This blog post was prompted by a presentation in a webinar on product characterization for cell-based therapy. I was particularly interested having just launched our online, on demand practitioner’s course Science-Based Banking and Testing for Cellular Therapies.

It was a rather nice presentation on regulatory issues for cell-based therapies, until the very last slide where the presenter veered from his regulatory focus to conclude with advice on cell therapy development. The trouble was that the slide contained at least three of the biggest strategic mistakes one can make in developing a cell-based therapy — all on that one final slide. Danger was staring me in the face. I wanted to yell “Shark!” I then realized that there is a problem in simply repackaging a regulatory perspective as development advice.

Successful life science development is 80-90% execution. If we approach it correctly and make good decisions, we’re going to give a technology its best shot. But good execution is hard and sometimes , dangerous strategy isn’t that obvious. So to help save the lives of a few cell therapies along with the livelihoods of a few cell therapists I’m posting a few danger signs.

Danger 1. Mistaking stem cell therapy for something deserving of special consideration. Regulators will have to allow special dispensations for stem cell therapies because, well, they are just so special.

Certainly. there will be a balance of risk and reward, but that will only get us so far. Many think the issues of safety in cell therapy are fairly new even though cell-based therapy has been around for over 20 years now, 17 years as FDA-approved products. The issues surrounding the use of stem cells are the same today as they were from day one. To bring this into sharp focus, imagine someone coming at you with a syringe full of unknown cells, determined to inject them into your abdomen. What would you want to know before you released your grip on their gloved hand? While we might be more worried depending on the source, our fundamenal concerns would be the same: “What do you have in that syringe? Where will the cells go? What could it do to me? Is it safe? ” The issues are the same, no matter where we start from and they are pretty straightforward.

Danger 2. Mistaking copious data for meaningful data. The dynamic biological nature of living cell-based therapies means that they cannot be fully characterized but we will deliver copious amounts of “characterization” data with our submission to show we know a heck of a lot about our cells.

The inability to fully characterize may be true in the literal sense but not in the practical sense, i.e., common sense. We can and must characterize what our therapy is and why it is what it is. Failure to do less can end in, well, failure. But this does not mean running every ‘omics screen under the sun, in fact, quite the opposite. The goal is elegant use of technology with well-targeted, highly relevant testing. It is possible to characterize and develop a perfectly safe and highly effective cell therapy without ever gazing at a chip. New technology is great, but it doesn’t get us off the hook of having to use it wisely. Even if we could characterize everything down to the last atom, we don’t have to. We just need to know what counts. We’ll also impress the regulators with our informed approach, which can’t be bad.

Dangers 3 and 4. We won’t invest too much effort on preclinical data. Our product definition will develop over multiple clinical trials because clinical trials are necessary to elucidate relevant biological function of our therapeutic.

Not really. Product definition develops with preclinical data. The product and the hypothesis as to its action should be defined well enough by the time we enter the clinic, to justify why the therapeutic is what it is. “Advancing” with less could be a financially lethal waste of time and money. Learning more about our therapeutic, refining and adding tests to further support safety or assure quality are not the same things as defining the product. The development advantage of cell therapy is that it is possible to support a rhyme and reason for its use, before we enter the clinic. Anything less is risk that can be avoided.

Many changes in the process will result in a biologically different product and we could be back to Phase I. ‘Do not pass go, do not collect $200.’ Expecting the clinical data, particularly small trials, to tell us the direction to go will leave us adrift . Preclinical data is the sextant that will get us to within site of land.

While there is always potential to learn something new about the activity of the therapy during human testing, preclinical bench and animal testing are the principle ways we’ll illuminate the biological function of our therapy. That function is what is then optimized and tested in the clinic for its potency. This faulty strategy may seem legitimized by examples of drugs or therapeutics that are effective without us really understanding how they work. However, this is an outdated pharmaceutical strategy doesn’t apply to cell-based therapy, where we can establish biological connectivity between the therapeutic and the disease process. That is one of the beauties of cell-based therapy and it is a shame not to use it.

Danger 5. Thinking our options will remain open. Clinical trials won’t change our ability to do additional product and process development.

Once a therapeutic enters the clinic changes become exponentially more difficult. Resources will be eaten up by the clinical effort and there will be increasing pressure to advance what we have. How many times have we read a press release on layoffs explaining that the company is downsizing R&D to focus on the clinical effort?

Danger 6. Being overly focused on regulatory goals at the expense of the medical and commercial goals for the therapeutic. The main goal is to get a product approved.

Satisfying regulatory concerns is certainly a goal but it isn’t the primary objective. The objective is to produce an effective, valuable product. It is always important for us to remember that the regulators do not really judge whether our product is worth the asking price and commercially viable for our business.

If you’re interested in taking our practitioners course, click here.

In an excellent post, the IN VIVO blog recently wrote that the 2010 BIO convention continued its ‘self-congratulatory’ tradition with little discussion on how the industry could better ensure they delivered something of value to patients — the number one risk for life science in the coming decade. We share their frustration and concern.

Not to pick on Dendreon any more than we have already, IN VIVO used Provenge® to illustrate BIO’s persistent focus on innovation for its own sake with little attention paid to the cost/benefit of biotech’s efforts. (It might be of interest to some that , BIO’s Chairman, Dr. Steve Sherwin, is the former CEO of Cell Genesys, a long-lived but product-less biotech company that was brought to its knees with the clinical failure its cellular immunotherapy GVAX for prostate cancer, now pursued by BioSante for other cancers.)

If there is a reluctance to discuss the value and cost effectiveness of a breakthrough product about to enter the market, we can bet that reluctance holds for other products currently in clinical trials. While it may be too late for advanced efforts to look under the rock and substantially improve their fate, newer efforts have a substantial opportunity to do better at delivering value, and they probably don’t have a choice.

The UK’s NICE commissioned a report on innovation last year, frustrated that they did not have more innovative, read effective, products to spend their limited healthcare dollars on. The cost effectiveness of a product, even novel ones, is increasingly challenged.

Unless you had patent issues to overcome, innovation for its own sake has never been the goal, it’s about producing something in a better way, delivering something better, of greater value to the patient. So should we care more that Provenge® is the first cell-based cancer vaccine or should we care more that it may extend the life of patient with advanced prostate cancer about 4 months? We know what the patient would say, and to IN VIVO’s point, that is who counts.

Does the progress of Provenge® signal a potential breakthrough for this beleaguered segment of biotech? Yes, but only if the products are worth it. If Provenge doesn’t perform in the market due to performance or production limitations, rather than basking in the glow, Dendreon’s reality could cast a shadow on other efforts, even the good ones. From a cell therapy perspective, to our knowledge no autologous therapy has yet made a profit. Granted. at $93K per treatment the likelihood is that it will, but will they be able to produce enough and will it be enough to satisfy expectations and justify the cost of development? In the future, costs and the sophistication and refinement of innovative processes will become increasingly important for commercial success as payers will judge acceptable costs based on the value a therapy delivers. Value will be a key factor in developing accurate market and financial projections.

To delve into the finer points of cell therapy development that will become increasingly vital to value, we invite fellow cell therapy practitioners to consider participating in our online course and tutorial: Science-Based Cell Banking and Testing for Cellular Therapies which begins, on demand, June 1st. You can find out more on our website: www.parenteaubc.com or by clicking here.

Lots of journalists, financial pundits and cancer experts are weighing in the on commercial potential of Provenge® and Dendreon’s future. Much of the media has hailed Provenge® as a blockbuster that will catapult Dendreon into the big leagues of biotech. But as a died-in-the-wool developer turned consultant, I look at the latest life science developments a little differently, often from the perspective of commercial competition. What will it take for Provenge® to really succeed commercially? If I were Dendreon, what would I be happy about or be worried about? If I were the competition, what would I worry about, be glad about?

If I were Dendreon, I would be proud to bring the first cell-based vaccine to the market. I would be happy that the clinical trial demonstrated enough benefit to gain approval and that it would now be able to help men with advanced prostate cancer. I would anxiously be looking forward to revenues. But I would worry about net profit and meeting expectations now that the honeymoon period is at an end. The $93K price tag telegraphs more than just confidence in the value of the product…

I would be worried about ramping up production. Personalized (autologous) therapies are costly in part because they can be labor-intensive with limited economy of scale. It is not a monoclonal antibody. The process requires harvesting cells from a blood sample, expanding those cells, maturing them into functional immune cells and sensitizing them to the antigen target and finally returning them to the patient so they can present the antigen to T cells and activate an immune response to that antigen — for each patient. This is no small task, particularly when you consider QA/QC for a regulated product. I would be concerned that margins would be lower than anticipated. (To learn more about cancer immunuotherapies and their development click here for a free ebook on the subject.)

I would worry whether clinical effectiveness would be enough to convince the average oncologist to use it repeatedly. I would be concerned that risk of stroke and modest survival benefit might lead some oncologists to pass on it for asymptomatic patients (the population Provenge is approved for). I would worry about not knowing how Provenge really worked since it doesn’t appear to actually kill the cancer cells (which is the primary purpose of a vaccine) or reduce PSA levels — measures both the clinician and patient rely upon to tell whether a therapy is doing something.

I would be concerned that payers would judge the price that I needed to meet financial projections based on real-life margins and patient numbers, just too darn high. There is a real concern that the rise in the number of $10K/month biologics to treat cancer (for modest survival benefit) is already severely straining the system.

And I would be concerned about the market lifecycle for Provenge® and the looming competition. M.D. Becker Partners has counted nine product candidates in clinical trials for prostate cancer.

Now, if I were the competition… I would be grateful to Dendreon for establishing precedent. I would be confident that if my cancer vaccine can actually target and kill prostate cancer cells, without major collateral damage, that it will deliver a superior clinical result. And if I weren’t developing a personalized cell-based vaccine, I would feel pretty confident about being able to deliver the drug at an acceptable cost, with better margins.

So now we should have some pretty motivated people both at Dendreon and elsewhere, all stoked by the challenge the Provenge approval has created. Dendreon’s real test is ahead of them. They now have to make money.

In the end, I hope the real winners in all these efforts will be the men with advanced prostate cancer.

Search the internet for regulatory consultants that know their way around FDA or EMEA regulations, documentation, proper forms, and jargon and you’re likely to turn up some great people, many of whom are former regulators. They’ll help you get your ducks in a row, submit a document that is accepted more often than not, and alert you to the standard must-have information. Very few pre-market biotech companies go through this process without the help of these experts.  Look on the FDA website and you’ll find a list of guidance documents that will lay out the basics of what is needed for your biologic, cell therapy, gene therapy..

What regulatory rules, regulations and guidelines don’t tell us is how to develop and validate the safety of the product to meet them. Successful development of novel biotechnology is not a check the boxes type of effort. It involves innovative ways to test intermediates, demonstrate bioequivalence or biological activity, quality and more. If you expect regulators to tell you what to do, or what is best for a novel biotechnology product, you will be sorely disappointed both in the length of time and the end result.

Not clear on what “they” want? Don’t throw the kitchen sink at them expecting the answers they seek to jump off the pages. The answers won’t, and you’ll have just demonstrated your lack of clarity to the reviewer — not a good thing if you can avoid it. If you don’t know what information is most relevant to the safety of your product, who does? If you haven’t used your intimacy with the product and process to ask yourself the right questions, the answers might not even be in those 50 volumes of data you just delivered.

In novel technology many “problems” will be without precedent (I know, regulators love precedent), you may be the first. Good! You can set the bar, make your case as you know best. That is where innovative thinking will be of great value. It is where thinking beyond the checkbox is key. Don’t be afraid to make a case to the FDA. Good science is good science and the FDA appreciates it, as well as your effort to best support your process and product. Really, they do.

The need for innovative thinking goes for company regulatory staff and consultants as well. Dogmatic, rigid thinking in this area can be very demoralizing, expensive, unproductive and downright poisonous. Sure, you can’t go to the clinic or make it to the market being rule averse cowboys, the requirements are there for a good reason. Fulfill the reason, and you’ve met the requirement. Rather than the wild west, maybe the better metaphor is thinking of it as conquering space; being brave, skilled and smart enough to ‘go where no man has gone before.’ Ta da, da dada da da…

Beginning June 1st, we’ll be covering how to advance novel cell -based therapies with just this sort of beyond the check box thinking in our online, on demand course: Science-Based Banking and Testing for Cellular Therapies. You can find out more about it here: http://bit.ly/cdNGsL. If you’re working in the stem cell or tissue engineering space, we hope you’ll beam up.

On her Pharma Strategy Blog, oncology drug expert Sally Church reflects on her experience bringing Gleevec® to market and offers a video presentation by Dr. Susan Desmond-Hellmann, former Genentech product development star on her experiences in bringing innovative science to market (link to post and video). An example is the development of anti-VEGF (Avastin). Church ponders why successful translation takes so long.

It not only sparked memories, but got me thinking of my own experience in developing graftskin (Aligraf ®) at Organogenesis and wondering if there is some common ground within the different experiences and backgrounds in how any science is translated into medicine.

I remember two Genentech scientists (one may have very well been Ferrara), working on VEGF visiting our Cambridge start-up in 1987. The medical use of a growth factor was fascinating and ripe with potential, even though Avastin® was still only a glimmer. I wondered how we might use it for what is now called regenerative medicine.  Having cut my scientific teeth on monoclonal antibody technology in its earliest days, I was also awed by colleagues’ ideas of using them to target cancer. I remember talks of a melanoma therapy not long after hybridoma technology was discovered in 1977.

At the start-up, I was charged with developing the concept of a living skin equivalent, a vision of MIT professor Eugene Bell, into a product. It would require long hours, innovation, dedicated, talented people who believed it was possible,and smart use of science both in therapeutic design and the clinic.

Ironically, the science most helpful to us was not that of Bell, but that of Howard Green, a rival of Bell while at MIT. Without that base of strong basic science and clinical vision from Green and his academic offspring (which I count myself as via my post-doctoral training with Bob Rice), I doubt the skin equivalent would have made it to becoming Apligraf (Organogenesis), both the first living cell and tissue engineering therapy approved by the FDA in 1998 — at least not in the time frame it did.

But there appears to be more to translation than time, the availability of information or even the existence of an example, as we are still waiting for encores from the regenerative medicine field 12 years later. I am still on a constant quest to better understand and explain it.

Why was Genentech successful in translating Folkman’s anti-angiogenesis concept when Entremed was not? What was the difference? The video by Desmond-Hellmann offers some of her considerable insight into successful translation.