Challenges In Translating Success From The Lab To The Clinic

A Perspective On Our Current Infrastructure And Suggestions On Ways To Improve It

Or…why aren’t we making more progress?

Lee M. Ellis, M.D.Departments of Cancer Biology and Surgical Oncology

Metastasis Research CenterUT MD Anderson Cancer Center

Houston, Texas, USA

“Progress” For Patients With Advanced Stage Disease (Solid Tumors)

Progress as Measured by Efficacy AND DurationTumor Type Durable Transient* Little None

GIST X

Breast X

NSCLC X

RCC X

CRC X

Hepatoma X

GBM X

Pancreas X

Sarcoma X

My own views: Although we may be achieving significant “p values” in studies, are we really make a difference in the lives of our patients?

* < 1yr improvement in PFS, more commonly < 6 mos

Barriers to Progress(And Potential Solutions)

• The Obvious– Mice are not humans– We need to learn how to use our murine

models correctly• Integrity• The “System” and The Lack of a Sense

of Urgency

Nature Medicine 2010

The Growth Rates of Tumors in Mice is Much Faster than Growth Rates in Humans

• Rapidly proliferating cells are more sensitive to nearly all therapies

• Duration of therapy is also shortened in mice • The Fix: Utilize models with smaller inoculums, allowing for

slower tumor growth, slower endothelial cell proliferation and increased stroma formation. Or use transgenics.– Allows for longer duration of therapy, which is more relevant to humans

Ellis, Fidler, Nat Med 2010

We Often Times Study Complex Regimens Into Patients Without Testing Them First In Mice

Most Patients With Metastatic CRC Will Receive FOLFOX

• Only 5 studies combined oxaliplatin and 5FU in CRC murine models

• Only one study used an orthotopic model

No Preclinical Studies Evaluated the Combination of 5-FU, Oxaliplatin, VEGF inhibition (standard of care)

AND inhibition of either EGFR, Hedgehog, or Cox-2

2 failed (or even harmful) Phase III trials

1 failed Phase II trial

Phase III trial in the adjuvant setting ongoing

Why Is It Important To Study Combination Therapy In Mice Even Though Experiments With 1-2 Agents

Seems Promising?

• Chemotherapies and targeted therapies lead to cytokine responses– Are these compensatory survival pathways?– Shouldn’t we know about this biology prior to

subjecting our patients to this therapy?• More is not better (and may even be worse)

– Chemo + Bev + EGFR MoAB in mCRC• PACCE• CAIRO-2

We Often Times Study Complex Regimens In Patients Without Testing Them First In Mice

• The Fix: We must study complex regimens in mice BEFORE moving these regimens into clinical trials– Should this be mandated by the FDA or CTEP?

My personal view:We should never subject humans to any regimen that

has not been studied in mice!

There Are Times When We Are Not Sure What We Are Studying In The Lab

Cell line contamination/misidentification has been thought to occur in up to 60% of cell lines commonly used

• 3 commonly used esophageal cancer cell lines were cell lines from other tumor types

data from these cell lines formed the foundation fora. several ongoing clinical trialsb. 100 publicationsc. 11 patents

• Many journals require or request validation of cell line within 6 months of use

- This should be mandatory for all publications• Institutes should also mandate (and offset costs) of cell line genomic fingerprinting

The 50% Rule for Drug DevelopmentYou Need to Make a Big Difference in a Mouse for It To

Translate Into a Meaningful Difference in a Human

• For every step along the way, the delta (D) in improvement in efficacy over the control arm decreases by ~50%

• Mice better mice models– SQ orthotopic or genetically engineered murine model

• Preclinical Phase Ib/II• Phase II Phase III

– Maitland et al CCR 2010

Viewing The Entire Spectrum From Mice To Humans

Chemo +/- Targeted Agents in Phase II/III Trials Examples of Trials Where PFS is Shorter in the Phase III

Study

Regimen PFS Phase II

PFS Phase III

NSCLC C/P +/- Bev 7.4 6.2Pancreatic Gem +/- Bev 5.4 3.8Pancreatic Gem +/- C225 3.8 3.4CRC FOLFOX +/- C225 10 7.9/8.6

Caveat: Most regimens advance to a Phase III study without having

been studied in a RANDOMIZED Phase II trialChan at al. JCO 2008

EI-Maraghi, Eisenhauer, JCO 2008Tang…Sargent. JCO 2010

The Disappointment of Progressing from Phase II to Phase III Trials

“Estimating from these data, the likelihood that a published phase II combination

chemotherapy trial will result in a subsequent trial showing an improvement in standard of care within five years was

0.038% (CI 0.016-0.064)”

Mark Ratain

Barriers to Progress(And Potential Solutions)

• The Obvious– Mice are not humans

• Integrity– Selective Reporting– “Massaging” Data to Stay Alive/Advance in

Academia• The “System” and The Lack of a Sense

of Urgency

Selective Reporting of Laboratory Studies

• Journals prioritize “positive” results– If a drug works in 2 cell lines, and does not in 8, we only

see the results on the 2 cell lines• Students, post-docs and faculty need publications

for advancement– “Publish or perish”– In many labs, 2 trainees work on the same project

competing with each other…guess who wins?• Therefore, we tend to report only the “positive”

data and ignore the negative data

But….There is Value In Reporting Negative Data (Targeted Therapies)

• Identification of biomarkers for resistance or sensitivity– Reporting of negative outcomes in the lab, may lead to new

insights into why the outcomes were negative• Understand a detrimental effect of combination

therapies• Saving costs and time invested by others in the field• It is the right thing to do (integrity)

– Unfortunately, that is not how the system currently works

The Fix for Selective Reporting of “Positive” Data

• Journals must provide a forum for publication (accessible in PubMed) of negative data– This can be:

• an independent on-line publication to save costs for the publishers and authors

• included within the manuscript, where both positive and negative data are reported

• Companies must allow reporting of negative data when writing contracts and MTAs – Universities/Cancer Centers must insist on this

• Authors must sign a statement confirming that all relevant data, both negative and positive, have been included in this publication

The Tougher Issue

Lapses in Integrity and the “Massaging” of Data

Combating Human Nature:The Need to Succeed at Any Cost

The “Perfect Story”• High impact journals, and their reviewers,

only accept the “perfect story”– Unfortunately, biology is not linear and never

presents a perfect story• Seeking to tell the perfect story leads to

– The temptation to “massage data” – Delays in submission for publication

• One investigator told me that it took him 9 yrs of work to publish an article in a high impact journal

– In the 9 yrs it took to publish this work, ~3,000,000 US patients died of cancer

The “Archeological Dig” of High Impact Publications

• The two layers of most high impact publications– The original manuscript has a well defined hypothesis

• and experiments– But…the final manuscript reports on a number of

studies that just don’t seem to fit…..these are done to appease the reviewer (who make investigators jump through hoops)

– The outcome of the experiments done for the revision must be perfect, as we are “oh so close”

– Trainees are sent to do these studies• Unspoken request: “come back with the data we need”

One Example of Our Focus on the Process Rather Than The Product

• Reviewers should estimate costs of extra experiments

• Academic editors should play a larger role and determine if studies will add to scientific value

• “Yes or No”..is this work of value?

Nature April, 2011

Can Our Academic Work Be Reliably Reproduced?

• Industry has to reproduce academic data before launching a program– My colleagues in Industry

tell me that preclinical studies from academia cannot be reproduced >50% of the time

The Fix for “Lapses” in Integrity

• Trainee’s careers should depend more on the mentor’s recommendation and less on high impact publications

• Journals must allow publication of “imperfect stories” as cancer rarely presents as a perfect story

• More credit should be given to teaching and mentoring– It is not just about grants and publications– We must succeed at multiple levels in academia

• Educate basic scientists on the reality of cancer– Have them attend tumor boards and clinics!

• Or at least have lunch in the lobby of the cancer center……• There must be more transparent opportunities for reporting

unethical behavior– Whistle-blowers (trainees) must be protected

Barriers to Progress(And Potential Solutions)

• The Obvious• Integrity• The “System” and The Lack of a Sense

of Urgency

Our System....(with a few exceptions)

• Is cumbersome and slow– A recent shift towards overemphasizing compliance

regulations that go beyond the issues of patient safety and confidentiality

• Does not encourage taking risks with innovative translational research and clinical trials – More on this later

• Is too focused on process and not focused enough on productivity (real advances)

To Administrators, Compliance Officers and Lawyers

• Make the effort to facilitate research rather than search for trivial issues that delay or obstruct the process– If our patients are safe, and our animal studies are

ethical, limit the “hoops” we have to jump through to do our work

• Accelerate approval of contracts, MTAs, IP issues– “the enemy is cancer, not each other”– Can Universities and Cancer Centers develop a common

template?• Let us do what we are here to do, rather than

spend our time on paperwork and trivial items

Grants• Reviews Take Too Long/Funding Takes Too Long

– By the time the grant is approved and funding is available for the work, 18-24 months have passed

• Reviewers are told to evaluate grants, but not to tell grantees how to do it better

• Why not?• Writing grants takes too long and keeps us from doing the

actual research– The ideas in the grant are what counts, not the accessory paperwork

(layman’s abstract, protocol approvals, etc)– Delay the submission of all accessory information until the funding decision is

made (expand the “Just in Time” program)

Write a grant due for Feb deadline

4 months

Study section meets

4 months later

Council meets2-3 months later and

pink sheets sentRepeat Process

The Fix for Our Grants System• The Fix

– Speed up reviews…...money talks• Cancer Prevention and Research Institute of Texas (CPRIT) pays

reviewers $2,000/day for a 2 day study section…and they attract outstanding reviewers

– Use a “Line Item Veto” and immediately fund the best aims/sections of grants, and don’t fund the less exciting aims• Quicker funding in exchange for lesser amounts of funding

– But MORE grants can be funded• We must provide good pay for the highly qualified grants

administrators who are comfortable and qualified to take on this increased work load

– Take the best projects from rejected P-01 and SPOREs and fund them independently and immediately

The “System” Does Not Reward Innovation or Boldness

• We lack the ability/courage to fund high risk/high impact laboratory and clinical studies– This is risky for young academic

investigators, but these are exactly the people who should be doing these studies and trials

– Too many “me too” drugs and “me too” trials with limited or marginal expectations

• It is not just about p values!– We need to train more Physician-

Scientists and we must provide the infrastructure for them to succeed

Science May 27, 2011

Lastly…..Our Loss of a Sense of Urgency

It takes too long to do….. everything!!

• Write grants and protocols

• Peer review of grants and protocols

• Company approval of protocols

• MTAs• IP issues (and fights)

• IRB approvals• Initiation of clinical

trials• Acquisition of

tissues for translational studies

In the time it takes to…Research Goal Time to

AccomplishNumber of people in

US who died of cancer during this

time periodSubmit a grant, revise it, get it funded, and activate funding

18 months 486,000

Submit a grant and publish first important results

36 months 972,000

Activate a Phase III clinical trial 600 days (max)

540,000

FDA approval of new drug application (NDA) (fda.gov)

10 months 270,000

In the US, 900 people die each day of cancer

We must do everything possible to accelerate all processes!!

The Overall Fix• All of these fixes require financial support and a change in

the “system”…we must renew our sense of urgency– Increase payment to Scientific Review Officers as they will need to

be more autonomous, and we must attract the best people for these important jobs

• Yes, this is tough……But, if we are to make advances in cancer therapy, EVERYONE needs to step up to the plate– NIH/NCI/DOD, etc– Journals and editors– Investigators and Universities– Congress and taxpayers

• After all, we are battling cancer, this is not a “game”– Let’s get serious about this

If We Are Not Satisfied With Current Outcomes, We Must Provide Suggestions on Moving Forward

“If you are not part of the solution, you are part of the problem”

Eldridge Cleaver

Credit Should be Given To:• NIH/CSR for shortening grants and grant reviews• NCI response to Institute of Medicine Recommendations

(ASCO Post, May 15, 2011) • Those who fund true innovation in the lab and the clinic• CTEP/Cooperative groups for shortening deadlines• The DOD (and other agencies) for providing suggestions

on how to improve studies in funded grants• Institutes/Universities who recognize a scientist’s value

that goes beyond a high impact publication

Thank you for your attention!

Now…let’s get moving!

Thanks to Chuck Blanke for reviewing these slides and for leading the ASCO Education Committee, 2011

Preclinical Findings Can Be MisleadingInterpretation of Results

2 4 6 815

20

25

30

35

40

45

Time (weeks)

Tum

or s

ize

(vol

ume)

• Basic Scientist interpretation– Inhibition of tumor

Growth (success)• Medical

Oncologist interpretation– Progressive

disease (failure)

Control Arm

Experimental Arm