Introduction

Protocol plays a central role in the efficient execution and completion of a clinical trial. Any change to the agreed protocol that affects the safety of subjects, scope and quality of study is considered unavoidable. These changes result in delays in Study timelines, lower patient retention rates, Site burdens, impending costs etc.. According to Tufts Center for the Study of Drug Development, the annual rate of procedures per protocol has increased from 6.5% to 8.7%, through the analysis of 57 Phase 2 and 3 protocols. This shows the increasing complexity of studies and consequent amendments to protocols.

The following are the key considerations and impact related to Protocol Amendments:

1. Impact of Protocol Amendments
   1. Cost – The cost of an average of 3 amendments to phase I and 7 amendments to phase II and III ranges from $250,000 to $450,000 according to Tufts CSDD study. The major expense is IRB fees for any amendment to be approved. The review of the change in the protocol submitted to the authority incurs review charges.
   2. Time – Amendments do happen before even the patient is administered the first dose as per the protocol. The actual time taken to identify the problem with the existing protocol, the filing of the amendment and final implementation of the refined protocol took more than two months.
   3. Regulatory burden – CRO or Sponsor are bound to make unbudgeted expenses towards protocol amendment filing, review and approval from the regulatory authorities. Site burden increases with the implementation for every amendment. Procedures performed on subjects have to be performed again leading to poor retention rates.
2. Factors leading to Protocol amendments
   1. Amendments occur in case of new Study dose information, variation in sample size, adverse events or serious adverse events, protocol design discrepancies, lower recruitment rates, changing regulatory demands all of these factors are responsible for changing the protocol. All of these factors are necessary to refine the protocol.
3. Trends in Protocol implementation
   1. Master protocol studies –  Master protocols reduce the cycle time and generate quick real-world evidence related to the hypothesis tested. They also reduce the costs as the various stakeholders involved can share the trial costs. Quantum Leap Healthcare Collaborative™ (QLHC) study “I SPY 2” is an ongoing Platform trial started in 2010 testing multiple therapies for Breast cancer and has recruited more than 1300 patients and has evaluated 12 drugs by 2018. There is an increase in the adoption of Master protocols as they are patient-focused and give out results much earlier compared to traditional designs.
   2. Evidence-based protocols – The evidence-based protocols are proven to minimize the costs, patient stay and study failure rates. There is a paradigm shift towards designing the protocol based on real-world health data analysis. For example, Health device data is used to create digital biomarkers via eTools capturing EHR/EMR data providing simplified protocols ,in turn, reducing amendments.
4. Industry strategies to tackle amendments.
   1. The Industry should typically plan and budget upfront for two amendments for every clinical trial so that the appropriate costs and timeline impact is accounted for without any surprises.
   2. Ensure proper continuous communication with the Sites as the protocol evolves in the study.
   3. Improving the protocol authoring practices and internal feasibility assessments will lead to reduced protocol amendments.
   4. The Clinical trial design process is evaluated along with predictive analytics, local expertise to come out with simple protocols less prone to amendments.
   5. Leverage technology solutions that capture the real-time amendment status, frequency, version and automated approval of protocol amendments.

References

https://static1.squarespace.com/static/5a9eb0c8e2ccd1158288d8dc/t/5aa2bccc9140b7f28066f810

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4053871/

https://journals.sagepub.com/doi/abs/10.1177/009286151104500307

https://www.nejm.org/doi/full/10.1056/NEJMra1510062?sort=oldest&page=-6

https://apps.who.int/iris/bitstream/handle/10665/260421/WHO-NMH-NVI-18.2-eng.pdf;jsessionid=1E1CB812E6DB70DFAC55380AFE1D2DF8?sequence=1

https://www.fda.gov/drugs/investigational-new-drug-ind-application/ind-application-reporting-protocol-amendments

https://www.pharmoutsourcing.com/Featured-Articles/333834-Diagnosing-Protocol-Amendment-Experience-to-Drive-Clinical-Trial-Performance/