Design of Clinical Trials for New Products in

Hemophilia

Recommendations of the FVIII/ FIX SSC

Subcommittee

SUMMARY

The mandate for the Project Group

on Clinical Trials for New Products

in Hemophilia (CTPG) arose not

only from pragmatic concerns about

the feasibility of populating and

conducting multiple simultaneous

new clotting factor trials, but also

from the perspective of

harmonization of these requirements

based on common principles. This

led to the question of whether

innovative and evidence-based

approaches to trial simplification

might increase feasibility without

compromising assessment of product

safety and efficacy. Based on this

rationale, the CTPG was tasked with

exploring alternative approaches for

the pre- and post- licensure study of

so called ‘me-too’ and novel biologic

replacement products for hemophilia

A and B. The group was constituted

on the basis of member expertise in

clinical care and investigation,

immunology, clinical trial design and

statistics, and included regulatory

science representatives from the

Food and Drug Administration

(FDA), USA, and the European

Medicinal Agency (EMA). Input

from critical stakeholders was

solicited at international and

FVIII/IX SSC Subcommittee

meetings; from the relevant industry;

and from selected experts in clinical

trial design methodology. The CTPG

ultimately narrowed the project

scope to encompass

recommendations for an alternative

approach to statistical analysis and

the clinical design and statistical

analysis of pre-authorization trials

for both ‘me-too’ and novel factor

VIII (FVIII) concentrates in

previously treated patents (PTPs).

This approach is rooted in the

combined agency regulatory goals

for pre-licensure studies, and

incorporates both current

immunological theories of

neoantigenicity and consensus

clinical efficacy endpoint definitions.

Innovative approaches to the clinical

design of new product safety

(immunogenicity) trials were

considered and based on the known

epidemiology and immunology of

FVIII inhibitor development in

congenital hemophilia A.

Recognizing that the optimal design

of pre-authorization clinical trials

remains hampered by poor

understanding of the precise nature

of the interactions between the

therapeutic FVIII products and the

recipient’s immune system, the

CTPG recommended a systematic

and harmonized collection of clinical

and biological data from subjects

entering pre- and post authorization

new product studies. The CTPG also

advocated for future exploration of

1) the feasibility of international

harmonized post-authorization

studies using existing national and

international database infrastructure

and consensus standardized

minimum datasets, and 2) eventual

EMA/FDA harmonization in critical

areas such as the evolving landscape

of inhibitor assays and the disparate

approaches to product authorization

in children.

INTRODUCTION

The Project Group on Clinical Trials

for New Products in Hemophilia

(CTPG) was assembled in February

2011 by the FVIII/IX Subcommittee

of the Scientific and Standardization

Committee (SSC) of the

International Society on Thrombosis

and Haemostasis (ISTH) to propose

alternative strategies for the design

of pre- and post-authorization

(licensure) clinical trials and studies

of ‘me-too’ and novel therapeutics in

hemophilia A and B, with and

without inhibitors. The CTPG

mandate arose predominantly from

pragmatic concerns about the

feasibility of populating and

conducting multiple concurrent new

clotting factor trials, but also from

the premise that regulatory

requirements could be harmonized at

an international level if based on

commonly agreed principles and

statistical calculations. The group’s

aim was to determine whether

innovative and evidence-based

approaches to trial simplification

might increase feasibility without

compromising assessment of product

safety and efficacy.

METHODS

The CTPG was constituted on the

basis of member expertise in clinical

care and investigation, immunology,

clinical trial design and

methodology, and regulatory science

with representation from both the

Food and Drug Administration

(FDA) of the United States and the

European Medicines Agency (EMA)

(Table 1). The group met monthly

between February 2011 and

November 2013 to 1) review the

known clinical data on factor VIII

and IX product immunogenicity (and

any emerging data for novel

therapeutics) in previously treated

(PTPs) and previously untreated

(PUPs) patients; 2) explore the

potential impact of alternative

statistical approaches and innovative

trial design on the pre-authorization

regulatory requirements for product

safety and efficacy determination; 3)

examine the current scientific

concepts of immunogenicity and

neoantigenicity and their potential

influence on clinical trial design and

novel approaches to antibody

surveillance; 4) develop consensus

safety and efficacy clinical endpoint

definitions (building on the work of

the Definitions Project Group); and

5) formulate recommendations.

Progress reports were provided and

input from stakeholders was solicited

at international meetings that

included the ISTH SSC (2011, 2012,

and 2013); World Federation of

Hemophilia (WFH) (2012); and the

WFH Global Research Forum (2011;

2013). The hemophilia therapeutics

industry was surveyed in 2012 for its

input with respect to perceived

regulatory barriers to efficient and

timely product registration;

suggestions for alternative

approaches to clinical safety and

efficacy monitoring in pre- and post-

licensure studies; and potential

benefits derived from strategic

harmonization of key FDA and EMA

regulatory requirements.

RESULTS

The CTPG ultimately narrowed the

project scope to the following

considerations for an alternative

approach to the clinical trial design

of pre-authorization trials for both

‘me-too’ and novel factor VIII

(FVIII) therapeutics in PTPs. This

approach is rooted in the overall

regulatory goals for safety and

efficacy determination prior to

product registration, and incorporates

both current immunological theories

of neoantigenicity and consensus

clinical efficacy endpoint definitions.

Clinical trial design for pre-

authorization trials

Regulatory goals for pre-

authorization trials

While the incidence of uncommon adverse events is

difficult to estimate in rare diseases, pre-

authorization trials are primarily sized to assess

FVIII product immunogenicity in PTPs (defined as

having previously had > 150 product exposure days

(EDs). Treatment efficacy has historically been

ascertained using non-standardized four point scale

patient-reported hemostatic outcomes evaluated in

single arm, open label pre-authorization studies and

reported by the sponsor as descriptive statistics.

However, there have been recent efforts to identify

objective criteria by which sponsors would pre-

specify statistical analysis to establish product

efficacy for episodic treatment, prophylaxis, and

surgery. Key aspects of regulatory agency guidance

for pre-authorization new product trials are

summarized in Table 2 (1-5).

Critical elements of clinical trial

design: Safety endpoints

The size of pre-authorization trials is

driven largely by the goal of ruling

out high levels of immunogenicity.

Currently, ≤ 1 inhibitor in 80

subjects is required to rule out a

6.8% inhibitor cumulative incidence

over 50 exposure days, based on the

upper level of the 95% confidence

interval in a Poisson distribution, the

current upper bound of cumulative

incidence adopted at a 2003 FDA

workshop (5). The simplest approach

to reducing sample size would be to

relax the threshold level of inhibitor

incidence that the trials are intended

to rule out. This is a safety debate

that can still be held within the

hemophilia community. However, to

achieve the same end, the CTPG also

considered innovative approaches to

the clinical design of new product

safety (immunogenicity) trials based

on the known epidemiology and

immunology of FVIII inhibitor

development in congenital

hemophilia A, a rationale we will

now describe in some detail.

The post FVIII-exposure inhibitor

incidence has a biphasic nature. As

depicted in Figure 1A, an early

exposure (20-50 EDs) high peak

‘epidemic’ rate (up to 30%) in

previously untreated patients (PUPs)

(6) is followed by a lifelong low

‘endemic’ incidence of 0.1 to 0.6%

per patient-year, particularly after the

>150 EDs that define PTPs (7-9).

Although the ‘endemic rate’ had

been considered constant and

unlikely to be influenced by product

switching (10), recent national

surveillance data suggest an increase

in inhibitor incidence after age 60

years(9) Initial new product trials

enroll PTPs who have already

successfully transited the ‘epidemic

phase’ without apparent inhibitor

development. They aim to detect a

higher than expected incidence of

inhibitors that could either augment

the ‘endemic rate’ (Figure 1B), or,

alternatively, constitute another

epidemic peak of antibody

development due to product

immunogenicity (Figure 1C).

The CTPG discussed how

methodology, based on known

epidemiology, might best inform the

traditional design of the single arm

pre-licensure new product study with

respect to subject number and study

duration. A predefined frequency to

be ruled out could be set with the

baseline frequency of inhibitor

development as an implicit

background figure, for which a

conservative estimate of 1/100

person-years (1% annualized

incidence) can be used. A two-phase

study should be considered, given

that the study design and sample

requirements required to detect

‘epidemic’ and ‘endemic’ deviations

from the expected rate are different.

To detect a product-related

‘epidemic’ elevation in inhibitor

incidence (11), the study is

temporally confined to the early

product exposure period, the

measured outcome is cumulative

incidence (events/people), and the

sample size is based on the

predefined risk of inhibitor

development to be excluded. This is

similar to the methodology currently

used in the design of FVIII trials.

However, to detect an elevated

‘endemic’ rate of inhibitor

development, the rate itself is the

effect measure (events/person-time),

and the sample size is dependent on

both the predefined rate of inhibitor

development to be excluded and the

person-time accrued in the study. In

other words, since the inhibitor

development rate is assumed to be

constant, it can be equally

ascertained by a group of persons

observed for two years or twice their

number for one year (annualized

rates).

In an exploration of how this model

might work, sample size

requirements for the first phase are

shown in Table 3. To rule out a

cumulative incidence of 6%, zero

inhibitors need to be observed in 60

patients, or no more than one among

91 patients (one-sided testing, 0.025

significance level). Note that this

follows the same reasoning as in the

2003 guidelines: observing ≤ 1

inhibitor in 78 patients rules out,

with the given confidence, a

cumulative incidence of 7 percent, as

≤ 1 in 80 would rule out 6.8%.

However, given the first phase in this

pre-authorization trial design is now

followed by a second phase, it may

be reasonable to relax the boundaries

for the first phase, and aim at ruling

out higher cumulative incidences,

i.e., to aim at ruling out 8% in the

first stage, for which zero events

should be observed in a study of 45

patients, one or less in 68, or two or

less in 88 patients.

If there was no increased

immunogenicity signal detected in an

analysis of this first phase, the

second phase of the study would

begin in which the subjects who

completed the first phase would be

followed for additional time, e.g., 2

years. Note, however, that the

strength of the approach is that one

could also design a study with more

patients in which the required

patient-years would accrue over a

shorter time period. As Table 4

shows, for instance, zero inhibitors

among 74 patients-years, or at most

one inhibitor over 112 patient-years,

would need to be observed to rule

out an incidence of 5 per 100 per

year. In this table, the bracketed

numbers represent the power to

detect a difference, assuming a true

rate of 1 per 100 person-years, the

assumed average rate of all currently

used products. To accrue 112

person-years, one would have to

follow 112 subjects for one year, or

56 for two years (or slightly more to

account for censored patients).

It is important to note that, in this

model, once a product gets through

stage 1, i.e., an ‘epidemic rate’ is

excluded; the observation experience

of stage 1 can now be merged with

stage 2. In other words, if 100

patients enter stage 1, and 2 or less

inhibitors are seen, this rules out a

cumulative risk of 8% (88 would

have sufficed). If this stage 1 takes a

year, and the patients are followed

for another year, nearly 200 patient-

years have accrued. If the total

number of inhibitors over the two

stages is 2 or less, an incidence rate

of 4% is excluded, too (181 patient-

years would have sufficed).

The final requirements depend on the cut-

offs chosen as ‘acceptable’, where the first

phase is mainly intended to catch strongly

immunogenic products early and abort. A

study of fewer than 100 (88) patients in

whom fewer than 2 inhibitors were seen,

would rule out a cumulative incidence of 8

percent over the time period of the study. If

no such high frequency occurred, a similar

number of subjects followed over 2 years

would be sufficient to exclude annualized

rates of 4/100 person-years. This would

conform to excluding a four-fold increased

incidence rates. These cut-offs are in the

range of elevated epidemic (11) and

endemic(6) reported in the literature, and are

therefore the recommended cut-offs of this

committee. This would typically result in

studies with less than 100 patients, to be

completed in less than two years. Study size

needs to be pre-specified in a registered

protocol, and cannot be changed once the study

has started. Additionally subjects should

represent the entire intended target population of

PTPs. Ultimately, in this proposed approach,

subject requirement and trial duration are

only moderately reduced from the current

regulatory requirements in order to hold to

the current standards of acceptable pre-

authorization product safety determination.

Of note, Bayesian and Adaptive Design

models were also discussed but not

determined to add to the efficiency of the

espoused model.

Critical elements of clinical trial

design: Clinical efficacy endpoints

The CTPG also feels that consensus

and, whenever possible, science-

based definitions of clinical safety

and efficacy (or effectiveness)

outcomes are crucial to the

standardization of outcomes in all

clinical trials. The CTPG deliberated

the definition of clinical endpoints

considered germane to new product

pre-authorization studies, building on

the work of the FVIII/IX

Subcommittee Definitions in

Hemophilia Project Group (12)

(Table 5). Adverse events should be

reported according to GCP

guidelines and any other

requirements in the country where

the trial is being conducted.

Immunogenicity refers to

measurement of antibody responses

to both the therapeutic agent as well

as residual adventitious proteins

present in the final product

formulation. The definitions of

clinical hemostatic efficacy in the

treatment of acute hemarthroses and

in the setting of surgery have been

kept consistent with current SSC

recommendations (12).

Additional Considerations in Study

Design

Reexamining the definition of PTP

These two-stage pre-licensure

studies are to be performed in

previously treated patients (PTPs).

All available evidence suggests that

the highest risk of inhibitor

development in previously untreated

patients (PUPs) is over by 50

exposures, and new data is emerging.

Nevertheless, given that the assumed

inhibitor incidence rates in this

model were predicated on the current

definition, and that potential PTP

subjects for trials are not as limited

as PUPs, we have considered but not

adopted a change in this definition.

However, the CTPG does

recommend the use of post-

marketing surveillance for the

continued epidemiological study of

inhibitor risk in the interval between

50 and 150 EDs, a PUP-PTP

transitional period about which we

lack this data, as well as additional

consideration of this definition as

data evolve.

Application of study design to factor

IX products

The same methodology outlined

above is recommended for

hemophilia B. However, there are

two important differences impacting

study design in hemophilia B: the

disorder has a fivefold lower

prevalence than hemophilia A, and

inhibitor development is rarer than in

hemophilia A. The second of these

would mandate trials designed to

rule out smaller incidences than

recommended for hemophilia A,

while the first renders such mandated

larger trials unfeasible. Therefore,

the CTPG recommends that the

schema outlined for hemophilia A be

also considered for factor IX product

trials i.e., 8% cumulative incidence

in the first stage and a 4/100 person-

years incidence rate in stage 2.

However, since the frequency of

inhibitor development is rare, studies

could be safely designed to observe

zero events, reducing the subject

requirements for each phase of the

study such that 50 subjects followed

for two years would suffice (45 in

stage 1, 93 person-years in stage 2).

Application of study design to long-

acting products

Modified clotting factor preparations

with a much longer plasma half-life

than the currently available FVIII

and FIX products have begun the

process of pre- authorization study.

While we believe that the proposed

study design based on known

inhibitor incidence rates will be

applicable to these products, the

concept of ‘exposure days’ may

require additional consideration.

Given the half-life of unmodified

factor VIII and IX products, infusion

and exposure days are relatively

synchronous. This may not be the

case with long-acting products for

which one infusion may result in

several days of ‘exposure’. However,

we recognize that our current

knowledge of product-related

immunogenicity precludes evidence-

based recommendations on the

appropriate definition.

The immunology of product

neoantigenicity

Regardless of the approach, the

optimal design of pre-authorization

clinical trials remains hampered by

poor understanding of the precise

nature of the interactions between

the therapeutic FVIII products and

the recipient’s immune system.

Limitations in knowledge derive in

part from the incomplete

characterization of the PTP subject’s

immune status relative to the

therapeutic product(s) received prior

to recruitment into a new product

trial. Immunological ignorance is not

routinely distinguished from active

tolerance. Information about genetics

and presence of a defective clotting

factor protein in the patient’s plasma

(‘cross-reactive material (CRM)’) is

also frequently lacking.

Consequently, when a PTP develops

an inhibitor during a trial of a new

product, an immunological break in

pre-existing tolerance cannot be

distinguished from new product-

associated neo-immunogenicity.

This is a critical point impacting the

accuracy of the published baseline

‘epidemic’ rate of inhibitor

development in PTPs, given that

prior studies have not systematically

categorized PTPs by age, product use

history, and treatment intensity or

bleeding pattern.

A systematic and harmonized

collection of clinical and biological

data from subjects entering pre- and

post authorization new product

studies will therefore be required to

scientifically address these questions.

Table 6 describes the data elements

suggested by the CTPG.

Complementary but integrated data

sets may be required to satisfactorily

address regulatory, scientific and

national/ international surveillance

priorities. The ultimate intent of this

harmonized data collection would be

a more evidence-based rational

design of clinical trials for new

therapeutics in which a smaller but

well characterized and homogenous

subject cohort would more precisely

define the risk for inhibitor

development in specific populations.

Recommendations for future projects

Role of post- authorization studies in

ascertaining product safety and

effectiveness

From a regulatory perspective, the

intent of new product post-marketing

surveillance is to use prospective

well-designed post-authorization

trials and observational studies to

expand a limited pre-authorization

dataset on product safety and

hemostatic efficacy (including PK)

in adults and children undergoing

episodic and prophylactic therapy.

Despite the requirement to perform

inhibitor and recovery testing on a

pre-defined sampling schedule, the

regulatory specifications for these

studies are generally flexible with

respect to safety (no product-related

inhibitor development (PTPs) or

unexpected rates of antibody

detection ( PUPs)) and effectiveness

endpoints (PK, as well as objective

and subjective assessments during on

demand as well as routine and

surgical prophylaxis). The CTPG

therefore recommends that the

FVIII/IX Subcommittee establish a

project group dedicated to

establishing the requirements for an

international harmonized post-

authorization studies using existing

national and international database

infrastructure and consensus

standardized minimum datasets.

Consideration should be given to the

incorporation of consensus clinical

outcomes definitions that, while

tailored to the specific period of

observation, are themselves

harmonized with pre-authorization

clinical endpoints in order to

maximize the potential for

continuous longitudinal data

collection on well characterized

populations. The CTPG also

suggests that such a coordinated

post- marketing effort could

potentially collect strategic data that

contribute to a greater understanding

of immunogenicity and the potential

implementation of novel more

sensitive antibody detection assays

that capture non-inhibitory

antibodies; specific inhibitory

antibodies to circulating FVIII

antigen; and the immunoglobulin G

subclass response. Effective use of

this epidemiologic approach will be

critical (13).

Priority areas for FDA/EMA

harmonization

Evolving landscape of inhibitor

assays

According to EMA and FDA

requirements, immunogenicity

should be investigated prior to

marketing authorization and

substantiated with post-marketing

studies. The occurrence of

neutralizing antibodies should be

investigated by the Nijmegen method

of the Bethesda assay. This method

is the current gold standard

quantitative assay of inhibitor titer. A

recent modification to the current

Bethesda/Nijmegen method

involving the replacement of FVIII-

deficient plasma by buffered normal

plasma promises to reduce cost and

inter-assay variability represents a

promising alternative method to the

conventional assay [S. Raut. SMIA:

A new approach in FVIII inhibitor

measurement and standardization,

58th

Annual SSC, 2012]. However,

the assay of antibodies to novel

biologics has required additional

product-specific assays, including an

electrochemiluminescent

immunoassay (anti-rFVIIIFc,

Biogen®) and radioimmunoassay

(N8-GP, NovoNordisk®) with

respective ng/ml and pg/ml

sensitivity for bound neutralizing and

non-neutralizing antibody (14, 15).

Moving forward on this landscape

will require further research and

harmonized coordinated efforts

between regulatory agencies.

Approach to product authorization in

children

While it is well accepted that

children are not small adults and that

there is need to have specific data in

small children to ensure safety and

efficacy in this population for many

therapeutics, it is important that this

requirement not be generalized for

all drugs and biologics. First, we

should consider the existing data and

experience with a therapeutic /

category of therapeutics to decide the

future approach to new entities

within a given category. In the case

of clotting factor concentrates, there

is sufficient data to show that, apart

from differences in PK, there have

not been additional pediatric-specific

concerns about product safety or

efficacy. It may therefore be

reasonable to adopt a worldwide

harmonized approach to market

authorization on the basis of adult

PTP- generated safety and efficacy

data, supplemented with PK data

from a limited number of children.

More extensive post-authorization

pediatric studies can be subsequently

undertaken, as necessary, and data

provided in a time bound manner.

The creation of appropriate models

for structured post-marketing

surveillance of product safety and

efficacy in both adults and children

is a critical aspect of this

consideration, and specific steps

towards that end have been included

in this document. Second, by

demanding more extensive pediatric

data prior to market authorization,

we risk delaying access to these

products for all hemophilia patients

for estimated periods of 2-3 years,

given the relative rarity of this

condition and logistics of conducting

such studies. Third, while the CTPG

acknowledges that pediatric

regulation (EC 1901/2006) in the EU

currently mandates a Pediatric

investigational Plan (PIP) to generate

pediatric clinical data to support

marketing authorization for clotting

factor use in children, it also

recognizes that the recommended

regulatory approach has already been

practiced in many other parts of the

world for several decades, and no

known product- related harm has

come to children using the clotting

factor biologics that have been

licensed in this way. Finally, the

CTPG is aware of past industry

approaches to product authorization

that have simultaneously fulfilled

both EMA and FDA requirements,

and continue to encourage this

practice pending any consideration

of further regulatory harmonization.

CONCLUSIONS

After 2 years of deliberation, the

CTPG believes that innovative and

evidence-based approaches to pre-

authorization trials in PTPs, based on

the known epidemiology of inhibitor

development in hemophilia A, might

indeed increase the feasibility of

studying multiple new products in

rare disease population without

compromising the assessment of

product safety and efficacy. Several

approaches are presented to the

hemophilia community for their

consideration. The CTPG

recommends that the incorporation

of consensus and evidence-based

definitions of clinical safety and

efficacy (or effectiveness) into the

trial design are crucial to the

standardization of outcomes across

studies. Furthermore, recognizing

that the optimal design of pre-

authorization clinical trials remains

hampered by poor understanding of

the precise nature of the interactions

between the therapeutic FVIII

products and the recipient’s immune

system, the CTPG also recommends

that a systematic and harmonized

collection of clinical and biological

data from subjects entering pre- and

post authorization new product

studies be considered to scientifically

address these questions and allow for

a more evidence-based rational

design of future clinical trials.

The CTPG additionally urges the

FVIII/IX Subcommittee establish a

project group dedicated to

establishing the requirements for an

international harmonized post-

authorization studies using existing

national and international database

infrastructure and consensus

standardized minimum datasets.

These data would complement

limited pre-authorization data on

product safety and hemostatic

efficacy, as well as contribute to a

greater understanding of

immunogenicity and the potential

implementation of novel more

sensitive antibody detection assays.

Finally, although the CTPG could

not recommend an FDA and EMA

consensus approach to all aspects of

pre-authorization new product trials,

it has suggested priority areas for

ongoing discussion.

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D, Ragni MV, Cheng G, Li E, et al.

Safety and prolonged activity of

recombinant factor VIII Fc fusion

protein in hemophilia A patients.

Blood. [Clinical Trial, Phase I

Clinical Trial, Phase II Multicenter

Study Research Support, Non-U.S.

Gov't]. 2012 Mar 29;119(13):3031-7.

15.Tiede A, Brand B, Fischer R,

Kavakli K, Lentz SR, Matsushita T,

et al. Enhancing the pharmacokinetic

properties of recombinant factor

VIII: first-in-human trial of

glycoPEGylated recombinant factor

VIII in patients with hemophilia A.

Journal of thrombosis and

haemostasis : JTH. [Clinical Trial

Multicenter Study Research Support,

Non-U.S. Gov't]. 2013

Apr;11(4):670-8.

Table 1 Members of the project

group on clinical trials for new

products in hemophilia

(affiliation/representation)

______________________________

______________________________

______________________________

______

Donna DiMichele (Chair; former

Clinical Investigator)

Nisha Jain (Regulatory

representative, FDA)

Anneliese Hilger (Regulatory

representative, EMA)

Alok Srivastava (Representative,

FVIII/IX Subcommittee of ISTH;

WFH Liaison; Clinical nvestigator)

Flora Peyvandi (Chair, FVIII/IX

Subcommittee of ISTH; Clinical

Investigator)

Sebastien Lacroix-Desmazes

(Expert, Immunology)

Frits R. Rosendaal (Expert,

Epidemiology and Clinical Trial

Design)

John Scott (Expert, Statistics and

Small Clinical Trial Design, FDA)

______________________________

______________________________

______________________________

_______

Table 2 Key regulatory guidance

for new FVIII product clinical

trials to assess safety (inhibitor

development)

-

______________________________

______________________________

______________________________

US Food and Drug Administration

(FDA)

______________________________

______________________________

______________________________

_

PTPs with > 150 EDs are most

appropriate study population

Total of 80 PTPs should be studied

for a minimum of 50 EDs

Recovery of activity measured after

50 EDs

Sponsor to define low, high, cut-off

inhibitor titers and assay

6.8% as upper bound of the two-

sided 95% confidence interval for all

inhibitors

Pediatric rather than PUP study

requirement; compulsory phase IV

pediatric studies

Post-marketing studies needed for

additional indications

___________________________________________________________________________________________

European Medicines Agency

(EMA)

______________________________

______________________________

______________________________

_

Severe hemophilia A defined as

baseline factor VIII level < 1%

PUPs are defined by lack of prior

exposure to factor concentrates

PTPs at low risk (> 150 EDs) are the

most appropriate study subjects for

evaluation of product-related

immunogenicity

PTPs and PUPs should be monitored for

≥ 50 EDs pre-approval; ≥100 ED are

required post-authorization

The Nijmegen modification of the

Bethesda assay is recommended for

inhibitor testing

Validated testing should be

performed in a central laboratory

The threshold for a low-titer

inhibitor is ≥ 0.6 BU; the threshold

for a high-titer inhibitor is > 5 BU

A positive inhibitor result should be

confirmed by a second assay of a

sample drawn shortly after the first

sample

Clinical signs should be monitored

and correlated with inhibitor test

results

______________________________

______________________________

______________________________

__________

BU: Bethesda units; ED: exposure

day; PTP: previously treated patient;

PUP: previously untreated patient

Table 3 Sample size to rule out epidemic

cumulative incidences over initial exposure*

Cumulativ

e

incidence

ruled out

(per 100)

Observed inhibitors

allowed

0 1 2

3 12

2

18

4

23

9

4 91 13

7

17

8

5 72 11

0

14

2

6 60 91 11

8

7 51 78 10

1

8 45 68 88

9 40 60 78

*one-sided α = .025; exact binomial model*used

according to current regulatory consensus.

See Supplementary Information for a further

discussion of the one sided- α

Table 4 Observation time and power (person-years

[power %])* to rule out endemic rates following initial

exposure stage

I

n

c

i

d

e

n

c

e

r

u

l

e

d

o

u

t

Observed inhibitors

allowed

0

1 2

(

p

e

r

1

0

0

p

e

r

s

o

n

-

y

e

a

r

s

)

2

1

8

5

[

1

6

%

]

2

7

9

[

2

3

%

]

3

6

2

[

3

0

%

]

3

1

2

3

[

2

9

%

1

8

6

[

4

5

%

2

4

1

[

5

7

%

] ] ]

4

9

3

[

4

0

%

]

1

4

0

[

5

9

%

]

1

8

1

[

7

3

%

]

5

7

4

[

4

8

%

]

1

1

2

[

6

9

%

]

1

4

5

[

8

2

%

]

6

6

2

[

5

4

%

]

9

3

[

7

6

%

]

1

2

1

[

8

8

%

]

7

5

3

[

5

9

%

]

8

0

[

8

1

%

]

1

0

4

[

9

1

%

]

8

4

7

[

6

3

%

]

7

0

[

8

4

%

]

9

1

[

9

4

%

]

9

4

1

[

6

6

%

]

6

2

[

8

7

%

]

8

1

[

9

5

%

]

*power assuming a true 1% inhibitor incidence

# one-sided α = .025#, binomial model used according to

current regulatory consensus.

See Supplementary Information for a further discussion of

the one sided- α

Table 5 Clinical trials for new

products of hemostasis for

hemophilia: Endpoints for the

assessment of safety and efficacy

outcomes

______________________________

______________________________

______________________________

______________________________

Pre-authorization studies (50 EDs

or 12 months):

1. Safety endpoints:

a. Serious adverse events (as per

GCP guidelines)

b. Adverse events (as per GCP

guidelines)

c. Immunological events of specific

interest: Inhibitor development,

immunogenicity, hypersensitivity

d. Hemostasis related events:

Thrombogenicity

e. Events related to transmission of

infectious agents

2. Efficacy endpoints:

A. Studies evaluating prophylaxis or

episodic (“on demand”)

replacement of CFC–

a. Number and location of all bleeds,

with special reference to joints,

muscle and CNS

c. Additional doses and frequency of

clotting factor concentrates (CFC)

used

d. Degree of resolution of clinical

symptoms, as per defined SSC

criteria

B. Studies evaluating surgical

hemostasis: (as per defined SSC

criteria)

a. Excellent:

Intra-operative and postoperative

blood loss similar (within 10%) to

the non-hemophilic patient

• No extra (unplanned) doses of

FVIII/FIX/bypassing agents needed

AND

• Blood component transfusions

required are similar to non-

hemophilic patient

b. Good:

Intra-operative and/or postoperative

blood loss slightly increased over

expectation

for the non-hemophilic patient

(between 10 and 25% of expected),

but the difference is

judged by the involved

surgeon/anaesthetist to be clinically

insignificant

• No extra (unplanned) doses of

FVIII/FIX/bypassing agents needed

AND

• Blood component transfusions

required are similar to non-

hemophilic patient

c. Fair:

Intra-operative and/or postoperative

blood loss increased over expectation

(25–50%) for

the non-hemophilic patient and

additional treatment is needed

• Extra (unplanned) dose of

FVIII/FIX/bypassing agents factor

needed OR

• Increased blood component (within

2 fold) of the anticipated transfusion

requirement

d. Poor/none:

Significant intra-operative and/or

postoperative blood loss that is

substantially increased

over expectation (>50%) for the

non-hemophilic patient, requires

intervention, and is not

explained by a surgical/medical issue

other than hemophilia

• Unexpected hypotension or

unexpected transfer to ICU due to

bleeding OR

• Substantially increased blood

component (>2 fold) of the

anticipated transfusion requirement

______________________________

______________________________

______________________________

______________________________

__________

*Apart from estimates of blood loss

during surgery, data on pre- and

post-operative

hemogloblin levels and the number

of packed red blood cell units

transfused may also

be used, if relevant, to estimate

surgical blood loss.

*Surgical hemostasis should be

assessed by an involved surgeon

and/or anaesthetist

and records should be completed

within 72 hours following surgery.

*Surgical procedures may be

classified as major or minor. A

major surgical procedure is defined

as one that requires hemostatic

support for periods exceeding 5

consecutive days.

Table 6. Clinical and biological

data to be systematic and

coordinated collected from

subjects on trials

Hemophilic status Mandator

y

Encouraged

†

Type of mutation +

CRM status +

Bleeding

pattern/treatment

intensity

+

Blood group +

VWF levels +

PK (recovery, half-

life) +

Immunologic

status

HLA haplotype +

Ethnic group +

Gene

polymorphisms:

TNF-α, IL-10,

CTLA-4, HO-1

+

Tolerance/ignoranc

e to FVIII used

before trial

+*

Vaccination,

infection, surgery

history

+

Immune follow-up

Anti-FVIII IgG

(Bethesda Assay) +

Anti-FVIII IgG

(ELISA or other

technology)

+

Anti-FVIII IgM

and IgG subclasses +

† Mandatory or encouraged data

collection parameters determined

empirically based on data from

available

publications or general knowledge

of immunological association, with

inhibitor risk

* Although labeled as mandatory, the

tools for determining a tolerogenic or

ignorance state of the immune

system towards FVIII are not

available as yet. This should be

considered as a strong incentive

towards the

delineation of such tools.

# Tools to be developed

`

Figure 1A

Figure 1B

Figure 1C

Additional Materials

One-sided versus two sided testing

It is important to note that sample

sizes and power presented here are

based on one-sided testing at the

0.025 significance level, or, in other

words, the sample size requirements

would have been the same if we had

set out for two-sided testing at the

conventional α = 0.05, in which case

the p-value (probability of exceeding

the limit) is divided over the two

extremes, i.e., for comparators A and

B it is 0.025 for A>B and 0.025 for

A<B. In a one-sided test, one is only

interested to test for one of these,

which is typically the case for tests

for safety: we wish to rule out that

the new product is less safe than the

conventional ones, and are not

interested if it is safer. Some feel that

in such a one-sided test the

conventional 0.05 value for α should

apply to this test (which is equivalent

to a value of 0.10 for two-sided

tests). This would lead to smaller

sample-sizes, as listed in tables 7 and

8.

Table 7 Sample size to rule out given epidemic cumulative

incidences over initial exposure

(one-sided α = .05; exact binomial model)

Cumulative

incidence ruled

out (per 100)

Observed inhibitors allowed

0 1 2

3 99 157 208

4 74 117 156

5 59 93 124

6 49 78 103

7 42 66 88

8 36 58 77

9 32 51 68

Table 8 Observation time and power (person-years [power %])* to

rule out endemic rates following

initial exposure stage (one-sided α = .05, Poisson model)

Incidence ruled

out (per 100

person-years)

Observed inhibitors allowed

0 1 2

2

3

150 [22%]

100 [37%]

238 [31%]

159 [53%]

315 [39%]

210 [65%]

4 75 [47%] 119 [67%] 158 [79%]

5 60 [55%] 95 [75%] 126 [87%]

6 50 [61%] 80 [81%] 105 [91%]

7 43 [65%] 68 [85%] 90 [94%]

8 38 [68%] 60 [88%] 79 [95%]

9 34 [71%] 53 [90%] 70 [97%]

*power assuming a true 1% inhibitor incidence