# Presentation: 556255

## SPECIMEN ISSUES

- 	Samples Update:
- A Cautionary Tale
- 	The Office of Biorepositories and Biospecimen Research  (OBBR) Revisits Sample Issues on the Eve of Post-Pilot Scale Up of TCGA
- 	TCGA Steering Committee Meeting
- 	December 4, 2008
- 	Carolyn Compton, M.D., Ph.D.
- 	Director, NCI Office of Biorepositories and Biospecimen Research

## Sample Entry Criteria for TCGA Pilot

**Tumor samples:**
**Primary tumor only**
**No neoadjuvant therapy**
**No metastasis**
**Snap frozen (preferred: liquid nitrogen, no OCT)**
**At least 200 mg in amount**
**No more than 20% necrosis (GBM ≤ 50%: reset by TGCA)**
**Of viable cells, 80% or more must be tumor cells**
**Matched normal sample**
**Blood (buffy coat/white cells) or ≥ 30μg high-quality DNA**
**Adjacent normal tissue**
**All “Tier One” Clinical Data Elements (approximately 15)**
**Basic key data on case: lowest common denominator**
**Pilot goal: 500 cases of each tumor type that meet ALL of these criteria**

## Entry Criteria (“Quality”) Requirements Determined by the Pilot Design 

**Set by the** **technical demands** of the molecular analysis platforms
- Respecting the basic premise of TCGA: **all CGCCs and GSCs would analyze exactly the same molecules** from the same samples from the same patient
- Molecules must be of sufficient quantity to satisfy all platforms and of **sufficient quality to yield interpretable data on **_**all**_** platforms**
- The target number of **500 cases per tumor type** was a statistically-based decision aimed at an agreed upon goal of achieving a defined depth of analysis and probability of finding genomic changes that occur infrequently
**All/any of these **_**could**_** be changed per policy decision or technology evolution: to date, no significant change has been acceptable/possible within TCGA**

## With the Exception of.....

**Changes based on specimen “pilot projects” executed to explore the impact of altering entry criteria cut-points (like % necrosis) on data generated by various platforms**
**Learned that great as 50% necrosis in GBM could be tolerated → criterion **_**changed**_
**New pilot specimen experiments:**
**Degree of tolerated necrosis in other tumor types**
**Degree of tolerated “contamination” by normal cells: lymphocytes, endothelium, neutrophils, etc.**

## Finding Specimens: Process Evolution

**Initial steps: Issue RFI to identify sample sets**
**Initial contacts with PIs to clarify RFI responses**
**Site visits**
**Starry-eyed phase: Initial estimate based on the above: **_**All**_** samples for TCGA pilot could be acquired from 4-6 tissue source sites (TSS)**
**Reality intrudes: Steep learning curve as specimen collection is attempted**
**Specimen availability quickly revealed to be THE limiting factor for TCGA **
**Specimen acquisition activities grew exponentially**

## Finding Specimens: Process Evolution

**Two years later – more reality: It’s even worse than we thought**
**OBBR at NCI assumed full responsibility in early 2008**
**Efforts to industrialize responsibilities:**
**Identify additional sources of samples **
**Make initial contact with each TSS and acquire commitment**
**Educate the sites re. **_**scientific benefits**_** to sample contributors (maintenance of patient identity link!)**
**Educate and guide sites re. qualifying appropriate samples**
**Educate TSS re. required processes: IRB approval, material transfer agreement (MTA), and contract**
**Act as point of contact to facilitate administrative requirements**
**Educate and guide sites re. prospective collection protocols**
**Follow up, follow up, follow up, follow up........**

## Strategies to Accelerate Process

**Biospecimen Access Working Groups (BAWGs): get help from the community in identifying sample sets**
**Telecons and site visits**
**Webinars**
**“****One Stop Shopping” training manuals and CDs**
**A tracking database to manage all aspects of TSS recruitment**
**Coordinated management teams**
**Continual communication and follow-up with TSSs **
**Continual review of roadblocks**
**Planning and prioritization of appropriate action**
**Communication with BCR**
**Consent form review and analysis**
**IRB information sheet**

## TCGA Sample Procurement

**We should have this issue solved by now, right?**
**Hint: Wrong is the right answer.**
**Why is this so difficult????**
**What have we learned????**
**What are we doing about it???**

## Lessons Learned: Identifying Qualifying Sample Sets

**Samples are added to most banks **_**without**_** QC**
**QC performed when samples are distributed**
**QC process is labor intensive, expensive**
**Characteristics of most banked samples are **_**unknown**_
**Conspiracy of ignorance: **
**Wild overestimation of the numbers/characteristics of sample sets was universal**
**Equally wild underestimation of the deficiencies**
**Large percentage of banked samples lack matched normals, even when protocol specified collection**
**Spectacularly inaccurate data (degree of inaccuracy unknown)**
**To date, TCGA has never gotten an accurate estimate from a TSS**
**Even Gaddy couldn’t make predictions under these conditions.**

## Lessons Learned: Identifying Qualifying Sample Sets

**Links to and definitions of clinical data elements were heterogeneous in type and often lacking**
**Underestimation of effort and time to collect and collate**
**Variable quality of clinical data (that’s how Rx’ed GBMs entered TCGA)**
**TCGA requirements extremely difficult  to meet retrospectively**
**Worst case examples: as few as 2% of samples in large sample sets found to meet the requirements**
**Target number of GBMs can only be reached through prospective collection – possibly other tumor types as well**
**Despite energetic education and outreach efforts, TCGA continues to get samples that fail entry criteria**

## Lessons Learned: Bottlenecks for Entry of Qualifying Samples into TCGA

**Administrative aspects of specimen entry**
**IRB approval**** ****(single/multiple – up to 46 institutions for a single clinical trials group tumor collection)**
**Proposal/application preparation by PI**
**Existing consent form review**
**IRB education about TCGA patient protection policies and procedures**
**Worst case scenario: apply under existing consent → reject → apply for waiver of consent → reject → reconsent of living patients (in as many as 46 different sites)**

## Lessons Learned: Bottlenecks for Entry of Qualifying Samples into TCGA

**Administrative aspects of specimen entry**
**MTA negotiation**
**Insistence on use of institutional MTA rather than TCGA MTA**
**Intellectual property disputes**
**Insistence on limitation of liability of institution (indemnity)**
**Specimen “ownership” rights disputes**
**Requests for guarantees of institutional recognition**
**Contract negotiation**
**Reimbursement ($$$$$$$$$$$$$$$) issues**

## Lessons Learned: Bottlenecks for Entry of Qualifying Samples into TCGA

**TSS complexities: organizational structures, processes, people (types, numbers, attitudes), and communication levels **
**All vary enormously  **
**ALL of the above represent potential time-limiting factors at TSS **
**Process steps often occur in series, not simultaneously**
**Any one of the steps/issues can derail the entire process !!!!!**
**TCGA’s ability to expedite any of the process steps is limited**

## We Do What We Can: Expediting IRB Approval

**TCGA Policy Revision:**
**Re-consent of living research participants is no longer required (per TCGA policy) for submission of biospecimens to TCGA**
**TSSs send original consent for biospecimen collection/use to TCGA**
**TCGA staff reviews the consent document(s) and provides a memo describing degree of consistency with TCGA**
**IRB at the TSS independently determines whether or not  the consent is sufficient or if a waiver of consent is appropriate**

## OBBR Consent Review 

**	****Within the context of TCGA, the following are considered **_**essential**_** elements for consent documents:**
**Use for genetic research **
**Sharing of data and biospecimens outside of the institution**
**Future research use**
**Risk of loss of privacy and confidentiality**

## Specimen Acquisition Timeline: 

**Tissue Source Sites**

**Average Time****to Completion**

**Despite huge effort to shorten these timelines, they remain unchanged.**
**Shortest: 4 month (miracle)**
**Longest: 2+ yrs and counting**

**BCR PIPELINE**

**Internal QC of Samples**
- (checking sample inventories and/ or performing frozen sections to determine how many match TCGA criteria)
**1-2 Months**

**NCI-NHGRI**
**Informed Consent Review**
**2 weeks**

## Escalating the Process of Acquiring Samples (Snapshot 2/1/08)

**EMORY**

**University of Colorado HSC**

**MD Anderson Cancer Center**

**Gynecologic Oncology Group**

**MAYO**

**Princess Margaret Hospital**

**OICR**

**University of California/ San Francisco**

**University of Pittsburgh**

**Total Number of Committed Contributing Groups: 24**
**Number actively shipping samples: 8**
**Number with completed paperwork as per protocol: 4**

- 1 tumor type
- >1 tumor type

**Escalating the Process of Acquiring Samples (Snapshot 2/1/08)**

## Total Number of Committed Contributing Groups: 53

**Total Number of Committed Contributing Groups: 53**

**Prince Charles Hospital – Brisbane, AU**

**University Hospital Network Toronto, ON**

**US Military Cancer Institute**

**University of Virginia**

**University of Florida**

**Norway**

**NCCCP: Hartford Hospital**

**Vanderbilt University**

**NCCCP: Catholic Health Initiative**

**NCCCP: Christiana Hospital**

**American College of Surgeons Oncology Group**

**Fox Chase Cancer Center**

**C. Besta Neurological Institute, Milan Italy**

**University of California/ Los Angeles**

**Imperial College - UK**

**Harvard University**

**Cedars-Sinai**

**Escalating the Process of Acquiring Samples (Snapshot 11/15/08)**

- 1 tumor type
- >1 tumor type

**EMORY**

**University of Colorado HSC**

**MD Anderson Cancer Center**

**Gynecologic Oncology Group**

**Case Western Reserve University Hospital**

**Memorial Sloan Kettering**

**MAYO**

**Princess Margaret Hospital**

**OICR**

**DUKE**

**Fred Hutchinson CRC**

**University of California/ San Francisco**

**University of Pittsburgh**

**BC Cancer Agency**

**UNC**

**Johns Hopkins**

**International Genomics Consortium**

## Due to complexity of project and the internal processes at the TSS, constant follow-up is required to assure timely completion of tasks
However, too much pushing leads to resistance
Sites resist beginning administrative paperwork until IRB proposals have been approved
Sites resist beginning pathology QC (frozen sections) of their samples until either IRB is approved and/or contract is executed
Sites cannot  perform pathology pre-QC (personnel/resource issue)
Sites resist the requirement to reconsent living patients (deal-breaker for some who do not have the resources to perform reconsent)
Sites resist gathering of clinical data elements due to unclear requirements (CDE list development for the 3 diseases has taken a year)

**Due to complexity of project and the internal processes at the TSS, constant follow-up is required to assure timely completion of tasks**
**However, too much pushing leads to resistance**
**Sites resist beginning administrative paperwork until IRB proposals have been approved**
**Sites resist beginning pathology QC (frozen sections) of their samples until either IRB is approved and/or contract is executed**
**Sites cannot  perform pathology pre-QC (personnel/resource issue)**
**Sites resist the requirement to reconsent living patients (deal-breaker for some who do not have the resources to perform reconsent)**
**Sites resist gathering of clinical data elements due to unclear requirements (CDE list development for the 3 diseases has taken a year)**

## Where We Are Now

| Type | Incoming  |  | In Queue  | Outgoing  |  | % Qualify
(Matched) | % Qualify (Un-matched) |
| --- | --- | --- | --- | --- | --- | --- | --- |
|   | New Match | Un-Match |   | Match | Un-Match |   |   |
| GBM | 497 | 264 | 65 | 167 | 63 | 39% | 24% |
| Ovary | 292 | 0 | 29 | 75 | 0 | 29% | 0% |
| Lung | 67 | 0 | 67 | 0 | 0 | 0 | 0 |
| Total | 856 | 264 | 161 | 242 | 63 | 35% | 24% |

## Slide 21

| # | Site | PI | Type | IRB Approved | MTA |  | BCR Conf call | ≥12 cases ready | TSS/SAIC Contract Executed | Green light for Biospec. Transfer Training Session | BTTS Complete |  Est.# cases - 1st Ship |
| --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- | --- |
|  |  |  |  |  | Init. | Exec. |  |  |  |  |  |  |
| 1 | Brigham and Women's  | Dr. Cramer | Ovary | 10/20 | 10/20 |   | 11/11 | 11/11 |   |   |   | 34 |
| 2 | Fondazione IRCCS Instituto Neuroligico C. Besta (Milan) | Dr. Finocchiaro | GBM | 7/3 | 4/15 | 8/5 | 9/18 | 10/27 |   |   | 9/18 – Conf Call | 24 |
| 3 | Prince Charles Hospital (Melbourne Aus) | Dr. Fong | Lung | 5/15 | 3/17 |   | 8/13 | 11/12 |   |   | 8/13 – Conf Call | 40 |
| 4 | Pr. Margaret Hospital | Dr. Tsao | Lung | 8/8 | 7/9 | 9/23 | 8/21 |   |   |   | 7/11 | 20 |
| 5 | Imperial College (UK) Brompton  | Dr. Lim | Lung |   | 11/10 |   | 12/3 |   |   |   |   |   |
| 6 | Imperial College (UK) | Dr. Gabra | Ovary | 10/15 | 10/20 |   | 11/19 |   |   |   |   | 40 |
| 7 | Duke | Dr. Berchuck | Ovary | 11/21 | 10/15 |   | 11/5 |   |   |   |   | 25 |
| 8 | St Joseph's HMC (PHX) | Dr. Shapiro | GBM |   | 10/17 |   | 2-Dec |   |   |   | 12/2  |   |
| 9 | Cedars – Sinai Med Center, Los Angeles | Dr. Black | GBM | 4/17 | 3/12 | 10/2 | 10/1 |   |   |   |   |   |
| 10 | Univ. of Fla. | Dr. Friedman | GBM | 6/30 | 8/11 | 11/24 | 11/25 |   | 7/31 |   | 7/15 |   |
| 11 | Ontario Institute for Cancer Research | Dr. Zanke | Lung |   | 7/22 |   | 9/3 |   |   |   | 7/11 |   |
| 12 | Ontario Institute for Cancer Research | Dr. Zanke | Ovary |   | 7/22 |   | 9/3 |   |   |   | 7/11 |   |
| 13 | MSKCC | Dr. Rusch | Lung |  12/2 | 7/30 | 8/12 |   |   |   |   |   |   |
| 14 | Johns Hopkins | Dr. Brock | Lung |   | 11/11 |   | 11/24 |   |   |   |   | 50 |
| 15 | University of Pittsburgh | Dr. Dhir | Lung |   | 11/11 |   | 12/1 |   | 5/9 |   |   |   |
| 16 | BC Cancer Agency | Dr. Huntsman | Ovary | 4/21 | 11/21 |   |   |   |   |   |   |   |
| 17 | Walter Reid | Dr.  Shriver | Breast |   | 11/21 |   |   |   |   |   |   |   |

## 20/20 Hindsight: If We Were to Do This Again We Would....

**Start 2 years ahead of time to:**
**Identify all possible tissue source sites**
**work with them to qualify their sample sets and clinical data**
**Work with them to complete all administrative steps**
**Do the “tissue pilot experiments” to prospectively set the entry criteria cut-points**
**Set up prospective collection immediately**
**Begin the analysis component AFTER the samples are in hand**
**Take a top-down approach to institutional commitment to insure timeliness of administrative activities**
**Educate early and broadly about TCGA requirements on all levels at source sites**
_**Bottom Line**_**: Reduce/eliminate unknowns *****before***** opening the analytical pipeline**

## Instead.......

**Change approach to fit reality and Steering Committee recommendation of July 2008**
**Continue to pursue goal of 500 total tumors per type for pilot but elongate timeline **
**Meanwhile, open TCGA to other tumor types – specifically, sample sets of any histological type from any anatomic site that:**
**Meet TCGA quantity and quality criteria**
**Meet TCGA CDE requirements**
**Include at least 50 qualifying samples per sample set per TSS**
**Build on existing TSS relationships, approvals, agreements**
**Add additional TSS and begin new processes *****now***

## Examples

**Inclusion of other lung, ovary and brain tumor types:**
- Lung: adenocarcinoma
- Ovary: endometrioid carcinoma, mucinous carcinoma
- Brain: astrocytoma, meningioma, other
**Examples of other types likely to be available:**
- Breast: ductal carcinoma; lobular carcinoma
- Uterus: endometrioid adenocarcinoma
- Kidney: clear cell carcinoma, papillary carcinoma
- Colon: adenocarcinoma, mucinous carcinoma
- Thyroid: papillary carcinoma, follicular carcinoma
- Lymphoma: diffuse large B cell lymphoma, follicular lymphoma, other
- Bladder: urothelial carcinoma, other
- Liver: hepatocellular carcinoma, cholangiocarcinoma
- Stomach: adenocarcinoma, signet-ring cell carcinoma, other
- Prostate: adenocarcinoma
- Sarcomas: leiomyosarcoma, osteosarcoma, chondrosarcoma, other

## SPECIMEN ISSUES

- 	Samples Update:
- A Cautionary Tale
- 	The Office of Biorepositories and Biospecimen Research  (OBBR) Revisits Sample Issues on the Eve of Post-Pilot Scale Up of TCGA
- 	TCGA Steering Committee Meeting
- 	December 4, 2008
- 	Carolyn Compton, M.D., Ph.D.
- 	Director, NCI Office of Biorepositories and Biospecimen Research