A family member of mine had exhausted all his available options in his battle with cancer. There was one experimental drug that we believed would help him one last time, but his lab values were not high (sick) enough to meet the eligibility criteria for the trial. So, together with some incredible caregivers we made the decision to allow him to “get worse” so he could get into the trial, in order to hopefully “get better.” After allowing his condition to deteriorate he was finally “sick enough” and allowed to enroll in the trial. Unfortunately, soon after he passed away, not from the cancer itself, but primarily due to secondary complications that occurred specifically when he was “getting worse.”
Needless to say, there are many questions I can’t stop asking myself. If the eligibility criteria were more inclusive would he have gotten into the trial without needing to “get sicker” first? If the trial sponsor had been able to find patients meeting their eligibility criteria faster, might the drug have been approved faster and been commercially available to my relative? Perhaps most importantly, what are we as an industry going to do about situations like this moving forward?
The Clinical Trial Conundrum
Anybody who has been in the research or biopharmaceutical industry for any period is likely aware of the major challenges involved with timely execution of clinical trials. According to the FDA, only six percent of clinical trials are completed on time, and 80 percent of all trials are delayed at least one month because of unfulfilled enrollment.  On average, it takes seven months from site identification to successful initiation. What is worse is that these numbers have remained essentially unchanged for more than 10 years, and everybody involved is paying a very high price for it. Patients–like my relative–miss out on potentially life-saving treatments and the industry struggles to bring new therapeutics to market at an estimated cost of $600,000 to as high as $8 million for every day of delay. 
During my past few years at TriNetX, one of the biggest misconceptions I hear from biopharma representatives is “my CRO does feasibility for me, so we don’t need to.” While it is true that CROs perform a great deal of valuable feasibility work, the disconnect is that protocols are nearly always written within the four walls of the biopharma company and finalized before going to a CRO or another external partner. CROs do indeed assess trial feasibility to inform their trial execution strategy. The problem is, they are dealing with a protocol that has already been finalized by the trial sponsor and limits what—if anything—they can do to make changes to the protocol. Their only option is recommending an amendment—at a median direct cost of $141,000 for a phase II protocol and $535,000 for a phase III protocol. 
Leveraging the Power of Real-World Data
What is a better alternative? Biopharma companies can use real-world data (RWD) internally during the protocol writing process. Protocols are typically written by scientists. Clinical development experts work largely from a scientific perspective, often referencing literature or copying criteria from previous studies in the same or a similar indication. All of these are necessary considerations for any study. Yet, what is often lacking is the patient perspective.
A protocol may well be optimally written to answer a key scientific question, but are the eligibility criteria so restrictive that patients who meet them don’t exist in the real-world? Are there opportunities to make minor modifications that will result in a far more successful operationalization of the study?
Over the past several years, most large biopharma (and many small and mid-sized) companies have embraced the use of RWD internally during the protocol design process. GSK has famously implemented their Protocol Design Lab,  and Sanofi has publicly stated that using qualitative and quantitative data sources such as TriNetX’s RWD and platform has helped them reduce their protocol amendments by more than 50 percent.  At least four of the top 10 global trial sponsors require that every protocol must be assessed using TriNetX.
The benefits of a biopharma company using RWD internally during the protocol writing process include helping with study execution, accelerating site ID and recruitment, reducing trial timelines, and helping patients live longer lives. Consider these examples:
- “Trial Sponsor A” is developing a diabetes medication investigating the impact of expanding the acceptable HbA1c score by 0.5% and determines that the resulting increase in potentially eligible patients is negligible and therefore decides to evaluate other criteria for modification instead. The result is that the sponsor avoids amending the protocol for reasons that may not have achieved the desired result.
- “Trial Sponsor B” learns that by changing the wash-out period of a medication from one-year to six months, the pool of potentially eligible patients is expanded dramatically.
- “Trial Sponsor C” has an inclusion criteria that a patient must have been on either Medication D, E, or F within the past 12 months. Upon evaluating TriNetX EHR data, they learn that by adding Medication G, H, and I to the list (all in the same class as D, E, and F), they substantially increase their cohort size.
In addition to increasing the size of the addressable patient cohort, working with TriNetX during the protocol writing process can help with many other areas including:
- Identifying sites that have the most patients that meet specific study criteria. The benefit? Being able to select the right sites.
- Identifying sites that do not have patients meeting specific study criteria. The benefit? Avoiding the wrong sites.
- Using the demographics information in the TriNetX platform, data, and network to improve diversity in clinical trials.
- Using RWD to augment trial data, or for the use of synthetic control arms
If you are in the process of writing a protocol that is not yet finalized, contact us for a free preliminary evaluation of your protocol. Our consulting team works with trial sponsors of all sizes, and we have engagement models that work for virtually every client.
 The Impact of Protocol Amendments on Clinical Trial Performance and Cost, by Kenneth A Getz, Stella Stergiopoulos, Mary Short, Leon Surgeon, Randy Krauss, Sybrand Pretorius, Julian Desmond, Derek Dunn, Ther Innov Regul Sci, July 2016