aid t p ti clii ltilf an industry perspective on clinical trials for · pdf file ·...

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A I d t P ti Cli i l T i l f

Drug Product for Biological Medicines – Novel Delivery Devices, Challenging Formulations and Combination products

An Industry Perspective on Clinical Trials for Combination Products

Mark Marley, BSRegulatory

©2012, Genentech

Jennifer Visich, PhDClinical Pharmacology

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• Combination Product Framework and Regulatory Interactions• US Regulatory Guidance

Agenda

• US Regulatory Guidance• FDA Feedback

• Combination Product Clinical Evaluation• Change in device configurations during development• Clinical studies limitations and assumptions• Clinical studies-limitations and assumptions• Device and clinical characteristics to consider• How do you choose?

• Case StudyPEGASYS

©2012, Genentech 2

• PEGASYS• New Scenario

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US Regulatory Guidance:Prefilled delivery devices

09/2006 Early Development Considerations for

3

09/2006 Early Development Considerations for Innovative Combination Products

04/2009 Technical Considerations for Pen, Jet, and Related Injectors Intended for Use with Drugs and Biological Products

WCBP CMC Strategy Forum – July17, 2012 3

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FDA Innovative Combo Product Guidance – Key Points

Overall Considerations:“…although a combination product may be comprised of an already

d d d l d d d i i tifi dapproved drug and an already approved device, new scientific and technical issues may emerge when the drug and device are combined or used together.” [lines 50-53]

“…FDA recommends that developers consider the scientific and technical issues raised by the combination product and its constituents and propose an approach that appropriately addresses these issues without requiring duplicative or redundant studies.” [lines 164-167]q g p [ ]

Device considerations:Consider the drug & device interaction (e.g. leachables/extractables, etc.)Apply/adapt relevant consensus standards (e.g. ISO11608)“It may be necessary to evaluate the human factors of device use … evaluate how users operate the system in realistic, stressful conditions.”[lines 376-377]


Summarized from: Guidance for Industry and FDA Staff - Early Development Considerations for Innovative Combination Products (2006)

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Innovative Combo Product GuidanceKey Points (continued)

•Drug/Biologic considerations:

Additional preclinical or clinical studies* may be needed if:o Approved drug/biologic with change in formulation, strength, route of administration

or delivery methodo New dosageo New patient populationo Change in approved indication

*“The goal of these studies would be to evaluate changes that may result in a different extent or distribution of drug constituent exposure.” [lines 321‐323]

Other drug development considerations:o “PK studies may be necessary” (if change in formulation, strength, route of

administration, dosing, population or other factors…) [lines 332-334]o Acute and repeat dose toxicity studies using the new route of administration or

method of delivery may be appropriate to determine no observed adverse effect level (NOAEL).


Summarized from: Guidance for Industry and FDA Staff - Early Development Considerations for Innovative Combination Products (2006)

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FDA Feedback: CT Design Considerations

Context: New biologic; intent to market both PFS and autoinjector

FDA referred to their general experience with devices:General concern regarding devices (i.e.: post-marketing reports, recalls).General concern patients might not successfully complete the injection with an autoinjector.Mentioned an example of two devices with different efficacy & the same molecule (specific product name was not provided).

Encouraged autoinjectors as supplemental BLAs to establish substantial evidence/demonstrate effective use.

Advised that the Phase 3 program should use both the PFS and the autoinjector, if intention to market both devices.Confirmed our understanding of which factors to consider:

Route of administration, delivery method, or dosage [FDA Guidance - Early Development Considerations for Innovative Combination Products (2006)]Dose, rate, and route of administration [FDA Draft Guidance - Pen, Jet, and Related


, , [ , ,Injectors (April 2009)]

Stated that additional focus needs to be on drug flow pathway:Where the drug resides, where it travels, and how it gets into the patient’s body

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Clinical Evaluation Framework

©2012, Genentech 7

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Clinical Evaluation Framework: Multidimensional and Risk-Based Clinical Assessment

Goal: Perform a risk assessment to develop a clinical evaluation strategy (that may or not include an actual clinical study) for thestrategy (that may or not include an actual clinical study) for the introduction of a drug delivery injection device

Examples of Clinical and Device Variables

Phase of Development• Pre-Phase II, Phase

II, Phase III, Post-Market, Phase IV

• Strategic context information about

Clinical Attributes• Therapeutic window• PK data variability• Experience with

drug

Device Change• Vial PFS• PFS Injector


product

NOTE: PFS: Pre‐filled Syringe

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Device change during drug development

LAUNCH

Ph I Ph II Ph III Post-Market

Program needs will drive changes

Technical and Clinical Assessment

Potential Changes:1. Vial to PFS2. Vial (1mL) to Vial (2mL)3. PFS to Injector4. Injector to next generation device

• Understand the timing for change (Phase of development)R li th t h d /d i bi ti i diff t d f d i i

WCBP CMC Strategy Forum – July17, 2012 9Pre‐filled Syringe (PFS)

• Realize that each drug/device combination is different and focus on designing programs that will help in assessment of the safety and effectiveness of the new drug/device combination

• Utilize bench-top testing results as much as possible to assess need for clinical studies/morecomplex clinical studies

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Change Scenarios and Assumptions

LAUNCHPh I Ph II Ph III Post-Market

LAUNCH

PFS

Vial PFS & InjectorVial

Vial Vial PFS

PFSVial PFS & InjectorVial PFS

Bridge to Injector

Vial PFS InjectorVial & PFS PFS

Bridge to Injector(Conduct clinical bridging assessment

parallel to Ph III)


Assumptions: No primary container change, no device component changes, and no formulation/material change;

g j(Conduct clinical bridging

assessment study post-Ph III)

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Pharmacokinetic Concepts: Exposure Drives Efficacy and in Some Cases Safety

Exposure Measures used for Bioequvalence:AUC- Area under the Concentration- Time CurveCmax- Maximum Concentration Observed

Effect Side Effect Effect Side Effect

Safety, ffi

Narrow therapeutic window

ConcentrationConcentration ConcentrationConcentration

efficacy


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Clinical Characteristics to Consider in Bridging Strategy Risk Assessment

Clinical Characteristics Relative Risk to Bridging Outcomes

‘Bench Top” Testing is rigorous and reproducible

Low

PK Data Variability Low

and

risk

Experience with Device (Mature Technology)

Low

Site rotation needed Low/Medium

Patient Population needed for study

Medium

se in

Com

plex

ity a


needed for studyMinimal experience with Biologic

High

Narrow Therapeutic Window

High

Incr

eas

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Clinical Studies for Bridging Strategy

Studies Assumptions and Limitation/Issues

Single Dose PK StudyComparison with historical or parallel

Assumption: dose in linear range, conduct study in HVLimitation: no site rotation, usually not powered

Multiple Dose PK StudyCompare with historical data

Assumption: dose in linear rangeLimitation: conduct study in patients

BE Study•Direct comparison of reference to new device configuration

Assumption: single dose, parallel design, PK is same in HV and patients, conduct in HVLimitation: no site rotation information patients may havem

plex

ity &

Ris

k

configuration Limitation: no site rotation information, patients may have different PK

BE Study in Patients (with or without PD component)•Direct comparison of reference to new device configuration

Assumption: single dose, parallel design, validated PD marker is availableLimitation: no site rotation information, may need large patient numbers due to high PK variability

Additional Ongoing Clinical Trials(Open label extension Phase, etc.)

Assumption: above studies are not possible or unsuccessfulLimitation: impact to development timelineIn

crea

se in

Com


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Device Configurations to Consider in Risk Assessment

Device Configurations Change

POSSIBLE Impact of Device Changes and Material Changes (examples)

Relative Risks related to Exposure Associated with Change

Vial PFS with NSD • Similar ergonomics larger overall size and finger flanges with LowVial PFS with NSD(needle safety device)

• Similar ergonomics - larger overall size and finger flanges with NSD may result in changes in hand posture/grip

• New primary container

Low-Potential for No Clinical Study

PFS with NSD Injector • New primary container• New hand posture / injection technique• Injection depth• Different pressure applied to injection site• Formulation Change: Viscosity, pH, other

Medium / Low –Potential for No Clinical Study or BE study

mpl

exity

& R

isk

Formulation Change: Viscosity, pH, other

PFS with NSDAutomated Injector

• Change in injection rate• Different Injection depth• New hand posture / injection technique• Formulation Change: Viscosity, pH, other

Medium / Low –Potential for No Clinical Study or Single Dose BE study

Vial Novel Device • New primary container• Change in injection rate• Different injection depth• Different pressure applied to injection site

N h d t / i j ti t h i

Medium/High –BE study probably required

Incr

ease

in C

om


• New hand posture / injection technique• Formulation Change: Viscosity, pH, other

Risk Assessment should be conducted to assess the impact of the change on clinical exposure: may dictate need for clinical study or no clinical study

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How Do You Choose What to do and When?

Phase of Development

Clinical Attributes

Device Configuration ChangeHigh RiskLow Risk

• Understand the timing for change (Phase of development)• Realize that each drug/device combination is different and focus on

designing programs that will help in assessment of the safety and effectiveness of the new drug/device combination

• Utilize bench-top testing results as much as possible to assess need

gLow Risk


p g pfor clinical studies/morecomplex clinical studies

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Case Study: PEGASYS (Background)

• PEGASYS (peginterferon alfa 2a) is approved for the treatment of• PEGASYS (peginterferon alfa-2a) is approved for the treatment of Hepatitis B and C

• PEGASYS approved configurations:– 180 mg/0.5 mL PFS (3 graduations: 180, 135 & 90 mg)– 180 mg/1 mL vial180 mg/1 mL vial

• Bioequivalence demonstrated between vial and PFS

• Disposable auto-injector (DAI) introduced– Luer to staked needle change (PFS)


g ( )

.Varunok P, Lawitz E, Beavers KL, Matusow G, Leong R, Lambert N, Bernaards C, Solsky J, Brennan BJ, Wat C.Evaluation of pharmacokinetics, user handling, and tolerability of peginterferon alfa-2a (40 kDa) delivered via a disposable autoinjector device. Patient Prefer Adherence. 2011;5:587-99. Epub 2011 Nov 24

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Case Study: PEGASYS (Regulatory)

• Technical qualification package between the two primary container configuration changes (staked needle from luer-lock needle)

• Single dose PK study performed for device assessment– 50 healthy subjects

PK d t d t hi t i l d t– PK data compared to historical data

• Clinical user handling study (requested by FDA)• Human Factor studies performed• Tolerability and Ease of Use study performed (requested by EMA)


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PEGASYS Bridging Strategy

DeviceDevicePhase of Development


P t M k t

Clinical AttributesClinical Attributes

Long t1/2, Crossover required 3-4 wks

washout

Significant historical PK database

Device Configuration

Change


Change

Primary containerPost Market:

Disposable Auto-Injector

(DAI)

PK database

High PK variability (CV ~50%)

Causes flu-like symptoms

container change:

Luer to staked needle, to DAI

with staked needle


Bridging Strategy:Conduct single dose PK study in healthy volunteer , compare to historical data

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PK Study Confirmed Effectiveness of DAI

Mean exposure similar to historical data (vial/PFS)historical data (vial/PFS)


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Outcomes and Impact on Program


• Product quality comparability data supported no additional clinical studies

Clinical Attributes

Device Configuration ChangeHigh RiskLow Risk

• Product quality comparability data supported no additional clinical studies

• Single dose PK study data confirmed DAI effectiveness

• In addition, User handling study showed the device was easy to handle, and there were no tolerability issues (studies done based on EMA request(


• DAI approved in 2011

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Bridging Strategy Example (Theoretical)Product background: SC administrationLaunch: PFS and AI



Product is

Clinical AttributesClinical Attributes

Clear Clinical endpoint


Change


Change

Vial PFSIntroduction ofProduct is

currently in Phase III

(with diagnostic)

p

Experience with drug

Need for Site rotation

Introduction of PFS in Ph III

Pre-Launch: Injector


Risk Assessment determined clinical bridging strategy:1) No Clinical bridging for PFS introduced in Ph III (analytical data exists)2) Clinical BE comparing PFS to AI Pre- launch

Timing of BE study: concurrent with Phase 3 launch

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Conclusions

• A risk assessment is a tool used to determine the extent of clinicalA risk assessment is a tool used to determine the extent of clinical evaluation that is required to support the introduction of a drug delivery device

• Studies can be designed based on the phase of development, the clinical attributes and technical device attributes, and in many cases , ythe Sponsors extensive knowledge of the product.

• The Sponsor acknowledges that many of the situations will be ‘Case-by-Case’ and that no one size fits all for these evaluations


aid t p ti clii ltilf an industry perspective on clinical trials for · pdf file ·...

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