March 12, 2018 – You know what you want your study to look like.  You have probably done your homework and know what your competitors have tried, what the regulators are expecting/requiring, and you’ve confirmed that you are aligned with current medical practice and any applicable treatment guidelines.  You may even have some key opinion leaders on your speed dial.  Now you want to take this concept to a full protocol, ready to be executed.  You hopefully have also decided that Lexitas Pharma Services is the best place for your study to become a reality.  It is a big step.  Congratulations!

Operationalizing a protocol is one of the most important things you can do.  When a protocol is operationalized well, it runs like clockwork, your stakeholders are happy, you reduce the impact of the inevitable bumps in the road, and you minimize the time and expense from concept to results.  And, if done well, when they study is over, you don’t have a laundry list of shoulda/woulda/coulda and instead, you have data that really answers your questions.  Whether you are from a large pharma organization or a small and nimble biotech, you need to have answers to your questions.

The Protocol:   The study protocol is probably the biggest key to your success.  First, it needs to be do‑able.  It also needs to be clear, directive, as concise as possible, and internally consistent…and did we mention compliant with principles of Good Clinical Practice and the International Conference of Harmonization?   The protocol needs to include assessments you determine are critical to answering your questions, but resist the urge to include the “nice to know” things.  Unnecessary assessments make your study more complex, and complexity has direct and indirect costs for everything that will follow.  Don’t make rules (example: tight study visit windows) unless they are important.  Consider holiday weekends.  Clearly define what happens in what order if it is important; however, allow flexibility if order doesn’t matter.  Collect time of assessment only if it is meaningful.  In short, be able to provide the rationale for everything you are planning to collect and think how you would use that data.  And most importantly, strike a good balance between your desire to learn everything you can about your product, and to make the protocol patient- and site-friendly.  In an NIH study, over 2/3 of subjects declined to participate in trials for which they were eligible because of “protocol issues” and “inconvenience”.

How do you know if you will have a protocol that is do-able? The burden of the study has to be worth the effort expended to participate.  For a serious, life-threatening or sight-threatening disease, prospective study participants will tolerate and agree to a great deal to participate.  If, however, the condition is not that extreme, the burden of the trial cannot really be substantially more than the burden of the condition itself.  These are factors that one must consider when designing the trial.  A good protocol should err on the side of being one in which patients can participate without totally disrupting their life. And one to which you would likely say yes, were you in their shoes.

Patients and research sites are not your only stakeholders.  Protocol stakeholders are also members of your extended team who have a vested interest in the success of your study.  Statistical input early on is essential to ensure that you are optimized for success.  How many and what kind of patients to include?  What study design is optimal to answer your questions?  What are your endpoints and what will changes in your endpoints mean in terms of statistical and clinical significance?  How will you rank/prioritize the primary and secondary analyses?  Are your assessments validated, standardized, reproducible, variable based on time of day (and how will you collect them)?  What treatments or other medical conditions are allowed and what must be excluded for safety or to avoid confounding the efficacy evaluations in your study?  When, after initiating treatment, might you expect to see a benefit?  And how will you manage the M & Ms:  Data Missingness and Multiplicity!

In addition to statistical input, allow time for review and input from your expert colleagues in manufacturing (packaging/labeling/and masking comparators [you need it when?]), regulatory, data management, clinical operations, product safety, quality, and scientific founders/executives.  If you are doing something novel and unprecedented, it is also good to get input from reliable Investigators and study coordinators too.  They will particularly help you organize your assessments into a do-able and feasible sequence of events.

A protocol cannot be made in a day….. be sure to budget your time to allow for multiple review cycles and take the time to have protocol review roundtables (at least 2). You will not be sorry.  You just might get away without a protocol amendment!

Patient Selection:  Patient selection is one of the factors in a protocol that gets the most discussion, and rightly so.  Most chronic diseases/conditions exist on a progressive continuum, and so you need to understand who you are trying to treat.  Even if your product is intended ultimately to benefit the universe of patients with this condition, studying too wide a swath of patients can be problematic.  On the other hand, studying too narrow a group may give you a good result initially, but set you up for surprises down the road when you must, of necessity, expand your patient selection to widen your indication and be referable to the larger universe of patients.  It is imperative to understand what effects your product is likely to induce, and to select a patient group that is capable of showing this change.  For example, if you are doing an ocular pain study, maybe minimal pain should be excluded (not much improvement possible).  On the other hand, too much pain might mean chronic changes that are refractory to improvement (not much improvement possible).  If you are trying to reduce pain as your primary endpoint, you need to understand your sweet spot, your “Goldilocks” patient group.  That, in a nutshell, can make the difference between a program that lives to see another study, or not….

Pay Attention to the Details:  Details matter. Overall organization of a protocol, with mindfulness about what can reasonably be done in what time frame, is important. There are only so many ophthalmic procedures that you can do 5 ± 1 minutes post-dose.   Anticipate questions that will be asked by study staff trying to comply with your protocol.  Be specific and describe what you know must be done, but consider reserving details, which are subject to change, for a supplemental Study Manual.  You can always update a Study Manual without the requirement to undergo a costly formal protocol amendment(s).  The mastery of details with aforethought saves time and money.  Moreover, it makes you look smart, avoids costly and time-consuming amendments, and instills confidence in your sites, your investigators, probably their patients, and your regulators.

Now let’s dive in!