Need trial amendments? It'll cost money and time

Print 22 April 2016
Brian Orelli / BioWorld

A new study in Therapeutic Innovation & Regulatory Science from the Tufts Center for the Study of Drug Development (CSDD) using data from 15 pharmaceutical companies and contract research organizations establishes price tags for the cost of implementing clinical trial amendments.

And they aren't cheap.

Each amendment for a phase II trial cost a median of $141,000. For a phase III trial, the median cost was more than triple that at $535,000. The figures only include direct costs – for instance, additional fees to institutional review boards and increased costs to existing vendors for change orders – so the authors estimate the actual cost, including indirect costs, is likely three to four times larger than the direct cost for phase III trials, especially if the amendment delays the time to get to the market.

Those estimated costs are per substantial amendment. And with each phase II and phase III trial having an average of 2.2 and 2.3 substantial amendments, respectively, the average direct cost to make changes to the protocols of phase III trials tops $1 million per study.

"The cost to implement an amendment in a phase III study is considerably higher than we initially expected," said Kenneth Getz, the lead author and a research associate professor and director of sponsored research at Tufts CSDD. "We estimate that the direct cost to implement amendments for active phase II and phase III studies in any given year may cost the industry upwards of $6 billion in unplanned costs."

Clinical trials with at least one substantial amendment ended up enrolling fewer patients – an average of 107 fewer patients than originally planned, compared to 49 more than planned for trials with no amendments. Getz hypothesized that the smaller trials may be because some of the amendments adjust eligibility requirements.

But the smaller trials didn't translate into shorter durations between when the protocol was approved and the last patient visit. Adjusting for phase and therapeutic area, on average, trials with at least one substantial amendment were three months longer than trials without amendments.

"The additional time that's required to implement the amendment is time that's ultimately carried to the rest of the study; it's not recouped," Getz told BioWorld Insight.

AVOIDING AMENDMENTS

With amendments costing time and money, it would make sense for companies to try and avoid them, but nearly half of amendments were classified as either completely avoidable (23 percent) or somewhat avoidable (22 percent), including things like design flaws and recruitment difficulties.

At the other extreme, 30 percent of amendments were deemed somewhat avoidable – for example, a change in the standard of care – while 25 percent were deemed completely unavoidable, including things like new safety information or regulatory agency requests to amend the protocol.

Durect Corp. has firsthand experience with the unavoidable variety. Earlier this month, the Cupertino, Calif.-based company said the FDA wants it to add an active control arm to its already-started phase III trial called Persist. The trial is comparing Posimir, an extended-release form of the pain reliever bupivacaine delivered via depot, to placebo in patients undergoing laparoscopic cholecystectomy (removal of the gallbladder), but the FDA wants Durect to add an arm measuring patients treated with standard bupivacaine. (See BioWorld Today, April 11, 2016.)

While the number of avoidable amendments are higher than what companies would like, Getz pointed out that knowing the types of avoidable amendments gives them a starting point for where to improve. "The concept of avoidability helps us to isolate ways that we can make improvements in the logistics and implementation of the study," Getz said.

One way to avoid putting items into a protocol that need to be changed later is by having standard protocols of procedures that have worked in the past. Transcelerate Biopharma Inc., the industry-established nonprofit tasked with speeding drug development for its members, is establishing common protocol templates for specific patient populations and therapeutic areas to help avoid unnecessary amendments.

"The use of protocol authoring framework helps force a higher level of feasibility and a closer alignment between the objectives and endpoints of the study and the procedures performed," Getz said.

Another avoidable area comes from clinical trials that are too burdensome, making it hard to enroll patients. Getz said many companies are getting input from patients and study site coordinators before the protocol is finalized to "understand and modify the feasibility to reduce the burden of participation in the trial."

Companies are also using committees to review the protocols before they're submitted to institutional review boards to ensure that the procedures match up with the goals of the study and push back when they don't.

Of course, planning ahead costs time and money, so initiatives to avoid amendments only makes sense if there's a net benefit from the time and money saved, but Getz noted that the data in the study can help companies make those calculations.

"Knowing that the typical amendment will require several months of time and has a direct cost associated with it, helps companies create that economic [return on investment] measure," Getz said. "It doesn't take much to see that even some small investment to reduce the number of amendments can be worth a tremendous amount of value for companies."

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