Timeline And Developmental Activities When Resources Are Limited

By Dave Casebier, principal, DSC Consulting LLC

It is increasingly rare that early-stage compounds or platform technologies are acquired without demonstration of clinical effect. Many years ago you could get funding for an idea, a piece of data, or a novel platform. With little exaggeration, funding could be generally raised as long as there was promise and the ability to tell a story, or until the concept was fully disproven. A new enzyme-based target, or even a quasi-crystalline idea, was sufficient for seed funding, and Phase 1 compounds were thought to be solid investments or acquisition targets.

Today, with translational/personalized/biomarker- driven medicine, we are in a much different environment. Nowadays, typical funding and investments are made in tranches and based on milestone events, so small biopharmaceuticals, with nominal funding for proof of concept and less chance of asset monetization (e.g., IPO, acquisition, large pharma partnership/licensing), find themselves with minimal budgets to get to IND (investigational new drug)-enabling studies or IND filing and possibly beyond a Phase 1 clinical trial. At the same time, given the pressures to be first to market, time is more a factor than ever in the making of critical decisions.

Outsourcing partners play an increasingly key role, but biotechs and other small companies may only have the resources to assign one or two people to work with the CDMO or manage the CDMO. Many of the activities that must be outsourced are nonnegotiable, meaning required for compound development, yet the implementation and administration can vary widely. Below I’d like to offer some reminders and a bit of advice to startups — or any drug developer — about what to expect and how to plan for what’s not expected in the process of advancing new drugs.

LIMITED RESOURCES IN A DEMANDING BUSINESS
We’ll start with the often-used saying of “fast, cheap, or good: you can only pick two.” Perhaps this is especially true for smaller companies. In other words, the intersection of fast and cheap precludes a good product. Obtaining a high-quality product on a reasonable budget is generally time-consuming, but for a resource-limited company, time is money. On the other hand, creating a quality product quickly generally requires, shall we say, pallets of cash.

First, here are a couple of comments on “cheap.” With limited resources (e.g., money and headcount), trying to advance as inexpensively as possible is a given. The life sciences industry is far from cheap, but there are activities that are at least flexible. The best descriptor of this might be the concept of phase-appropriate development, and spending only as the program progresses, throttling immediate spend, but achieving milestones that trigger subsequent funding.

Second, let’s look at “fast.” Time is money, especially in the sense that a small company generally has fixed costs that mount on a month-by-month basis; the faster you can get to first-in-human experience, the better. However, this requires spending a great deal of that preclinical cash very rapidly, generally in a six-to-10-month time frame. A balance needs to be struck between an exhaustive comprehensive study and one that is more minimalistic, or even skeletal.

Finally, there is “good.” In the biopharmaceutical industry, good is of course not optional, but it does have varying degrees. So how do we define good? While a vague term in general, it can be parsed into several components and addressed individually. I’ll describe them here briefly as safety, manufacturing controls (quality), and clinical (and projected commercial) efficacy. Safety of course is nonnegotiable. In vitro and in vivo profiling are required by the FDA and other regulatory agencies. The holistic design of IND-enabling trials, with alternative plans for using feedback from early in-life experience, will generally save money and be faster overall than walking through the menu of initial studies sequentially.

cGMPs, while they may vary by product, process, and aspect of supply chain, have sufficient components in common as to be understandable to even the nonexpert receiving adequate training in standard operating procedures. However, quality — the result of cGMP implementation and controls — can elevate what might appear to be a straightforward production of a relatively inexpensive material into an unexpectedly costly budget section. The third component, clinical efficacy, may be indicated by preclinical studies, but is really definitively proven in Phase 3 trials. The end result is very difficult to anticipate or accommodate in almost any environment, let alone the resource-limited one we are focusing on.

DIVIDE (TASKS) AND CONQUER?
Henry Ford famously said that nothing is particularly hard if you divide it into small jobs. Investors and senior management at startups might agree, and they will add that they like to see a sense of urgency to get projects moving. However, I know from experience that a holistic plan will better assist both the operational and administrative stakeholders.

I’d advise creating the entire list of activities — as far as you can identify them — from in vitro testing and solubility profiling to canine/primate repeat dosing, even nationalization of patents. Since many or all of these activities are outsourced, the complete landscape can allow for coordinating, scheduling, and budgeting more efficiently. Particularly, (1) create each study, or set of common-purpose studies, as an individual unit (e.g., Ames, micronucleus, and caco-2; receptor binding/ inhibition panels; physico-chemical studies and preformulation), then build these out with dependencies and timing, with best estimates for expense; and (2) place more flexible activities in gaps that typically occur in development (repeat dosing studies or report generation from service providers). Once these are interlocked, the budgeting becomes significantly easier to project. I like to clearly identify activities that are flexible but still must be completed by certain filing, publication, presentation, or commercialization target dates. These hard-target dates need to be monitored in order to prevent a seemingly small developmental activity from delaying the advancement of an entire program.

A major advantage of an integrated plan is the coordination of internal and external studies and activities. If external study plans are synthesized with internal activities, the resulting plan can eliminate material shortages and at the same time help avoid redundant activities and expenses (not to mention maximizing safety and data acquisition). These plans may also help project needs for subsequent manufacturing and supply demands, something every contract manufacturing organization and sponsor knows is difficult to anticipate at best.

I typically advocate starting to work with potential commercial API, drug substance, and drug product CMO partners as soon as possible. Late-stage technology transfer is much more challenging, and often more expensive overall, than selecting a partner that can provide services for process optimization into clinical trial supply and through to commercialization. Generally, if a company has helped commercialize a compound, it is also able to contribute that experience to your advancement.

MANAGING EXPECTATIONS AND MAKING CHOICES
Finally, I’d like to address the concept and great challenge of designing, performing, and particularly accepting the results of the “killer experiments.” These are the critical experiments that companies undertake and which will determine “in black and white” the viability of a program. Unfortunately, and perhaps too often, when negative results are indeed received, attempts to salvage the asset begin, thus seriously compromising the entire premise of the experiments. Everyone should be aware that while early failure of a drug saves money for the company and investors – and is, in a way, planned for – those running the business have a vested interest in keeping the program (and their positions) alive. Therefore, setting expectations, adhering to principles, and maintaining original targets are tough. It takes a good deal of discipline to face the failure of a program and shut it down rather than continue in the hope of finding a lifeline.

Even short of results that could end development, virtuals, startups, and biotechs particularly should prepare the members of their organization for the unexpected. Material can suddenly fail on stability, prompting a reformulation, limiting storage or packaging conditions, and shortening expiry. Issues may arise in scale-up that change the impurity profile enough to require a bridging safety study. A good policy is to list the potential ways that things could go wrong and provide guidance to executive management regarding their cost should those contingencies arise. Working with your partners — CROs, CDMOs, consultants — can help ameliorate negative impacts. Exact costs are almost impossible to project, but even “greater than ‘X’ and smaller than ‘Y’” can help to get folks’ attention as to the magnitude of any risk.

All stakeholders participating in a small biotech need to be in agreement as to plans, activities, timing, possible risks and remediation, and all known and potential costs. With everyone on board, have confidence in your plan and stick with it. Very few organizations have the challenge of wondering what to do with all the cash and free days on their hands. Smaller drug developers especially need to make the best of all their resources.