The document discusses considerations for developing medical products to treat osteoarthritis (OA) using structural endpoints. It notes that while modifying disease pathophysiology and changing the natural course of OA is desirable, there are challenges to reliably assessing a product's ability to alter disease progression. Specifically, there is a lack of standard definitions for progression and validated endpoints. Additionally, the relationship between structural changes and symptoms/function is variable. The document advises that substantial evidence would be needed to accept a structural endpoint for accelerated approval and reliably predict clinical benefits like reduced pain and increased function. The ultimate goal is to avoid joint failure and replacement while preserving function and relieving pain.

1. Morten Karsdal,
CEO, Nordic Bioscience, Herlev, Copenhagen Denmark
Professor, SDU, Odense, Denmark
Disclosure Information
I
I have financial relationship(s) with: EMD Serono, Tissuegene, Novartis, Galapagos, Abbvie, Biogen,
Pfizer, Lilly, Servier, Intercept, Allergan, Gilead, NGM, BMS, Novo, Genentech, Roche and many
smaller biotechs in relation to clinical trial design and biomarkers
AND
My presentation does not include discussion of off-label or investigational use.

2. THE DOCUMENT

3. Updated FDA Draft Guidance on OA Treatments (2018)
II. CONSIDERATIONS FOR DEVELOPMENT
Sponsors should consider the following regarding structural endpoints for developing medical products for
the treatment of OA:
• FDA recognizes that OA can be a serious disease with an unmet medical need for therapies that modify
the underlying pathophysiology of the disease and potentially change its natural course to prevent long-
term disability. However, there are several ongoing issues with developing such products, including the
multifactorial and complex etiopathogenesis of the disease, the well-recognized discordance between
structural changes and signs/symptoms/function, the lack of standard definitions of disease progression,
and, correspondingly, the absence of endpoints to reliably assess the ability of a product to alter OA
disease progression.
• Because of the complex and variable pathologic changes through which OA impairs function and leads to
long-term disability and/or joint replacement, at this time it is unclear what magnitude of change in
structural endpoints would translate to a clinically meaningful benefit to patients (i.e., reliably predict both
reduced pain and increased function or prolonged time to end-stage disease). Thus, no structural endpoints
have been used for traditional or accelerated approval in OA to date.
• To accept structural endpoints as valid outcome measures for accelerated approval, there should be
substantial confidence, either based on empirical evidence from randomized, controlled comparisons from
clinical trials and/or based on a comprehensive understanding of the disease process and product
mechanism of action, that an effect on the candidate structural endpoint will reliably predict an effect on
the clinical outcomes of interest. The ultimate goal of treatments related to inhibition of structural damage
or targeting the underlying pathophysiology associated with OA is to avoid or significantly delay the
complications of joint failure and the need for joint replacement, and also to reduce the deterioration of
function and worsening of pain.

4. ACCELERATED APPROVAL
LESSONS LEARNED FROM NASH
4
Surrogate Endpoint
Surrogate Endpoint
Outcome
Outcome
Liver biopsy
N= 800-1000
52/104 weeks 4/5 years
LiverForum8, Paris, April 2018

5. CLINICAL TRIAL ENDPOINTS
Accelerated approval designated new drugs for serious or life-threatening illnesses - are
allowed:
– Intermediate Clinical Endpoint: A measurement of a therapeutic effect that can be measured
earlier than an effect on irreversible morbidity or mortality and is considered reasonably likely
to predict the drug’s effect on irreversible morbidity or mortality or other clinical benefit.
– Surrogate Endpoint: A marker, such as a laboratory measurement, radiographic image, physical
sign, or other measure, that is thought to predict clinical benefit, but is not itself a measure of
clinical benefit.
• Plus post marketing continuation of the phase III program to define efficacy on hard
clinical endpoints e.g. NASH
5 FDA, CFR title 21 – Subpart H, 2017

6. BEST RESOURCE (SEPT 25, 2017)
Term definition
Surrogate endpoint:
An endpoint that is used in clinical trials as a substitute for a direct measure of how a patient feels, functions, or
survive. A surrogate endpoint does not measure clinical benefit of primary interest in and of itself, but rather is
expected to predict that clinical benefit or harm based on epidemiologic, therapeutic, pathophysiologic, or other
scientific evidence
Candidate surrogate endpoint:
An endpoint still under evaluation for its ability to predict clinical benefit
Reasonably likely surrogate endpoint:
An endpoint supported by clear mechanistic and/or epidemiological rationale but insufficient clinical data to
show that it is a validated surrogate endpoint. Such endpoints can be used for accelerated approval for drugs or
expedited access for medical devices.
Assessing the effect of the intervention on the clinical beneficial endpoint of interest will be collected in the
post marketing setting to verify whether an effect on the reasonable likely surrogate actually predict benefit in
the specific context under study
Validated surrogate endpoint:
An endpoint supported by a clear mechanistic rational and clinical data providing strong evidence that an effect
on the surrogate endpoint predicts a clinical benefit. Therefore it can be used to support traditional approval
without the need for additional efficacy information.
6

7. LESSONS TO BE LEARNED FROM OTHER TAs ?
7
DISEASE PHASE 2B PHASE 3 POST-APPROVAL OUTCOME STUDY
OR SUB-PART H
Osteoporosis
Alendronate,
Zoledronic acid,
PTH, calcitonin,
Abaloparatide, and
Denozumab
N:
200-400 patients
Endpoint:
Imaging by x-ray, BMD
Duration:
6 months to 2 years
N:
2000-8000 patients
Endpoint:
Fractures determined by X-ray
Duration:
1.5 to 3 years
NASH
Elafibrinor,
Cenicriviroc,
Obetocolic acid
N:
200-400 patients
Endpoint:
Histology by liver biopsy
Duration:
6 months to a year
N:
2000-2400 patients
Conditional approval endpoint:
Histology by liver biopsy
Duration:
52 weeks
N: same patients as Phase III
2000-2400 patient
Outcome measures:
Liver decompensation and death
Duration
4-5 years
T2D
GLP-1s, SGLT2s,
PPARs
N:
200-to 450 patients
Endpoint:
HbA1c
Duration:
3-6 months
N:
400 to 1500 patients
Endpoint:
HbA1c
Duration:
6 months to 2 years
OUTCOME STUDY
N:3300- to 10500 patients
years
Endpoint: MACE 3, cardiovascular
outcome
Duration:
1-3 years
OA
Calcitonin, FGF-18,
Risedronate,
Cindunistat
N:
200-550-1500 patients
Endpoints:
Structure by Imaging such as X-ray or MRI
Function:
PRO such as WOMAC
Duration:
6 months to a year or more
N:
1000-2500 patients
Endpoints:
Structure by imaging such as imaging or MRI
Function:
PRO, such as WOMAC
Duration:
2 years or more
N:
1000-2000 patients
Endpoints:
The topic of this discussion

8. ACCELERATED APPROVAL
Osteoarthritis
8
Surrogate Endpoint Outcome
MRI
X-RAY
BIOMARKER
WOMAC
PAIN
6 minutes walking
TJR
Conditional
APPROVAL
N= ???
??? weeks ??? years

9. PRECISION MEDICINE
OAC, Karsdal & Kraus, 2014

10. STRATIFICATION AFTER SCREENING PRIOR TO RANDOMISATION

11. ENRICHMENT
X XX
X
X
XX X X XX
X
X
XX XOO OO
OO OO

12. STRATIFICATION
X XX
X
X
XX X X XX
X
X
XX X
OO OO
OO OO
OO OO
OO OO

13. Prognostic enrichment strategies using
cartilage metabolic status
10-7-201913
Pre-stratification
MedialJSNonsignalknee(mm)
(MeanwithSEM)
Placebo sCT
-3
-2
-1
0
1
2
3 ns
Post-stratification
MedialJSNonsignalknee(mm)
(MeanwithSEM)
Placebo sCT Placebo sCT
-3
-2
-1
0
1
2
3
* *
Low hsPRO-C2 High hsPRO-C2
C D