparing the incidence of antibovine Type I collagen antibodies in SOC and dibotermin alfa /ACS-treated patients in the long-boneand other orthopaedic studies and 2) comparing the incidence of anti-bovine Type I collagenantibodies in SOC and dibotermin alfa /ACS-treated patients in the oral surgery studies.
The difference between SOC and dibotermin alfa /ACS-treated patients in the long-bone and otherorthopaedic studies was significant (p=0.0010), the result of this analysis for the oral surgery studies
was not (p=0.5132).
A review of the immune response to dibotermin alfa and to bovine Type I collagen in a subset ofpatients enrolled in 6 dental craniofacial studies was also carried out. A separate evaluation of thisdental craniofacial subgroup of patients was thought to be relevant because they were enrolled instudies designed to have a longer follow-up (up to 5 years). There was no time-dependent emergenceof manifestations associated with the presence of autobodies to dibotermin alfa /ACS or to bovine
Type I collagen.
It is not clear why patients in the SOC group developed antibodies to bovine collagen. A review of the
medical history for these patients indicated they were not exposed to other medical products
containing bovine collagen. Overall, patients receiving 1.50 mg/ml dibotermin alfa /ACS experienced
a 19% incidence of anti-bovine Type I collagen antibodies.
No association between the presence of circulating anti-bovine type I collagen antibodies and clinicalsymptoms of an immune/allergy response was noted. Since the bovine type I collagen in the product isclearly immunogenic, the occurrence of hypersensitivity reactions cannot be ruled out.
All of the patients with positive titers to bovine type I collagen were tested for the presence of an
immune response to human type I collagen. Cross-reacting antibodies were not found.
Thus far there is no evidence of an association of antibody response to dibotermin alfa and loss of
efficacy or undesirable effects. However, the current database is too limited to be conclusive.
The applicant will continue to address this issue in ongoing studies and post-marketing surveillance.
The immunogenicity of the product is reflected in the SPC.
Based on the current database, both the local safety of the product, in terms of adverse events affecting
the anatomical region of interest, and general safety appears favourable. The fact that an increased
incidence of inflammation, infections and wound/soft tissue healing abnormalities was not reported
compared to control group in the target population is reassuring. No deleterious effect on woundhealing was observed, but actually a potentially favourable outcome in the high dose group despite.
The favourable wound healing profile altogether is also a reflection of the patient population selected
for the pivotal trial (e.g. the number of diabetic patients was small). Furthermore, hardware failures
were clearly less frequent in the dibotermin alfa /ACS 1.5 mg/ml group compared to SOC group.

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4.

Overall conclusions and benefit/risk assessment

Quality
The quality of this product is considered to be acceptable when used in accordance with the conditions
defined in the SPC. Physicochemical and biological aspects relevant to the uniform clinicalperformance of the product have been investigated and are controlled in a satisfactory way.
Viral Safety and Batch to batch consistency has been documented and the relevant test will be
performed according to the agreed specifications. Appropriate post-approval commitments related to
the ACS matrix and the stability testing of the vialed protein have been agreed.
Preclinical pharmacology and toxicology
Locally administered dibotermin alfa /ACS results in the induction of new bone at the site of
implantation. Pharmacodynamic studies in rats, dogs, rabbits, sheep, goats and nonhuman primates
were conducted to show the safe and efficacious use of dibotermin alfa /ACS. The submitted in vitro
data describe several bone forming related effects of dibotermin alfa . From the in vivo studies it canbe concluded that depending on the dose of dibotermin alfa used, new formed bone by dibotermin
alfa /ACS was as strong as native bone. A clear dose-dependent effect, however, was not always
observed. Furthermore, in long-bone critical-sized defect studies, especially in nonhuman primates,
the bone formation effect of dibotermin alfa /ACS was variable and not always reproducible.
Dibotermin alfa is an endogenous protein which distribution is restricted to the blood
volume/extracellular volume and dibotermin alfa is rapidly degraded in the liver and excreted via thekidneys. After implantation 0.1 % of the implanted dose is released systemically. The half life ofdibotermin alfa is approximately 15 minutes.
The toxicity of rhBMP was studied in rats and dogs either by i.v. injection or by a dibotermin alfa
/ACS implants. The only effects observed were related to the pharmacodynamic action of dibotermin
alfa , i.e. bone formation. Antibodies to dibotermin alfa were monitored in the toxicity studies, thereporting of these studies was not complete therefore a final conclusion can not be reached.
Reproduction and fertility in male and female rats was not affected by dibotermin alfa .
Embryo-fetal development studies in gravid rabbits treated with dibotermin alfa did not result insystemic maternal toxicity, embryo lethality or gross fetal abnormalities at dosages up to
1.6 mg/kg/day.
Treatment of rats with high intravenous doses of rhBMP (1.6 or 0.5 mg/kg/day) during organogenesis
resulted in increased foetal weight in 2/3 experiments. Additionally, some skeletal variations wereobserved indicating a more advanced foetal development.
From preclinical studies no clear optimal dose can be extrapolated for the clinical use of this productdue to efficacy differences between used models and species. With the exception of bone formation,
local inflammatory changes, possible effects on skeletal variants in teratology studies and antibody
formation, no significant effects were observed in the preclinical toxicology studies. The fact that allof the studied species were sensitive to the primary pharmacologic action is naturally reassuring andthe main reason for the differences in sensitivity between species may well be the species-specificdifferences in bone formation kinetics. The absence of a sufficiently sensitive method to quantify
dibotermin alfa in human plasma following implantation of the product makes it impossible tocompare systemic exposure between experimental animals and man.
Efficacy
Clinical efficacy of dibotermin alfa /ACS is mainly based on one pivotal trial in 450 patients (C953011). This was a multinational, multicenter, single blind, stratified, randomised, controlled study in 450
patients with open tibial shaft fractures that required surgical management with IM nailing. Patientswith all fracture severity levels were included, excluding only patients at high risk of amputation(Gustilo classification IIIC). Furthermore, patients were required to undergo immediate woundtreatment (to reduce the infection risk), fracture reduction and stabilisation with IM nailing, which
represents the standard of care for tibial shaft fractures at the participating sites. Patient treatment
assignments were stratified by Gustilo classification. Patients were randomised to 1 of 3 treatment
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groups: standard of care (SOC), 0.75 mg/ml dibotermin alfa /ACS, or 1.50 mg/ml dibotermin alfa
/ACS. In each of the 3 treatment groups, patients received standard surgical management of thefractured tibia (including IM nailing) and soft tissue. In the dibotermin alfa /ACS treatment groups,
patients received standard surgical management plus 0.75 or 1.50 mg/ml dibotermin alfa /ACS
implanted at the time of definitive wound closure (DWC).
Primary efficacy endpoint was the proportion of patients who required a secondary intervention topromote fracture healing within 12 months of DWC. Secondary endpoints were healing rate at
6 months, acceleration of fracture union. Additional endpoints were the combined clinical andradiographic endpoint, time to prescription of secondary intervention, and number and invasiveness ofinterventions actually performed.
Treatment with 1.5 mg/ml dibotermin alfa /ACS produced a significant reduction in the rate ofsecondary interventions prescribed to promote fracture healing, and in the invasiveness of the secondand subsequent interventions actually performed. The treatment was associated with a significantly
increased rate of clinical fracture healing at 6 months after definitive wound closure, with significant
improvement in fracture healing rates seen as soon as 10 weeks after DWC, and further confirmed
through 12 months after DWC.
As regards the acceptability of the single pivotal trial for marketing authorisation, it is concluded thatwith the exception of external validation (suitability for extrapolation) and consistency of effect acrosssubgroups, the criteria for acceptance have been fulfilled. These two deficiencies have been resolved
through restriction of the therapeutic indications and appropriate description of study results in the
SPC.
SafetyWith respect to safety, data presented up to date has not revealed any concerns. In particular, there wasno difference in the occurrence of infections across treatment groups, dibotermin alfa /ACS does notappear to increase the incidence of bone disorders, such as local soft tissue or heterotopic ossification.
Furthermore, findings from histologic analysis were unremarkable. Antibody formation was not acause for a significant safety concern. Until now, 15 malignancies (most skin cancers) were reported
in 13 patients. However, safety data are limited to 1000 patients with a mean follow up of 54 weeks.
This time period is considered to be too short for the development and diagnosis of malignancies, andfor the formation of antibodies. The applicant will continue to monitor this issue in ongoing studies
and post-marketing surveillance.
Benefit/risk assessment
From a quality and pre-clinical point of view, appropriate post-marketing commitments have beenmade. The product information reflects the pre-clinical findings.
It is concluded that efficacy and safety of dibotermin alfa /ACS are acceptable for the patient
population studied, that is: for patients with an open tibial shaft fracture requiring surgicalmanagement with intramedullary nailing. The use of more than one kit should be avoided.
dibotermin alfa /ACS is not recommended for use in•in children and in elderly patients,•
in large segmental defect repair of long bones, in which significant soft tissue compression canoccur,•
in patients with any malignancy.
Efficacy and safety have not been demonstrated in patients with other long-bone fractures that require
open surgical management. Although one might suppose that dibotermin alfa /ACS will beosteoinductive in these fractures, the benefit for the patient in reduction of secondary intervention andtime to fracture healing in patients with other long-bone fractures is not clear.

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The Applicant has made the following commitments:
to conduct a controlled, randomised clinical trial of InductOs (plus standard care) versus•
standard care in patients treated with reamed IM nails.
•
studying long-term risks of dibotermin alfa /ACS, especially for the development ofmalignancies and antibodies.
Based on the CPMP review of data on quality, safety and efficacy, the CPMP considered by consensus
that the benefit/risk profile of InductOs was favourable in the treatment of acute tibia fractures inadults, as an adjunct to standard care using open fracture reduction and intramedullary nail fixation.

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London, 17 February 2005
Product name: INDUCTOS
Procedure No. EMEA/H/C/408/II/07

SCIENTIFIC DISCUSSION

1TABLE OF CONTENTS
Page
1. INTRODUCTION ..................................................................................................................... 3
2. QUALITY REGARDING THE MEDICAL DEVICE........................................................... 3
3. NON-CLINICAL ASPECTS .................................................................................................... 4
3.1 Discussion on non-clinical aspects .................................................................................... 8
4. CLINICAL ASPECTS .............................................................................................................. 9
4.1 Clinical Pharmacology....................................................................................................... 10
4.2 Clinical Efficacy ................................................................................................................ 11
4.3 Clinical Safety.................................................................................................................... 20
5. OVERALL DISCUSSION AND BENEFIT/ RISK ASSESSMENT..................................... 29
5.1 Non-clinical data ................................................................................................................ 29
5.2 Clinical efficacy ................................................................................................................. 29
5.3 Clinical safety .................................................................................................................... 31
5.4 Benefit/Risk assessment..................................................................................................... 34
6. CHANGES TO THE PRODUCT INFORMATION .............................................................. 35
7. CONCLUSION .......................................................................................................................... 37

2

1. INTRODUCTION
This type II variation application aims to extend the therapeutic indications for InductOs (diboterminalfa). The proposed additional new indication is:“InductOs is indicated for single-level (L4 - S1) anterior lumbar spine fusion as a substitute for
autogenous bone graft in adults with degenerative disc disease who have had at least 6 months of nonoperative treatment for this condition.”
For this indication, InductOs must be used with the LT-CAGE® Lumbar Tapered Fusion Device.
The currently approved therapeutic indication reads as follows:“InductOs is indicated for the treatment of acute tibia fractures in adults, as an adjunct to standard careusing open fracture reduction and intramedullary nail fixation.”
The MAH claims significant medical benefits of InductOs in spine fusion surgery as a direct
replacement for autogenous bone graft. These include relief from the symptoms of degenerative discdisease, achieved without the pain and morbidity associated with a second surgical site to harvest
autogenous bone graft, less blood loss during surgery and shorter operative times.
Outside of the EU, dibotermin alfa/ACS (Absorbable Collagen Sponge) is currently approved formarketing, under the name ‘INFUSE Bone Graft’ in the USA, Canada and Mexico. In the USA, it isapproved as a medical device for both anterior lumbar spine fusion procedures and acute tibia
fractures, whereas in Canada and Mexico, it is approved for anterior lumbar spine fusion procedures
only.
2. QUALITY REGARDING THE MEDICAL DEVICE
Following validation of the application, the MAH has provided information regarding the LT-CAGE.
The proprietor is Medtronic Sofamor Danek.
The LT-CAGE Lumbar Tapered Fusion Device consists of a hollow, perforated, machined cylinder
with opposite flats. The cage has a tapered design with an angle of 8.8o and is available in diameters
ranging from 14 mm to 18 mm end of taper, 17 to 22 mm at the wide end of the taper, and in lengths
ranging from 20 mm to 26 mm. There are two holes on each of the two flat sides. On each of the tworounded aspects, there is a single rounded slot. The implants have a helical screw thread on the outersurface. One end of the device is closed and is used to engage the drive instrument for insertion of thedevice.
The LT-CAGE Device is made from implant grade titanium alloy (Ti-6A1-4V) described by suchstandards as ASTM F136 or its ISO equivalent.
Technical drawings of the device and the Package Insert have been provided. The Package Insert is incompliance with the EU Medical Devices Directive (93/42/EEC), and is subject to an annual review
by the designated EU Notified Body.
The CHMP noted that the indications for use of the LT-CAGE Lumbar Tapered Fusion Device are inline with the proposed therapeutic use of this device with InductOs i.e. for spinal fusion procedures inskeletally mature patients with degenerative disk disease (DDD) at one level from L2-S1. Patientsshould have had at least six months of nonoperative treatment prior to treatment with LT-CAGE.
According to the Package Insert, the device is indicated for use with autogenous bone graft.
Therefore, the CHMP concluded that the therapeutic indication for InductOs should also specify thatpatients should have a history of at least six months of nonoperative treatment. The MAH agreed with
the CHMP’s proposal and amended the initial proposed indication to insert that patients should have ahistory of at least six months of nonoperative treatment.

3

Additionally, the CHMP proposed to delete the sentence “that InductOs must be used with the specific
LT-CAGE Lumbar Tapered Fusion Device” from the initially proposed indication since it blocks theuse of other devices. Since so far experience is limited to the LT-CAGE, this must be mentioned in
section 4.2 “Posology and method of administration” in the SPC. The MAH agreed on the CHMP’s
proposal.
3.

NON-CLINICAL ASPECTS

InductOs is a bone inductive agent consisting of recombinant human Bone Morphogenetic Protein-2(rhBMP-2) and Absorbable Collagen Sponge (ACS). rhBMP-2 is a glycosylated, disulfide-bonded,dimeric protein produced by mammalian cell culture methods. Local administration of rhBMP-2
results in the induction of new bone tissue at the site of implantation. To facilitate surgical application,rhBMP-2 is combined with a matrix, the ACS, resulting in a moldable cohesive implant. As bone isformed, the matrix is degraded as is the rhBMP-2 component.
The ACS matrix is the Helistat Absorbable Collagen Hemostatic Sponge manufactured from bovine
type I collagen derived from tendons. It is CE-marked in Europe, and sold commercially in the US,
Europe, Japan, and Canada as an intra-operative hemostatic agent which can be left in the surgical site.
Helistat has a long (>20 years) commercial history of safe use in medical applications.
At the time of surgical implantation, the ACS is wetted with a solution of rhBMP-2 to form theproduct (rhBMP-2/ACS). While application of rhBMP-2 alone is sufficient for osteoinduction, ACS asa carrier for rhBMP-2 provides a couple of functions. ACS localizes rhBMP-2 to the surgical site, andincreases the retention of rhBMP-2 at the desired site compared to rhBMP-2 in buffer alone. This isimportant for optimal and localised bone formation. The pharmacological studies previously submitted
have demonstrated that rhBMP-2/ACS induces bone formation, heals bony defects, and augments
fracture repair. These studies suggested that bone formation initiated by rhBMP-2/ACS is a selflimiting process, ie, only a defined volume of bone is created. This self-limitation is due to eventual
loss of rhBMP-2 from the implant site, as well as the presence of BMP inhibitors in the surrounding
tissues. In addition, several studies indicate that there is a negative feedback mechanism at themolecular biology level that limits bone induction by BMPs.
The product used in the interbody spine fusion application with the LT-Cage is identical to that
described in the InductOs MAA in terms of protein formulation, carrier matrix and concentration.
Therefore, previously reported toxicology and pharmacokinetic data are applicable to the indication
described in this submission. With general safety of rhBMP-2 and rhBMP-2/ACS established, thefocus of the nonclinical studies is on spinal fusion efficacy and safety. This submission contains thenonclinical information to demonstrate that rhBMP-2/ACS is effective for use in an interbody spinal
fusion application and safe for use in a spinal application in proximity to the spinal canal and nerveroots.
The pharmacology studies, with the exception of the 1 spinal safety study, were not performed inaccordance with Good Laboratory Practice (GLP) regulations.
The six non-clinical studies include lumbar fusion studies in nonhuman primates and sheep and a
cervical fusion study in goats. Two of the studies most relevant to the proposed indication had
treatment groups that allowed for direct comparison of rhBMP-2/ACS to autograft for promoting
spinal fusion in titanium interbody cages.
Study report RPT-52965: Graft Materials for a Titanium Threaded Interbody Fusion Device forAnterior Interbody Fusion in a Sheep Lumbar Spine Model
The primary purpose of this study was to compare the effectiveness of rhBMP-2/ACS to that of
autograft in promoting interbody spinal fusions using a titanium fusion cage. Twelve skeletally mature
sheep underwent L4-L5 interbody spinal fusion using the titanium cages. Animals were randomised4

into one of two treatment groups specifying the material to be used inside the fusion cage (autogenous
iliac crest bone or 0.43 mg/mL rhBMP-2/ACS). Animals were sacrificed at 24 weeks. Both study
groups resulted in 100% fusion rates as assessed via manual palpation. Biomechanical stiffness results
were reported in all autograft and five of six rhBMP-2/ACS treated animals and there was no
statistically significant difference between the two groups. A trend toward greater stiffness to flexion
with rhBMP-2/ACS was demonstrated. However, both the rhBMP-2/ACS and autograft treatmentgroups were found to be statistically significantly stiffer than untreated normal disc spaces fromunoperated spinal segments. Changes in interbody height were also analysed and no differences were
found between rhBMP-2/ACS treated animals and autograft controls. Histologic analyses showed a
37% fusion rate with autograft filled cages, as opposed to 100% fusion for the rhBMP-2/ACS group.
The rhBMP-2/ACS treated animals had dense remodeled bone growing through the holes in the cagewalls and trabeculae bridging adjacent vertebral bodies.
Study Report RPT-52963: Cervical Interbody Fusion Cages: An Animal Model With and Without
BMP
Although this nonclinical study was performed in a cervical model as opposed to a lumbar spinemodel, it is considered relevant to the proposed application of InductOs because it compares rhBMP2/ACS to iliac crest autograft inside a titanium fusion cage in an interbody fusion model.
The primary purpose of this study was to compare the effectiveness of rhBMP-2/ACS to that of
autograft in promoting interbody spinal fusions using a titanium fusion cage. Fourteen skeletally
mature goats underwent 3 contiguous cervical interbody spinal fusions using threaded interbody fusion
cages. Animals were randomised into one of 2 treatment groups specifying the bone graft material to
be used inside the fusion cage (iliac crest autograft or 0.40 mg/mL rhBMP-2/ACS). The same bone
graft material was used in all 3 cages within each animal.
Animals were sacrificed at 12 weeks. Levels were graded as having a successful fusion, a failed
fusion, or an intermediate result based on analysis of microradiographs and histologic sections.
Ninety-five percent (95%) of the rhBMP-2/ACS-treated levels had a successful fusion as opposed toonly 48% for the autograft treated levels. The remaining 5% of the rhBMP-2/ACS filled cages had an“intermediate” result (presence of some fibrous tissue) in comparison to 38% of the autograft filled
cage group. The failed fusion rate was 14% for the autograft versus 0% for rhBMP-2/ACS.
Biomechanical stiffness results did not reveal any statistical differences in the 2 treatment groups. In
addition, there was no statistically significant difference in stiffness in any loading mode by fusion
result. The lack of statistically significant differences may have been due to the stability provided by
the cage itself. Histologic analysis revealed that the use of rhBMP-2/ACS increased the rate of boneformation within and around the cage and accelerated the time to bone revascularization compared toautograft.
Study Report RPT-52962: Laproscopic Anterior Spinal Arthrodesis with rhBMP-2/Helistat® in a
Titanium Interbody Threaded Fusion Cage in the Non-Human Primate
The purpose of this study was to compare the effectiveness of various doses of rhBMP-2/ACS inpromoting interbody spinal fusion using titanium interbody cages. Eight adult Macaca mulatta (rhesus)
monkeys underwent L7-S1 interbody spinal fusion using a titanium cage. Animals were randomised
into 1 of 3 treatment groups according to the concentration of rhBMP-2 to be used inside the fusion
cage (0.0, 0.75, or 1.50 mg/mL rhBMP-2/ACS). One animal at 0.75 mg/mL died on postoperative day
3 due to a complication of the surgical procedure which was unrelated to rhBMP-2. The remaining 7
animals were sacrificed at 4 weeks.
All animals treated with rhBMP-2/ACS had solid fusions at 24 weeks as assessed by palpation, CT
analysis, and histologic analysis. Animals in the 0.0 mg/mL rBMP 2/ACS group did not have solid
fusions as assessed by the same 3 methods. CT scans of the 0.75 and 1.50 mg/mL rhBMP-2/ACStreated animals showed continuous bone through the cage in all animals, while the CT scans of the 0.0
mg/mL rhBMP-2/ACS animals showed some bone growth at the vertebral bodies that was notcontinuous across the disc space. The bone formed using the higher dose (1.50 mg/mL) of rhBMP-2
5

appeared to be denser than that formed using the lower dose (0.75 mg/mL) of rhBMP-2. Histologic
analysis confirmed the results of the
CT analysis. The cages filled with 0.0 mg/mL rhBMP-2/ACS were filled primarily with fibrous tissue
while the cages filled with 0.75 and 1.50 mg/mL rhBMP-2/ACS had normal trabecular bonethroughout. No animal had neurologic compression inside the spinal canal from newly forming boneor extension of bone formation to an unintended area.
Study Report RPT-52966: Evaluation of rhBMP-2/ACS in a Non-Human Primate Anterior Interbody
Fusion Model Utilizing a Freeze-Dried Allograft Cylinder
The purpose of this study was to assess the safety and effectiveness of rhBMP-2/ACS in an allograftbone dowel in promoting an interbody spinal fusion in a non-human primate. This study is considered
to be relevant to the proposed application of InductOs since in compares iliac crest autograft torhBMP-2/ACS in a higher order animal interbody fusion model. Six skeletally mature rhesus monkeys
underwent an anterior L7-S1 interbody lumbar fusion. The animals were randomised into 1 of 2
treatment groups according to the concentration of rhBMP-2 to be used inside the allograft bone dowel(iliac crest autograft or 1.5 mg/mL rhBMP-2/ACS). One animal from each group was sacrificed at 3
months and the remaining 4 at 6 months.
At 3 months, the rhBMP-2/ACS treated animal was manually, radiographically, and histologically
fused while the autograft control was not fused. The use of rhBMP-2/ACS also significantly increased
the rate of incorporation of the allograft bone dowel. The dense cortical bone dowel which was visible
radiographically immediately postoperative could not be detected in any of the three rhBMP-2/ACS
animals at 3 months. This observation was confirmed histologically. The allograft had undergone
almost complete incorporation. Evidence of creeping substitution was observed on a small piece of
allograft remaining at 3 months. No inflammatory or immune response was observed. In addition, noectopic or overgrowth of bone was observed around critical neural structures. In contrast, theappearance of the allograft dowels filled with autograft on the 3 month CTs was the same as theappearance immediately postoperative. The autograft controls had some osteoclastic resorption
occurring and new bone deposited on the allograft surfaces, but not to the extent seen with rhBMP2/ACS.
At 6 months, both of the remaining 2 animals treated with rhBMP-2/ACS were fused along with oneof the 2 autograft controls. The authors concluded that this study demonstrated the efficacy of rhBMP2/ACS and a cortical allograft dowel in promoting anterior interbody fusion in a nonhuman primate
model. The rate of new bone formation and fusion with the use of rhBMP-2/ACS and the corticalallograft dowel was superior to that of autogenous cancellous iliac crest graft with the cortical allograft
dowel.
Study Report RPT-52964: Safety of Recombinant Human Bone Morphogenetic Protein-2 After Spinal
Laminectomy in the Dog
The purpose of this study was to assess the effects of rhBMP-2/ACS on exposed dura and neural tissue
after standard decompressive lumbar laminectomy using a canine model. This study was conducted incompliance with GLP regulations. Twenty skeletally mature beagles underwent a spinal laminectomy
at the L5 spinal level. One-half of the animals also received a “dural nick” made with a 22 gauge
needle in the posterior midline of the spinal cord until cerebro-spinal fluid was noted to egress fromthe nick. Then, either autogenous bone graft or rhBMP-2/ACS was implanted directly on the exposed
spinal cord in the laminectomy defect. Animals were randomised into one of four treatment groups(Rib autograft with or without dural nick (N=5), rhBMP-2/ACS (0.10 mg/mL) with or without duralnick (N=5). This concentration of rhBMP-2 was previously shown to be effective in promoting spinal
fusion in a canine model. Animals were sacrificed at 12 weeks. Evaluation consisted of clinical,
neurological and radiographic examination and histological analysis. The clinical exam involved
weekly body weights, monthly blood tests and cerebrospinal fluid analysis at necropsy. Neurology
consisted of weekly gait observations and placing reflex, patellar reflex and the pain withdrawal ofboth hind limbs. Radiographic analyses were done on a monthly basis assessing changes in the spinal

6

cord, surrounding spinal canal and graft material using pre-established measurement parameters.
Histology was used to study the effect of rhBMP-2/ACS in direct contact with neurological tissue.
Neither rhBMP-2/ACS nor the dural nick presented deleterious consequences to the animals. The
implants resulted in a physical depression of the dural membrane which was radiographicallyapparent, suggesting that the implant came to rest adjacent to the thecal sac. The rhBMP-2/ACS
stimulated transient bone growth around the margin of the spinal canal. This suggests that the rhBMP2/ACS came in direct contact with the dural membrane. It may even have leaked into theneuroforamina since there was a bony reaction there. There was no radiographic evidence ofmineralization within the thecal sac. There was no evidence clinically of any neurologicalabnormalities in these animals. There was no evidence of any clinical abnormalities in these animals
based on blood and cerebrospinal fluid analyses.
Study Report RPT-52961: Binding Properties of rhBMP-2 to Absorbable Collagen Sponge After
Various Fluid Expression Amounts
Since ACS is compressible, it is possible that during intraoperative handling fluid will be expressedfrom the rhBMP-2/ACS. This fluid may contain rhBMP-2. The purpose of this study was to determine
the amount of rhBMP-2 in fluid expressed from rhBMP-2/ACS under different handling conditions.
For this study, 2.5 x 5 cm rhBMP-2/ACS strips were prepared by evenly distributing 1.4 mL of 1.5
mg/mL rhBMP-2 solution onto each of 30 ACS strips. The rhBMP-2/ACS were allowed to soak for 15
or 120 minutes and then rolled and compressed using forceps to intentionally express fluid. Strips
were subjected to 1 of 3 handling conditions based on the volume of expressed fluid (X): Group 1: 100µl < X < 250 µl, Group 2: 300 µl <X <650 µl, Group 3: 750 µl < X. The amount of rhBMP-2 in theexpressed fluid from each group (n=5) was determined by RP-HPLC.
It was determined that fluid expressed from rhBMP-2/ACS did contain rhBMP-2; however, only asmall amount of rhBMP-2 was released from ACS with compression, and this decreased with soaking
time. The rhBMP-2 concentration of the fluid expressed from ACS under different handling conditions
was consistent when compared at specific soak time. The mean concentration in the expressed fluid
was 35% of the applied concentration for the 15 minute soak time and 20% of the applied
concentration for the 120 minute soak time. Since the concentration of the expressate was consistent
the amount of rhBMP-2 lost from the ACS increased with increased fluid expression in a linear
fashion. With the most mild compression tested in this study (Group 1), the amount of rhBMP-2
retained was 95% for the 15 minute soak time and 97% for the 120 minute soak time.
In an attempt to gain clinical perspective on these study results, the amount of fluid loss was recorded
during rolling and placement of hydrated ACS into an LT-cage. For this part of the experiment, a 2.5
cm x 5 cm ACS was placed into a 14x20 LT-cage. The fluid volume lost ranged from 13 to 27 µL.
This study verifies the effectiveness of ACS in incorporating and retaining rhBMP-2 for surgicalimplantation. Using compression and handling conditions that seem to be extreme relative to what
would occur in normal intraoperative handling and placement in the LT-cage, the ACS still retained atleast 95% of the applied rhBMP-2 dose.

7

3.1

Discussion on non-clinical aspects

The non-clinical safety of rhBMP-2/ACS has been established based on information submitted in theoriginal Marketing Authorisation Application previously. The MAH has submitted additional nonclinical data to support the use of rhBMP-2/ACS in the proposed new therapeutic indication. The useof InductOs for spinal fusion naturally entails new risks, especially the risk of rhBMP-2 leakage fromthe implant and LT-cage and potential excessive bone formation or bone formation close to sensitive
neural structures. Furthermore, there is a risk of local inflammation and oedema potentially leading toneural and/or vascular complications.
The pharmacology studies, with the exception of the spinal safety study in dogs (RPT-52964), were
not performed in accordance with Good Laboratory Practice (GLP) regulations. This is a clear
drawback and reflects the device-oriented development of the product. However, since the studies areadequately reported, the CHMP concluded that this does not preclude approval of the variation.
The six non-clinical studies include lumbar fusion studies in nonhuman primates and sheep and a
cervical fusion study in goats. Two of the studies most relevant to the proposed indication had
treatment groups that allowed for direct comparison of rhBMP-2/ACS to autograft for promoting
spinal fusion in titanium interbody cages.
Except for RPT-52962 and RPT-52966, the preclinical pharmacodynamic/safety studies used a lower
concentration of dibotermin than that proposed for clinical use (1.5 mg/ml). Although the studies are
relevant in terms of showing the primary pharmacological action (bone formation and spinal fusion),
their relevance for safety assessment is less obvious. Furthermore, in study RPT-52966, InductOs wasused together with cortical allograft.
Non-clinical data underline the importance of following the instructions given in the SPC on theappropriate preparation and handling of the implant to avoid leakage of rhBMP-2. The company
should commit to produce suitable educational material for surgeons and other medical staff.
Since the non-clinical data relevant for the proposed indication do not provide a strong justification to
use the 1.5 mg/ml concentration of dibotermin alfa, the CHMP during its September 2004 plenary
meeting requested the MAH to discuss the possibility that a lower concentration could have a morefavourable benefit/risk profile.
Following the provision of supplementary information from the MAH, the CHMP noted that thecompany argued that the results of the nonhuman primate interbody fusion study support the choice ofthe higher 1.50 mg/ml concentration for clinical use. It is correct that while the nonhuman primate
interbody fusion study (RPT-52962) showed that both 0.75 and 1.50 mg/mL concentrations resulted in
100% fusion rates, increased bone density was observed by the investigators with the higher
concentration and the rate of bone formation appeared to be slower with the 0.75 mg/ml concentration.
It is agreed that more important information for the choice of the dose come from other approved andexperimental clinical applications of Inductos, suggesting increased rate of healing with the 1.5 mg/ml
compared to lower concentrations. However, the MAH’s conclusion that there are no safety concernswith Inductos in the applied indication is not correct. It is not known if the 1.5 mg/ml concentration is
optimal in terms of safety in this clinical application as it is possible that complications, e.g.
inflammation and excessive bone formation are concentration-related. Nevertheless, from the efficacy
perspective the CHMP agreed that the issue is resolved and the safety concern can be dealt with bygiving appropriate information in the SPC and educational material.
During its plenary meeting in September 2004 the CHMP commented that although the spinal safety
study had a relevant design to examine the potential undesirable effects of application of InductOs
near dural membrane, it is was unfortunate that the concentration of rhBMP-2/ACS used was very low(7% of the concentration intended for clinical use) limiting the relevance of the study significantly.
The CHMP requested the MAH to comment on a major drawback that was the lack of evaluation of
direct neurotoxicity or rhBMP-2/ACS.
8

Following the provision of supplementary information by the MAH, the CHMP noted that thecompany argued that use of low rhBMP-2 concentration in the canine laminectomy safety study was
justified in view of the higher sensitivity of the species to the pharmacological effects of rhBMP-2
compared to man. This is accurate in view of the previously submitted non-clinical studies in rodents,
dogs and non-human primates. The MAH believes that use of a higher concentration would have led
to excessive bone formation in dogs and would not have been relevant for safety assessment. This may
well be the case. The canine laminectomy study was designed to model a “worst case” scenario in
which rhBMP-2/ACS is implanted inside the spinal canal in direct contact with exposed dura. The
actual implantation of rhBMP-2/ACS in this location would not be anticipated under any conditions ina clinical setting.
With these considerations, the CHMP noted that the MAH’s approach is reasonable and concluded
that the issue was resolved.

4.

CLINICAL ASPECTS

Degenerative disc disease (DDD) is a leading cause of low back pain and one of the most prevalent
health problems in the world. Non-operative treatments for DDD, including medication, exercise, andmanipulation, are the first-course standard of care. Many patients respond to non-operative treatment.
However, others continue to experience chronic back pain that can be debilitating. When nonoperative forms of treatment have failed to provide sufficient relief from pain and disability for thesepatients, lumbar spine fusion is considered a viable operative treatment option.
A standard care in Europe for surgical treatment of DDD is fusion of the involved spinal segments,
and anterior lumbar interbody spine fusion (ALIF), using autogenous bone with interbody fusion
cages, represents about 20-25% of these cases. One such interbody fusion cage is the LT-CAGE
Lumbar Tapered Fusion Device, which is CE-marked and has been commercially available in Europe
since 1997. The cage may be inserted using either an open or a laparoscopic surgical approach after
the removal of the painful, degenerated disc (Figure 1). The function of the cage is to re-establish theproper spinal curvature, realign and decompress the facet joints, relieve stress on the musculature, retension the disc annulus, enlarge the foraminal space (thus relieving nerve root pressure), and provide
stability to the spinal segment – all with the aim to provide relief of the symptoms of DDD. The
autogenous bone graft then facilitates the fusion process in the stable environment provided by thecage, and the fusion makes the treatment permanent. Due to the volume of autogenous bone requiredby the procedure, the standard practice is to harvest the autogenous bone graft from the iliac crest.
This harvest is not infrequently associated with significant morbidity, including complications andpain that may last for several weeks, months, or even years at the harvest site.
Figure 1. LT-CAGE with InductOs.

Because of rhBMP-2’s osteoinductive properties, it was believed that rhBMP-2 had the potential toprovide significant medical benefit in spine fusion surgery as a direct replacement for autogenous bone9

graft harvested from the iliac crest. The potential benefit for the patient is relief from the symptoms of
DDD, achieved without the additional pain and morbidity associated with autograft harvesting.
Since rhBMP-2/ACS had not been used in a human spine fusion application previously, the initialhuman exposure was planned for a small-scale pilot clinical study. It was anticipated that the results ofthis study would help confirm the appropriateness of the dosage in producing fusion and expose
possible safety issues that needed to be addressed in larger clinical studies. In the pilot study, patients
received a single-level anterior lumbar interbody fusion procedure using either 1.50 mg/mL rhBMP2/ACS or autogenous bone harvested from the iliac crest delivered in 2 LT-CAGE Lumbar Tapered
Fusion Devices. Two large-scale, prospective clinical studies were planned. Together, these studies
focused on determining the effectiveness of the product to fuse the treated spinal level and to relieve
pain and on assessing the product’s safety. In order to reflect a clinical benefit, a primary endpoint wasdeveloped that incorporated both efficacy and safety features into a single variable termed “overall
success.” Safety and efficacy of the investigational treatment would be proclaimed if the overall
success rate for the investigational treatment patients was statistically non-inferior to that for astandard of care control group. In the pivotal Phase III study, rhBMP-2/ACS was implanted with the
LT-CAGE Device using an open surgical approach. This study had a prospective, randomized,
controlled design. An open surgical approach was chosen due to its popularity among surgeons. A
second large-scale study was planned to support the safe use of the same product using a laparoscopic
surgical approach, a method that is also popular among surgeons but is used to a much lesser degree.
The second study had the same design except that it did not have a randomized control group. It wasthought that the results from this laparoscopic surgical approach study would be complementary to theopen surgical approach data and that the data would support a label claim for single-level (L 4 -S 1)
anterior lumbar spine fusion in adults with degenerative disc disease, irrespective of surgical approach.
The clinical studies that are the basis for this application were performed in the United States and wereconducted in accordance with applicable US FDA regulations for devices. The FDA regulations were
written in the spirit of the Declaration of Helsinki and good clinical practice.
4.1

Clinical Pharmacology

No new clinical pharmacology data have been provided. The clinical pharmacology comments
provided in the Clinical Overview at the time of the first submission for the Marketing Authorisationin Europe are applicable to this application since this variation covers the same formulation for
InductOs. However, the pilot study evaluating the feasibility of InductOs when used together with the
LT-Cage device has been reviewed.
CSR-52093 (Study 3100N3-117-US): A Prospective, Randomised Feasibility Investigation of
Recombinant Human Bone Morphogenetic Protein-2 (rhBMP-2) and Absorbable Collagen Spongewith the Tapered Interbody Fusion Device for Anterior Lumbar Interbody Fusion in Patientswith Degenerative Disc Disease
Efficacy Results
Based on either CT or x-ray assessments, the fusion success rate at 12 and 24 months for theinvestigational treatment group was 100.0% (7/7 subjects treated by open surgical technique and 4/4
subjects treated by laparoscopic approach). All three control subjects were treated using an open
approach and were evaluated as fused after 12 months, but one subject had an additional surgicalprocedure at 18 months postoperative, which caused the subject to be considered a treatment failure at
24 months postoperative.
Safety Results
The study determined that there were no safety issues to hinder implantation of the rhBMP- 2/ACS inlarger pivotal clinical trials. There were no additional surgical procedures required in theinvestigational treatment group. No investigational subject had an antibody response to rhBMP-2.
Three of the 11 investigational subjects had antibody responses to bovine collagen. Subjects who had
antibody responses to bovine collagen were not found to have positive antibody responses to human

10Type I collagen. In addition, there were no medically important differences in the complete bloodcount or serum chemistry screening results between the investigational and control groups.
Two subjects (18.2%) in the investigational group and one subject (33.3%) in the control group had
surgical procedure changes (endcaps not used due to difficulties). One subject (9.1%) in theinvestigational group and one subject (33.3%) in the control group had hardware failures relating to
the endcaps to the LT-CAGE Device (ie, would not engage properly or dislodged after surgery). No
complications were noted from these events. The snap-on endcaps, which had been used for this pilot
study, were not used in any other rhBMP-2/ACS studies.
4.2

Clinical Efficacy

To support the proposed indication the MAH submitted 3 clinical studies:-

A pilot study (3100N3-117) was performed to assess the feasibility of executing larger clinical
trials with rhBMP- 2/ACS as a replacement for autogenous bone harvested from the iliac
crest, when used with the LT- CAGE Device;
An open surgical approach study (3100N3-303) which was considered as the pivotal trial;
A laparoscopic study (3100N3-304), which was considered as supportive to the pivotal trial.

Study 3100N3-117 (Pilot study):This was a prospective, multicentre, randomised (3:1) clinical study in 14 patients receiving either two
rhBMP-2/ACS-filled LT-CAGE Devices in an anterior (7 subjects) or laparoscopic (4 subjects)
surgical approach or two autogenous bone filled (control) LT-CAGE Devices in an open anterior
surgical approach (3 subjects). The devices were implanted at 1 level from L2-S1.
Successful fusions occurred in all 14 (100%) subjects receiving the investigational treatment at 24
months postoperative, compared with 2 (66.7%) of the 3 of subjects who received the standard of care
control treatment. No significant safety issues were noted during the study. One-year follow-up datafrom the pilot study were deemed necessary to characterize the outcomes before larger pivotal studies
could commence. Based on these data the open surgical approach study and the laparoscopic approachstudy were designed.
Study 3100N3-303 (open surgical approach study, pivotal trial)
Study Design:
In this study, the patients had at least 6 months of nonoperative treatment for the pain associated with
DDD, still had documented pain from the condition, were seeking additional treatment, and wererecommended for spine fusion by their physician. A nonsurgical treatment option was not practical or
ethical for this subject population because nonsurgical treatments had already failed to provide needed
relief; instead, fusion was recommended to alleviate the pain. Thus, the subject population for thisopen surgical approach study was a subset of subjects with DDD—those subjects with back pain who
had not responded to 6 months of nonoperative treatment and for whom spine fusion had been
recommended.
The open surgical approach study was open-label with respect to subjects and surgeons.
Subjects were randomised (1:1) either to the investigational treatment group (rhBMP-2/ACS) or to thecontrol group (autogenous bone harvested from the iliac crest). Subject and surgeon blinding was notpossible after treatment group assignment because it is necessary for the surgeon to obtain autogenous
bone from the iliac crest as part of the control treatment. However, the independent radiographic
reviewers who evaluated the radiographs and CT scans were blinded to treatment group. This was
included in the study design to eliminate bias in determining radiographic outcomes between the 2treatment groups. Subjects had only 1 investigational surgery in the study and received rhBMP-2 at aconcentration of 1.50 mg/mL during the surgery.
11

The length of subject follow-up (24 months) was sufficient to evaluate the safety and efficacy of
rhBMP-2/ACS, including the osteoinductive properties and beneficial effects of using rhBMP-2/ACS
instead of harvesting autogenous bone. The 24-month follow-up time also allowed sufficient time toobserve fusion induced by rhBMP-2/ACS, which was expected to occur by 12 months following
surgery.
A non-inferiority trial design was used on the premise that the control treatment was recognized as avery effective treatment from earlier clinical studies with fusion rates of at least 89.4% at 24 months.
Non-inferiority was considered to be reasonable based on the standard that the control had establishedand on the fact that the investigational treatment would offer the additional benefit of eliminating thesecond surgery to harvest bone.
Inclusion and exclusion criteria:
Male and female subjects, age ≥18 years, with DDD as noted by back pain of discogenic origin, withor without leg pain, with degeneration of the disc confirmed by subject history and radiographic
studies with one or more of the following: a) instability, b) osteophyte formation, c) decreased discheight, d) thickening of ligamentous tissue, e) disc degeneration or herniation, and/or f) facet joint
degeneration. Subjects were required to have a preoperative Oswestry score ≥35, no greater than
Grade 1 spondylolisthesis (utilizing Meyerding’s Classification), and single-level symptomaticdegenerative involvement from L4 to S1. Subjects should not have responded to 6 months of nonoperative treatment (eg, bed rest, physical therapy, medications, spinal injections, manipulation, and/ortranscutaneous electrical nerve stimulation (TENS)).
Main exclusion criteria:
A subject meeting any of the following criteria was excluded from the study:• Previous anterior spine fusion surgical procedure at the involved level.
• Posterior spinal instrumentation (which will not be removed) stabilising the involved level or aprevious posterior lumbar interbody fusion procedure at the involved level.
• Presence of active malignancy.
• History of autoimmune disease.
• History of exposure to injectable collagen implants.
• History of hypersensitivity to protein pharmaceuticals (monoclonal antibodies or gamma
globulins) or collagen.
• Any previous exposure to any/all BMPs of either human or animal extraction.
• History of allergy to bovine products or a history of anaphylaxis.
• Osteopenia, osteoporosis, or osteomalacia to a degree that spinal instrumentation would becontraindicated; history of endocrine or metabolic disorder known to affect osteogenesis(eg, Paget’s disease, renal osteodystrophy, Ehlers-Danlos syndrome, or osteogenesis imperfecta)• Presence of active malignancy or infection (local or systemic)• Obesity (ie, weight >40% over ideal for their age and height)• Medications that could affect fusion (e.g. corticosteroids)
Efficacy variables:
The primary efficacy variables for Studies 3100N3-303 and 3100N3-304 were:
1) fusion—measured by independent radiographic reviewers using methods recommended by
FDA;2) pain/disability status—measured by the subject in response to the Oswestry Low Back Pain
Disability Questionnaire.
The Oswestry questionnaire records a subject’s response to 10 questions, which focus on pain,
personal care, lifting, walking, sitting, standing, sleeping, sex life, social life, and ability to travel.
Oswestry scores can range from 0% to 100%, with a lower percentage indicating less pain anddisability. The Oswestry Questionnaire was administered preoperatively as well as at eachpostoperative visit.

12

Primary efficacy endpoints:
The primary efficacy endpoints were the fusion success status at 24 months and the Oswestry(pain/disability) success status at 24 months.
Overall success was the primary endpoint of the study comprising the following safety and efficacy
variables:1) radiographically demonstrated fusion,2) Oswestry pain/disability improvement,3) maintenance or improvement in neurological status,
4) no Grade 3 or 4 adverse event classified as implant-associated or implant-/surgical procedureassociated, and5) no additional surgical procedure performed that was classified as a “failure.”
Fusion success was defined as:• Evidence of bridging trabeculae, based on the presence of a continuous bony connection from thesuperior vertebral body to the inferior vertebral body in at least 1 of the following areas: lateral,
medial, anterior, posterior, and/or through either one or both of the implants. The primary methodof assessment was radiographs. If evidence of bridging trabeculae could not be observed withradiographs, CT scans were permitted as a secondary method only. The study design included
scheduled radiographs and CT scans for all subjects.
• No evidence of motion, as defined by:o
No more than 3 mm difference in translation on the lateral flexion/extension
radiographs, as determined by superimposing the 2 views one upon the other, andoLess than 5° difference in angular motion between flexion and extension, as seen on
lateral flexion/extension radiographs.
• No evidence of radiolucency surrounding greater than 50% of either LT-CAGE Device. This
determination was made with radiographs.
Statistical methods:
The study was designed as a non-inferiority trial. A frequentist method was utilised to assess the study
hypotheses.
The study hypotheses defined in the statistical plan were one-sided equivalence (non-inferiority)
hypotheses. A non-inferiority margin (d) of 0.10 was defined for all of the variables except for
Oswestry success, where a margin of 0.15 was specified. Justification of the delta choices was basedon an FDA point-to-consider document.
The primary outcome variables were analysed using Blackwelder’s one-sided equivalence procedure.
Pooling data from all the study sites was planned for final statistical analyses for assessing the study
hypotheses. The Breslow-Day test procedure would be used for assessing homogeneity of treatment
outcomes across study sites (i.e. interaction between study site and treatment) to justify the pooling.
Two (2) interim analyses and one final analysis were defined in the statistical plan using the Fleming,
Harrington, and O’Brien procedure.
A non-inferiority trial design was used on the premise that the control treatment was recognised as avery effective treatment from earlier clinical studies with fusion rates of at least 90%. Non- inferiority
was considered to be reasonable based on the standard that the control had established efficacy and on
the fact that the investigational treatment would offer the additional benefit of no second surgical site
to harvest bone.
Three (3) primary efficacy variables and 3 primary safety variables were considered in thedetermination of sample size in the original statistical considerations for the study. The resulting
sample size hinged on the variable “Oswestry pain/disability success,” which required the largest
sample size of all of the variables. The basic assumptions were as follows: significance (one-sided
alpha) level of 0.05, power of 0.80, non-inferiority margin of 0.15, and success rate of 68.5% in boththe investigational and control treatment groups. The final sample size was estimated to be a total of13270 subjects, with 135 in each treatment group, after adjusting for approximately 10-15% lost-tofollow-ups.
During the conduct of the study, the statistical plan and protocol were amended to allow Bayesiananalyses in order to assess results prior to completion of the 24-month follow-up and to define thecomposite variable overall success as the sole primary endpoint of the study. In preliminary
consultations with Regulatory Authorities, frequentist statistics were requested as the primary analysis.
No interim analyses using frequentist statistical methods, as defined in the original protocol, were ever
performed because of subsequent protocol changes. Therefore, there is no need for alpha adjustments.
The original protocol defined 3 primary efficacy variables (fusion success, Oswestry success, andneurological success) and 3 primary safety variables (Grade 3 or 4, product-associated, adverse events;
additional surgical procedures classified as failures; and Grade 3 or 4, permanent adverse events). The
variable overall success was defined but not indicated as either a primary or a secondary endpoint in
the original protocol and statistical plan. In the amendments to these documents, overall success was
defined as the sole primary endpoint to measure efficacy and safety of the investigational product. The
main reason for the change was to avoid the statistical multiplicity issues.
Finally, for the study report, a “per protocol” analysis dataset, which was the primary analysis dataset
minus the 9 subjects with protocol deviations, was defined and also analyzed for the primary study
endpoint overall success.

•Clinical results:

In total, 143 subjects completed the investigational treatment, and 136 subjects completed the control
treatment in the clinical study. Subject disposition for the clinical study through 24 months
postoperative is presented in the table below:

14

Results on the fusion success rates for the investigational and control treatment groups at 12 and 24
months after surgery for the primary analysis dataset are shown in the table below:
Fusion success rates at 12 and 24 months – primary analysis dataset:

A “missing-equals-failure” analysis dataset was constructed for analysis of the primary study endpoint
overall success. In this dataset, all missing observations from all the study subjects (143
investigational and 136 control subjects), including subjects missing observations, deaths, andadditional surgery “failures,” were included in the denominators of the calculated rates (ie, assumed as“failures”). A missing-equals-failure analysis is also presented for both primary efficacy parameters,
fusion and pain/disability, and for the safety parameter, neurological success.
The “per-protocol” dataset was constructed in the exactly same way as the primary analysis dataset,
except that 9 subjects with the protocol deviations were excluded. This was a simple subset of the
primary analysis dataset, also just for analysis of the primary study endpoint overall success.
Fusion success rates at 12 and 24 months – ”missing equals failure” dataset:

By considering missing data as treatment failures, the outcome rates in the “missing-equals-failure”
analysis were lowered in both groups at 24 months postoperative. The fusion success rate wasnumerically higher in the investigational treatment group than that in the control group at 24 months.
The non-inferiority of the investigational treatment to the control treatment is clearly established infusion success at 24 months, with a non-inferiority margin of 0.10.
For both treatment groups at all postoperative time periods, mean overall Oswestry scores significantly
improved (p<0.001), as compared to the preoperative scores. The mean improvement in Oswestry
scores was also similar for both treatment groups at the various clinical time periods. Oswestry scoresfor the investigational treatment group improved by an average of 29.2 points from surgery to 24
months, as compared to an average of 29.9 for the control group.
The primary endpoint of the study was overall success at 24 months, consisting of 2 efficacy and 3
safety components. The overall success rate at 24 months for the investigational treatment group was
found to be statistically non-inferior (p=0.0029) to the control group rate, with the predefined noninferiority margin of 0.15 (Table below).

15

Overall Success Rates at 12 and 24 Months – Primary Analysis Dataset

The overall success rates for “missing-equals-failure” subjects at 12 and 24 months postoperative areshown below.
Overall Success Rates at 12 and 24 Months – ”Missing-Equals-Failure” Dataset

By considering missing data as treatment failures, the outcome rates in the “missing-equals-failure”
analysis were lowered in both groups at 24 months postoperative. The overall success rate was higher
for “missing-equals-failure” subjects in the investigational treatment group than for “missing-equalsfailure” subjects in the control group at 24 months. The non-inferiority of the investigational treatment
to the control treatment is shown.
The overall success rates for “per protocol” subjects, or subjects who did not have a major protocol
deviation are shown in the following table:

At 24 months postoperative, the overall success rate for the “per protocol” subjects was similar
between the groups, and the criterion for declaring non-inferiority was met, not only with a noninferiority margin of 0.15 but also with a margin of 0.10.
The secondary efficacy variable (graft site pain status, disc height measurement, general health status
and pain status) results support the primary efficacy and combined overall treatment success endpoint
results and suggest similar efficacy in terms of Quality of Life, global perceived effect by patient andphysician, back and leg pain. The absence of pain related to bone graft harvesting is naturally asubstantial benefit of rhBMP-2/ACS LT-CAGE treatment

16

Study 3100N3-304 (laparoscopic surgical approach study, supportive trial)
This Study used a laparoscopic surgical approach instead of an open surgical approach for the
implantation of rhBMP-2/ACS in ALIF procedures. Except for the change in the surgical approach,the purpose, primary objectives, and procedures of the laparoscopic surgical approach study were thesame as those for the open surgical approach study.
The secondary efficacy variables for this study were
• Disc Height Measurement• General Health Status• Pain Status (back pain, leg pain)
Neurological status was assessed preoperatively and postoperatively by the investigational team using
a comprehensive neurological status scale. Neurological status is based on 4 types of measurements(sections): motor, sensory, reflexes, and straight leg raise. The motor and sensory sections of the scale
were developed and validated by the American Spinal Injury Association (ASIA), Chicago, Illinois.
Serum samples were taken from each subject preoperatively, to establish their baseline condition, andat 3 months following surgery. The samples were analyzed by enzyme-linked immunosorbent assay(ELISA) for the presence of antibodies specific for BMP-2 and bovine Type I collagen. If a subject
had a positive response to bovine Type I collagen, the serum was also tested for antibodies to humanType I collagen.
The design for the laparoscopic approach study included using a concurrent, non-randomised control.
Because using the control group from the open surgical approach study would not address all potential
biases, only nonstatistical comparisons were planned and conducted between the investigational
treatment group of study 3100N3-304 and the control group of study 3100N3-303. The intention was
to nonstatistically compare results from study 3100N3-304 with those from the control group of theopen surgical approach study, because all other methods and endpoints of the 2 studies were
essentially identical and both studies investigated the safety and efficacy of rhBMP-2/ACS.
Study Design:
As described above, the Study Design was similar to Study 3100N3-303 with the above-mentioned
exceptions. The original statistical plan for the laparoscopic approach study used the control groupfrom study 3100N3-303 (in which subjects were implanted with a combination of autogenous bone
graft and the LT-CAGE Device via an open surgical procedure, which is considered to be the standardof care) as the control group for study 3100N3-304. However, as statistical differences were noted
between subjects of both studies for some important demographic characteristics, the MAH decided
that it was not appropriate to statistically compare the two groups from these studies.
The concentration of reconstituted rhBMP-2 administered to subjects was constant at 1.50 mg/mL,with the total dose of rhBMP-2 varying according to the quantity of rhBMP- 2/ACS required. The
quantity of rhBMP-2/ACS required was determined by the size of cage used. Based on the cages in theclinical study, the quantity of rhBMP-2/ACS that was placed into the cages was either 2.8 or 5.6 mL(for 2 cages). This equated to a total dose of 4.2 or 8.4 mg rhBMP-2.

17

Clinical results:
In total, 134 subjects completed this study (see table below).

Of the rhBMP-2/ACS treated subjects, 57.5% were female, their mean age was 42 years and 24.6%
had had previous back surgery. Preoperatively, instability was present in 8.2%, osteophytes in 26.9%,
decreased disk height in 88.8%, thickened ligaments in 20.1%, disk herniation in 34.3% and facet joint
degeneration in 40.3% of subjects.
The majority of patients received treatment for L5-S1 DDD (84.3%).
Efficacy:
The primary analysis dataset included all 134 subjects in this study who received study implants andcompleted surgical procedures. Primary statistical analyses were based on the observed data, andmissing data due to lost-to-follow-up or invalid radiographic assessments were not imputed.
According to the protocol, subjects who had additional surgical interventions were deemed as failuresfor overall success, if the additional surgical procedures were classified as failures according to theprotocol definition. In addition, fusion status was also considered as a failure if these additional
surgical procedures were due to purported failed fusion as reported by the investigator, regardless ofwhat radiographic evidence showed.
A ”missing-equals-failure” analysis dataset was constructed for analysis of the primary study endpoint
overall success. In this dataset, all missing observations from all 134 subjects in this study, including
subjects missing observations, deaths, and additional surgery failures, were included in the
denominators of the calculated rates.
The fusion success rates for this study were over 90% at both the 12- and 24-month time points(94.1% and 92.9%, respectively). In the ”missing equals failure” dataset, the corresponding figures
were 70.9% and 68.7%.
The Oswestry success rates for this study were 79.8% and 85.6% at 12 months and 24 months,
respectively. The corresponding figures in the ”missing equals failure” analysis were 67.9% and66.4%.

18

The secondary efficacy variable success rates are shown in the table below:
Secondary efficacy variable success rates (primary analysis dataset)

Throughout this study, subjects were asked about their overall satisfaction with the study treatment. At
24 months postoperative, 81.7% (85/104) of the subject group responded that it was ”definitely true”
or ”mostly true” that they were satisfied with the results of the surgery. Over seventy-five percent(75.7%, 78/103) of the subjects at 24 months postoperative responded that it was ”definitely true” or”mostly true” that they were helped as much as they thought they would be by the surgery. At 24
months postoperative, 83.5% (86/103) of the subject group responded that it was ”definitely true” or”mostly true” that, all things considered, they would have the surgery again for the same condition.
At 12 and 24 months following surgery, 72.8% (83/114) and 77.9% (81/104), respectively, of subjects
in this study indicated that they had either ”completely recovered” or were ”much improved”.
At 12 months following surgery, the investigators´ global evaluation was that 84.8% (95/112) of thesubjects from this study were in excellent or good condition. At 24 months, the corresponding figure
was 86.4%.
The primary endpoint of this study was overall success at 24 months, consisting of 2 efficacy and 3
safety components. According to the primary analysis dataset, overall success was reported in 69.2%
of patients at 12 monts and in 68.3% of patients at 24 months. The corresponding figures in the”missing-equals-failure” analysis were 55.2% and 53.0%. In the primary analysis dataset, neurologicalsuccess rates at 12 months and 24 months were 93.8% and 90.3%, respectively.

19

4.3

Clinical Safety

Patient exposure:
A total of 455 subjects were enrolled in the 3 studies, and 427 were treated and provided safety data. A
total of 288 subjects received a single implantation of rhBMP-2 at a concentration of 1.50 mg/mL on
an ACS.
Synopses of additional 11 studies are provided in the dossier. These additional studies supplement thesafety from the 3 main studies to support the use of rhBMP-2/ACS in anterior lumbar spine fusion,
when used in combination with the LT-CAGE device. some of these studies use a concentration orquantity of rhBMP-2/ACS or a matrix that differs from that which is the subject of this variation (i.e.aconcentration of 1.5 mg/mL, a total dose of up to 12 mg, and absorbable collagen sponge/ACS
matrix). In each case, dibotermin alfa is used in combination with a medical device other than the LTCAGE device.
Altogether 612 patients have received rhBMP-2/ACS in these additional 11 clinical trials, several ofwhich are ongoing.
Safety information in support of the use of rhBMP-2/ACS in combination with the LT-CAGE Device
in ALIF procedures comes mainly from the same 3 studies that support efficacy. In these studies a
total of 455 subjects were enrolled, and 427 were treated and provided safety data. A total of 288
subjects received a single implantation of rhBMP-2 at a concentration of 1.50 mg/mL on an ACS.
Although not directly relevant to the use of rhBMP-2/ACS in combination with the LT-CAGE Device
in anterior lumbar spine fusion procedures, supporting safety information also comes from additionalsafety information collected in 13 other clinical studies, 6 of which are ongoing. Six hundred and four(604) subjects have received treatment with rhBMP-2 in these additional studies, compared with 716
subjects who were treated with another device for comparison. These figures are based on the final
report or last annual report for the various studies. Some of these trials use a different concentration orquantity of rhBMP-2/ACS or a matrix that differs from the one proposed in this variation (ie, aconcentration of 1.50 mg/mL, a total dose of up to 12 mg, and absorbable collagen sponge matrix). In
addition, in each case, rhBMP-2 is used in combination with a device other than the LT-CAGE
Device. The safety information from these studies has been reviewed and is considered not to
influence the safety profile observed in the 3 main studies.
Adverse events
The table below summarises the number of subjects of the three submitted studies who have adverse
events by organ system according to COSTART code, through the 24-month evaluations:20This review does not suggest that subjects reporting adverse events for any of these body systems werein larger proportions after rhBMP-2/ACS exposure. More patients in the active treated group had
adverse events in the nervous system (32.9%) versus 25.0% in the control group. This was mainly due
to neuropathy and urinary retention. One report of neuralgia in the investigational group wasconsidered to be possibly related to the implant.
Four types of adverse events were observed in ≥10% of all subjects: “Accidental Injury,” “Back Pain,”“Bone Disorder,” and “Neuralgia.” These events were equally observed in investigational and control
subjects, suggesting that they were related to subjects’ condition rather than to rhBMP-2/ACS.
Study 3100N3-303 (open surgical approach study, pivotal trial)
SafetySafety criteria were analyses of adverse events, additional surgical procedures, neurologicalstatus, laboratory analyses of antibodies to rhBMP-2 and bovine collagen, and histological analysis ofany explanted/removed implants.
Neurological status was assessed preoperatively and postoperatively by the investigational team using
a comprehensive neurological status scale. Neurological status is based on 4 types of measurements(sections): motor, sensory, reflexes, and straight leg raise. The motor and sensory sections of the scale
were developed and validated by the American Spinal Injury Association (ASIA), Chicago, Illinois.
Due to the proteinaceous nature of both rhBMP-2 and ACS, the development of antibodies wasassessed as part of the study protocol. Subjects were considered to have an authentic antibody
response if their preoperative sample was negative (titer <50) and the postoperative sample waspositive (titer ≥50) or if the preoperative sample was positive and the postoperative sample titer was 3fold higher than the preoperative titer. Serum samples were taken from each subject preoperatively, toestablish their baseline condition, and at 3 months following surgery. The samples were analysed byenzyme-linked immunosorbent assay (ELISA) for the presence of antibodies specific for rhBMP-2 andbovine Type I collagen. If a subject had a positive response to bovine Type I collagen, the serum wasalso tested for antibodies to human Type I collagen.
Overall: The primary endpoint for the study was “overall success.” This variable was comprised of thefollowing efficacy and safety criteria:
1. Radiographically demonstrated fusion
2. Oswestry pain/disability improvement
3. Maintenance or improvement in neurological status
4. No Grade 3 or 4 adverse event classified as implant-associated or implant-/surgical procedureassociated
5. No additional surgical procedure classified as a “failure”
Each subject was followed for 24 months after surgical treatment, with study evaluations occurring
preoperatively and at 6 postoperative time points (surgery/discharge, 6 weeks, 3 months, 6 months, 12months, and 24 months). Evaluations included the following:• Radiographic assessment by independent radiographic reviewers of the spinal level that was
treated surgically• Neurological assessment by the investigational staff• Treatment outcomes as perceived by the subject and the investigator• Documentation of adverse events (AEs)• Documentation of subsequent treatments classified as additional surgical procedures• Documentation of classes of concomitant medications• Collection of serum samples to measure antibody formation to rhBMP-2, bovine Type I collagen(from which the ACS is made), and human Type I collagen21

•

Safety results:

Because this study was designed and performed as a device study, clinical laboratory analyses, vital
signs and other physical findings were not recorded.
The total number of subjects who received rhBMP-2/ACS during surgery was 143 (78 male and 65
female patients). There were no large differences between treatment groups in type of adverse events.
Patients in the investigational group experienced more ileus (7.0%), arthralgia (8.4%), neuropathy(7.7%), urinary retention (7.7%) and abnormal ejaculation (3.5%) compared to control patients (4.4%,
5.1%, 4.4%, 1.5%, 0.7% respectively). Patients in the control group had more abdominal pain thanpatients from the investigational group (3.7% versus 0.0% respectively).
A total of 11 subjects had adverse events related to oedema. Six (6) of these events involved
investigational subjects. Five subjects experienced lower extremity swelling, and 1 subject
experienced laryngeal oedema shortly after surgery. The latter subject tested negative postoperatively
for both rhBMP-2 and bovine Type I collagen antibodies. The oedema events occurring in the 5control subjects were due to lower extremity swelling (4 subjects) and scrotal swelling (1 subject).
None of these events were believed to be implant-related.
An overview of the commonly reported adverse events in study 3100N3-303 is shown in the tablebelow:
Body System
Adverse Event
Body as a Whole
Abdominal Pain
Allergic Reaction
Cyst
Chest Pain
Edema
Granuloma
HeadacheHerniaInfection
Neck Pain
Pain
Surgical Procedure Changea
Cardiovascular System
Syncope
Thrombosis
Digestive System
Cholelithiasis
Constipation
Diarrhea
Fecal Incontinence
Ileus
Intestinal Obstruction
NauseaNausea and Vomiting
Musculo-Skeletal System
Arthralgia
Arthritis
Bone Fracture Spontaneous
Tenosynovitis
Nervous System
Depression
Hypesthesia
Neuropathy
Paresthesia
Urinary Retention
Respiratory System
Dyspnea
Pneumonia
Skin and Appendages
Rash
Urogenital System

Investigational

Control

Total

0.0% (0/143)
2.1% (3/143)
0.7% (1/143)
1.4% (2/143)
3.5% (5/143)
0.0% (0/143)
2.1% (3/143)
4.9% (7/143)
7.7% (11/143)
3.5% (5/143)
7.0% (10/143)
1.4% (2/143)

3.7% (5/136)
2.2% (3/136)
2.2% (3/143)
0.0% (0/136)
2.9% (4/136)
1.5% (2/136)
1.5% (2/136)
0.0% (0/136)
9.6% (13/136)
2.2% (3/136)
5.9% (8/136)
1.5% (2/136)

1.8% (5/279)
2.2% (6/279)
1.4% (4/279)
0.7% (2/279)
3.2% (9/279)
0.7% (2/279)
1.8% (5/279)
2.5% (7/279)
8.6% (24/279)
2.9% (8/279)
6.5% (18/279)
1.4% (4/279)

0.7% (1/143)
0.7% (1/143)

1.5% (2/136)
2.2% (3/136)

1.1% (3/279)
1.4% (4/279)

1.4% (2/143)
1.4% (2/143)
1.4% (2/143)
0.0% (0/143)
7.0% (10/143)
0.7% (1/143)
4.9% (7/143)
2.1% (3/143)

0.0% (0/136)
3.7% (5/136)
0.7% (1/136)
1.5% (2/136)
4.4% (6/136)
1.5% (2/136)
4.4% (6/136)
2.2% (3/136)

0.7% (2/279)
2.5% (7/279)
1.1% (3/279)
0.7% (2/279)
5.7% (16/279)
1.1% (3/279)
4.7% (13/279)
2.2% (6/279)

8.4% (12/143)
2.1% (3/143)
1.4% (2/143)
2.1% (3/143)

5.1% (7/136)
0.0% (0/136)
2.2% (3/136)
2.9% (4/136)

6.8% (19/279)
1.1% (3/279)
1.8% (5/279)
2.5% (7/279)

1.4% (2/143)
2.1% (3/143)
7.7% (11/143)
3.5% (5/143)
7.7% (11/143)

2.2% (3/136)
0.7% (1/136)
4.4%( 6/136)
5.1% (7/136)
1.5% (2/136)

1.8% (5/279)
1.4% (4/279)
6.1% (17/279)
4.3% (12/279)
4.7% (13/279)

0.0% (0/143)
0.0% (0/143)

2.9% (4/136)
1.5% (2/136)

1.4% (4/279)
0.7% (2/279)

1.4% (2/143)

0.7% (1/136)

1.1% (3/279)

22

Body System
Adverse Event
Investigational
Control
Total
Abnormal Ejaculation
3.5% (5/143)
0.7% (1/136)
2.2% (6/279)
Cystitis
1.4% (2/143)
1.5% (2/136)
1.4% (4/279)
Hematuria
1.4% (2/143)
0.0% (0/136)
0.7% (2/279)
Impotence
1.4% (2/143)
0.7% (1/136)
1.1% (3/279)
Kidney Calculus
2.1% (3/143)
0.7% (1/136)
1.4% (4/279)
Urinary Tract Infection
3.5% (5/143)
2.2% (3/136)
2.9% (8/279)
a: Category does not belong to the COSTART dictionary of terms. The category was generated to account for adverse events
that occurred when changes were made during the surgical procedure (ie, due to abnormal subject anatomy).

A total of 53 subjects in the investigational group (37.1%) had at least one Grade 3 or 4 adverse event.
However, only 11 of those subjects (7.7%) were reported to have had a Grade 3 or 4 adverse eventclassified as possibly related to the implant by the MSD clinical staff. It is important to stress that, forcomplications classified as possibly related to the implant, causality assessments did not separate
whether the complications were caused by the cage or by rhBMP-2/ACS. Hence, related events werereported in both treatment groups. For the control group, of 41.9% subjects with Grade 3 or 4 adverse
events, 8.8% were deemed related.
Serious adverse events and deaths:
One subject who received rhBMP-2/ACS and two subjects who received autogenous bone graft diedwithin 48 months of receiving treatment. In the opinions of the study investigators, none of the deaths
were related to the investigational treatment.
Antibody development:
The presented data on antibodies do not indicate difficulties in that area. However, as a result offollow-up measures 025 and 026 the applicant has developed and validated a new antibody ELISA for
antibodies to rhBMP-2 that has the potential to detect all antibody isotypes. In addition a neutralisation
assay for antibodies to rhBMP-2 has been developed and validated. Since it is assumed that the data
presented have been collected using the old method, the applicant is requested to submit data collectedwith the new assays from retrospective or prospective studies.
Study 3100N3-304 (laparoscopic surgical approach study, supportive trial)
Safety results:
Through the 24-month postoperative evaluations, 1 or more adverse events were reported by 98/134(73.1%) subjects who received the rhBMP-2/ACS treatment.
The most commonly reported adverse event was accidental injury (20.9% of subjects). The othercommon (1-10%) adverse events are listed in the table below:

23

No subjects died within 24 months of receiving this study treatment.

One or more Grade 3 or 4 adverse events were reported by 48 subjects (35.8%) through the 24-month
postoperative time period. Adverse events of severity Grade 3 or 4 considered to be at least possibly
related to the implant are summarised in the table below, grouped according to specific categories
according to COSTART codes:

24

Two implant removal procedures occurred in this study. Both of these removals occurred early in the
postoperative phase of this study and are described below.
• Subject # 31: This removal occurred as a result of issues associated with cage placement andmigration. At 8 weeks postoperative, this subject underwent a secondary surgery including
laparoscopic lysis of adhesions, exploration of the L5- S1 fusion site, removal of a displaced rightcage, and the placement of posterior instrumentation at the L5-S1 level. The retrieved
investigational cage underwent histological and metallurgical analyses. In these analyses, vigorous
osteogenesis by the intramembranous pathway was observed, and the site of the cage appeared tobe healing well. There were no cytological findings to suggest any inflammatory response otherthan that seen with normal wound healing.
• Subject # 426: This removal occurred at 1 day postoperative as the result of a malpositioned cage.
Due to the close proximity in time to surgery, a histological analysis was not performed.
Supplemental fixations occurred at a rate of 5.2% in this study (7/134 subjects). Three supplemental
fixations were due to an investigator diagnosis of a possible pseudarthrosis. Two other subjects had
supplemental fixations due to cage removals. Another subject had a supplemental fixation due toadjacent disc degeneration at the level above the initial surgery. One subject underwent a laminectomy
and supplemental fixation at 7 months postoperative due to spinal stenosis.
One patient had a postoperative sample that was positive for antibodies to rhBMP-2 three months
following surgery. The preoperative sample was not available. The determination was conservatively
designated as an authentic response. To determine if the antibody response to rhBMP-2 persisted, aserum sample was collected from the subject 12 months after surgery and tested for antibodies to
rhBMP-2. This follow-up sample was negative, and the subject was conservatively considered to have
had a transient antibody response to rhBMP-2. The subject had 2 AEs. There was no evidence thatthese adverse events were related to the implant. The incident was used to calculate the anti-rhBMP-2
antibody formation rate for this study, which was 0.8% (1/129).
Antibodies to bovine Type I collagen were detected in the postoperative serum samples of 56 subjects
in this study. Of these 56 subjects, 32 subjects were considered to have an authentic antibody
response. The remaining 24 subjects had a positive preoperative result without a substantial increase inpostoperative titer and thus did not qualify as authentic antibody responses. Three subjects from thisstudy with positive preoperative samples had no postoperative samples for testing.
Sixteen of the 32 subjects in this study who had an authentic positive antibody response to bovine
Type I collagen were classified as an overall success at 24 months. Two additional subjects wereclassified as an overall success at 12 months (ie, 24-month data for overall success determination wasincomplete). One subject was a failure in the pain component of overall success at 12 months (ie, 24month data were not available for this subject). Nine subjects were failures in other areas at 24 months
in pain status, 4 in neurological status, and 2 in pain and neurological status. Two subjects wereoverall success failures due to an additional surgical procedure that was classified as a failure in the
protocol. The final 2 subjects who had authentic positive antibody responses did not return for 12- and24-month evaluations, so no overall success information was available.

25

There were 27 subjects in this study with evaluable data who had positive baseline titers of bovine
Type I collagen antibodies. Only 3 (11.1%) of these subjects developed an authentic response
following their surgeries. This finding also indicates that a pre-existing antibody response to bovine
collagen is not stimulated by surgery or treatment with rhBMP-2/ACS.
None of these subjects had a positive response to human Type I collagen.
Routine clinical chemistry, haematology and vital sign listings and analysis is not included in the study
report. These data were not collected.
One patient (0.8%) had a transient antibody response to rhBMP-2 administration. The adverse events
reported by this patient are not considered to be associated with the antibody response and the patientachieved overall treatment response at 24 months.
Antibody response to bovine type I collagen was very commonly reported in this study (authentic
antibody response in 32 patients, i.e. in patients who were not antibody positive at baseline). The
possibility that these antibody responses could adversely impact treatment outcome (efficacy) cannot
be excluded, since overall response was reported in only 50% of these patients. However, there is noclear evidence of stimulation of immune reaction in the majority of patients with existing bovine type I
collagen antibodies.

Other clinical studies supporting the safety of the medicinal product in the proposed therapeutic
indication
Synopses of additional 11 studies are provided in the dossier. These additional studies supplement thesafety from the 3 main studies to support the use of rhBMP-2/ACS in anterior lumbar spine fusion,
when used in combination with the LT-CAGE device. Some of these studies use a concentration orquantity of rhBMP-2/ACS or a matrix that differs from that which is the subject of this variation (i.e.aconcentration of 1.5 mg/mL, a total dose of up to 12 mg, and absorbable collagen sponge/ACS
matrix). In each case, dibotermin alfa is used in combination with a medical device other than the LTCAGE device.
Further details are given here of Study Number C9806: A Prospective, Randomized, Clinical
Investigation of Recombinant Human Bone Morphogenetic Protein-2 and Absorbable Collagen
Sponge with the INTER FIX ™ Device for Posterior Lumbar Interbody Fusion in Patients with
Degenerative Disc Disease. One issue of note in this clinical study was the appearance of new boneformation posterior to the placement of interbody fusion cages implanted from the posterior surgicalapproach. The posterior bone formation was not observed in all patients, but was present in both theinvestigational and control groups, although more so in the investigational group. This finding isbelieved to be related to the posterior surgical technique and did not appear to be correlated withclinical outcome. The patients receiving rhBMP-2/ACS in this study had similar, or better, outcomesthan the patients receiving autograft bone.
Based on the safety assessments, the MAH considers rhBMP-2/ACS at 1.50mg/mL a safe alternative
for autogenous bone graft, but the particular methods for implanting the INTER FIX™ Device, whichcontains the rhBMP-2/ACS, should be carefully considered and further investigated when using a
posterior surgical approach. Heterotopic ossification (includes abnormal or excessive bone formation)
was reported in two patients in the rhBMP-2/ACS group.

26

Postmarketing information
In the PSUR covering the period 09 September 2003 to 08 March 2004, two topics are discussed indetail with cumulative summaries of the available data. Seven reports (covering 16 patients) of
localised edema wherein dibotermin alfa/ACS was used off label in the cervical spine have beenreviewed. Though causality has not been established, an association between dibotermin alfa/ACS andlocalized edema is possible and Wyeth is amending the reference safety information (RSI) to reflect
this information. An all time review of the cases of exuberant bone growth did not identify a newsafety signal.
During this reporting period, the MAH received nine spontaneous reports involving 12 different
suspected serious and unlisted ADRs; all were from the US in the setting of spine surgery. There wereno reports of death, lack of efficacy, drug interactions, drug abuse/misuse, pregnancy exposure,malignancy, bone necrosis, or intestinal obstruction.
Fourteen clinical trials, performed in North America under device regulations by Wyeth’s business
partner, MSD, have been identified for inclusion in the variation application. Wyeth reviewed theinformation from these 14 MSD clinical trials and identified several possible suspected serious
adverse drug reactions that meet the criteria for expedited reporting for medicinal products.
In the previous PSUR, four reports of localized edema coincident with the use of rhBMP-2/ACS in thecervical spine were discussed. During the current reporting period, the MAH received follow-up
information on three of the reports, one of which noted that this AE occurred in 10 patients at thesite. In addition, three new reports have been received. Consequently, a full review of this topic
is included in the PSUR.
In general, post-operative soft tissue complications following anterior cervical discectomy (ACD)
include airway complications, dysphagia, and hoarseness. Airway compromise can occur secondary tohematoma, allergic reactions, and pharyngeal edema and most reviews that discuss localised edema inthe setting of cervical spine surgery describe it in the context of airway complications.
The MAH database was searched all-time through 08 March 2004 for reports of swelling,inflammation, and edema in patients treated with rhBMP-2. A total of nine reports were identified.
The reports contained the preferred terms Swelling (n=7), Inflammation (n=2), Oedema (n=1), andInflammation localised (n=1). The number of events exceeds the number of reports since two reports
contained two of these terms. One report described a patient who received rhBMP-2/ACS in the
lumbar spine and experienced localised inflammation associated with a large hematoma.
One report described several patients who experienced swelling in the setting of an “immune-like”
response to rhBMP-2/ ACS. The remaining seven reports describe localised cervical edema following
rhBMP-2/ACS implantation.
In all of the cases the product was used off-label in the cervical spine. In general, the patients had an
uneventful post-operative course and presented 1.5-7 days after surgery with neck swelling. Six of thepatients recovered, with many receiving corticosteroids. In one report, the outcome is unknown. At
least two of the patients had evidence of airway compromise; both had complicated spine surgery. Oneof these patients required an emergent cricothyrotomy for airway protection and eventually recovered
with some residual swallowing problems. The other patient recovered with conservative measures
including steroids. Another patient required surgical decompression three days after surgery; thesurgeon noted that the rhBMP-2 had been hyperconcentrated on the sponge.
Localised edema has been noted in nonclinical and some clinical studies evaluating rhBMP-2/ACS,
though a clear causal association has not been established. Similarly localized edema has beenreported after routine ACD, though the actual incidence is difficult to ascertain. Pharyngeal edema istypically discussed in the context of airway complications, which have been noted in up to 6% of
patients undergoing ACD, generally in the early post-operative period.

27

Though causality has not been established, overall the data suggests that rhBMP-2/ACS may be
associated with, or contribute to, the development of localised edema. Such edema is more likely
to be symptomatic and visually discernable in the neck area. Given the potential clinical importance ofthe observed events Wyeth is planning to add wording to the SmPC to caution physicians about thepotential of localised edema coincident with the use of rhBMP-2/ACS, and to warn against use in thecervical spine.
Four spontaneous reports of ectopic, heterotopic, or exuberant bone growth were reviewed in the
PSUR. In three of the cases a posterior surgical approach was employed; the surgical technique was
not specified in the fourth case. In addition, three of the patients had symptoms including sciatica, leg
weakness with back pain and foot drop, though it is not clear if the symptoms were related to the bone
growth. The RSI describes the potential of these AEs as follows: “Use of InductOs may cause
heterotopic ossification in the surrounding tissues, which can result in complications.” Hence, basedon this review, no new safety signals for rhBMP-2 are identified.

28

5. OVERALL DISCUSSION AND BENEFIT/ RISK ASSESSMENT
5.1 Non-clinical dataNon-clinical data were submitted previously by the MAH in the context of FUM 024 and assessed atthat time (Final AR dated 19-05-2004). No new non-clinical data were submitted.
According to the MAH both in vitro and in vivo studies performed by the MAH as part of a FUM did
not demonstrate a tumour growth promoting effect. Published studies gave conflicting results and were
not reproduced. The MAH concluded that the non-clinical data showed no evidence for tumour
induction and the potential for tumour growth promotion is low.
Although the CHMP initially agreed with the conclusions of the MAH, in view of the clinical findingsof malignancies, the CHMP endorsed some additional comments:−

The MAH studied a range of tumour cell lines amongst which 3 pancreas tumour cell lines for thepresence of BPM-2 receptor mRNA. The MAH concluded that 10 tumour cell lines were positive,
but none of the pancreas cell lines. However the CHMP commented that the limits were set
arbitrarily and that in fact all, but two (amongst which one pancreas tumour cell line) were in fact
positive (i.e. had higher levels of BMP-2 mRNA than the negative control).

−

The MAH tested only those cell lines in an in vitro system that were judged positive for BMP-2.
Consequently no pancreas tumour cell lines were investigated any further.

−

In an in vivo model, using xenografts in nude mice, 6 cell types were tested. None of these tumour
types showed enhanced growth following rhBMP-2 treatment. But again although the choice ofthe cell types was logical, the study did not investigate pancreas tumour cell types.

In view of the malignancies seen in the clinical studies, the CHMP suggested that the MAH further
investigates the growth-promoting properties of other tumour cell types that have not been
investigated so far. For instance a study with pancreas tumor xenografts (e.g BXPC3 or Capan2) innude mice.
5.2 Clinical efficacy
The CHMP had raised concerns that non-inferiority with respect to standard therapy has not been
demonstrated.
The CHMP noted that the statistical method used to evaluate non-inferiority of the investigational
treatment in the main clinical study is not in compliance with CPMP/ICH guidance. The
recommended method to show non-inferiority is to use two-sided 95% CI for the difference between
treatment arms and to compare this with the predefined non-inferiority delta.
Therefore, the CHMP requested the MAH to discuss on this issue.
Further to the discussion by the MAH, the CHMP noted that the predefined margins were 15% foroverall success and Oswestry, and 10% for fusion and neurological success.
It is agreed that in all of the datasets (per protocol, primary dataset and missing-equals-failure), noninferiority of Inductos+LT-CAGE treatment to autograft+LT-CAGE was shown with regards to theprimary efficacy variable “Overall success” by comparing the lower bound of two-sided 95%
Confidence Interval to the chosen 15% non-inferiority margin both at 12 and at 24 months. The results
are hence robust and consistent. With regards to the fusion success rates, non-inferiority was also
consistently shown in all datasets. The Oswestry Pain score success and neurological success rates
were similar in the treatment groups, but formal non-inferiority was consistently shown only for theOswestry scores.
Since the definition of fusion criteria of the FDA was used, the CHMP requested the MAH to indicate
what the sensitivity/accuracy of this assay was. Additionally, the MAH should justify the choice of the
non-inferiority margins.
For studies 3100N3-303 and -304 fusion was determined from radiographic evidence of bridging
trabeculae. If such evidence could not be seen in radiographs, CT scans could then be used. CT scans
29have increased ability for detecting bridging bone. According to the company’s response, both
radiographs and CT scans were reviewed to determine fusion. Additional criteria had to be fulfilled
before fusion could be declared: no radiographic evidence of motion (using accepted criteria to assessmotion, taking into consideration the inherent measurement errors) and no evidence of radiolucency
surrounding greater than 50% of either of the implanted LT-CAGE devices. The fact that both plainradiographs and CT scans were used for detecting fusion makes the results more solid. The methods
used in the clinical trials, albeit representing surrogate evidence of fusion, have been used in otherpublished clinical trials and can be considered reliable, sensitive and accurate. Use of invasive
methods would not have been possible. It is unlikely that use of these methods has introduced any bias
in favour of Inductos+LT-CAGE treatment arm. On the contrary, the non-inferiority analysis is likely
to be conservative due to the presence of mineralised bone inside the LT-CAGE in the bone
autograft+LT-CAGE treatment arm.
The company has reviewed available published data on efficacy of anterior lumbar interbody fusion
procedures. The CHMP agreed that the results of the clinical trials with LT-CAGE with autograft or
Inductos are in line with published data from other studies, showing generally fusion rates of 90% or
higher. Fusion rate is expected to be negligible without surgical intervention and, therefore, thecompany has a strong argument in favour of using the 10% non-inferiority margin for fusion success.
The 15% non-inferiority margin used for Oswestry Pain score and overall success is more difficult tojustify. However, based on review of published literature on clinical trials that have used other surgicalmethods and have included Oswestry scores among their endpoints the choice of “delta” can be
defended.
The CHMP noted that high response rates have been reported for autograft-induced spinal fusion.
However, the MAH was requested to specifically review the results of autograft treatment(radiological and functional endpoints, i.e., all components of the primary endpoint) in published trials
using the same device and surgical approach relevant to the current application to further justify thechosen noninferiority margin.
The MAH noted that there are no published studies directly comparing the efficacy of fusion
procedures with fusion cages with non-surgical treatment. However, the study by Fritzell et al. (Spine
2001; 26(23):2521-2534) is helpful in establishing that patients with severe chronic low back pain andlumbar spine disc degeneration are unlikely to experience any significant relief of pain without
surgical intervention as judged by changes in Oswestry score over 2 years vs. posterolateral fusion
procures. As concluded in the review of MAH’s response, the CHMP considered that the 15% noninferiority margin for Oswestry Pain score success is reasonable. A remarkable improvement in
Oswestry score was observed in both treatment groups in the main study -303. Taking into
consideration the reported minimal or no improvement in patients treated conservatively, the noninferiority delta of 15% can be considered justifiable and conservative for Oswestry success andoverall success (Oswestry was part of overall success evaluation).
It was noted that in a non-inferiority trial, the main focus is on the per protocol analysis. Only the
results of per protocol dataset analysis of the primary combined efficacy/safety endpoint have been
provided. To be able to further assess the validity of noninferiority conclusion, the MAH should
provide the per protocol dataset analysis results for the two primary efficacy endpoints in the main
clinical study, and a new non-inferiority analysis for the combined endpoint and efficacy endpoints
using the recommended method and all protocol defined datasets.
The results of the per protocol dataset analysis for the two primary efficacy endpoints (Oswestry andfusion) and for the combined endpoint of overall success have been provided. This analysis utilizes
two sided 95% confidence intervals for the difference between treatment arms.
For the per protocol dataset analysis, the absolute value of the lower limits of the 95% two-sided
confidence intervals are all smaller than the non-inferiority margins that were pre-defined in the
protocol at both 12 and 24 months. The predefined margins were 15% for overall success andOswestry, and 10% for fusion. For the per protocol analyses at 24 months, the absolute value of thelower limit of the two-sided 95% confidence interval was 11.20% for Oswestry, 1.53% for fusion, and10.72% for overall success.

30

Thus, non-inferiority with respect to the standard therapy has been demonstrated with the per protocol
analysis, as well as with the primary data set and missing-equals-failure dataset. This issue have been
considered resolved.
The CHMP noted that non-clinical and clinical data underline the importance of following instructions
given in the SPC on the appropriate preparation and handling of the implant to avoid leakage ofdibotermin alfa. Therefore the CHMP concluded that MAH should commit to produce suitableeducational material for surgeons and other medical staff. This material should be submitted to the
CHMP for review.
The draft brochure is considered a helpful start. However, the MAH should consider producing avideo outlining the correct preparation of IndusctOs for use in spine infusion procedure, handling anduse of Inductos with LT-CAGE device. This educational material should be available in a reasonable
deadline for its submission for review.
The CHMP raised a concern since the MAH states that it is a minor omission that no donor-site pain
data have been collected for the investigational subjects. Donor-site pain is the reason why rhBMP-2 isused instead of autogenous bone graft. The CHMP concluded that if donor-site pain is included in the
total pain score the MAH should have conducted a superiority trial and not a non-inferiority trial forthe endpoint pain.
Pain from donor site played a role in the first 6 weeks to 3 months after surgery, but was minimal at 12
and 24 months. With adjustment of the Oswestry score by donor-site pain, the lower limit of theconfidence interval for Oswestry pain and Overall success at 24 months shifted slightly to morenegative values, but was still within the predefined limit of -15%. The CHMP concluded that this issue
is resolved.
The CHMP noted that in the LT-CAGE study lower success percentages were reached with the LTCAGE filled with autologous bone as in study 3100N3-303. The CHMP requested the MAH to givean explanation for this.
The additional data provided by the MAH show that fusion rates are similar in both studies (data arefrom the primary analysis set), but Oswestry Pain/Disability Improvement and therefore Overall
Success are still lower in the IDE G9 50165 study. The MAH argued that surgeons have become morefamiliar with the fusion technology with the LT-CAGE Device at the time of the main study. Thisshould be kept in mind when comparing the results of both studies.
Although there is no proof, the CHMP considered this issue to be answered sufficiently and therefore
resolved.
The CHMP raised a concern on the maximal total dose used in the clinical study 3100N3-303-US). In
this study maximal total dose was 8.4 mg of rhBMP-2 for the 2 cages (size 18 mm x 26 mm) which isdifferent from the dose as applied for given in the table of the SPC sect. 4.2 which amounts to 6 mg
per cage (size 18 mm x 26 mm) resp. 12 mg of rhBMP-2. This dose has not been tested. The MAH is
asked to explain this discrepancy with respect to any dose effects.
The MAH has proposed to resolve the issue by changing the number of large LT-CAGE in section 4.2
in the SPC from 3 to 2 to reflect the number of pieces of InductOs used in the clinical studies.
5.3 Clinical safety
The safety profile of rhBMP-2/ACS when used with the LT-CAGE for anterior single-level lumbar
spine fusion appears acceptable and favourable compared to LT-CAGE + bone autograft. Thisconclusion is based on the pivotal clinical trial where an open surgical approach was used. In general,the profile of adverse events was expected in the clinical context. However, certain adverse events thatare not uncommon after spinal fusion procedures (joint disorder, neuralgia, neuropathy, urinary
retention and abnormal ejaluation) were more frequently reported in the rhBMP-2/ACS group31

compared to autograft group. Therefore the CHMP requested the MAH to discuss on these adverse
events.
The CHMP concluded that all of the adverse events reviewed (“joint disorder”, “neuralgia”,“neuropathy”, “urinary retention” and “abnormal ejaculation”) may well be related to the surgicalprocedure as such or to the progression of degenerative disc disorder at other levels of the spine. The
concern was related to the fact that the individual adverse events appear to be more frequently reported
in the Inductos+LT-CAGE group than in the control group. When the neurological success and overall
success rates are compared, there is no sign that the higher frequency of adverse events might berelated to inferior efficacy of the investigational treatment. Neurological success rates were similar inboth treatment arms. Urinary retention and abnormal ejaculation are not infrequent adverse events
following spinal fusion procedures. Furthermore, none of the differences between the treatment arms
were statistically significant. Finally, the aggregate analysis of neurological adverse events does notsuggest a clear difference between the treatment arms.
The CHMP concluded that the MAH should closely monitor neurological events in clinical use.
The CHMP raised a concern on a case of spinal stenosis reported in the laparoscopic study andrequested the MAH to discuss in more detail.
Further to the discussion by the MAH, the CHMP concluded that the review of the detailed
information provided on the reported case of spinal stenosis does not allow drawing any firm
conclusion as to the role of Inductos+LT-CAGE treatment. However, the patient’s history and clinicalfindings suggest that the condition may be secondary to degenerative disc disease rather than to theinvestigational treatment. This issue was considered resolved.
The presented data on antibodies do not indicate difficulties in that area. However, as a result offollow-up measures 025 and 026 the MAH has developed and validated a new antibody ELISA for
antibodies to rhBMP-2 that has the potential to detect all antibody isotypes. In addition a neutralization
assay for antibodies to rhBMP-2 has been developed and validated. Since it is assumed that the data
presented have been collected using the old method, the CHMP requested the to submit data collectedwith the new assays from retrospective or prospective studies.
The preliminary analysis of samples from clinical trials using the “old” and newly developed ELISA
assays suggests that a higher frequency of rhBMP-2 antibodies is detected with the new assay. The
new data should be included in the SPC after the MAH has submitted the data and assay details forreview by the CHMP. It is unfortunate that the samples have not yet been tested in the neutralisation
assay. The company should keep the CHMP up to date with regards to the evaluation of the assay
details by the FDA.
If neutralising antibodies are detected, the MAH should also consider and examine potential crossreactivity of neutralising antibodies with other members of the TGF-ß family, and to provide a detailed
discussion on clinical relevance. The possibility of developing neutralising antibodies is also important
to consider in the context of safety in pregnancy.
The CHMP agreed with the MAH’s view to maintain the contraindication for pregnancy. Although the
CHMP does not believe that the non-clinical data indicate serious risks for pregnancy, the CHMP
agreed that the lack of information on the potential effects of antidibotermin neutralising antibodies on
pregnancy is an important reason to maintain pregnancy as contraindication. Indeed, The CHMP does
not know whether neutralising antibodies are formed. Also the effects of such antibodies have notbeen studied. Therefore the answer cannot be given at this time. If neutralising antibodies are formed it
is conceivable that such antibodies have an effect on foetal development. Yet if neutralising antibodies
are formed and they would adversely affect foetal development, a contraindication alone might not beenough. In fact in that case pregnancy ought to be prevented as long as immunological memory for
dibotermin is present. This should be further discussed when data on neutralising properties ofantibodies found in clinical studies have been made available.
The CHMP concluded that this issue is unresolved and therefore the MAH should commit on theprovision of these data.
The CHMP raised concern on malignancy and during its plenary meeting in December 2004 the
CHMP adopted a follow-on request of supplementary information to be addressed by the MAH. With32

reference to the summarisation on malignancy cases reported in the clinical trials sponsored by Medtronic
Sofamor Danek (MSD) the MAH was requested to submit more detailed information on the cases ofmalignancy.
The CHMP concluded that the MAH has presented detailed information on the cases of malignancy. With
respect to the cases of pancreatic cancer Wyeth and MSD conducted site visits and detailed trip reports
were provided. The MAH has made efforts to retrieve all relevant information. Though one cannot say forcertain, it appears unlikely that if rhBMP-2 induced malignant transformation of cells, the patients would
present within a year with symptomatic/metastatic disease. The available information does not allow tocomment on what role rhBMP-2 might play in stimulating pre-existing neoplasms. This may beparticularly relevant for those cancers (e.g. pancreatic and liver cancer) found in the proximity to the siteof implantation, as the overall systemic exposure to rhBMP-2 is brief.
The CHMP noted that the data from MSD shows an imbalance in the proportion of patients with reportsof SEER (Surveillance, Epidemiology and End Result) malignancies in the active and in the control arms.
Therefore the MAH was requested to discuss on the difference of the malignancy cases between the active
group and the control group. Further to the provision of responses to this issue, the CHMP concluded thatit could be doubted that one-year difference in mean age will have contributed significantly to theobserved imbalance in malignancies. Post study surveillance in a single arm indeed may introduce areporting bias. However, incidence rates were determined according to protocol-mandated follow-up time.
Therefore, the CHMP concluded that it is unlikely that these factors may confound the interpretation of
the data.
The CHMP noted that the data from MSD shows an imbalance in the proportion of patients with reportsof SEER (Surveillance, Epidemiology and End Result) malignancies in the active and in the control arms.
Therefore the MAH was requested to compare the observed rates of these malignancies to those expected
for age and gender matched controls.
The CHMP noted that observed rates of malignancies were compared to the frequency of cancer in thegeneral US population. It should be remarked that not all studies were conducted in the US. The tibiafracture study (450 patients), for instance, was conducted in South Africa, Australia and Europe.
However, the approach can be accepted.
The overall frequency of malignancies was comparable to the expected rate, but there were morepancreatic cancers. The MAH may be right that one cannot conclude that rhBMP-2 increases the risk ofpancreatic cancer based on this evaluation, but it cannot be refuted either. The MAH has submitted adetailed description of the three patients. One cannot conclude with certainty that there is no relationship.
It is appreciated that the MAH plans to obtain expert review of the data and pursue the feasibility of aformal epidemiological study to evaluate any association between rhBMP-2 and pancreatic cancer.
The CHMP requested the MAH to compare the data from Wyeth studies and MSD studies and discuss thedifferences.
In its responses, the MAH mentioned a number of factors that can contribute to the differences in data
between Wyeth and MSD studies. The CHMP noted that treatment indication, comorbidity, pre-existingrisk factors and age are factors that might explain the difference. The CHMP concluded that a concern isthe fact that this higher ”background incidence” of malignancies could be the target for an effect ofdibotermin alfa.
There is an imbalance in the total (or total SEER) number of malignancies in rhBMP-2 treated patientscompared to control patients. However, when the rates are adjusted for the differences in duration offollow-up time between the two groups, they are not statistically significant. Also, when compared to thefrequency of cancer in the general US population, the overall frequency of malignancy was comparable tothat expected, but there were more pancreatic cancers.
In the light of three reports of pancreatic cancer in the rhBMP-2 treated patients, further causality
evaluations were performed. For the time being, causal relationship with the observed cases of malignant
tumours in patients who have received InductOs cannot be concluded. Therefore the MAH should submit
a proposal for pro-active monitoring of malignancies.

33

Although it appears unlikely that locally administered dibotermin alfa could affect tumour cells at distantsites, due to its low systemic availability and short duration of action, the occurrence of a higher than
expected number of pancreatic cancers does raise some concern, as this site is relatively close to the site of
implantation in lumbar spine fusion. Another cause of concern is the fact that the target population for the
proposed indication is generally older than tibia fracture patients, resulting in a higher “backgroundincidence” of malignancies that could be the target for an effect of dibotermin alfa.
The CHMP endorsed the MAH’s plan to obtain expert review of the data and pursue the feasibility of aformal epidemiological study to evaluate any association between rhBMP-2 and pancreatic cancer. The
MAH has provided a summary of the expert panel meeting, which was held on 31 January 2005. The
conclusions of this meeting give no cause for further comments.
The PSUR cycle should be kept at one year for the moment.
5.4

Benefit/Risk assessment

Based on the review of the data provided, the CHMP considered that the variation application for
InductOs, for the proposed new indication of spine fusion is approvable, provided that the MAH
commits to further investigate the growth-promoting properties of other tumour cell types that have notbeen investigated so far, to submit a proposal for pro-active monitoring of malignancies and to explore
further the possibility of a formal epidemiological study.

34

6. CHANGES TO THE PRODUCT INFORMATION
Further to the assessment of the different proposals of the Marketing Authorisation Holder to amend
the Product Information and in the light of the assessment of the submitted data, the CHMP requested
the following additional amendments of the SPC:
Section 4.1“Therapeutic indication”

The therapeutic indication has to be in line with that of the LT-CAGE device and clinical trial study
population: therefore it was added that patients should have at least six months of nonsurgicaltreatment. The sentence “For this indication, InductOs must be used with the LT-CAGE® Lumbar
Tapered Fusion Device” has been deleted and it has been moved to section 4.2.
Section 4.2“Posology and method of administration”

The following sentence has been inserted immediately below the heading “Instructions for use inanterior lumbar spine fusion surgery”: InductOs should not be used alone for this indication, but must
be used with the LT-CAGE Lumbar Tapered Fusion Device.
Following the CHMP’s concern on the maximal total dose used in the clinical study, the number oflarge LT-CAGE has been changed from 3 to 2 to reflect the number of pieces of InductOs used in theclinical studies.
4.3

Contraindications“Pregnancy” is maintained as contraindication.
4.4

Special warnings and special precautions for use

The MAH has committed to update this section after the submission of data from the newly developed
ELISA assays.
4.6

Pregnancy and lactation

The following sentence has been inserted: “Animal studies have shown reproductive toxicity (seesection 5.3). The potential risk for humans is unknown. Due to the unknown risks to the fetus
associated with the potential development of neutralising antibodies to dibotermin alfa, InductOs iscontraindicated in pregnancy (see sections 4.3 and 4.4).”
When new data on neutralising antibodies become available, the wording in this section has to bereconsidered.

4.8

Undesirable effects

Further to the provision of supplementary information by the MAH on some adverse events (“joint
disorder”, “neuralgia”, “neuropathy”, “urinary retention” and “abnormal ejaculation”) the CHMP
concluded that none of the differences between the treatment arms were statistically significant andthat the aggregate analysis of neurological adverse events did not suggest a clear difference between
the treatment arms. Therefore the proposed text from the MAH does not need any further revision.
5.1

Pharmacodynamic properties

The sentence on donor-site pain has been deleted (“As expected, patients who received autogenous
bone graft reported pain at the site of graft harvest, with 31% of them still experiencing some graft-site
pain at 24 months”) and the overall success rates have been included.
35

5.3

Preclinical safety data

This paragraph has been updated in line with the revision proposed by the CHMP (i.e. “Preclinicaldata reveal no special hazard for humans on conventional studies of pharmacology, acute and repeat
exposure toxicity. Animal studies do not indicate direct or indirect harmful effects with respect topregnancy, maternal toxicity, embryolethality, or fetotoxicity. However, in reproductive toxicity
studies in rats, where dibotermin alfa was administered intravenously to maximize systemic exposure,increased fetal weight and increased fetal ossification was observed and a treatment related effectcould not be ruled out. The potential effects of anti-dibotermin antibodies have not been investigated.
InductOs has not been tested for in vivo carcinogenicity. Dibotermin alfa has demonstrated variable
effects on human tumour cell lines in vitro. Although the available in vitro data suggest a low potential
for promotion of tumour growth, the use of InductOs is contraindicated in patients with an active
malignancy or in patients undergoing treatment for a malignancy (see also section 4.3
Contraindications). InductOs has been studied in a canine spinal implantation model. InductOs was
implanted directly onto the exposed dura following a laminectomy. Although narrowing of theneuroforamen and stenosis was observed, no mineralization of the dura, no spinal cord stenosis, andno neurological deficits subsequent to the application of InductOs were observed. The significance of
these data for humans is not known.”).

Where relevant changes are also reflected in the Package Leaflet.
Additionally, the CHMP requested the following additional amendments in the Package Leaflet.
2.

BEFORE YOU RECEIVE InductOs

In the paragraph “The following are precautions for use of InductOs to be discussed with your doctor”
the following sentence has been inserted “You should inform your doctor if you have any bonedisease”.

36

7.

CONCLUSIONThe CHMP considered this Type II variation to be acceptable and agreed on the proposed wording to
be introduced into the Summary of Product Characteristics and Package Leaflet based on theobservations and the appropriate conclusions, subject to the additional follow-up measures undertakenby the Marketing Authorisation Holder (see Annex 9 of this Assessment report).
The CHMP adopted on 17 February 2005 an Opinion on a Type II variation to be made to the terms of
the Community Marketing Authorisation, as amended.

37