UC-Davis Stem Cell Ethics Conference, Part 4

So here it is, y’all– the fourth installment! This is the LAST “notes from raw slides” section, SO please keep hanging in there… because this is important. Reading these notes may not the most entertaining activity on earth; believe me, I know. (I had to transcribe them from horrible blurry pics!) But there’s a lot to be gleaned here. If you’ve ever wondered how a drug goes from concept to market, this is one you want to read. (Just go down to Slide 9.)


Remember those old Donald Duck cartoons on the Disney Channel? Remember how Donald had a goofy Austrian uncle duck who was a scientist? I was irresistibly reminded of this when I hearD Dr. Gerhard Bauer’s speech. It was also hard not to think of the German rocket scientist who showed up to make an expert pronouncement on Santa Claus Conquers the Martians. But the content—while occasionally dry—tended to rein in the mind of the listener whenever it threatened to wander too far. There were some startling nuggets of information, such a list of the entire slate of stem cell apps in the pipeline at UC-Davis at that very moment, as well as a succinct summary of the FDA approval process up to the Phase I trials.


Cellular and gene therapy product manufacturing for novel clinical applications:

Is tight regulatory oversight wanted or needed?

Gerhard Bauer

Associate professor, Internal Medicine

Director, UC-Davis GMP facility.


Picture of patients in hospital beds

Caption:Cutting edge treatments are available! Let’s get them now!


The History

In 1901, diphtheria patients were routinely treated with antitoxin derived from the blood serum of horses. There were no central or uniform controls in place and the antitoxin was often manufactured in local plants.

In St. Louis, Missouri, that combination had tragic consequences. Thirteen children died of tetanus after being treated with diphtheria antitoxin made from the blood of tetanus-infected, retired, milk wagon horse named Jim.


Downside of Unregulated Clinical Research with Cellular Products

 While there is a lot of exciting stem cell research conducted by legitimate groups, there is also some very disturbing news generated by other groups

 A 2008 study in the Journal PloS Medicine documents the case of an Israeli boy who had gone to Russia to have fetal stem cells injected into his brain and spinal cord.

 He developed a brain tumor as a result of the treatment, although the tumor was slow-growing and benign.


 Recently, authorities in Germany closed down a stem cell clinic called the Xcell-center.

 It had operated through a loophole in the country’s regulations for unapproved experimental treatments.

 The clinic had been implicated in the death of an 18 month old boy after a stem cell treatment. A 10 year old almost died after receiving something similar.


 Picture of patient in bed and a stem cell lab. Caption:Goal: improve patient care through cutting edge research. At the same time: DO NO HARM!


 Picture slide. It goes kind of like this…Idea—basic research (picture of mouse, efficacy and toxicity testing)—translational research (lab/GMP)—MORE GMP LEADS TO—manufacturing of a safe and potent product for patient administration (GMP—clinical research—GCP)


What is Required to Safely Bring a Novel Cellular Therapy to Patients?

 GMP= Good Manufacturing Practice: a national standard for the production of pharmaceuticals that ensures safe and effective drugs (21 CFR 210, 211).

 GCP = Good Clinical Practice: an international ethical and scientific quality standard for designing, conducting, recording, and reporting trials that involve the participation of human subjects.

SLIDE NINE—important!

 Products currently manufactured in the UC-Davis GMP facility

 Bone marrow CD34 + cells (ischemic retina) under UC-Davis IND

 Mobilized peripheral blood CD34+ cells, transduced (HIV treatment)

 MSC’s, non transduced and transduced (Huntington’s disease, critical limb ischemia)—CIRM—UC-Davis Disease Team Grant

 Retinal progenitor cells from donor tissue (retinitis pigmentosa)

 Corneal cells from donor tissue (cornea repair)

 Micro-organs for drug delivery (transduced)

 Hesc derived neuronal stem cells (ALS, Huntington’s disease)

 iPSC derived, gene corrected keratinocytes (Epidermolysis Bullosa)

 AAV vector for direct injection into the brain (Tay-Sachs Disease, MPS III)

 Lentiviral vector (HIV gene therapy, critical limb ischemia and Huntington’s disease)

 Retroviral vector (cancer treatment)

 Novel drug formulations (allopregnanolone for traumatic brain injury) under UC-Davis IND

 Drugs and placebo formulations for other clinical trials


To bring such a novel, gene modified cellular product to the clinic

The following regulatory agencies have to approve

Stem Cell Research and Oversight Committee (SCRO)

NIH Recombinant DNA Advisory Committee (RAC)

Institutional Biosafety Committee (IBC)

Institutional Review Board (IRB)


Then a Phase I clinical study—a SAFETY STUDY—can be initiated.


Picture slide

‘If you really want to go ahead—follow this timeline”

0 to 16-18 months



How to Start a clinical trial involving a novel gene modified stem cell product

 Produce pre-clinical data according to Good Lab Practice (GLP

 Have everything completely documented (good lab books)

 Use cell lines that can be completely traced and are characterized

 Have detailed information on the reagants available

SLIDE THIRTEEN – important; this outlines what is needed to get to Phase I

 Suitable pre-clinical data for a Phase I Clinical Trial (a safety study) are:

 SAFETY DATA; in vitro and in vivo (relevant animal model)

 EFFICACY DATA: in vitro and in vivo (relevant animal model)

 The product should be safe and should be able to produce therapeutic results that will translate into human studies

 When it’s time to write an IND (investigational new drug) application, put all the hierarchy for the clinical study in place.

 You need to consider GCP and GMP

 Define the endpoints of the clinical study and the timeframe of clinical followup.

 Followup for gene therapy clinical trials is 15 years.


 REQUEST a pre-IND meeting with the FDA

 Submit a short writeup of the planned IND, and discuss it with the panel of FDA regulators

 Submit the IND to the FDA.

 If you don’t hear back within four weeks, you are automatically approved. However, this is VERY UNLIKELY. Rather, expect a phone call from the FDA right before the end of the four week period.



12 months…14 months… 16 months. Clinician increasingly buried underneath a pile of paperwork, finally waving a white flag.

16 to 18 months—FDA APPROVAL.


 Cellular manufacturing at the UC Davis GMP facility.


Large-scale “”.

Picture slide.

People in lab.

10 layer cell factory (traditional method)

Closed system hollow fiber bioreactor (modern approach)


 Large scale gene therapy vector manufacturing at the UC Davis GMP facility.

 Picture slide.

 New method developed in conjunction with Terumo.

 Less contamination prone, less user dependent

 Significant vector volume increase over 10 layer cell factories

 Significant overall increase in vector particle number

 Can possibly be run in a non-classified space

 Closed system hollow fiber bioreactor (modern approach)

Okay, tomorrow—we’re back to actual writing. 😉 Stay tuned.

Cathy Danielson
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Cathy Danielson

In 2011, my life was shattered when I was diagnosed with a mysterious, incurable disease that always ends in blindness. The only hope on the horizon was a drug that broke all barriers in early testing. This drug, which replaces damaged cells in the eye, comes from the new class of stem cell based treatments that could cure the incurable, providing hope for patients with cancer, heart failure, ALS, cerebral palsy, and many more fatal and disabling diseases.

I survived the disease, and I now have the only remission on record. But a remission is not a cure. The stem cell drug I need for a real cure is now rapidly moving towards approval in the rest of the world, but in the USA, it—and all other cellular therapies-- are still stuck behind prejudice, ignorance, and lack of funding. Hundreds of millions of desperate patients with incurable diseases need these drugs.

That’s why I’ve gone on to fight for greater public education on stem cell drugs, knowing that our laws must be changed so that all of us can get access to the best treatments instead of our health and our lives being held hostage by special interests.

I’m now a patient advocate whose work on stem cells and patients’ rights has been published in outlets such as the Oregonian. I am a manager at popular science and financial blog www.stemcellinvestor.com and a frequent speaker at many venues across the spectrum, including churches, scientific conferences, and atheist groups, and everything in between. I’m also an advocate for Right to Try laws that would allow access to experimental medication for terminal patients at the state level. Read the entire story in my upcoming book, And the Blind Shall See: A Skeptic Patient Surprised by Faith, Science, Family, and Miracle Cures.
Cathy Danielson
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