Protocol amendments make it more likely that trials will complete successfully, but they can be risky, burdensome and expensive.
Understanding why and when to make a modification is vital, say experts. A protocol change can work wonders – just ask AstraZeneca. In August, AstraZeneca’s systemic lupus erythematosus candidate anifrolumab achieved the primary efficacy endpoint in an amended trial called Tulip-2.
Originally Tulip-2 was the same endpoint as a prior study called Tulip-1. However, when anifrolumab fell short in the earlier trial, the firm opted to rejig the protocol with a new endpoint, BICLA.
AstraZeneca spokesman Matthew Kent said: “The BICLA was chosen as the primary endpoint for TULIP 2, following a full evaluation of the previous phase e trial TULIP 1, which did not meet its primary endpoint of SRI4.
“Systemic lupus erythematosus is a complex, heterogenous disease with many unanswered questions about what drives disease activity, and both the SRI and the BICLA are widely used for assessing disease activity.
“An analysis of anifrolumab data supported the BICLA as a more appropriate measure to assess the potential of anifrolumab in TULIP 2,” Kent said.
All change?
Most clinical trial protocols are changed at some point. Analysis by the Tufts Center for the Study of Drug Development (Tufts CSDD) indicates nearly 60% of studies are subject to amendments.
AstraZeneca’s motivation for amending was obvious, but there are many reasons to make a change. In some cases, patient eligibility criteria are modified to speed recruitment. In other instances, evolving standards of care prompt amendments.
The nature and number of protocol revisions usually depends on the study phase, said Chris Learn, Senior Therapeutic Strategy Lead Director, Therapeutic Science and Strategy unit at IQVIA.
“Earlier phase studies, such as phase 1 a/b, first-in-human or dose escalations with or without combination, typically require fewer amendments than trials in later phases of development,” Learn said, explaining that this is mainly by design.
Late phase clinical trials are more complex and involve more patients, which makes amendments – including relating to patient safety – more likely, Learn continued.
“The patient sampling size increases, as well, increasing the degrees of freedom within phase 2 and 3 trial parameters that may need to be better controlled and or accounted for in terms of safety, efficacy and beyond.”
Trials in children
Protocol amendments are also common in trials involving children. The European Medicines Agency is not responsible for approving or overseeing the conduct of clinical trials, and therefore is not involved in clinical trial protocol amendments.
However, when it comes to paediatric trials, the agency does get involved, according to spokesman Henry Fitt.
Flitt said: “Sponsors of paediatric implementation plans (PIPs) need to contact EMA’s Paediatric Committee (PDCO) in case changes are foreseen for a study included in a PIP for which they would then possibly have to submit a modification of an agreed PIP and apply for a change in protocol through the national clinical trial authorisation procedures.
“These modifications occur regularly,” he continued, adding that in 2018, the PDCO dealt with 223 requests for such a modification.
Challenges
So protocol amendments occur often and can be beneficial. However, the steps involved in making such a change are complex, according to Kenneth Getz, recently appointed Deputy Director at Tufts CSDD.
“There are many challenges associated with substantial amendments, including suspending the trial and all external service support, modifying the protocol, resubmitting it to the ethical review committee, re-consenting study volunteers and re-engaging investigative site and contract service staff.”
All these processes take time and cost money. According to research by FDAMap, a protocol amendment can cost between $72,000 and $500,000.
These figures are roughly in keeping with Tufts’ analysis, according to Getz, who said: “Our 2016 study of nearly one thousand protocols found that two-thirds of phase 3 protocols and 77% of phase 2 protocols have at least one amendment with 2.3 (phase 3 protocols) and 2.2 (phase 2 protocols) amendments on average.
“Each phase 2 amendment costs $141,000 on average in direct costs to implement, and $535,000 on average in direct costs to implement a phase 3 amendment.”
Product complexity
The drug industry’s evolution from a provider of chemical-based medicine into a developer of larger molecule drugs and cell and gene therapies is likely to result in an increase in protocol amendments.
Trials of such products are usually more complex than trials of small molecule drugs and, according to Kenneth Getz, more complex protocols are associated with a higher incidence of amendments.
“We typically see more amendments in oncology and CNS. We also see a higher incidence and average number of amendments in later stage phase 2 and 3 studies.
He added: “There are many factors that contribute to complexity, including more targeted and stratified patient populations, emerging safety issues, crowded drug classes and even the duration of time that multiple functions can provide design input.”
This view is shared by Chris Learn, who said immunotherapy studies are more prone to amendments than other types of research.
“In comparison to other therapeutic platforms, my observation has been that these trials experience more amendments due to the unknown, unexpected impacts that the host’s immune system brings into play, in addition to those resulting purely from the drug and or drug product alone.”
Flexibility
Protocol amendments provide drug developers with the flexibility needed to conduct scientifically robust research, said Jenny Fam, Associate Director, Global Regulatory Affairs, IQVIA.
Fam said: “Innovation in drug research does come with new challenges. All stakeholders (clinicians, patients, regulators, etc, not just sponsors, should be prepared for unexpected outcomes and build contingencies.”
Fam also said the ability to amend protocols is particularly important in emerging areas of research.
“For example, in the case of a failing lot of autologous cell therapy, sponsors need to ensure reserve samples are available, clinicians need to ensure patients are not at risk for missing a dose and regulators need to allow for flexibility in treatment protocols to ensure risk-benefit measures are implemented under such challenges.”