Mini-Clini's

Mini clini’s are, as the name implies, small clinical trials. These are clinical trials of 6-10 patients at pharmacologically active doses. They are stand-alone: you cannot perform meta-analysis across these studies. Each study may have distinct protocols, patient types or even drugs. Most studies will have a separate owner within the sponsoring pharmaceutical company. Owners can come from any research, clinical or commercial department [Figure 1].

Many short arrows all pointing in similar direction, representing mini-clini's 

Figure 1. Illustration of the Mini-Clini Concept. Diagram illustrates the concept of clinical trials as smaller, numerous and designed to be directional rather than definitive. We would expect to see a few outliers (results contrary to the overall direction) but we are neither overly worried about these results nor do we ignore their implications.

Mini clini’s use early human clinical trial results to set the direction for research. They use human clinical outcomes to guide the selection and design of high-volume research activities (e.g., in-vitro, in-vivo, and ex-vivo). We use mini clini's, for example, to guide selection of the most appropriate animal models.

Mini clini’s are directional not definitive. No one trial is make-or-break in the overall chain of evidence. The intent is to develop a body of clinical trials across technical disciplines that collectively points in the direction of success. In the end we don’t add up the mini clini’s; we do look across them subjectively to get a sense of the overall direction.

Mini clini’s allow human trial results to be a common touchstone across all the disciplines in R&D. We run hundreds of mini clini’s simultaneously, trying out (intelligently) many different drugs on many types of patients for many indications. We build a constellation of patient types and disease indications that makes our drug commercially viable.

APPLICABILITY OF MINI CLINI’S

Mini clini as an approach is best suited for research where not too many avenues of inquiry have prematurely been shut down. We seek simultaneous optimization across the molecule, safety, surrogate measures, disease indications, and other dimensions.

We’re looking for interocular+ results: results that hit you between the eyes. If we have to use complicated statistics to tease out results, then mini clini’s are too unwieldy. The noise from running small clinical trials will swamp any signals+ of the benefits. Mini clini’s are perhaps of limited use for me-too+ drugs.

When we seek innovative drugs in a competitive market we need to be far out in front of the published science. We must go beyond the facts. Laboratory tests and animal models have yet to be established. Surrogate measures are still open to definition. The FDA is learning, along with the industry, what constitutes relevant evidence for drugs in this area. These pursuits are the natural home for mini clini’s.

BENEFITS OF MINI CLINI’S

The primary benefit of mini clini’s is they ensure everyone is working on the right pursuit. We simultaneously select the drug molecule, the surrogate measure, the target patient population, etc. to give us the best shot at a successful drug. Innovative drugs often end up far a field from their intended use (e.g., Viagra) and mini clini’s allow us to adjust the pursuit based on trial results, always with an eye on the commercial goal.

From a behavioral standpoint, mini clini’s greatly lower the barrier to decision-making (they’re ‘bite-sized’). Researches routinely kick off human clinical trials as integral to their evidence claims, with much lower consequences for getting them wrong. We agonize less over the decision whether to run a trial or not, and spend more time reviewing data from completed clinical trials.

‘The great game’ of FDA approval is largely based on numerical association from pivotal trials. Good products can suffer when the numbers go bad. Mini clini’s give us a much clearer understanding of the variables underlying the numbers. To use a baseball analogy, we know which patients constitute a ‘home run’ (i.e., miracle drug) and which a single (i.e., just as good as currently-available therapies). We get better at playing the game by scheduling our batting line-up to give us the best chance of approval. We become better at defending against common co-morbidities because we’ve run mini clini’s that excuse our drug.

DEVELOPMENT CHANGES WITH MINI CLINI’S

Table 1. Cursory Listing of Challenges Facing a Mini-Clini Approach. Table lists the major variables to be considered when running a clinical trial and discusses the impact of a mini-clini approach on those variables.
Mini clini is a keystone initiative. In order for it work we have to collapse existing practices in today’s R&D and rebuild them using mini clini’s as the keystone. Table 1 lists many of the development challenges.. The challenge of mini clini becomes most stark when we talk about using them to optimize drug molecules. We try a molecule in patients to see if it works. If not, then try a different one. Visions of the next TeGenero+ or Fialuridine (FIAU) go whirling through our collective minds.

CHANGING THE CLINICAL MINDSET

Imagine finding what you consider to be a blockbuster+ drug using the mini clini approach only to be told you need to go back and redo the evidence using a traditional approach (e.g., Phase II pivotal trials). Your boss has retired in place+ (RIP) and doesn’t have the inclination to think beyond his accustomed cheap heuristics+. What if the numbers go against us in the Phase III pivotal trials and we haven’t done Phase II pivotal trials. He justifies the decision by expediency or convention.

Figure 2. The Amoeba Diagram

The amoeba diagram [Figure 2] illustrates what could be the most important concept in our discussion of mini clini’s: that we often restrict ourselves to within artificial boundaries. It suggests a game plan for mini clini’s. We define the compulsories+ [Figure 3]. How would we expect researchers and managers to demonstrate enough responsibility (e.g., deep concern for patient safety) to allow them to pursue a mini clini approach in their work? How do we qualify individuals who are no longer subject (or are only conditionally subject) to the artificial boundaries?

Regulators see the good, the bad and the ugly. They set artificial boundaries, the regulations, as tight as possible. Any crisis occasions a public hue and cry for more rules, and those who write the rules often pen them having in mind the worst possible offender. We all become artificially constrained by this new rule, even if the original crisis is far removed from our current situation.


Figure 3. The Compulsories

We want room to maneuver beyond the conventions, which suggests the following paths forward:

  • A ‘master of mini clini’ certification which provides its holder a kitchen-pass to pursue a mini clini approach
  • A transition+ to the mini clini approach, using fast-path to get to the IND with backfilling of earlier evidence claims using mini clini’s
  • Selective use of existing molecular entities to test claims prior to the IND

Also, much can be borrowed from today’s approaches in Oncology. But many more challenges and opportunities remain to be uncovered. Just get started.

I can’t just include the quantitative results from my experiments in the shared database. People will misinterpret the raw data without the contextual insights I gathered during the course of the experiment. Only I knew which rats were naturally calm or naturally aggressive, something that the raw data just doesn’t show. Only I knew when a normally dominate and active rat was just having a bad day, even without the treatment. I can share the results of my study, but I refuse to share the data because others will just use it out of context. Pharmaceutical Industry Client (2005). Personal Communication


It’s discouraging how often I hear the comment: “we’ve tried that and it didn’t work.” I rarely hear the postscript: “…but then we tried this and it worked.”  The pharmaceutical industry cannot stay with the status quo. You may find mini clini’s impractical and perhaps odd if you look at them through the lens of today’s overly cautious R&D practices. For mini clini’s to succeed, as illustrated above with the RIP boss, the overall R&D governance model must change. Uses of quantitative approaches in Early R&D will be greatly restricted.

You can look at these as challenges but the need for change in the industry should perhaps make them look more like opportunities.

wcrdadmin
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Joined: 01/20/2010
Does this mean an end to the phrase Pre-clinical in Pharma?

Yep. Clinical starts right back at the beginning in basic research.