Part 5 in Cell Therapy Industry 2027 series
A short time ago, I had the immense pleasure of driving through the Napa Valley bathed in a warm pastel sunset. The view was accompanied by a two-chord soundtrack: the reassuring chinking of several bottles of the region’s finest and an American radio show discussing scientific research funding. A perfect Sunday afternoon for an oenophile with a passion for life science translation? Sadly not.
Besides the unreasonably low speed limit, there was a far more pressing issue with impacts extending far beyond my idyllic Sunday afternoon. The interviewee believed the number of patents published to be an appropriate proxy for the societal impact of biomedical research. In reality, such an analysis is tantamount to ascribing a linear relationship between the number of tennis racquets in a player’s bag and the likelihood of winning the game ahead. And then it dawned on me: is the cell therapy industry actually committing the same statistical faux pas, but with respect to its use of clinical trials?
A broken equation
True or false: the number of cell therapy clinical trials today is an accurate indicator of the number of regulatory approved cell therapy products tomorrow?
In order for this statement to be valid, there would need to be a linear relationship between the frequency of cell therapy clinical trial commencement and cell therapy clinical trial success (regulatory approval). This simply is not the case.
1. Clinical Trial Attrition Rates
Attrition describes the proportion of clinical studies that do not progress between phases; for example, from phase one to phase two or, most critically, phase three to marketing authorization. In other words, a proxy for trial ‘failure rates.’
A trial may fail for a number of reasons, including insufficient patient recruitment, a lack of funding and/or limitations in the critical quality attributes of products – safety, potency and efficacy. The exact ‘modality of trial failure’ is an important consideration when predicting industry growth, as issues independent of the technology, such as the availability of risk capital, are often more easily remedied than inherent limitations in the therapeutic technologies.
(It is important that in time, when there is a sufficient body of historic data, that a systematic review is undertaken of cell therapy clinical trials in order to ascertain whether attrition rates for cell therapy trials are fundamentally different to conventional trials and, if so, evaluate the source of any such differences through statistically valid meta-analyses. Editor’s note: For those interested in this topic, it was touched on by two speakers at the 2012 Till & McCulloch Meeting. See summaries here and here.)
2. A ‘Combinational Challenge’
A large number of cell therapy clinical trials will be for ‘combinational products,’ for example, a cellular medicinal product plus a device and/or scaffold. Therefore, the regulatory scope is extended to encompass numerous components of the product and numerous regulators, thereby increasing regulatory uncertainty and risk(s) and the interdependency of numerous regulatory paths for a single product.
3. Defining a Cell Therapy Clinical Trial
Finally, what is a cell therapy clinical trial? This is an important consideration when defining the scope of any review of on-going and historical trials. In principle I am a proponent of considering multiple technological modalities within the ambit of cellular therapies – including gene therapies – but it is highly unlikely – I’m even willing to go out on a limb and say impossible – that such technological heterogeneity is likely to support homogeneity in clinical trial outcomes.
For example, efficacy is a relative metric; therefore, in some circumstances where a product’s on label indication offers significant unmet medical needs, even marginal efficacy will appear to be significant versus a comparator representing the existing standard of care or lack thereof. And let’s not forget long-standing items in the regulatory ‘Pandora’s box’ including what exactly constitutes a transplant versus an advanced medicinal product and what is permissible as a point-of-care device.
Indicative does not equal representative
Truth, like gold, is to be obtained not by its growth, but by washing away from it all that is not gold. –Leo Tolstoy
To conclude, increasing numbers of cell therapy clinical trials worldwide is a welcome step towards the Cell Therapy Industry 2027. However, to use a mechanics analogy, industry success is very much a vector quantity – having both magnitude (number of clinical trials) and direction (positive trial outcomes). Subsequently, failing to evaluate the utility of clinical trial growth in the context of the likelihood of historic trial outcomes is short-sighted.
Clinical trial growth, when appropriately presented, can be a valid metric for industry growth; but it is not a perfect representative proxy. And all members of the growing cell therapy industry must remain mindful of this when portraying the industry to stakeholders.
A useful aide-memoire, inspired by the financial sector, may be the familiar: “historic performance may not be an accurate indicator of future performance!” Just as there is a low fidelity in the translation pathway from scientific innovation to ‘first in man’ clinical trials, there is a low fidelity in the translation pathway between clinical trial and broad patient access which, after all, is what we’re aiming for.
To close as we began, the origin of the Napa Valley’s fame or fine wines isn’t solely the result of the large number of vines planted by its vintners; it is more a reflection of the art of the wine making process: how harvested wines are processed and blended and the terroir of the lands(s) from which the vines were harvested.
Therefore, the cell therapy industry should not focus solely on the growth of registered clinical trials, more important is the manner in which clinical trials, and the translatory ecosystem in which they are conducted, are managed. Only in this way will the industry ensure that cell therapy clinical trials registered in 2013 support a good vintage of products in 2027!
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