Establishment Inspection Report 3011123156 Howard M. Gross ... · Establishment Inspection Report...

Establishment Inspection Report Howard M. Gross; M.D, Dayton; OH 45240

TABLE OF CONTENTS

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Su1runa1y ............................................................................................................ ; .............................. 1 Administrative Data .................................................. , ....................................................................... 3

IBstory ............................................................................................................................................... 4 Interstate Co1n1nerce & Jurisdiction ................................................................................................. 5 Individual Responsibility and Persons Interviewed .......................................................................... 5

Authority and Administration ........................................................................................................... 6

Protocol ........................................................................................................................................... 10

Instih1tio11al Review Board ........................ , ... , ................................ ,, ........... , .. , ............ , .. , .. , .... , ....... 20 Human Subject Records .................................................................................................................. 21

Financial Disclos111·e ..................... ,, .. ,,.,, ...................... ,., .. , .............................................................. 24 Test Article Accountability ............................................................................................................. 24 Reports to Sponsor and Monitoring ................................................................................................ 25

Objectionable Conditions and Management's Response ................................................................ 25

Refi1sals .. ................................. , .. ,, .. , ... , , ,, .. ,, .. , ,. , .. , ............ , .. , .. , ... , , ..... , , ...... , ....... , ............................... 36 General Discussion with Management ........................................................................................... 36

Additional Information ................................................................................................................... 37

Sarnples Collected ........................................................................................................................... 37 Voluntary Corrections ..................................................................................................................... 37 Exhibits Collected ........................................................................................................................... 37

Attachtnents .................................................................................................................................... 42

SUMMARY

This unannounced, initial, for-cause inspection of a clinical investigator was conducted in response to OSI complaint numbers 5086, 4706, and 4697, under FACTS assignment number 11487375. It is a FY15 High-Priority CDER For-Cause Clinical Investigator Data Validation Inspection using the Bioresearch Monitoring Compliance Program (CP 7348.811).

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(b) (4) ; nd 2) the

Howard M. Gross, M.D., was identified as the Principal Investigator· of both studies,

I conducted a review of 100% of subject records for both studies. The records reviewed for both protocols include: regulatory records (IRB approvals and correspondence, FDA 1572s, financial disclosures, monitoring visit logs, audit records), subject source records, informed consent forms, laboratory data, drug dispensing and accountability records, and electronic case report fonns.

The inspection revealed that a research nurse who had many responsi~ both studies covered in this inspection, had falsified and modified some information in the lllilltud)\ rendering other data umeliable. The inspection also revealed that there was inadequate oversight from the principal investigator over the various studies being conducted.

(b) (6)

On 01/14/2015, at the close-out of the inspection, a 3-item FDA 482, Inspectional Observations, was issued to Howard M. Gross, M.D., Principal Investigator. The three observations were:

1. An investigation was not conducted in accordance with the signed statement of investigator and investigational plan. (For both protocols)

2. Informed consent was not properly documented in that the written informed consent used in the study was not signed by the subject or the b · e l 11 th · d · tative at I I

.Zb) (4) -the time of consent. (For protocol numbered 3. Failure to prepare or maintain adequate and accurate case histories with respe~ .tions and data pertinent to the investigation. (For protocol numbered 1illllll

Five discussion items were also brought to Dr. Gross' attention during the closeout meeting:

1. Inadequate staff training 2. Accountability of off-site research locations

3. Selecting qualified personnel 4. Maintaining better source documents 5. 2 subinvestigators did not appear on two of the FDA 1572s for protoco (b) (4)

After the issuance of the FDA 483, Dr. Gross was informed of the 15 business day timeframe to submit a written response to the FDA 483 to the district He was also made aware of the possible outcomes of the inspection, including voluntary action indicated as well as official action indicated such as data invalidation, warning letter, and disqualification of a clinical invesqgator.

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No refusals were encountered and no samples were collected dming this inspection.

FACTS data was reviewed and updated to reflect changes in the following: firm name, firm physical address, firm mailing address, and establishment type.

ADMINISTRATIVE DATA

Inspected firm:

Location:

Phone:

FAX: Mailing address:

Dates of inspection:

Days in the facility: Participants:

Howard M. Gross, M.D. 3123 Research Boulevard Suite 150 Dayton, OH 45240 937-775-1350

3123 Research Boulevard Suite 150 Dayton, OH 45240

11/19/2014, 11/20/2014, 11/21/2014, 11/24/2014, 11/25/2014, 11/26/2014, 12/1/2014, 12/8/2014, 12/9/2014, 12/10/2014, 12/11/2014, 12/16/2014, 12/17/2014, 12/18/2014, 12/19/2014, 1/14/2015 16 Richard W. Berning, Investigator

On 11/19/2014, credentials were presented and an FDA 482, Notice oflnspection, was issued to each of the following:

• Ms. Mary E. Ontko, Acting Executive Director of the Dayton Clinical Oncology Program ( refened to as MEO for the remainde1· of this repo1i)

• Mr. Sidney J. Pin1rns, President and CEO of the Dayton Clinical Oncology Program (referred to as SJP for the remainder of this rep01i)

• Dr; Howard M. Gross, M.D., Principal Investigator (referred to as HMG for the remainder of this report)

On 1/14/2015, credentials were presented and an FDA 482, Notice oflnspection, was issued to each JvIBO and HMG to continue the inspection for closeout after not being at t}le firm since 12/23/2014.

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On 01/14/2015, I issued a 3-itemFDA 483, Inspectional Observations, to Howard M, Gross, M.D., Principal Investigator,

HISTORY

This.inspection of Dr. Howard M. Gross was focused on his role as a sponsor and investigator for the following investigational drug studies:

This study will be hereafter referred to in this repo11 as

This inspection revealed that a research nursemiallllwho had many responsibilities in both studies covered in this inspection, had falsified and modified some information in the-study, rendering other data umeliable, During the spring of2013,-was ill while another employee was on maternitymi, The employee filling in for-oticed a 6 month gap in study data for the protocol ' There were issues such as source documents not matching what was in subject's medical record files. After some con:frontation--esigned effective 6/17/2013. These details were confirmed to be true with Ms. Ontko and Dr. Gross. ~s point onward, study monitors came in to begin reviewing and fix.in as much data for theail study as possible. As a result of the discovery of these probleins 1ho oversaw theillailliiy, ordered an external audit on two additional studies conducted by DCOP, including th~tudy,

The majority of this inspection was conducted at Dayton Clinical Oncology Program (DCOP), located at 3123 Research Boulevard Suite 150 Dayton, OH 45240. Per MEO, this business was

'funded by th or over 20 years. Approximately 10 years ago, the CEO ofDCOP decided that the firm should sta11 doing clinical pharmaceutical studies as a separate operation from the -tudies. ·

:MEO stated that DCOP's Human Resources are contracted by therefore everyone at DCOP is technically aBtmployee.

(b) (4) • nd

DCOP has stopped conducting clinical trials, except for a few studies where there are still patients active in post-treatment follow up status. No subjects are receiving any investigational products in

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the remaining active studies. MEO states that DCOP realized that they did not have adequate resources to p.rly oversee clinical trials as well asllltudies, so the firm has scaled back to only conduct studies.

Dr. Gross is in charge of all .studies and clinical trials studies conducted at DCOP. Dr. Gross' CV is included as Exhibit 1.He also ractices for ut of several locations, but mainly Dr. Gross is no longer a principal

-

. t' t ny studies, but he is a subinvestigator on several studies conducted atm1p-1-p---The organization chart for DCOP is included at Exhibit 2.

All official FDA correspondence should be addressed to:

Dr. Howard M. Gross, M.D.

Dayton Clinical Oncology Program

3123 Research Boulevard

Suite 150 ·

Dayton, OH 45240

INTERSTATE COMMERCE & JURISDICTION

FDA regulates clinical studies authorized under sections 505(i) (drugs) of the Federal Food, Drug, and Cosmetic Act. This inspection is of a clinical investigator responsible for data generated in support of ND As numbered 1Bfmdllllll

INDIVIDUAL RESPONSIBILITY AND PERSONS INTERVIEWED

Howard M. Gross, M.D., Principal Investigator - Dr. Gross is the Principal Investigator for both studies covered during this inspection, and has oversight of all studies conducted at DCOP. He has been a Principal Investigator on various studies since 1990, He is responsible for ensuring all requirements of clinical research studies are met.

Mary E. Ontko, Acting Executive Director - Ms. Ontko took on the role of Acting Executive Director beginning the first day of this inspection, upon Mr. Pink.us' retirement. Her current responsibilities are oversight ofDCOP. Prior to this role, she was the Clinical Di.rector for DCOP, She moved into this position when issues were discovered with several studies. As Clinical Director, she worked on protocol alongside study monitors to identify all issues, submit data, coordinate monitoring visits, and develop coffective action plans, All clinical staff report to Ms. Ontko.

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Amy Dempe, Regulatory Director - Ms. Dempe has been the Regulatory Director at DCOP since December of 2013; prior to this position she had worked as a Regulatory Coordinator at DCOP since 2010. She oversees all regulatory aspects of NCI-funded studies and pharmaceutical clinical studies.

Karen L. Jacobs, Research Coordinator - Ms. Jacobs has worked as a Research Coordinator from December 2012 onwards. She was responsible for following patients on both th!3IJ@lanc1llDl@W .studies. She is currently responsible for following up with the patients still on active protocols.

(b) (6) Consultant (formerly CEO & President of DCOP) --aallwas present on the first day of the inspection as well as the closeout of the inspection. He retired the day the inspection began. He bad overall responsibility for all operations ofDCOP for 15 years prior to his retirement. He currently serves in a consulting capacity to ease the transition of the firm into new management.

AUTHORITY AND ADMINISTRATION

A list of all studies conducted by Dr. Gross at DCOP was obtained and is included as Exhibit 3. A list of all studies conducted by Dr. Gross a as obtained and is included as Exhibit 4.

Additionally, a list of all studies in whicl as involved with since 2012 was collected and is included as Exhibit 5. was a research nurse involved in both protocols who altered and created source documents across both studies covered in this inspection; she did this to make the studies appear to be compliant with the protocol. This is covered more in depth in the Protocol section of this report.

For all clinical studies conducted through DCOP, Dr. Gross stated that the concept of the study was presented to DCOP initially by a study sponsor, and then it is presented to Dr. Gross, who agrees or disagrees to conduct the study as a Principal Investigator. If Dr. Gross agrees to the study, then a group affiliated with DCOP votes whether or not to undertake the study.

(b) (4)

The FDA 1572s for this study ,vere collected and are included as Exhibit 6.

It is located at-ts Chairperson during the study was

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ocations listed on the 1572s, as

• • •

(b) (4)

(b) ( 4) - _ _

(b) (4)

• (b) (4) -- - ---------~~--- - ~

--- ----

The Delegation of Authority Log for this study is included as Exhibit 7. This log gavd-W lfRIIW a research nurse, authority over the following study areas: inf01m subject/obtain subject's informed consent, determine subject eligibility, perform key trial measurements, medical assessments ( e.g. AB/SAE rep01ting), make CRF entries/corrections/resolve DCFs, receipt/storage of IMP, dispensation/accountability of IMP, take blood/lab samples, and DCF Management.

Significant dates for authority & administration:

• 2/21/11 - Initial FDA 1572 signed by Dr. Gross (Exhibit 6, pgs 1-2)

• 3/2/11 - New FDA 1572 signed by Dr. Gross (Exhibit 6, pgs 3-4)

• 4/18/11 - Initial IRB approval of Protocol & Informed Consent Form (ICF), pending revisions to ICF(Exhibit 8)

• 4/25/11 - Initial Informed Consent approved (Revision 1)

• 9/19/11 - Informed Consent Form "ICF Version 8-22-11 '' (Revision 2) approved by IRB (Exhibit 9)

• 1/23/12 - Protocol Amendment B approved by IRB (Exhibit 10)

• 1/16/12 - First subject (subject 2100) screened and consented.

• 2/8/12-First dispensation of test article to a subject (subject 2100)

• 2/13/12 - New FDA 1572 signed by Dr. Gross (E.xhibit 6, pgs 5-6)

• 3/12/12 - New FDA 1572 signed by Dr. Gross (Exhibit 6, pgs 7-8)

• 3/19/12-Annual IRB protocol review and reapproval (Exhibit 11)

• 4/16/12- "Revised Informed Consent, Version 3')(Revision 3) approved by IRB (Exhibit 12)

• 6/12/12-New FDA 1572 signed by Dr. Gross (Exhibit 6, pgs 9-10)

• 8/20/12 - "Revised Informed Consent, Version 4" (Revision 4) approved by IRB (Exhibit 13)

• 8/24/12 - Study closed to enrollment (Exhibit 14)

• 9/18/12- IRB notified of closure of study to emollment (Exhibit 14)

• 11/19/12- "Revised Informed Consent, dated 10-2012" (Revision 5) approved by lRB (Exhibit 15)

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• 12/1711.2 - Protocol Amendment C approved by IRB (Exhibit 16)

• 12/19/12-New FDA 1572 signed by Dr. Gross (Exhibit 6, pgs 11-12)

• 3/18/13 -Annual IRB protocol review and reapproval (Exhibit 17)

• 7/15/13 - Current informed consent annual re-approved by IRB (Exhibit 18)

• 7/19/13 -Final FDA 1572 signed by Dr. Gross (Exhibit 6, pgs 13-17)

• 12/4/13 - Closure of studyQJNby study sponsor (Exhibit 19 pgs 1, 3-4)

• 2/24/14 - Annual IRB protocol review and reapproval (Exliibit 20)

• 3/3/14 - JRB notification of study closure (Exhibit 19 pg 2)

• 6/10/14 -Final closeout visit and inactivation of the protocol (Exhibit 21)

• 7 /21/14 - Notification of study inactivation submitted to IRB (Exhibit 21)

Laboratories used in the study observed to have cunent certification.

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(b) (6) ~ On the FDA 1572s for this study dated 3/2/11 and 2/13/12 nd (b) (6)

were not listed as subinvestigators. These discrepancies were brought up at the closeout meeting as Discussion Item 5.

-The FDA 1572s for this study are included as Exhibit 22.

This study was initially approved by transferred to the central IRB for the stu

• he IRB Chair during the study was • This was done becaus • :vas acting as the central IRB for many of the other study sites as well, and streamlined the study IRB process.

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Subjects were seen at the following locations for this study:

•

e

•

Significant dates for authority & administration:

• 11/17 /11 - Initial FDA 1572 signed (Exbibit 22, pgs l-2)

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• 11/23/2011 - Initial 1RB approval by -of the protocol, patient ID card, Patient Information Leaflet, Study Participant Guide, ICF version "APPROVED AS MODIFIED Nov 22, 2011 '\ ICF for Optional Donation of Frozen Tumor Tissue, and Pregnant Partner Informed Consent Form (Exhibit 23)

• 4/12/12 - First subject, subject 0001, consented

o 4/27/12-First subject, subject 0001, administered test article

• 6/1/12-Second FDA 1572 signed (Exhibit 22, pgs 3-4) • 11/8/12 - IRB annual review and reapproval of study (Exhibit 24)

• 12/13/12-IRB approval of protocol Amendment Band ICF version "APPROVED AS MODIFIED Dec 13, 2012" (Exhibit 25)

• 12/17/12 - IRB continued approval of Patient Information Leaflet and Study Participant Guide (Exhibit 26)

• 7/24/13 -Third FDA 1572 signed (Exhibit 22, pgs 5-8)

• 6/13/13 - IRE approval of administrative letter dated 4/3/12 (Exhibit 27) • 9/6/13 -IRB approval oflCF version "APPROVED AS MODIFIED Sep 06, 2013" (Exhibit

28 • 10/8/13 - IRB approval of request for reconsideration of re-c.onsent instructions (Exhibit 29)

• 11/18/13 - Annual review and reapproval by IRB of study (Exhibit 30)

• 11/22/13 -IRB approval of Amendment C (Exhibit 31)

• 12/11/13 - IRB notified of study accrual closure (Exhibit 32) • 12/18/13 - IRB approval of revised version of Amendment C (Exhibit 33)

• 5/12/14 - IRB approval ofICF addendum (Exhibit 34)

• 7 /7 /14 - IRB annual review and reapproval of study (Exhibit 35)

Laboratories used during the course of the study:

•

• •

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• • •

•


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Subjects were provided with a Patient Information Leaflet (Exhibit 36) as part of study recruitment, and upon entry received a Study Paiiicipant Guide (Exhibit 37).

A copy of the site's screening log and enrollment log were collected as Exhibits 38 and 39,

The "AUTHORIZATION FORM", which functions as the delegation of authority log for this study, is included as Exhibit 40.

PROTOCOL

(b) (4)

Per the assignment, copies of the original protocol and amendment B included as Exhibits 41 & 42. Amendment A was not collected due to unavailability and amendment C was not included because it is a duplicate of the version provided with the inspection assignment. Copies of all Protocol Signature Pages, where Dr. Gross signed as understanding the protocol (and each subsequent amendment) and following the procedures therein, is included as Exhibit 43.

The site did follow the protocol with regards to number of subjects enrolled, randomization scheme and administration of the investigational product.

However, the site did not follow the protocol in the following areas: subject selection (with regards to inclusion and exclusion criteria), required procedures & evaluations.

Protocol DeviaNons

Many protocol deviations were discovered with this study. Several of these deviations were prevalent across several subjects in the study, and resulted in Inspectional Observation 1. The sponsor of the an audit of the firm after becoming aware of the misconduct of the research nurse A list of these protocol deviations discovered during the sponsor's audit of the firm was compiled into a Clinical Tracking Log, included with this report as Exhibit 44. This was submitted to Dr. Gross on 9/24/13, and was submitted to the IRB on 10/13/13.

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Per the inspectional assignment, the primary endpoint for this study was evaluated, and was determined to have not been followed per protocol.

Protocol section 10.1, "Efficacy Measures", states "Patients may be emailed on study with measurable or nonmeasurable disease based on RECIST, v. 1.1. Disease assessment will be undertaken at baseline (within 21 days prior to randomization) and then every 8 weeks(± 7 days) as calculated from the first dose of study therapy. Patients will be evaluated for response according to RECIST, v. 1. 1 guidelines (Eisenhauer et al. 2009)."

4 of the 5 subjects enrolled in this study who receiv_ed study treatment had measurable disease to be evaluated per REC I ST v. 1.1 guidelines. However, not one of these subjects had disease measurement evaluation per RECIST v. 1.1 guidelines concurrent with their tumor imaging assessments. This resulted in Inspcctional Observation 1, sub-item l(A)(i)(a)

Additionally, a memorandum sent out discussing retroactively assessing subject number 2104's tumors states that the subinvestigator caring for the subject stated that he was unable to complete the tumor assessment per RECIST because he is not trained (Exhibit 45).

The firm retroactively created Disease Measurement Forms around July 2013 for each subject by retrieving available CT scans for each subject and faxing the scans off to the subinvestigators responsible for the subjects. In the case of Subject 2104, Dr. Gross had to complete the Disease Measurement Form due to the designated subinvestigator not being adequately trained to complete the evaluation. Inadequate training of staff involved with studies, and also the need for increased accountability of off-site locations used in the study were brought up during the close-out meeting as Discussion Items 1 and 2, respectively. Ms. Ontko stated that the subinvestigators were evaluating the tumors with each scan, but not according to RECIST as the protocol required. Disease Measurement Forms were collected for every subject except 2103, who never received study drug. Subject 2102's Disease Measurement Form (DMF) is blank because his disease was of the nonmeasurable variety. Also included with this repmt are the concurrent, non-RECIST tumor assessments for each subject, in the form of patient progress notes and radiology repo1ts. Some of the radiology reports are indicated as being sourced from a "shadow chait" - this is a term used by the fum to describe the files maintained b~ and contain markings from her. Often, they have lesions identified and numbered, either as a target or nontarget lesion. Per Ms. Ontko, the shadow charts were often missing data and therefore for this study, she made duplicate subject record files, which will be designated as "clean copy" when a distinction has to be made vs a shadow chait. Per the Delegation of Authority Log, she was authorized to "perfonn key trial measurements" and make "medical assessments (e.g. AB/SAE reporting), areas which her CV (Exhibit 46) does not indicate any qualifications for tumor assessments. Discussion Item 3 at the inspectional closeout revolved around selecting qualified personnel for both subinvestigators and support staff.

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• Subject 2100 -DMF is Exhibit 47, patient progress notes are Exhibit 48, shadow chait radiology reports are Exhibit 49, and clean copy radiology reports are Exhibit 50.

• Subject 2101 - DMF is Exhibit 51. (This DMF is blank because subject 2101 had noruneasurable disease, therefore no measurements were made to place on this form.)

• Subject 2102 - DMF is Exhibit 52, patient progress notes are Exhibit 53, and clean copy radiology reports are Exhibit 54,

• Subject 2104- DMF is Exhibit 55, shadow chart radiology reports are Exhibit 56, patient progress notes are Exhibit 57.

• Subject 2105 - DMF is Exhibit 58 and shadow chat·t radiology reports are Exhibit 59.

In addition to not conducting RECIST measurement for primary efficacy evaluation per protocol,

Dr. Gross and his sub.investigators did not meet the disease assessment timeframes per protocol. As

stated above, subjects had to have their target and nontarget lesions evaluated per RECIST at

baseline and then every 8 weeks(± 7 days) as calculated from the first dose of study therapy.

4 of the 5 subjects who received study treatment have out of window scans for disease assessment.

For these 4 subjects, 50% or more of their required CT scans for evaluation were either conducted

out of the protocol-de.fined ti.meframe or in some cases not at all. This resulted in Inspectional Observation 1, sub-item l(A)(i)(b).

Subject 2100 - first dose of study therapy on 2/8/12.

Acceptable Date Week Post- Range for Scan Actual Date of Done per Exhibits to

Initial Treatment Based on Therapy Closest Scan protocol? Reference Start Date

Week8 3/28/12-4/11/12 3/27/2012 No Exhibit SO, pages

3-4

Week 16 5/23/12 - 6/6/12 5/29/2012 Yes Exhibit 50, pages

5-6 Exhibit 49, pages

Week24 7/18/12-8/1/12 7/13/2012 No 4-5

Exhibit SO, pages 7-9

Exhibit 49, pages

Week32 9/12/12 - 9/26/12 9/11/2012 No 6-9

Exhibit 50, pages 10-13

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Subject 2102- first dose of study therapy on 3/27/12. Acceptable Date Actual Range for Scan Date of

Vleek Post-Initial Treatment Based on Therapy Start

Closest

Date Scan

Week8 7/6/12- 7/20/12 7/10/2012

Week 16 8/31/12- 9/26/2012 9/14/12

Week24 10/26/12-

Not Done 11/9/12

Week32 12/21/12- Not Done 01/04/12

Subject 2104 - first dose of study therapy on 8/15/12. Acceptable Date Actual Range for Scan

Date of Week Post-Initial Treatment Based on

Therapy Start Closest

Date Scan

Week8 10/3/12- 10/3/2012 10/17/12

Week 16 11/28/12-

11/29/2012 12/12/12

Week24 1/23/13 - 2/6/13 3/19/2013

Week 32 3/20/13 - 4/3/13 3/19/13 ·

Week40 5/15/13 -

. 6/25/2013 5/29/13

Week48 7/10/13 - 7/31/2013 7/24/13

Week56 9/4/13 -9/18/13 9/5/2013

Subject 2105 - first dose of study therapy on 8/21/12, Acceptable Date Actual Range for Scan Date(s) of

Week Post-Initial Treatment Based on Therapy Sta1t

Closest

Date Scan(s)

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Done per protocol?

Yes

No

No

No

Done per protocol?

Yes

Yes

No

No

No

No

Yes

Done per protocol?

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Exhibits to Reference

Exhibit 54 pages 10-15


None -scan not done

None-·scan not done





Exhibit 56, pages 9-10·





Establishment Inspection l{eport


Week8

Week 16

Week 24

Week32

Week40

10/9/12-10/23/12 12/4/12-12/18/12 1/29/13 -2/12/13

3/26/13 - 4/9/13

5/21/13 - 6/4/13

9/4/12, 10/29/12 10/29/12, 1/03/13 1/03/13, 3/08/13 3/08/13, 4/29/13 4/29/13, 7/9/13

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No

No

No

No

No

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Exhibit 59, pages 8-11, 15-16




Exhibit 59, pages 3-6,

Dr. Gross also did not ensure that Subjects 2100 and 2102 met all necessary inclusion and exclusion criteria, resulting in Inspectional Observation 1, sub-item 1(A)(ii).

Both of these subjects had baseline urinalysis protein levels over 2, which per protocol requires a 24-hour protein retest to be eligible for inclusion in the study. Neither received a protein level retest within 24 hours as required per protocol section 8.1, "hlclusion Criteria".

This section states "Patients are eligible to be included in the study only if they meet all of the following criteria:» and goes on to inclusion criteria #9, which reads "Routine urinalysis showing ~1+ protein or protein/creatinine ratio <0.5. For proteinuria 2:2+ or urine protein/creatinine ratio 2::0.5, 24-hour urine protein should be obtained and the level must be <l gram of protein in 24 hours for patient enrnUment."

Subject 2100 had a baseline urine protein result of 2102 had a baseline urine protein result of a second test within 24 hours.

dated 1/31/2012 (Exhibit 60). Subject dated 5/16/12 (Exhibit 61). Neither received

Additionally, Subject 2100 met one of the exclusion criteria. Protocol section 8.2, Exclusion Criteria, states "Patients will be excluded from the study if they meet any of the following criteria:,, and goes on to exclusion criteria #15, which reads ''The patient is receiving chronic therapy with nonsteroidal anti-inflammatory agents (NSAIDs; for example, indomethacin, ibuprofen, naproxen, or similar agents) or other anti.platelet agents (for example, clopidogrel, ticlopidine, dipyramidole, anagrelide.)" This subject was on clopidogrel 75 mg treatment from 1/03/12 tbrnugh 03/02/12 according to source documents and the eCRF (Exhibit 62). During this period of clopidogrel treatment, the subject was consented and enrolled into the study and received study drug treatments on 2/8/12 and 2/22/12.

Another significant area of protocol deviation was coagulation assessments. Four of the five subjects who received study treatment missed one or more of their protocol required coagulation assessments, resulting in Inspectional Observation 1, sub-item 1(A)(iii).

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Per Attachment 1 of the protocol, titled, "Protocor- Study Schedule", coagulation profiles must be collected during the Baseline Period and then at Cycle 4, Cycle 8, Cycles 9-X, Summary Visit, and 30-Day Follow-Up Visit. The designation of Cycles 9-X meant that coagulation assessments were required for every study cycle from cycle 9 onward. The following coagulation assessments were not performed per protocol for the following subjects:

• Subject 2100: missing coagulation assessments for Cycles 4 and Cycles 8 through 17.

• Subject 2102: Missing coagulation assessment for Cycle 4.

• Subject 2104: Missing coagulation assessments for Cycles 4, Cycles 8, and Cycles 13 through 17.

• Subject 2105: Missing coagulation assessments for Cycles 1, 4, 8 through 15, Cycle 17, Cycles 19 and 20, and Cycles 22 and 23.

A majority of these deviations are noted in Exhibit 41, pages 3-10. However, for later cycles there is no evidence to support that they are missing other than they me not in any laboratory data or in the eCRFs.

The final pa1t of the first inspectional observation, Inspectional Observation 1, sub-item l(A)(iv), is that a majority of the vital sign requirements were not fulfilled for all subjects receiving study treatment.

Per Attachment 1 of the protocol, titled, "Protocol. Study Schedule", vital signs are "To be obtained at every treatment visit, immediately prior to and at the completion of each infusion of ramucirumab DP/placebo. If there is a post-infusion observation period, then vital signs measurements should also be obtained at the end of the observation period." The only evidence of ~ were from the eCRF documents for each subject, as the source documents created by ...... for vital signs were determined to not be verifiable for a majority of the cycles for

each subject. Per the eCRFs;

• Subject 2100: Out of a total of 15 cycles of study treatment visits, only 3 pre-infusion vitals were taken. No immediate post-infusion vitals or one hour post-infusion vitals were taken. (Exhibit 63)

• Subject 2101: This subject only had one cycle of study treatment. No pre-infusion or one hour post-infusion vitals were taken. (Exhibit 64)

• Subject 2102: Out of a total of 6 cycles of study treatment visits, 4 pre-infusion vitals were taken, 3 immediate post-infusion vitals were taken, and O one hour post-infusion vitals were taken. (Exhibit 65)

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• Subject 2104: Out of a total of 18 cycles of study treatment visits, 0 pre-infusion vitals were taken, 1 immediate post-infusion vitals were taken, and O one hour post-infusion vitals were taken (Exhibit 66).

• Subject 2105: Out of a total of 8 cycles of study treatment visits, vitals were only taken once (pre-infusion, immediately post-infusion, and one hour post-infusion) (Exhibit 67).

--Copies of the original version of this protocol, amendment B, amendment C, and revised amendment C were collected per the inspectional assignment as Exhibits 68-71. Amendment A was not collected due to unavailability. Copies of the "INVESTIGATOR'S SIGNATURE SHEET FOR PROTOCOV' for each version of the protocol were collected and compiled into Exhibit 72.

Available study-article promotion articles were collected. These consist of available Site Newsletters (Exhibit 73) and Study Newsletters (Exhibit 74).

The site did follow the protocol with regards to number of subjects enrolled, randomization scheme and administration of the investigational product.

However, as with the -protocol, the site did not follow the protocol in the following areas: subject selection (with regards to inclusion and exclusion criteria), required procedures & evaluations.

Protocol Deviations

A list of all protocol deviations reported to the IRB as of 12/11/14 was collected and is Exhibit 75.

Deviations observed during the course of this inspection include not reporting a serious adverse event within the sponsor-defined timeframe of24 hours, reversing drug therapy order, not following post-drng administration observation periods, and not performing protocol-required laboratory tests. These observations are included in Inspectional Observation 1.

Observation 1, sub-item 1 (B)(i): A serious adverse event was not reported to the study sponsor within 24 hours as required per protocol. Per protocol section 7 .2.2., "Reporting of Serious Adverse Events (Immediately Reportable)", "Any clinical AE or abnormal laboratory test value that is serious and which occurs during the course of the study (as defined in Section 7.1.1.3 above), regardless of the treatment arm, must be reported to fllfwithin 24 hours of the Investigator becoming aware of

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the event (expedited reporting)."

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(l:lt(4)-- - - - -- - - --- ------

(b) (4)_ _ _ . _ -------- -- --- --- -- ---- --~::-c-- _ -_--- _ --- -------- - - ---- - - --- - - ------- - --------- ______ -_- --------~-----

(b) (4) -_-------------_------- - - - -

of pseudomonas sepsis, which resulted in her being admitted to a hospital on 6/1/12. There is a telephone record of the patient calling her study physician on 6/6/12 to notify him that she was in the hospital in inpatient status, and indicates that the research nurse who is authorized to report serious adverse events was notified on this date. However, this serious adverse event was not submitted to the study sponsor until 6/14/12.

Exhibit 76 consists of docum~? this SAE. Page 1 is a record of a telephone message dated 6/6/12, left for ........ the subinvestigator on the study responsible for subject 0001). The message was left to make the~· aware that she was inpatient at a hospital, and the record of the message indicates~as also aware. Pages 2-10 are the submission pages to the study sponsor regarding the AE, dated 6/14/12. Pages 11-20 are patient chart notes and patient progress records noting the chain of events leading up to and including the hospitalization,

Observation 1, sub-item B(ii): The protocol-defined study drng treatment therapy order was

reversed for 5 out of subject 0006's 18 total study treatment cycles. Protocol section 6.1.3, ''Non-

Anthracycline Based Chemotherapy (TCH)", states' followed by (~) (4) . For Cycles 4, 7, 10, 11, and 12, the was given

before Exhibit 77 contains the requisite pages from subject 0006's eCRF showing

the reversed treatments.

Observation 1, sub-item B(iii): The protocol-defined i•ieatment observation period was not observed properly. Protocol section 6.1.3.2, "Notes on • Target treatment", subsection (b) (4) . , states that "The initial dose of-will be administered over 90 (±10)

minutes and patients observed for at least 30 minutes from the end of the infusion for infusion

related symptoms such as fever, chills etc.'' "If the infusion is well tolerated, subsequent infosions

may be administered over 30 (±10) minutes and patients will be observed for a further 30 minutes."

The subsection -Placebo" states "The initial dose o lacebo will be given

after the infusion ofMN I (following the observation period and administered over 60 (±10)

minutes with patients to be observed for a fmiher 60 minutes." "If the infusion is well tolerated,

subsequent doses may be administered over 30 (±10) minutes and patients will be observed for a

fmther 30 1ll.ll1utes for infusion-related symptoms such as fever, chills."

All 4 of the study subjects had treatment cycles where the observation period betvvee1 (b) (4)

administration and MN placebo administration was not observed per protocol. This observation period was not followed for the following cycles for the following subjects:

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• Subject 0001: 2 total cycles of treatment; both cycles had observation periods of less than 5 minutes. Exhibits 78 and Exhibit 79 are the source infusion chart and eCRF records, respectively, of the treatment cycles,

• Subject 0003: 18 total cycles of treatment. 11 observation periods were under 6 minutes, 1 was 22 minutes, 5 were in accordance with the protocol, and 1 visit states (b)(4)

- ---- - -- ---

treatment began 1 minute prior t~reatment ending. Exhibits 80 and 81 are the source infusion chart and eCRF records, respectively, of the treatment cycles.

• Subject 0006: 18 total cycles of treatment. 2 observation periods were under 8 minutes, 11 were in accordance with the protocol, and 5 could not be observed because study treatment order was reversed. Exhibits 77 and 82 are the source infusion chart and eCRF records, respectively, of the treatment cycles.

• Subject 0007: 18 total cycles of treatment. 4 observation periods were under 5 minutes; the other 14 cycles were in accordance with the protocol. Exhibits 83 and 84 are the source infusion chart and eCRF records, respectively, of the treatment cycles.

For all foul' subjects, there were study cycle visits where protocol-defined laboratory tests were not conducted as they were required to be, resulting in Observation 1, sub-item B(iii).

The protocol's Table 8, ''Schedule of Assessments - Screening and Treatment Period" indicates that Liver Function Tests must be completed within 7 days of Screening, then at Cycles 1-6, 9, 13, and 18. The footnote on this table for these assessments states "Liver function tests include: ALP, ASAT, ALAT, LDH; and total, direct, and indirect bilirnbin. At baseline, liver function tests should be completed within 7 days prior to randomization.

The protocol's Table 8 "Schedule of Assessments-, Screening and Treatment Period" indicates that Hematology and Biochemistry assessments must be performed within 7 days of screening, and then within 3 days prior to Day 1 of Cycles 1 -8, 9, 13, and 18. The footnote on this table for these assessments states "Hematology and biochemistry should be completed pre-dose on Day 1 of each indicated cycle ( or up to 3 days before). Hematology tests ( complete blood count) include counts of hemoglobin, white blood cells, neutrophils and platelets. Biochemistry tests include serum creatinine, blood urea nitrogen and electrolytes (P-, Ca2+, Mg2+, Na+, K +, Cl-). At baseline, hematology and biochemistry should be completed within 7 days prior to randomization,"

The following are the missing liver function tests for each subject:

• Subject 0001 (Laboratory source documents are Exhibit 85 and corresponding eCRF records are Exhibit 86):

o Direct and Indirect Bilirubin assessments were not completed for Screening, Cycle 1, and

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• Subject 0003 (Laboratory source documents are Exhibit 87 and corresponding eCRF records are

Exhibit 88):

o No liver function tests were completed at Cycle 1

o Direct and Indirect Bilirubin assessments not completed at Screening, Cycle 2-6, Cycle 9, and Cycle 18.

o The liver function tests of ASAT, ALAT, and ALP were not completed for Cycle 3.

o LDH assessments were not done on Cycle 2, Cycle 4, and Cycle 9.

o No biochemist1y assessments performed for Cycles 1 or 7

o Serum creatinine, blood urea nitrogen, Ca2+, Cl-, Na+, and K + assessments not pe1formed at

Cycle 3

o Mg2+ assessment not performed at Cycle 6 and Cycle 8

o P- assessment not performed for Cycles 2, 4, 6, and 8.


Exhibit 90):

o Direct and Indirect Bilirubin assessments not complete for Cycles 1-5, Cycle 13, and Cycle

18

o LDH assessment not complete for Cycle 3

o No liver function tests completed for Cycles 6 or 9

o P- not done for Cycle 2, Cycle 3, Cycle 5, Cycle 6

o No biochemistry assessments done for Cycle 9.


Exhibit 92):

o No liver function tests completed for Cycle 6

o Direct and Indirect Bilirubin assessments not complete for Cycles 1 ;.,6

o P- assessment not performed for Cycles 2, 8, and 9.

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o Mg2+ assessments not performed for Cycle 8

INSTITUTIONAL REVIEW BOARD

(b)(4)__

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It is located at mll ts Chairperson during the study

IRB approval was obtained properly for all protocol and informed consent document versions, as well as promotional materials, No lapses were observed in approvals of study documents.

The timeline for IRB approvals of protocols, amendments, consent forms, and other documents can be found in the previous PROTOCOL section of this repo1t.

Communication with the IRB began at a standard pace, communicating back and ~als and notifying the IRB of adverse events. However, once the issues resulting from__._ were discovered (as described later in this report in the HUMAN SUBJECTS RECORD section), monitoring increased and the IRB became heavily involved with this study, requiring updates after monitoring visits. A sample of this increased activity is included as Exhibit 93, a collection of a response from DCOP with a corrective action plan submission for a list of protocol deviations identified bylllfllastudy staff received re-training on the protocol and requh'ed procedures as a result of this.

-This study was initially approved by transfened to the central IRB for the stud

IRB approval was obtained properly for all protocol and informed consent document versions, as well as promotional materials. No lapses were observed in approvals of study documents.

The timeline for IRB approvals of protocols, amendments, consent forms, and other documents can be found in the previous PROTOCOL section of this repo1t.

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The IRB correspondence for_this _study increased in freq~ency i~ a similar.n to th~QPI study, due to an external audit bemg ordered by the IRB 111 reaction to the study issues. Correspondence increased from just the standard approval and AE notices to several times per week, covering issues discovered in the study and corrective action plans implemented by DCOP.

HUMAN SUBJECT RECORDS

Deficiencies in source documentation were found for both studies. In addition to the issues contributing to Inspectioual Observations 1, 2, and 3, I discussed the impo1iance of keeping better source documentation and the usefulness of creating site-specific forms for keeping track of necessary study procedure documentation as Discussion Item 4.

(b) (4)

Informed Consent

No informed consent issues were discovered during the review of the. protocol. Consent was performed prior to enrollment, and the appropriate version was used.

Per the assigmnent, a blank version of each informed consent version was collected:

• Revision 1 is Exhibit 94


• Revision 3 is Exhibit 96 • Revision 4 is Exhibit 97 (for this version a subject-signed version had to be collected. It is

also significantly shorter than other revisions because it is an addendum to Revision 3)


Source Documents

The source documents for this study were not well maintained~id not maintain full case histories for each subject during her employm.ith DCOP, and as a res~d to make separate case histories for all subjects in the ' study. She maintaine-~les as "shadow charts'' then created her own file for each subject, filling in all the datalll --charts ,vere missing, as well as correcting and/or removing e1rnneous data put in the files by (b} (6)

(b) (6) I Ms. Ontko provided information on the data that alsified. The site-identified falsifications are:

• Forged patient progress note for subject 2100, dated 9/25/12. This document was apparently generated to make it appear as though subject 2100 had a study visit with all protocol

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requirements for that date. The AE report with the progress note attached is included as Exhibit 99.

• Forged CT scan report date for subject 2102. Per the AE report,-modified the date of a CT scan from 4/13/12 to 4/27/12 to make it meet eligibility requirements (Exhibit 100)

• There is an apparent forged infusion chati for subject 2104 dated 1/29/13. There are two infusion charts for the same date, with different infusion dosages. (Exhibit 101).

In addition to these instances, I discovered another apparent forged pati~tes, thls one for subject 2102. There was a patient progress cha1i dated 5/18/2012 inlUlilalllllllcharts for the subject, but no visit indicated in the electronic medical record of the subject. Ms. Ontko stated that the agreed with the finding. There is a record in the subject's electronic medical record dated 5/10/12 where the body of the rep01t matches the one in the shadow chart. Ms. Ontko stated that it. is likely that -changed the date. These records are included with Exhibit 102.

These discoveries resulted in Inspectional Observation 1, Sub-item 2.

IJllllllalso maintained forms for each subject documenting their vital signs (pulse, temperature, blood pressure, and respiratory rate) for prior to test article/placebo administration, just after test aiiicle/placebo administration, and one hour after test article/placebo administration as required per protocol. However, these forms were not signed 01· dated and frequently had con·ections indicated, also with no initials, signature, or date to identify them. I have included the set of these documents for subject 2104 as Exhibit 103. Due to the unreliability of these source documents, the vast majority of vital sign measurements previously entered into the eCRF for the subjects in the rtpJ@&tudy were deleted and therefore considered not done per protocol (Inspectional Observation 1, sub-item 1(A)(iv). The few remaining vital sign measurements are ones that were verified through another source document such as a patient progress form.

'Additionally, no logs for recording adverse events or concomitant medications were created until the very end of the study. This resulted in Inspectional Observation 3. The AE logs were created for subjects on the following dates:

• Subject 2100 - 11/8/13 (on study beginning 2/6/12). Exhibit 104. • Subject 2101 - 11/14/13 (on study beginning 3/20/12). Exhibit 105. • Subject 2102- 11/18/13 (on study beginning 5/17/12). Exhibit 106. • Subject 2103 - 11/8/13 (on study beginning 7/30/12). Exhibit 107. • Subject 2104 - 11/14/13 (on study beginning 8/14/12). Exhibit 108. • Subject 2105 - 11/14/13 ( on study beginning 8/15/12). Exhibit 109.

The Concomitant Medication logs were created for subjects on the following dates: • Subject 2100 - 11/8/13 (on study beginning 2/6/12). Exllibit 110. • Subject 2101 - 11/14/13 (on study beginning 3/20/12). Exhibit 111. • Subject 2102-11/18/13 (on study beginning 5/17/12). Exhibit 112.

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• Subject 2103 - 11/8/13 (on study beginning 7/30/12). Exhibit 113. • Subject 2104 - 11/14/13 (on study beginning 8/14/12). Exhibit 114. • Subject 2105 - 11/14/13 (on study beginning 8/15/12). Exhibit 115.

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Also as paii oflnspectional Observation 3, concurrent records ofRECIST tumor evaluation were not maintained for any of the subjects in the rem study.

Case Report Forms (CRFs)

(b) (6) was initially responsible for data entry into the electronic CRF for each subject. Data was entered from source documents into the eCRFs. When it was discovered that she was falsifying data and subsequently resigned, Ms. Ontko was in charge of goin~. h the CRFss and verifying or deleting all data for each subject in the period after discoverin~sconduct in both studies in 2013.

The data from the retroactive disease measurement forms was used to enter disease progression or regression endpoint analysis into the CRF for each subject, as well as identify target and nontarget lesions.

-J1?formed Consent

(b) (6) was responsible for collecting informed consent from prospective and current subjects in this study up until her resignation. There were inconsistencies with subject 000 l's and 0003 's informed consent which resulted in Inspectional Observation 2.

Subject 0001 was originally consented on 4/12/12 (Exhibit 116). According to source documents, the subject withdrew consent by phone on 6/16/12 for all aspects of the study except for phone contact at the end of the study to determine vital status only (Exhibit 117). The subject then subsequently signed off on a "SUBJECT WITHDRAW AL OF CONSENT" form on 1/31/13 confirming her withdrawal and indication to only contact her at study closure to determine vital status only (Exhibit 118). However, there is an apparent additional informed consent form dated· 5/6/13 with an apparent subject signature on it, purpmtedly from subject 0001 (Exhibit 119). Additionally, there is no signature in the "Person Conducting Informed Consent Discussion Signature" or "lnvestigator/Designee Signature" box on this informed consent form.

Ms. Ontko could not verify that this was an actual subject signature or provide a reason why a consent form would be signed after a subject withdrew consent and left the study. Additionally, the signatures on Exhibit 116 and Exhibit 118 do not appear to be from the same individual.

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Subject 0003 was originally consented 011 5/18/12 (Exhibit 120). On this consent form, the subject indicated that she did not want to donate a sample for the genetic study. There is an ?P~arent signed informed consent f~nn dated 1/23/13 p~by th~ subject in w~~h it is md1cated that she does want to provide a sample for the.........,genetic study (Exh1b1t 121). The subject signature on this form is dissimilar to the original signature. The firm did not collect a sample on this date, and in fact did not collect a sample for this until the subject was reconsented on 12/18/13 (Exhibit 122). The signature on the consent form dated 12/18/13 is similar to the original signature. Your firm stated that the form dated 1/23/13 could not be verified to be legitimate, and that the subject was reconsented on 12/18/13 to get her current on informed consent

(b) (4) versions and collect the sample.

Per the assignment, blank copies of each ICF version were collected:

• ICF version "APPROVED Nov 22, 2011" (Exhibit 123) • Pharmacogenetic Consent form approved 11/22/11 (Exhibit 124) • ICF version "APPROVED AS MODIFIED Dec 13, 201211 (Exhibit 125) • · ICF version "APPROVED AS MODIFIED Sep 06, 2013" (Exhibit 126) • ICF Addendum version 11APPROVED May 12, 2014 11 (Exhibit 127)

Source Documents

No instances of source document forgery or modification was found in the review of protocol II Source documents were well-organized and complete compared to the[ll@lprotocol. -

Case Report Forms (CRFs)

This protocol is still an open study, so the CRFs are not locked. -compiled each subject's ct1n·ent (at the time of inspection) CRF into a pdf file format for review during the inspection. Information is also transcribed from source documents to the electronic CRF for this study.

FINANCIAL DISCLOSURE

Financial disclosure forms were completed for all subinvestigators for both studies.

TEST ARTICLE ACCOUNTABILITY

For both protocols no issues were identified with test article accountability. DCOP has one employee, who is responsible for ordering, storing, and dispensing investigational

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product. The investigational product for bothlWland llllllwas received in powder fonn, then would be logged out and delivered to a pharmacist on-site where the subject was to be seen.

The master drng inventory logs for the- study and-study are included as Exhibits 128 and 129, respectively.

REPORTS TO SPONSOR AND MONITORING

-, There was routine monitoring activity ofthcP study prior to the discovery of the data issues. Beginning May 2013, there was at least one monitoring visit every 2 weeks, each of which could last multiple days. The monitoring Site Visit Log is included as Exhibit 130. This lasted until December of 2013. The results of these monitoring visits were reported to the IRB.

-No monitoring visit log was collected for-. Correspondence with monitor showed contact via email with study site to be frequent.

OBJECTIONABLE CONDITIONS AND MANAGEMENT'S RESPONSE

Observations listed on form FDA 483

OBSERVATION 1

An investigation was not conducted in accordance with the signed statement of investigator and investigational plan.

Specifically,

I) Several instances were discovered during the inspection in which protocol-required procedures were either not followed or were conducted in a manner inconsistent with the protocol.

lb) (4)

i. Primary efficacy endpoints were not determined per protocol, and disease assessment timeframes were not met per protocol.

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Protocol section 10.1, "Efficacy Measures", states "Patients may be enrolled on study with measurable or nonmeasurable disease based on RECIST, v. LI. Disease assessment will be undertaken at baseline (within 21 days prior to randomization) and then every 8 weeks (± 7 days) as calculated from the first dose of study therapy. Patients will be evaluated for response according to RECIST, v. 1.1 guidelines (Eisenhauer et al. 2009)."

a. 4 of the 5 subjects enrolled in this study who received study treatment had measurable disease to be evaluated per REC I ST v. 1.1 guidelines. However, not one of these subjects had disease measurement evaluation per RECIST v. 1.1 guidelines concurrent with their tumor imaging assessments. Additionally, a memorandum sent out discussing retroactively assessing subject number 2104 's tumors states that the subinvestigator caring for the subject stated that he was unable to complete the hunor assessment per RECIST because he is not trained.

b. 4 of the 5 subjects who received study treatment have out of window scans for disease assessment.


Week Post- Acceptable Date Range Actual Dnte Done per Initial for Scan Based on of Closest

Trentment Therapy Start Dote Senn protocol?

Week& 3/28/12-4/11/12 3/27/2012 No

Week 16 5/23/12- 6/6/12 5/29/2012 Yes

Week24 7/18/12- 8/1/12 7/13/2012 No

Weck32 9/12/12-9/26/12 9/11/2012 No

Subject 2102 - first dose of study therapy on 3/27/l2.

Weck Post- Acceptable Date Rnnge Actual Date Done per Initial for Scan Based on of Closest protocol?

i Treatment Therapy Start Date Scan

Week& 7/6/12- 7/20/12 7/10/2012 Yes

Weck 16 8/31/12-9/14/12 9/26/2012 No

Week24 I 0/26/ I 2 - 11/9/12 Nol Done No

Wcck32 12/21/12- 01/04/12 Not Done No

Subject 2104 - first dose of study therapy on 8/15/ 12.

WcckPost- Acceptable Date Rnngc Actual Dale Done per Initial for Scan Bnsed Oil of Closest

Treatment Therapy Start Date Scan protocol'/

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Week&

Week 16

Wcck24

Week32

Week40

Wcck48

Week 56

10/3/12-10/17/12 10/3/2012

11/28/12 - 12/12/12 l 1/29/2012

1/23/13 - 2/6/13 3/19/2013

3/20/13 - 4/3/ 13 3/19/13

5/15/13-5/29/13 6/25/2013

7/10/13- 7/24/13 7/31/2013

9/4/13-9/18/13 9/5/2013


Weck Post· Acceptable Date Range Achrnl

Initial for Scan Based on Date(s) of

Treatment Therapy Start Date Closest Scan(s)

Week 8 10/9/12- 10/23/12 9/4/12, 10/29/12

Week 16 12/4/12-12/18/12 10/29/12, 1/03/13

Week24 1/29/13 - 2/12/13 l/03/13, 3/08/13

Week 32 3/26/13-4/9/13 3/08/13, 4/29/13

Week40 5/21/13-6/4/13 4/29/13, 7/9/13

ii. Subjects 2100 and 2102 did not meet study inclusion criteria.


Yes

Yes

No

No

No

No

Yes

Done per protocol?

No

No

No

No

No

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Neither of these subjects received a protein level retest within 24 hours as required to determine eligibility per protocol section 8.1, "Inclusion Criteria". This section states "Patients are eligible to be included in the study only iflhey meet all of the following criteria:" and goes on to inclusion criteria #9, which reads "Routine urinalysis showing :51 + protein or protein/creatinine ratio <0.5. For proteim1ria 2:2+ or urine protein/creatinine ratio 2:0.5, 24-hour mine protein should be obtained and the level must be <1 gram of protein in 24 hours for patient enrollment." Subject 2100 had a baseline uri~esult o80Ja dated 1/31/2012. Subject 2102 had a baseline urine protein result of Ulllllllll dated 5/16/12. Neither received a second test within 24 hours. Additionally, Subject 2100 met one of the exclusion criteria. Protocol section 8.2, Exclusion Criteria, states "Patients will be excluded from the study if they meet any of the following criteria:" and goes on to exclusion criteria # 15, which reads "The patient is receiving chronic therapy with nonsteroidal antiinflallllllatory agents (NSAIDs; for example, indomethacin, ibuprofen, naproxen, or similar agents) or other antiplatelet agents (for example, clopidogrel, ticlopidine, dipyramidole, anagrelide.)" This subject was on clopidogrel 75 mg treahnent from 1/03/12 through 03/02/12 according to source documents. During this period of clopidogrel treahnent, the subject was consented and enrolled into the sh1dy and received study drug treahnents on 2/8/12 and 2/22/12.

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iii. Four of the five subjects who received study treatment missed one or more of their protocol required coagulation assessments. Per Attachment 1 of the protocol, titled, "Protocol llJIStudy Schedule", coagulation profiles must be collected during the Baseline Period and then at Cycle 4, Cycle 8, Cycles 9-X, Summary Visit, and 30-Day Follow-Up Visit.

a. Subject 2100: missing coagulation assessments for Cycles 4 and Cycles 8 through 17.

b. Subject 2102: Missing coagulation assessment for Cycle 4.

c. Subject 2104: Missing coagulation assessments for Cycles 4, Cycles 8, and Cycles 13 through 17.

d. Subject 2105: Missing coagulation assessments for Cycles 1, 4, 8 through 15, Cycle 17, Cycles 19 and 20, and Cycles 22 and 23.

iv. A majority of the vital sign requirements were not fulfilled for all subjects receiving study treatment.

Per Attachment l of the protocol, titled, "Protocol [6))1111 Study Schedule", vital signs are "To be obtained at eve1y treatment visit, immediately prior to and at the completion of each infusion of

(b) (4) placebo. Ifthere is a post-infusion observation period, then vital signs measurements should also be obtained at the end of the observation period." o Subject 2100: Out of a total of 15 cycles of study treatment visits, only 3 pre-infusion vitals were

taken. No immediate post-infusion vitals or one hour post-infusion vitals were taken.

o Subject 210 I: Thls subject only had one cycle of study treatment. No pre-infosion or one holU' post-infusi~n vitals were taken.

o Subject 2102: Out of a total of 6 cycles of study h·eatment visits, 4 pre-infusion vitals were taken, 3 immediate post-infusion vitals were taken, and O one hour post-infusion vitals were taken.

o Subject 2104: Out of a total of 18 cycles of study treahnent visits, 0 pre-infusion vitals were taken, 1 immediate post-infusion vitals were taken, and O one hour post-infusion vitals were taken.

o Subject 2105: Out of a total of 8 cycles of study treatment visits, vitals were only taken once (preinfusion, immedia).ely post-infusion, and one hour post-infusion).

B) For the study protocol numbere (b) (4) ',titled' (b) (4)

i. A serious adverse event was not reported to the sh1dy sponsor within 24 hours as required per protocol. Per protocol section 7.2.2., ''Reporting of Serious Adverse Events (Immediately Reportable)", "Any clinical AE or abnonnal laboratory test value that is serious and which occurs during the course of the sh1dy ( as definecl'in Section 7 .1.1.3 above), regardless of the treatment arm, must be reported tolIQ Within 24 hours of the Investigator becoming aware of the event (expedited repo1ting)."

Sub· ect number 0001 consented into the protocol munbe · ' • m (b) (4) - - - - - - - ---- - - - -

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(b) (4) 11, had a serious adverse event of

pseudomonas sepsis, which resulted in her being admitted to a hospital on 6/1/12. There is a telephone record of the patient calling her study physician on 6/6/12 to notify him that she was in the hospital in inpatient status, and indicates that the research nurse who is authorized to report serious adverse events was notified on this date. However, this serious adverse event was not submitted to the study sponsor until 6/14/12.

ii. Study drng treatment therapy order reversed for 5 out of subject 0006's 18 study treatment cycles. The protocol, section 6.1.3, "Non-Anthracyc]ine Based Chemotherapy (TCH)", states (b) (4)

followed by-placebo IV". For Cycle 4, Cycle 7, Cycle 10, Cycle 11, and Cycle 12, rmJU 'placebo IV was given before ...

ill. Observation period not followed per protocol. The protocol section 6.1.3.2, "Notes ontllllrarget treatment", subsection"- states that "The initial dose of-vill be administered over 90 (±10) minutes and patients observed for at least 30 minutes from the end of the infusion for infusion-related symptoms such as fever, ch.ills etc." "If the infusion is well tolerated, subsequent infusions may be administerecj over 30 (±10) minutes and patients will be observed for a farther 30 minutes." The subsection "[llltllla>lacebo" states "The initial dose offmJU 'placebo will be given after the infusion of DU :ro11owing the observation period and adrninistered over 60 (± I 0) minutes with patients to be observed for a further 60 minutes." ''If the infusion is well tolerated, subsequent doses may be adru.inistered over 30 (±10) minutes and patients will be observed for a fmther 30 minutes for infusion-related symptoms such as fever, chills."

4 of 4 subjects had treatment cycles where the observation period betweer-dministration and-placebo administration was not observed per protocol. This observation period was not followed for the following cycles for the following subjects:

a. Subject 0001: 2 total cycles of treatment; both cycles had observation periods of less than 5 minutes.

b. Subject 0003: 18 total cycles of treatment. 11 observation periods were under 6 minutes, l was 22 minutes, 5 were in accordance with the protocol, and 1 visit states tmlDIIIIIIIII h·eahnent began 1 minute prior to -·eatment ending.

c. Subject 0006: 18 total cycles of treatment. 2 observation periods were under 8 minutes, 11 were in accordance with the protocol, and 5 could not be observed because study treatment order was reversed.

d. Subject 0007: 18 total cycles of treatment. 4 observation periods were under 5 minutes; the other 14 cycles were in accordance with the protocol.

ill. For several cycles for several subjects, protocol-required laboratory tests were not performed.

a. The protocol's Table 8, "Schedule of Assessments-Screening and Treatment Period" indicates that Liver Function Tests must be completed within 7 days of Screening, then at Cycles 1-6, 9, 13, and 18. The footnote on this table for these assessments states "Liver function tests include: ALP, ASAT, ALAT, LOH; and total, direct, and indirect bili.rubin. At baseline, liver fimction tests should be completed within 7 days prior to randomization.

Several subjects had missing assessments for liver function tests:

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• Subject 0001:


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o Direct and Indirect Bilirnbin assessments were not completed for Screening, Cycle 1, and Cycle 2. This subject only went through 2 cycles of treatment.

• Subject 0003:

o No liver function tests were completed at Cycle 1

o Direct and Indirect Bilirubin assessments not completed at Screening, Cycle 2-6, Cycle 9, and Cycle 18.

o The liver function tests of ASAT, ALAT, and ALP were not completed for Cycle 3.

o LDH assessments were not done on Cycle 2, Cycle 4, and Cycle 9.

• Subject 0006:

o Direct and Indirect Bilirnbin assessments not coinplete for Cycles 1-5, Cycle 13, and Cycle 18

o LDH assessment not complete for Cycle 3

o No liver function tests completed for Cycles 6 or 9

• Subject 0007:

o No liver function tests completed for Cycle 6

o Direct and Indirect Bilirnbin assessments not complete for Cycles 1-6

b. The protocol's Table 8 "Schedule of Assessments - Screening and Treatment Period" indicates that Hematology and Biochemistiy assessments must be performed within 7 days of screening, and then within 3 days prior to Day 1 of Cycles 1-8, 9, 13, and 18. The footnote on this table for these assessments states ''Hematology and biochemisn·y should be completed pre-dose on Day 1 of each indicated cycle (or up to 3 days befo11:). Hematology tests (complete blood count) include counts of hemoglobin, white blood cells, neutrophils and platelets. Biochemistry tests include serum creatinine, blood urea nih·ogen and electrolytes (P-, Ca2+, Mg2+, Na+, K+, Cl-). At baseline, hematology and biochemistry should be completed within 7 days prior to randomization."

3 of the 4 study subjects had missing biochemistry assessments for several Cycles of treatment.

• Subject 0003:

o No biochemistty assessments perfonned for Cycles I or 7

o Sernm creatinine, blood urea nitrogen, Ca2+, Cl-, Na+,'and K+ assesslllents not perfonned at Cycle 3

o Mg2+ assessment not performed at Cycle 6 and Cycle 8

o P- assessment not performed for Cycles 2, 4, 6, and 8.

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• Subject 0006:

o P- not do11e for Cycle 2, Cycle 3, Cycle 5, Cycle 6

o No biochemish-y assessments done for Cycle 9.

• · Subject 0007:

o P- assessment not performed for Cycles 2, 8, and 9.

o Mg2+ assessments not performed for Cycle 8

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2) The signed FDA 1572, Investigator's Statement, was not followed by your firm in the following manners:

A You failed to follow Section 9, Line 2: "I agree to personally conduct or supervise the described investigation( s )."

A research nurse was designated by you across both studies reviewed during this inspection to have study responsibilities including managing the informed consent process (including informing the subject and obtaining the subject's informed consent properly), confirming subject's eligibility for the study with regards to inclusion and exclusion criteria, managing safety infonna1ion, and maintaining subjects' medical records.

The nurse referenced above created false chemotherapy worksheets, a forged patient progress record, and modified a CT scan record for the protocol number ' in an effort to make these records appear to meet protocol-required study parameters. False chemotherapy worksheets were created for all 4 subjects in this study who received study drng, for every infusion visit, except for cycles 9 through 11 for subject 2100. These documents contain false records of vital signs which were entered into the case report fonns by this nurse. This led to the case report having vital sign records deleted as they could not be verified.

Under your supervision, subjects were enrolled into this study who failed to meet one or more of the inclusion/exclusion criteria.

Reference: 21 CPR 312.60

Supporting Evidence and Relevance:

SUB-ITEM 1(A)

Exhibits 47 - 59·· of disease measurement forms and radiology repo1ts to show that none of the subjects on th study were being evaluated per RECIST criteria during the study as required by the protocol for primary endpoint analysis.

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The information for out of window tumor assessments is sourced from the subjects' radiology repmts.

• Subject 2100-Exhibits 49 & 50

• Subject 2102-Exhibit 54 • Subject 2104 - Exhibit 56

• Subject 2105 - Exhibit 59

Study inclusion and exclusion criteria for subjects 2100 and 2102 are sourced from eCRF pages (Exhibits 60 & 62 for subject 2100; Exhibit 61 for subject 2102).

Some, but not all of the coagulation measurements were verified to be missing due to the sponsor catching the missed assessments in the Clinical Tracking Log (Exhibit 44). The others were confirmed to be missing by the firm but no mention of them not being collected could be found in the eCRF.

The missing vital sign measurements were found in the subjects' eCR.Fs in the "VITALS" section (Exhibits 63-67).

SUB-ITEM l(B)

A collection of documents demonstrating the late reporting of subject 000 I's SAE is compiled as Exhibit 76.

The eCRF records that show all 77,

(b)(4) • lacebo plus (b) (4) or subject 0006 are Exhibit

The eCRF records for!IUU /placebo and (b) (4) - I or each subject are:

• Subject 0001 -Exhibit 79




For the missing protocol-required laboratory assessments, each subject has both source laboratory documents and eCRF pages to show that the laboratory assessments are missing:

• Subject 0001: (Laboratory source documents are Exhibit 85 and corresponding eCRF records are Exhibit 86).

• Subject 0003 (Laboratory source documents are Exhibit 87 and corresponding eCR.F records are Exhibit 88).

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• Subject 0006 (Laboratory source documents are Exhibit 89 and co1Tesponding eCRF records are Exhibit 90).

• Subject 0007 (Laboratory source documents are Exhibit 91 and con~sponding eCRF records are Exhibit 92).

Exhibits 99-102 are the forged and/or modified subject records discovered during the inspection.

Discussion with Management:

Dr. Gross stated he would reply in writing.

OBSERVATION 2

Informed consent was not properly documented in that the written informed consent used in the study was not signed by the subject or the subject's legally authorized representative at the time of consent.

Specifically,

For protocol number (b) ( 4)

• Subject 0001 was originally consented on 4/12/12. According to source documents, the subject withdrew consent by phone on 6/16/12 for all aspects of the study except for phone contact at the end of the study to detennine vital status only. The subject then subsequently signed off on a "SUBJECT WlTHDRA WAL OF CONSENT" fonn on 1/31/13 confirming her withdrawal and indication to only contact her at study closure to determine vital status only. However, there is an apparent additional informed consent fonn elated 5/6/13 with an apparent subject signature on it, purportedly from subject 0001.

However, there is no signature from a person conducting an informed consent ·discussion or an investigator/designee signature. Your finn could not verify that this was an actual subject signature or provide a reason why a consent form would be signed after a subject withdrew consent and left the study.

• Subject 0003 was originally consented on 5/18/12. On this consent form, the subject indicated that she <lid not want to donate a sample for the pharmacogenetic/genetic study. There is an apparent signed informed consent fom1 dated 1 /23/ I 3 purpo1tedly signed by the subject where it is indicated that she does want to provide a sample for the pharmacogenetic/genetic study. The subject signature on this form is dissimilar to the original signature. Your firm did not collect a sample on this date, and in fact did not collect a sample for this until the subject was reconsented on 12/18/13. The signature on the consent fonn dated 12/18/13 is similar to the original signahll"e. Your firm stated that the form dated 1/23/13 could not be verified to be legitimate, and that the subject was reconsented on 12/18/13 to get her current on informed consent versions and collect the phannacogenetic sample.

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Reference: 21 CFR 50.27(a)


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For subject 0001, Exhibit 116 is the initial informed consent dated 4/12/12, Exhibit 117 documents her withdrawal from the study verbally by phone on 6/16/12, Exhibit 118 is an official signed written withdrawal of consent dated 1/31/13, and Exbibit 119 is the apparent new informed consent signed 5/6/13.

For subject 0003, Exhibit 120 is the initial informed consent dated 5/18/12, Exhibit 121 is the apparent informed consent form, with a very unsirnilar signature to the other two informed consents, dated 1/23/13, and Exhibit 122 is the final informed consent dated 12/18/13.



OBSERVATION 3

Failure to prepare or maintain adequate and accurate case histories with respect to observations and data pertinent to the investigation. ·

Specifically,

For protocol number (b) (4)

• Adverse Event logs were not maintained contemporaneously with their occtmence for all subjects. Adverse Event logs were not generated for each subject until November of 2013. • 2100 - 11/8/13 ( on study beginning 2/6/12) • 2101 - 11/14/13 (on study beginning 3/20/12) • 2102- 11/18/13 (on study beginning 5/17/12) • 2103 - 11/8/13 (on study beginning 7/30/12) • 2104 - l l/14/13 (on study beginning 8/14/12) • 2105 - l l/14/13 (on study beginning 8/15/12)

• Concomitant Medication logs were not maintained contemporaneously with their occurrence. No source documentation of concomitant medication logs were generated until: • 2100 - 11/8/13 (on study beginning 2/6/12)

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Howard M. Gross, M.D, Dayton, OH 45240

• 2101 - 11/14/13 (on study beginning 3/20/12) • 2102-11/18/13 (on study beginning 5/17/12) • 2103 - 11/8/13 (on study beginning 7/30/12) • 2104 - 11/14/13 (on study beginning 8/14/12) • 2105 - l 1/14/13 (on study beginning 8/15/12)

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• There is not source documentation for any s11bject to indicate that the subjects were being evaluated for response according to RECIST v 1.1 guidelines per protocol. The source documentation for subject tumor measurement visits does not include any language about assessment of tumors according to RECIST v. 1.1. The only documents observed during the inspection which referenced RECIST v. 1. 1 , identified as "DISEASE MEASUREMENT FORM", were not generated concmTently with tumor assessments. Your firm stated they were made after later review of subject tumor assessments and then signed off on by either the principal investigator or sub-investigators. • Subject 2100: On study 2/06/12 - 10/10/12; Disease Measurement Form signed 9/10/13. • Subject 2101: On study 3/20/12 - 4/10/12; subject had an unmeasurable tumor but the blank Disease

Measurement Form was signed 11/14/13. • Subject 2102: On study 5/17/12 - 8/08/12; Disease Measurement Form signed but is undated. • Subject 2103: On study 7/30/12 - 8/08/12; no Disease Measurement Form. Subject never received study

drug. • Subject 2104: On study 8/14/12 - 6/24/13; Disease Measurement Form signed I 0/09/13. • Subject 2105: On Study 8/15/12 - 9/11/13; Disease Measurement Form signed 7/24/13.

Reference: 21 CFR 312.62(b)


The AE logs created retroactively for the subjects are included as follows

• Subject 2100 - Exhibit 104. • Subject 2101 -Exhibit 105. • Subject 2102 - Exhibit 106. • Subject 2103 - Exhibit 107.

~

• Subject 2104 - Exhibit 108. • Subject 2105 - Exhibit 109.

The Concomitant Medication logs created retroactively for the subjects are included as follows: • Subject 2100 -Exhibit 110. • Subject 2101 - Exhibit 111. • Subject 2102 - Exhibit 112. • Subject 2103 - Exhibit 113. • Subject 2104 - Exhibit 114. • Subject 2105 - Exhibit 115.

The Disease Management Forms created retroactively for the subjects are included as follows:

• Subject 2100 - Exhibit 47,

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Howard M. Gross; M.D. Dayton> OH 45240

• Subject 2101-Exhibit 51. • Subject 2102 - Exbibit 52. • Subject 2104 - Exhibit 55. • Subject 2105 - Exhibit 58.



REFUSALS

No refusals were encountered during this inspection.

GENERAL DISCUSSION WITH MANAGEMENT

Present at closeout to represent the firm:

• Howard Gross, M.D., Principal Investigator

• Mary Ontko, Acting Executive Di.rector

• Amy Dempe, Regulatory Director

• • • •

(b) (6) ·

(b) (6)

(b) (6)

(b) (6)

Research Coordinator

Regulatory Coordinator

Research Coordinator

Administrative Assistant

• - Research Coordinator • · tllllllllllconsultant • -Member, Board of Directors

(b) (6) • · Research Manager

I was the sole representative for FDA.

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Prior to issuing the FDA 483 to Dr. Gross, I discussed the potential outcomes of this inspection, including a warning letter, data invalidation, and disqualification of the investigator.

I read the FDA 483 aloud. Dr. Gross replied to each item that a written reply would be sent in by the firm. I then went over 5 discussion items with the firm:

1. Staff training appeared to be inadequate. Dr. Gross agreed and stated that any treatments done off-site at private practice not employed by a research fum posed a risk.

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2. Off-site locations need more accountability. I stressed to Dr. Gross the importance of ensuring that subinvestigators are truly subinvestigators who are both qualified and accountable. Dr. Gross had no comment.

3. I reiterated the importance of selecting qualified personnel, both for subinvestigators and supp01i staff. Dr. Gross stated he is cognizant of the issues and about having better oversight.

4. Discussed having better source documentation> and how having pre-made forms could assist in keeping track of required protocol procedures. Mary Ontko agreed.

5. 2 subinvestigators, and do not appear on two versions of the FDA 1572 fortheUIU] study, 1572s dated 3/2/11 ai1d 2/13/12. Dr. Gross had no cmmnent.

ADDITIONAL INFORMATION

No additional information was collected for this inspection.

SAMPLES COLLECTED

No samples were collected during the course of this inspection.

VOLUNTARY CORRECTIONS

This is the first inspection of the firm, so there are no coffections to observe.

EXHIBITS COLLECTED

Ex. 1 Curriculum Vitae for Dr. Gross 4 Pages

Ex. 2 DCOP Organizational Chart 1 Page

Ex. 3 List of all studies conducted by Dr. Gross at DCOP 13 Pages

(b) (6) Ex. 4 List of all studies conducted by Dr. Gross at 3 Pages

Ex. 5 List of all studies with which was involved 3 Pages

Ex. 6 1572s for 17 Pages

Ex. 7 Delegation of Authority Log for- 10 Pages

Ex. 9 -IRB approval of ICF Version 8-22-11, dated 9/19/11 4 Pages 1-----+----==

Ex. 10 Amendment b IRB approval dated 1/23/12 3 Pages

Ex. 11 IRB annual approval of L.d..:.:.at.:__e_d_:_3.!_/1..:.:.9_.!._/_12 ____ ---''-6_Pa--=g'-e_s __J

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Ex. 12

Ex. 13

Ex.14

-IRB approval of ICFverslon "Revised Informed Consent, Version 3", dated 4/16/12

flD1II !RB approval of ICF version "Revised Informed Consent, Version 4 11

, dated 8/20/12

Notification to IRB that Bstudy closed to enrollment effective 8-24-12, dated 9/18/12

mJIIRB approval of ICF version "Revised Informed Consent, dated

4 Pages

4 Pages

1 Page

Ex. 15 10-2012 11, dated 11/19/12 3 Pages

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Ex.16

Ex. 17

-Amendment c IRB approval dated 12/17 /12 4 Pages ------'----'-------i-----=---;

IRB annual approval of • dated 3/18/13 6 Pages '-----'----'-------+--"'---I

tmJIIIRB re-approval of previous informed consent form, dated Ex. 18 7/15/13 1 Page

Sponsor notification of early closure oflllm 12/4/13 with IRB Ex. 19 notification on 3/3/14 4 Pages

Ex. 20 IRB annual approval of dated 2/24/14 6 Pages !-----+-------- ----~-----+---~-----, Ex. 21 Study Inactivation Notice 2 Pages

Ex.23

Ex.24

Ex. 25

Ex. 26

Ex.27

Ex. 28

Ex. 29

Ex.30

NII@ Initial JRB approval b{IRllof the protocol, patient ID card, Patient Information Leaflet, Study Participant Guide, ICF version

"APPROVED AS MODIFIED Nov 22, 2011", ICF for Optional Donation of Frozen Tumor Tissue, and Pregnant Partner Informed Consent Form 4 Pages

Annual review & approval of dated 11/8/12 4 Pages --~---'-----+--~-----i

Dlllapproval o mendment Band revised informed consent form version "APPROVED AS MODIFIED Dec 13, 2012"

rmJP)pproval of Patient Information Leaflet and Study Participant Guide, dated 12/17/12

pproval of Administrative Letter dated 4/3/12

tllllapproval of BIG 4-11 Informed Consent Form version "APPROVED AS MODIFIED Sep 06, 2013"

llllapproval of "Request for Reconsideration of (08-07-2013) ReConsent Instructions, dated 10/8/13

ontlnulng review and approval to-dated 11/18/13

... pproval of Revised Protocol (11-07-2013) Incorporating

3 Pages

2 Pages

2 Pages

3 Pages

3 Pages

4 Pages

Ex. 31 Amendment C, dated 11/15/13 1-E-x-. -3-2-t-----.[m .. ,-1•miiil•o_t_lf-ic-a-ti-on-of--...• • tudy accrual closure, dated 12/11/13

3 Pages

3 Pages

Ex. 33

Ex.34

ll9Papproval of Revised Protocol (12-03-2013) Incorporating Amendment C (revised), dated 12/18/13

· [QJll]approval of Ml@W1nformed C.Form addendum SO (version APPROVED May 12, 2014 dated 5/12/14

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3 Pages

3 Pages

Establishment Inspection R.eport


Ex. 35

Ex.36

FBI: El Start:

El End:

4 Pages

5 Pages

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Ex. 37 12 Pages

Ex.38

Ex. 39

Ex. 40

Ex. 41

Ex. 42

Ex. 43

Ex.44

Ex.45

Ex. 46

Ex. 47

Ex.48

Ex.49

Ex.so

Ex.51

Ex. 52

Ex. 53

Ex. 54

Ex.55

Ex.56

Ex. 57

Ex. 58

protocol amendment b

Investigator Signature Pages

"Clinical Tracking Log 11 for[GJallstudy, listing all discovered protocol deviations identified by the study sponsor, dated 8/9/13

Memorandum stating lllllllllllvas not trained In RECIST for evaluation of tumors for •

(b) (6) CV ubject 2100 Disease Measurement Form, dated 9/10/13

subject 2100 patient progress notes

tllU,ubject 2100 Radiology Reports for scans reported on Disease

1 Page

1 Page

9 Pages 116 Pages

131 Pages

4 Pages

10 Pages

2 Pages

4 Pages

1 Page 17 Pages

Measurement Form, blank 9 Pages

fBJubject 2100 Radiology Reports for scans reported on Disease Measurement Form, marked with Initial lesion assessments- shadow

chart 13 Pages

IJlsubject 2101 blank Disease Measurement Form, signed & dated 11/14/13 1 Page

[D subject 2102 Disease Mi;asurement Form, signed but not dated

1 Page

ubject 2102 patient progress notes 9 Pages

.subject 2102 radiology reports for scans reported on Disease Measurement Form 18 Pages

Bsubject 2104 "DISEASE MEASUREMENT FORM" dated 9/13/13 1 Page

tlJlsubject 2104 shadow chart radiology reports for scans reported on Disease Measurement Form 21 Pages

Ullsubject 2104 patient progress notes 12 Pages

-ubject 2105 Disease Measurement Form, signed and dated 8/15/13 · 2 Pages

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Ex.59

Ex.60

Ex. 61

Ex.62

Ex. 63

Ex.64

Ex. 65

Ex.66

Ex.67

Ex.68

Ex. 69

Ex. 70

DIii subject 2105 radiology reports for scans reported on Disease Measurement Form

tlJlsubject 2100 baseline urinalysis eCRF pages showing 24 hour test not performed

subject 2102 baseline urinalysis eCRF page showing 24 hour test - not performed

subject 2100 eCRF page showing exclusion criteria met

Subject 2100 Vitals eCRF





-Initial Protocol, dated 6/28/11 Protocol Amendment B, dated 11/1/12

Protocol Amendment C, dated 11/7 /13

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24 Pages

2 Pages

1 Page

1 Page

45 Pages

3 Pages

49 Pages

24 Pages

149 Pages 167 Pages

148 Pages 157

Ex. 71 Protocol Amendment C, dated 12/03/13 Pages

Ex. 72 Investigator's Signature sheets fo protocol 14 Pages ----+---- ~-------~-Ex. 73 lte Newsletters - Issues 1, 2, 3, 4, 6 28 Pages

Ex. 74 tudy Newsletters - Issues 3-7, 9-11 38 Pages

Ex, 75

Ex. 76

Ex. 77

Ex, 78

Ex. 79

Ex.80

Ex.81

Ex.82

Ex.83

Ex. 84

Ex.85

List of al protocol deviations reported to the IRB as of

12/11/14

Documents showing subject 0001's SAE was not reported in an appropriate timeframe

Subject 0006 eCRF pages for (b) (4) administration

Subject 0001 infusion chart records

(b) (4) Subject 0001 eCRF pages for administration

Subject 0003 infusion chart records (b)(4) · ~ Subject 0003 eCRF pages fo dministration

Subject 0006 infusion chart records

Subject 0007 Infusion chart records

Subject 0007 eCRF pages for (b) (4) • dministration

Subject 0001 laboratory source documents

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31 Pages

20 Pages

2 Pages

7 Pages

2 Pages

18 Pages

2 Pages

9 Pages

4 Pages

2 Pages

10 Pages

FBI: Establishment Inspection Report Howard M. Gross> M.D. EI Start: Dayton, OH 45240 EI End:

Ex. 86 Subject 0001 non-test article eCRF pages

Ex.87 Subject 0003 laboratory source documents

Ex.88 Subject 0003 non-test article eCRF pages

Ex. 89 Subject0006 laboratory source documents


Subject 0007 laboratory source documents

Ex. 91


DCOP response and corrective action plan for ' " discovered

Ex, 93 protocol deviations 1-----J-----,-------ffl!!

Ex. 94 !CF Revision 1

Ex. 95 ICF Revision 2

Ex. 96 CF Revision 3



Ex. 99 AE report for the forged progress note for subject 2100

Ex. 100 AE report for forged CT scan date for subject 2102

Ex. 101 Duplicate infusion charts for subject 2104 dated 1/29/13

Ex. 102 Forged progress note for subject 2102 dated 5/10/12

Ex. 103 Vital signs worksheets for subject 2104

Ex. 104 AE log for subject 2100, dated 11/8/13






Ex. 110 log for subject 2100:dated 11/8/13

Ex. 111 og for subject 2101 dated 11/14/13

og for subject 2102 dated 11/18/13

Ex. 112

Ex. 113 log for subject 2103 dated 11/8/13

og for subject 2104 dated 11/14/13

Ex. 114

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20 Pages

18 Pages

14 Pages

18 Pages

14 Pages

21 Pages

24 Pages

25 Pages

25 Pages

6 Pages

26 Pages

3 Pages

2 Pages

2 Pages

2 Pages

14 Pages

5 Pages

2 Pages

3 Pages

2 Pages

3 Pages

1 Page

2 Pages

3 Pages

3 Pages

2 Pages

3 Pages

Ex. 115 log for subject 2105 dated 11/14/13 1 Page

tllllllsubject 0001 informed consent signature pages dated

Ex. 116 4/ 12/12 5 Pages

ubject 0001record of verbal withdrawal by phone on

Ex. 117 6/l6/12 1 Page

[QJIIWlsubject 0001 record of official written withdrawal of consent

Ex. 118 dated 1/31/13. 1 Page

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Ex. 119

Ex. 120

Ex. 121

Ex. 122 Ex. 123

Ex. 124

Ex.125 Ex, 126

Ex. 127

Ex. 128

Ex. 129

Ex. 130

NW subject 0001.informed consent signature pages dated 5/6/13

subject 0003 informed consent signature pages dated

5/18/1.2

llDl@-subject 0003 informed consent signature pages dated

1/23/13

[G>JlfMsubject 0003 informed consent signature pages dated

12/18/13

ICF version "APPROVED Nov 22, 2011"

Pharmacogenetic Consent form approved 11/22/11

ICF version "APPROVED AS MODIFIED Dec 13, 2012"

CF version "APPROVED AS MODIFIED Sep 06, 2013"

ATTACHMENTS

FDA 482, Notice of Inspection, dated 11/19/2014, issued to Ms. Mary

Att. 1 E. Ontko, Acting Executive Director, DCOP.

FDA 482, Notice of Inspection, dated 11/19/2014, issued to Mr.

Att. 2 Sidney J. Pinkus, President and CEO, DCOP

FDA 482, Notice of Inspection, dated 11/19/2014, issued to Dr.

Att. 3 Howard M. Gross, M.D., Principal Investigator

FDA 482, Notice of Inspection, dated 11 21 2014 issued to

Att. 4 11111 Manager, at

FDA 482, Notice of Inspection, dated 1/14/2015, issued to Ms. Mary E.

Att. 5 Ontko, Acting Executive Director, DCOP,

FDA 482, Notice of Inspection, dated 1/14/2015, issued to Dr. Howard

Att. 6 M. Gross, M.D., Principal Investigator

FDA 483, lnspectional Observations, issued to Dr. Howard M. Gross,

Att. 7 M.D., Principal Investigator

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Establishment Inspection 1lepor<t Howard M. Gross, M.D.

Dayton, OH 45240

~-/¼:~ Richard W. Berning, Investigator

FEI: EI Start: El End:

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3011123156 11/19/2014

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