CBER Compliance Update

22th Annual GMP by the SeaCambridge, Maryland

August 30, 2017Mary Malarkey, Director

Office of Compliance and Biologics Quality

1

Office of Compliance and Biologics Quality

OCBQ – Director, Mary MalarkeyOCBQ –Deputy Director – Melissa Mendoza

Division of Case Management DCM Director, Bob Sausville

Division of Inspections and SurveillanceDIS Director, Carrie Mampilly

Division of Manufacturing and Product QualityDMPQ Director, Jay Eltermann

DMPQ Deputy Director – Laurie Norwood

Division of Biological Standards and Quality ControlDBSQC Director -VACANT

2

OCBQ’s mission is to ensure the quality of products regulated by CBER over their entire lifecycle through pre-market review

and inspection, and post-market review, surveillance, inspection, outreach and compliance

3

4

Summary

• Lot release initiative

• The numbers

– Recalls and DRC

– Compliance actions

– Stem Cell Update

Lot Release

5

6

What is Lot Release?• “Requests for samples and protocols; official release” (21 CFR 610.2)• (a) Licensed biological products regulated by CBER. Samples of any lot

of any licensed product together with the protocols showing results of applicable tests, may at any time be required to be sent to the Director, Center for Biologics Evaluation and Research (see mailing addresses in 600.2(c) of this chapter). Upon notification by the Director, Center for Biologics Evaluation and Research, a manufacturer shall not distribute a lot of a product until the lot is released by the Director, Center for Biologics Evaluation and Research: Provided, That the Director, Center for Biologics Evaluation and Research, shall not issue such notification except when deemed necessary for the safety, purity, or potency of the product.

• (b) Licensed biological products regulated by CDER. Samples of any lot of any licensed product together with the protocols showing results of applicable tests,……

www.fda.gov

7

How does it work?

• For CBER and CDER products:

– Samples and protocols are submitted to CBER’s Sample Custodian (CBER/OCBQ/DMPQ/Product Release Branch)

• Protocols by paper, CD-ROM or electronically

– Protocols are reviewed by experts

– Testing is performed, per Testing Plans, in CBER/OCBQ/DBSQC laboratories, using test methods that are accredited by A2LA to ISO 17025 standards

– Lots are released if within specification

www.fda.gov

8www.fda.gov

Protocol Type* Lot CountPercentage Submitted

eLRP 3696 51.53%

cLRP 419 5.84%

pLRP 3058 42.63%

Grand Total 7173 100.0%

* eLRP = Gateway/ESG Electronic Lot Release ProtocolcLRP = CD-ROM Electronic Lot Release ProtocolpLRP = Paper Lot Release Protocol

Total Lots submitted June-2016 thru June-2017

FDA Lot Release (Biologics)http://wcms.fda.gov/FDAgov/BiologicsBloodVaccines/GuidanceComplianceRegulatoryInformation/Post-MarketActivities/LotReleases/ucm2006025.htm?ssSourceSiteId=null&SSContributor=true

9www.fda.gov

* eLRP = Gateway/ESG Electronic Lot Release ProtocolcLRP = CD-ROM Electronic Lot Release ProtocolpLRP = Paper Lot Release Protocol

Workload Submission TypesJune-2016 thru June-2017

FDA Lot Release (Biologics)http://wcms.fda.gov/FDAgov/BiologicsBloodVaccines/GuidanceComplianceRegulatoryInformation/Post-MarketActivities/LotReleases/ucm2006025.htm?ssSourceSiteId=null&SSContributor=true

Workload eLRP cLRP pLRPGrand Total

ALLERGENICS 0 6 503 509

IVDs 0 0 1212 1212

HEMATOLOGICS 779 234 1044 2057

MISCELLANEOUS 34 4 20 58

VACCINES 2883 175 279 3337

Grand Total 3696 419 3058 7173

10

Facts:

• Most companies have more than one product

• Most companies submit protocols using multiple formats, e.g. some products paper and some electronic

11www.fda.gov

* eLRP = Gateway/ESG Electronic Lot Release ProtocolcLRP = CD-ROM Electronic Lot Release ProtocolpLRP = Paper Lot Release Protocol

Submission Types: June-2016 thru June-2017

FDA Lot Release (Biologics)http://wcms.fda.gov/FDAgov/BiologicsBloodVaccines/GuidanceComplianceRegulatoryInformation/Post-MarketActivities/LotReleases/ucm2006025.htm?ssSourceSiteId=null&SSContributor=true

Protocol Types*

Submission Types/

number of Companies

Overall Percentage

Company Excusively Submitting

by Type

Overall Percentage

eLRP 14 15.38% 8 11.94%

cLRP 16 17.58% 5 7.46%

pLRP 61 67.03% 54 80.60%

12

Improvements to Streamline Process• Encourage electronic lot release – outreach to companies to assist

• Updated CBER website on lot release and including more information on how to submit electronically through the Gateway (ESG):

• Lot Release: https://www.fda.gov/biologicsbloodvaccines/guidancecomplianceregulatoryinformation/post-marketactivities/lotreleases/default.htm

• About ESG: https://www.fda.gov/forindustry/electronicsubmissionsgateway/aboutesg/default.htm

• More about ESG: https://www.fda.gov/forindustry/electronicsubmissionsgateway/default.htm

13

Alternatives to Lot Release

• 1993 Federal Register notice (58 FR 36771; July 20, 1993) noting that firms that have a product(s) with a good history may apply for alternatives to lot release .

• Encourage contact with CBER if interested in pursuing.

• Requires approval of a Prior Approval Supplement.

14

Contents of Supplement

• Recommend discussion with CBER first

• Data elements include:

– Lot data, including rejects, OOS

– Lot disposition

– Product complaints

– Product recalls

– Major process changes

The Numbers

15

FY11-16 – RecallsProduct FY12 FY13 FY14 FY15 FY16

Blood 1275 1240 540 528 455

Source

Plasma401 279 79 66 90

Derivative 7 5 1 2 2

IVD 10 8 6 3 1

Vaccine 8 4 2 2 2

Allergenic 5 5 3 5 1

Device 33 33 22 8 10

HCT/P 55 105 25 37 14

TOTAL 1794 1679 678 651 575

16

17

Direct Recall Classification (DRC)• What is DRC?

Direct Recall Classification (DRC) refers to the classification of recalls directly by personnel in the Center for Biologics Evaluation and Research in lieu of more traditional methods that require additional hours of work by personnel located in each FDA district office. DRC was designed to utilize current information technology to streamline recall classification of biological products. Through the use of an electronic interface between two existing agency databases, the time and resources previously needed to review and classify recalls of biological products have been greatly reduced.

18

What does DRC mean for you?• If you are a consumer, DRC means that recalls of biological products are

posted in the public domain in a more timely manner.• If you are member of the biologics industry, you will be able to provide

information to FDA regarding a recall you are conducting of biological products electronically, thus reducing the burden of copying manual records and sending them to an FDA district office. DRC also facilitates communications with the agency to answer questions or to gather more information regarding a recall.

• For the agency, DRC has decreased the amount of time previously used by the district office and CBER to gather, evaluate, review and classify a firm’s recall action. The average amount of time from learning of a firm’s recall action to classification of the recall has decreased from years to weeks and through the use of DRC, continues to decrease. For the agency, as well as for the public, DRC decreased the resources needed to classify and publish recalls, and allows the reallocation of resources to other agency priorities related to protection of the public health.

Direct Recall Classification

0

200

400

600

800

1000

1200

1400

1600

1800

2000

FY12 FY13 FY14 FY15 FY16 FY17*

Number of Recalls

DRC

19* As of March 31, 2017

0

10

20

30

40

50

60

70

80

90

100

FY12 FY13 FY14 FY15 FY16 FY17*

%DRC

%DRC

*as of March 31, 2017

21

Compliance Actions

Compliance Actions:CBER Biological Drugs and Devices

0

1

2

3

4

5

6

7

8

9

10

FY11 FY12 FY13** FY14 FY15 FY16**

Warning Letters Untitled Letters

FY17***

** Warning Letter based on inspection of multiple facilities ***as of August 25, 201722

23

FY17 Untitled Letters

• Dr. PRP America

• Assured Bites

• Antera Therapeutics

• Registrant of www.americanpumpkins.com

• Darwin Life, Inc.

www.fda.gov

24

Dr. PRP America

• Website for Dr. PRP kit:– “PRP (Platelet Rich Plasma) The PRP theraphy (sic) is

gaining in popularity as “the blood injection of miracle.””

– “Dr.PRP is a medical device exclusively designed for PRP separation.”

• Lack of premarket approval/clearance –adulterated and misbranded

www.fda.gov

25

Assured Bites and Antera

• Websites for Hello Peanut!™ and Aralyte

• Statements of intent to prevent peanut allergies in children beginning in infancy

• Both companies were responsive to FDA, making needed corrections

www.fda.gov

26

www.americanpumpkin.com

• Website promotes the In Home Blood Test for HIV 1 and 2 and the Oral In Home Saliva Test for HIV 1 and 2, both unapproved HIV test kits

• No premarket approval; adulterated and misbranded

• Registrant took appropriate action to discontinue the sale of these unapproved products.

• FDA found same kits on other sites that also took appropriate action to discontinue sales.

www.fda.gov

27

Darwin Life, Inc.

• Use of mitochondrial replacement technology (MRT) to form a genetically modified embryo in the United States for subsequent export

• Dr. John Zhang and the firm committed:

– “until an effective IND is in place, and a clinical trial is authorized by FDA, Darwin [L]ife will not use its spindle transfer technology again within the United States to support ex-US studies or procedures.”

https://www.fda.gov/downloads/BiologicsBloodVaccines/GuidanceComplianceRegulatoryInformation/ComplianceActivities/Enforcement/UntitledLetters/UCM570225.pdf

28

Darwin Life, Inc. continued

• Despite that commitment, Dr. John Zhang and the firm continue to market MRT to prevent the transmission of mitochondrial disease and to treat infertility.

• Dr. Zhang and the firm are in the process of taking corrective action.

August 4, 2017 - Advisory on Legal Restrictions on the Use of Mitochondrial Replacement Techniques to Introduce Donor

Mitochondria into Reproductive Cells Intended for Transfer into a Human Recipient

The clinical use of MRT in the United States falls within FDA’s regulatory authority. Since December 2015, Congress has included provisions in annual federal appropriations laws that prohibit FDA from accepting applications for clinical research using MRT. Therefore, clinical research using MRT in humans cannot legally proceed in the United States. FDA maintains the authority to investigate and take enforcement action in the event that it becomes aware of noncompliance with the laws and regulations administered by FDA.

30

FY 17 Warning Letters

• Fenwal

• Richard K. Burt

• Ark Biomedical Canada Corporation

• US Stem Cell Clinic LLC

www.fda.gov

31

Fenwal

• Intersol Platelet Additive Solution

• Slide presentation to blood establishments promoting efficacy with complete omission of risk information – repeat violation

• Misbranding

• Firm took appropriate corrective actions and WL closed

www.fda.gov

32

Richard K. Burt

• Sponsor and clinical investigator

• Violated regulations governing the proper conduct of clinical studies involving investigational new drugs, as published in Title 21, Code of Federal Regulations (CFR) Part 312.

• Dr. Burt took appropriate corrective action and the Warning letter was closed.

33

Ark Biomedical Canada Corporation

• Currently marketed device differs from the originally cleared device.

• Untitled letter issued in FY16

• Need for 510K for the currently marketed device.

• Under Import Alert 89-08, until a new 510K is cleared.

34

Stem Cell Update

35

FDA warns US Stem Cell Clinic of significant deviations –August 28, 2017 –

On August 24, 2017, FDA issued a warning letter to US Stem Cell Clinic of Sunrise, Florida and its Chief Scientific Officer Kristin Comella for marketing stem cell products without FDA approval and for significant deviations from current good manufacturing practice requirements, including some that could impact the sterility of their products, putting patients at risk.

https://www.fda.gov/NewsEvents/Newsroom/PressAnnouncements/ucm573431.htm

36

US Stem Cell Clinic - continued• The FDA recently inspected US Stem Cell Clinic and found that

the clinic was processing adipose tissue (body fat) into stromal vascular fraction (stem cells derived from body fat) and administering the product both intravenously or directly into the spinal cord of patients to treat a variety of serious diseases or conditions, including Parkinson’s disease, amyotrophic lateral sclerosis (ALS), chronic obstructive pulmonary disease (COPD), heart disease and pulmonary fibrosis.

• The FDA has not reviewed or approved any biological products manufactured by US Stem Cell Clinic for any use.

• At least 256 lots of the stem cell product manufactured under these conditions

37

FDA acts to remove unproven, potentially harmful treatment used in ‘stem cell’ centers targeting vulnerable patients - August 28, 2017

• Vaccinia Virus Vaccine (Live) seized after being used inappropriately in vulnerable cancer patients– Decisive action to prevent the use of a potentially dangerous

and unproven treatment belonging to StemImmune Inc. in San Diego, California, and administered to patients at the California Stem Cell Treatment Centers in Rancho Mirage and Beverly Hills, California.

– On behalf of the FDA, on Friday August 25, 2017, the U.S. Marshals Service seized five vials of Vaccinia Virus Vaccine (Live) – a vaccine that is reserved only for people at high risk for smallpox, such as some members of the military.

38

Seizure continued

• The seizure comes after recent FDA inspections at StemImmune Inc. and the California Stem Cell Treatment Centers confirmed that the vaccine was used to create an unapproved stem cell product (a combination of excess amounts of vaccine and stromal vascular fraction – stem cells derived from body fat), which was then administered to cancer patients with potentially compromised immune systems and for whom the vaccine posed a potential for harm, including myocarditis and pericarditis (inflammation and swelling of the heart and surrounding tissues). The unproven and potentially dangerous treatment was being injected intravenously and directly into patients’ tumors

https://www.fda.gov/NewsEvents/Newsroom/PressAnnouncements/ucm573427.htm

39

Statement from FDA Commissioner Scott Gottlieb, M.D. on the FDA’s new policy steps and enforcement efforts to ensure proper oversight of stem cell therapies and regenerative medicine August 28, 2017 –

https://www.fda.gov/NewsEvents/Newsroom/PressAnnouncements/ucm573443.htm

Public Access to CBER

CBER website:http://www.fda.gov/BiologicsBloodVaccines/default.htm

Phone: 1-800-835-4709 or 301-827-1800

Consumer Affairs Branch (CAB) Email: ocod@fda.hhs.govPhone: 301-827-3821

Manufacturers Assistance and Technical Training Branch (MATTB)Email: industry.biologics@fda.govPhone: 301-827-4081

Follow us on Twitter https://www.twitter.com/fdacber

40