How to Address Early Obstacles in Phase I

It’s no secret that getting new drugs or biological products approved by the FDA is a challenging task. The low rates at which drugs make it all the way through the research process is a favorite topic of blogs and journalistic outlets alike.

Some drugs fall by the wayside due to unfavorable efficacy or underpowered data in the middle and later phases.

Many others, though, fall victim to administrative or technical challenges that arise as early as the nascent stages of phase I. 

What steps can sponsors and CROs take to position their early-stage studies for success and expedite their final market approval? In this article, we’ll explore three obstacles that researchers face early in phase I studies, as well as some insight into how the right eClinical suite can overcome those challenges.

Challenge #1: Phase I Recruitment

Across all phases of research, challenges in patient recruitment are often accounted for by a lack of awareness and skepticism of the tested compound’s efficacy compared to existing treatments. Recruitment challenges in phase I, however, have their own additional causes.The most notorious of these is the “guinea pig” fear: as the drug’s safety and tolerability profiles have not yet been established, potential subjects often worry it may pose a danger to their wellbeing.¹

Clear and concise communication between patients and clinicians is critical in phase I to dispel any fears and discuss what is expected during the trial. Yet, unclear or incomplete physician communication during the enrollment process of phase I trials is a leading source of patient dropout.

Nearly 30% of phase I trial participants reported that their clinician did not fully address the impact that the trial could have on their quality of life.²

When phase I participants were able to discuss their fears and concerns about participating in research with a healthcare provider, it was shown to increase their comfortability and autonomy with decisions about their enrollment.² 

Creating opportunities for patients to engage with their healthcare team is critical to not only answer their questions, but also to build confidence, trust, and appreciation.

Lack of motivation is another common factor, as most phase I trials involve healthy volunteers with no medical necessity for the tested compound. The exception to this, of course, is phase I oncology trials, which enroll sick patients. But even here, patients with an advanced condition and limited time are often reluctant to try a treatment with undetermined efficacy.

To combat this, healthcare teams should find ways to show appreciation for the role patients play in the success of early-stage studies. 

• Pre-Screening Phase: Use this as a time to clearly, concisely, and directly explain patient expectations, answer specific questions, and discuss the importance of phase I trial participation. 
• Throughout the Trial: Check in with patients regularly and offer a space for questions. Be sure to explicitly enquire about issues, offer appreciation for their time, and make them aware of additional trial support options.
• Study Conclusion: Reaffirm your appreciation for the role patients played in clinical research, thank them for it, and do your best to make them feel appreciated. 
• Sharing Results: Encourage patients to share their experience or volunteer again by keeping them updated on the outcome of the study so they can see the difference they have made. 

Challenge #2: Site Negotiations

Before dosing begins in a clinical trial, there is a period of negotiation dedicated to hammering out details related to administrative matters like site payments.

Most sponsors aim to complete site negotiations within 20 days, but due to the unpredictable nature of negotiations, 23% of discussions extend beyond 60 days.³  

The time spent on negotiations with clinical research sites tends to decrease as research moves from one clinical phase to the next. This is due to the fact that as research progresses, the protocol becomes better established and there are fewer unknowns in the budgeting process.

Therefore, it follows that the negotiation period tends to be longest in phase I. In fact, phase I site negotiations often last more than twice as long as other phases³. These lengthy negotiation periods threaten to derail timelines even before research has begun.

To combat this challenge, sponsors should aim to build scalable processes that sprint their early-stage negotiations:

• Understand Your True Study Value—The value gap in a trial is widest between sponsors and sites during early-stage trials. For every percentage that a sponsors’ initial offer was away from the final agreed amount, it added 1.4 days to the cycle time.³ Sponsors should conduct research and be more precise in their offers to sites to reduce negotiation times. 
• Tailor Your Offer—Half of sponsors approach potential sites with the same initial offer.³ Studies found that the median time to negotiate site contracts dropped one week by tailoring initial offers based on historical data of a particular site. 

Challenge #3: Protocol Uncertainties

As phase I oncology trials enroll sick patients instead of healthy volunteers, eligibility criteria can be strict and dropout rates are notoriously high.

This places the protocols of these trials at particularly high risk of unexpected changes. 

A study by the Tufts Center for the Study of Drug Development found patient recruitment struggles to be a common cause of protocol amendments, with many amendments aiming to change patient eligibility criteria.⁴

Additionally, 57% of protocols had at least one amendment, and nearly all amendments were deemed as “avoidable”. 

Outside of oncology, there is another risk: the Tufts study reported that 40% of protocol amendments take place before patient enrollment begins, and therefore create delays in the nascent stages of a trial that may be difficult to recover from as research progresses.⁴

Although some mid-study changes are unavoidable, there are steps sponsors can take to minimize their impact on early-stage study budget and timelines:

• Take additional time for trial design upfront 
• Challenge protocol by taking them through several stages of review
• Seek patient input on protocol design 
• Unify your eClinical suite for streamlined study management

An eClinical Solution to Overcome These Obstacles

With these challenges lying in wait, researchers can benefit from entering their phase I trials equipped with the tools necessary to address them. The right eClinical solution can provide both mitigate and streamline early phase I challenges. 

Medrio’s EDC makes it easy to perform mid-study changes, a feature that eases complications arising from protocol amendments.

And our drag-and-drop interface enables researchers to build studies in weeks instead of months, creating time savings that can offset any delays stemming from patient recruitment or site negotiations. Best of all, our integrated eSuite empowers sponsors across all phases of clinical research to accelerate their studies while maintaining control and reducing costs. 

The outcomes of phase I trials set the tone for the rest of the research process. The value of a strong start is impossible to overstate. While these trials face considerable challenges in their early stages, a robust and intuitive eClinical like Medrio is available to mitigate those challenges.

References:

1. The ‘myth’ of the clinical trial guinea pig
2. Shiraj Sen, MD, PhD , Sarah Moreland, MD (2020). ‘Screening for Phase 1 Clinical Trials: An Opportunity to Evaluate Psychological States and Re-educate Patients on Prognosis?’.Cancer Network. 
3. Glass, L. ‘Speeding Negotiations with Investigator Sites’. Applied Clinical Trials. November 6, 2015.  
4. https://www.appliedclinicaltrialsonline.com/view/speeding-negotiations-investigator-sites