A Johnson & Johnson Product

Comprehensive Demonstration of BLA

Devang BarotXiao Yin

Phani Venkata Sekhar PuppalaHiral Parikh

Instructor: Beverley Lach, MS R.A

Sr. Lecturer

Introduction & Description

What is Evarrest and what is it used for?

Evarrest is a surgical product used in adults to help stop bleeding during surgery when standard methods for controlling bleeding are not sufficient.

It is made of absorbable material coated on one side with two active substances, fibrinogen and thrombin, and is available as 10.2 cm x 10.2 cm patches

Regulatory Information Evarrest is considered as a combination

product (Biologic/Device) BLA # STN: BL 125392/0 Proper Name: Fibrin Sealant Patch –

Human Fibrinogen and Human Thrombin Trade name: EVARREST™ Manufacturer: Omrix Biopharmaceuticals,

Ltd Distributed by: Ethicon, a subsidiary of

Johnson and Johnson Inc.,

 The original BLA for EVARREST Fibrin Sealant Patch was submitted to the FDA on 19th November 2010.

Following review of the submission, FDA issued a Complete Response (CR) letter on 19th September 2011.

It got approval on 7th December 2012. Indication: For use with manual

compression as an adjunct to hemostasis for soft tissue bleeding during open retroperitoneal, intra-abdominal, pelvic, and non-cardiac thoracic surgery when control of bleeding by standard surgical methods of hemostasis (e.g., suture, ligature, cautery) is ineffective or impractical.

Regulatory Information Continued…

What takes Evarrest into Jurisdiction of CBER?

The combination fibrin sealant product under review, EVARREST, contains a device component the backing layer composed of Polyglactin 910 (PG910) non-woven fibers and an oxidized regenerated cellulose (ORC) supporting layer.

A consultative review with CDRH regarding the device component of EVARREST raised the following concerns about the ORC component of EVARREST (an email correspondence from

Reason for Our Interest Towards Evarrest

The FDA approval of EVARREST™ is a significant milestone in advancing patient care. We believe this technology has the potential to drive a paradigm shift in the treatment of problematic bleeding during surgery.

Clinical studies demonstrate that EVARREST™ is 98% effective in stopping bleeding and maintaining hemostasis compared to the current standard of care at 53%, potentially minimizing disruption to the surgical procedure

Non-clinical study guidanceThe FDA accepts harmonized recommendations from the International Conference on Harmonization (ICH) regarding various non-clinical safety studies which are needed to support human trials. FDA’s Guidance for Industry: Good

Pharmacovigilance Practices and Pharmacoepidemiologic Assessment

ICH’s E2E pharmacovigilance planning: Harmonised Tripartite Guideline

The FDA’s Guideline for the Format and Content of the Non Clinical Pharmacology/Toxicology Section of an Application

GLP guidance and regulations published by the FDA (October, 1997).

FDA’s guidance documents applicable to Evarrest

Clinical Study Guidance Guidance for Industry: Content and

Format of Investigational New Drug Applications (INDs) for Phase 1 Studies of Drugs, Including Well-Characterized, Therapeutic, Biotechnology-derived Products. (CDER/CBER November 1995)

Guidance for Industry: Population Pharmacokinetics. (CDER/CBER February 1999)

The FDA’s Guideline for the Format and Content of the Non Clinical Pharmacology/Toxicology Section of an Application

Guidance for Clinical Investigators, Sponsors, and IRBs: Adverse Event Reporting to IRBs — Improving Human Subject Protection （ OC/CDER/CBER/CDRH/GCPP January 2009）

FDA’s guidance documents applicable to Evarrest Contd…

FDA’s guidance documents applicable to Evarrest Contd…

CMC and GMP section Guidance for Industry: Environmental

Assessment of Human Drug and Biologics Applications. (CDER/CBER, July 1998)

Guidance for Industry: Container Closure Systems for Packaging Human Drugs and Biologics. ( CDER/CBER, May 1999)

Guidance for Industry: IND Meetings for Human Drugs and Biologics Chemistry, Manufacturing, and Controls Information. (CDER/CBER, May 2001)

Guidance for Industry: Nonclinical Studies for the Safety Evaluation of Pharmaceutical Excipients.( CDER/CBER, May 2005)

CMC and GMP section continued… Guidance for Industry: Quality Systems

Approach to Pharmaceutical Current GMP Regulations. (CDER/CBER/CVM/ORA, September 2006)

Guidance for Industry: Process Validation: General Principles and Practices.( CDER/CBER/CVM, January 2011)

Labeling and Promotion Guidance for Industry: Content and

Format for Geriatric Labeling. (CDER/CBER, October 2001)

Guidance for Industry: Providing Regulatory Submissions in Electronic Format - Content of Labeling.(CDER/CBER, April 2005)

FDA’s guidance documents applicable to Evarrest Contd…

FDA’s guidance documents applicable to Evarrest Contd…

Labeling and Promotion continued… Guidance for Industry: Patient-Reported

Outcome Measures: Use in Medical Product Development to Support Labeling Claims.(CDER/CBER/CDRH, December 2009).

Pre-Clinical Safety and Efficacy Data

Expectations from the Pre-Clinical studies: Achieve hemostasis at the Target Bleeding Site (TBS) without any noticeable Adverse Events (AE).

The safety profile for fibrin pad cannot definitively be established based on pre-clinical data.

Pre-clinical studies included safety pharmacology (rats), efficacy (rats, minipigs, and beagles), local tolerance (rabbits, minipigs, and dogs), antigenicity (guinea pigs, rats, and minipigs), mutagenicity, degradation, immunogenicity (guinea pigs), and acute toxicity studies (minipigs and dogs).

Toxicology Studies As Evarrest is directed to be used only

topically, much of the pharmacology studies do not apply for the activity profile of Evvarest.

PREGNANCY (Category C):Animal reproduction studies have not been conducted with Evarrest. Fetal harm is unknown and it is strongly advised for pregnant women to administer Evarrest , only when no other options exist. PHARMACOKINETICS:Animal studies with topically applied Evarrest showed incomplete resorption of the patch at 8 weeks after application. Human pharmacokinetic studies have not been performed. Because Evarrest is only applied topically, systemic exposure or distribution to other organs or tissues is not expected.

Toxicology Studies (Continued…)

Carcinogenicity, Mutagenicity and Impairment of Fertility:

• Long-term studies in animals to evaluate the carcinogenic potential of EVARREST, or studies to determine the effects of EVARREST on genotoxicity or fertility have not been performed.

• An assessment of the carcinogenic potential of EVARREST has been performed to demonstrate minimal carcinogenic risk from product use.

Observations Evarrest was acutely tested in animals at

up to 10 times the intended clinical dose (~1 standard size pads/surgery; 10 pads tested) in a single procedure, for up to two weeks without any adverse events reported. Pharmacokinetic studies demonstrate that degradation of the fibrin sealant component of Evarrest begins within hours, as the fibrin is metabolized by fibrinolysis and phagocytosis.

However, small remnants of Evarrest may be present up to 8 weeks after application (~5% of patch remaining in animal studies), with remnants degrading exponentially. There is a safety concern regarding immunogenic responses from foreign components of Evarrest being introduced to patients following administration, until complete degradation of Evarrest occurs.

Key events being monitored in

Post Market Surveillance As reported by FDA, Incomplete

absorption due to extraneous material in Evarrest is causing immunogenicity & resorption of Evarrest which are two current clinical monitoring targets as post-marketing commitments in both acute and long-term surgical settings. In limited non-clinical studies, Evarrest does not appear to be antigenic and did not likely result in anaphylaxis.

Sponsor’s IND Clinical and Investigational Plan for Evarrest Ethicon conducted four clinical trials to

assess safety and efficacy. Total 239 subjects were given EVARREST.

Study 400-07-002: Multi-center (U.S. sites only), randomized

trial, 141 subjects Range: 26 to 89 years. To assess safety and efficacy with

oxidized regenerated cellulose (ORC). ORC is an absorbable hemostat, when used as an adjunct to control bleeding after primary methods to achieve hemostasis (suture, cautery, ligature) proved ineffective or impractical.

EVARREST or ORC was applied immediately to the actively bleeding Target Bleeding Site (TBS).

Hemostasis was assessed at 4 minutes from randomization, and following an additional 6 minute observational period.

Success was defined as the achievement of hemostasis at 4 minutes and no further bleeding requiring treatment during the additional 6 minute observation period.

Randomized method: Total 90 subjects; 60 treated with EVARREST and 30 treated with ORC Nonrandomized method: Total 51 subjects; All treated with EVARREST

Sponsor’s IND Clinical and Investigational Plan for Evarrest

Continued…

Study 400-08-002: 59 subjects were treated with this

EVARREST. Randomized, controlled study Conducted outside the US To evaluate the efficacy of EVARREST in

comparison with Standard of care methods.

Study 400-10-001: Total 59 subjects: 39 treated were treated

in a randomized, controlled study Conducted outside the US To evaluate the efficacy of EVARREST to

the Standard of Care methods used to control bleeding in the hepatic parenchyma.

Sponsor’s IND Clinical and Investigational Plan for Evarrest

Continued…

Study FL-PN-001-IS: Ten (10) subjects undergoing surgery for

partial nephrectomy were treated in this non-IND phase 1 study conducted in Israel.

Continue study: Phase 3 studies to evaluate the safety

and hemostatic effectiveness of EVARREST versus standard of care treatment in controlling parenchymal bleeding during hepatic surgery.

It is randomized, parallel and open label study.

Estimated enrollment: 90

Sponsor’s IND Clinical and Investigational Plan for Evarrest

Continued…

Inclusion Criteria:• Subjects ≥ 18 years of age, requiring

elective or urgent, open hepatic surgery.• Presence of an appropriate bleeding

hepatic parenchymal Target Bleeding Site (TBS) as identified intra-operatively by the surgeon• Subjects must be willing to

participate in the study, and provide written informed consent.

Sponsor’s IND Clinical and Investigational Plan for Evarrest

Continued…

References:1. http://

www.fda.gov/downloads/BiologicsBloodVaccines/BloodBloodProducts/ApprovedProducts/LicensedProductsBLAs/FractionatedPlasmaProducts/UCM331131.pdf

2. http://www.fda.gov/downloads/BiologicsBloodVaccines/BloodBloodProducts/ApprovedProducts/LicensedProductsBLAs/FractionatedPlasmaProducts/UCM342850.pdf

3. http://clinicaltrials.gov/ct2/show/NCT01993888?term=evarrest&rank=3

4. http://www.thefreelibrary.com/FDA+Approves+EVARREST(TM)+Fibrin+Sealant+Patch.pdf

5. http://www.prnewswire.com/news-releases/fda-approves-evarrest-fibrin-sealant-patch-182520941.html

6. http://www.massdevice.com/news/fda-oks-ethicon-biosurgerys-evarrest-surgical-patch

7. http://www.fda.gov/downloads/BiologicsBloodVaccines/BloodBloodProducts/ApprovedProducts/LicensedProductsBLAs/FractionatedPlasmaProducts/UCM334054.pdf

Thank You