There is a noble tradition at the Drug Information Association (DIA) conferences. Presenters never speak of money.

The assumption is that industry-sponsored research is so exalted that dollars and euros need never be mentioned. Rather, it would seem, large sponsored clinical trials are fueled by hugs and smiles.

At this year’s DIA gathering, however, there was at least one session that departed from that tradition. That session discussed the real costs of changing clinical trials that are under way.

The costs of protocol amendments, in both dollars and time, are yet another elephant in a crowded room of clinical trial elephants—chronic, apparently intractable issues. “Protocol amendments are a very large problem for our industry,” says Anne Cropp, executive director at Pfizer.

Broad Issue

She moderated the DIA session and was blunt about amendments. “They are our solution,” she said, “to poor protocol quality.”

The session didn’t explore the origins of bad protocols. But most life science organizations employ physicians and medical writers to assemble protocols. Neither type of professional can be said to possess vast operational or financial insight into how a protocol will unfold in the real world. Structured, specialized software to design and draft protocols is infrequently used.

Instead, protocols are written with general-purpose word processing software, which permits wide latitude for individual variation and scientific improvisation. Such flourishes please their authors, but prove expensive to remedy when trials veer off course. Industry's method of protocol creation explains part of the chronic persistence of costly amendments.

Hunting for the reasons for 500 amendments inside 200 Microsoft Word documents would not be feasible for most clinical trial professionals. The industry would rather indulge technology-challenged doctors—and shoulder huge risks for trial cost, complexity and punctuality—than use a more modern method.

Protocol QA

In her introduction to the session, Cropp recommended a post-trial debriefing exercise to evaluate what caused the amendment. “These avoidable amendments can be eliminated through a change in your process in the protocol review,” she said. Naming and categorizing what happened, she suggested, is one step to avoiding some amendments in the first place.

Rachael Zuckerman, a senior research analyst at the Tufts Center for the Study of Drug Development, presented research on the issue. She gathered protocol information from 17 sponsors, manually inspecting 3,413 protocols and 3,596 amendments with almost 7,000 individual changes.

Stomach Trouble

More than half of the amendments were in Phase I. Those were of less interest, so Zuckerman’s presentation focussed on those in Phase II and III. Each amendment included a mean of eight separate changes. Gastrointestinal trials tended to have more amendments per trial (4.4) than anti-inflammatory projects (1.8).

Zuckerman noted that few companies had systems or processes to track what triggered amendments. She also analyzed the ripple effects of each amendment on an overall study budget.

After tabulating all the hourly wages of those who must handle the amendments, she estimates that each amendment costs $450,000. Zuckerman reports that the sponsors helping on the Tufts project agreed with that figure, which only includes hard, direct budget items related to implementing the amendment. The fully loaded internal cost of making an amendment is probably three or four times as large.

Avoidable vs. Unavoidable

Naturally, each amendment takes time to put into place. At least two months, to be exact.

All the panelists agreed that some amendments, required by regulators or related to changing medical practice, are likely to be permanent fixtures of the clinical trial landscape. But a sizable slice of amendments are avoidable, and attributable to what can only be described as less-than-smart decisions before a trial begins. “Over a third of the amendments are either completely or somewhat avoidable,” Zuckerman said.

Anna Hindle also spoke at the DIA session. She formerly served as a medical writer at Biogen-Idec, and thanked her employer for the chance to present some of its costs in detail now that she’s working on her own. Hindle offered only a glimpse of the considerable real-world financial impact of amendments. But it was a welcome snapshot all the same.

Hindle related that Biogen, like most other firms in the industry, was struggling to handle its clinical workload with available staff. The company invariably ended each year spending more on research than it had planned, and eventually decided to investigate the roots of the problem. “We spent an enormous amount of money that wasn't planned initially for the study,” she said.

Hundreds of Hours

Not surprisingly, amendments emerged as a big problem. By Hindle’s estimate, the average, typical amendment requires a staggering 150 hours of medical writing and hundreds of additional hours from people with 17 different job descriptions.

There is considerable variation from year to year. In one recent year, the firm spent $59 million on amendments alone. When the hours were added up, perhaps two dozen people were handling nothing but amendments. “That is quite impactful—to have 26 people working on amendments,” Hindle said.

She cited data from contract research organization (CRO) PPD. An expert at that firm believes amendments cause even longer delays than suggested by the numbers from Tufts. According to PPD, an amendment before a trial's launch typically adds three months to the timeline.

Vetting Process

As a partial remedy, Hindle reports, Biogen is now keeping a list of changes requested by regulators. It’s intended to be a company archive of the hard-won knowledge about amendments. If France, for example, has new policies about pharmacokinetic studies, other members of the Biogen team may be able to anticipate those policies in a future protocol.

It also sounds like there is more senior management scrutiny of amendments at Biogen, to a degree that might save money. Some proposed amendments turn out, with further thought, to be unnecessary. Avoiding those changes until they are deemed essential, she suggested, can help contain the budget and focus the team.

Hindle said the forced, rushed changes invariably turn out to require additional amendments to the amendments. “Last minute changes are a killer, almost guaranteed,” she said. “If you change something at the last minute, you will have to amend it the next day.”

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