Saving a Struggling Safety Study

Selecting a contract research organization (CRO) from among the 1,000 or so competitors is a challenging task for any sponsoring pharmaceutical or medical device company. But, it is particularly difficult for an inexperienced team at a startup just entering Phase 1 human trials with their first new product. Such young companies are often working under extreme deadlines imposed by shortsighted venture capitalists clamoring for a press release announcing the start of clinical testing to buoy the stock price.

 A typical misstep is to blanket dozens of contract research organizations with a hastily-prepared RFP (“Request for Proposal”), often little more than an early draft of the study protocol. As is the poignant criticism of clinical research in general, a company in any other industry, from aerospace to waste management, would spend weeks to months preparing detailed specifications, task definitions, and responsibility matrices before submitting an RFP for such a long, complex, expensive project as a clinical trial.

In our industry, that rarely occurs, sometimes even with the sophisticated multinational pharmaceutical giants. Even in a small trial, there are dozens of difficult-to-estimate factors (number of subjects, location of sites, data points, trial duration, rate of enrollment, etc) any one of which can have a significant impact on the cost (and success) of the trial. Left to their own hopefully-educated guesses, the CROs bids can vary wildly, sometimes by a factor of 2 or 3.

An ethical and experienced contract research organization will try to clearly delineate the many assumptions that go into preparing their particular bid and then iteratively work with the sponsor to better define a set of expectations and corresponding specifications. Unfortunately, this can be a dog-eat-dog business full of hungry commission-based sales executives, and even some of the best known CROs seem unconcerned with forging long-term win-win relationships. Some contract research organizations will knowingly underbid with the hope of later generating dozens of change orders to boost profitability. Others, not wishing to be bothered by a small upstart, will artificially inflate their numbers hoping to win on name recognition alone, or on the credentials of quickly-paraded staff that will never actually work on the project.

Eventually, the list gets narrowed down, astonishingly sometimes by simply picking a high, low and mid-range quote, and the selected proposals get hastily passed up to a senior executive having little time to conduct proper due diligence. In the end, it might come down to something as dubious as an ill-informed recommendation by a friend-of-a-friend or perhaps which CRO has the splashiest advertisement in the latest trade journal. It’s not that some sponsors don’t put a lot of effort into the process; sometimes, they often just don’t know what they don’t know.

Such was the experience a few years back of a young company with a novel new drug for treating cancer. The contract research organization they selected was well known and had been recommended by a consultant hired to write the protocol. Most any CRO can manage the typical outpatient trial of an oral medication, but this trial was far from typical. Soon after the study got underway, that fact, and the inadequacies of the selected CRO, became painfully apparent.

The drug had to be shipped on dry ice, stored at -20C, and precisely diluted under a sterile chemo cabinet by a licensed pharmacist mere minutes before dosing. Unfortunately, this CRO never considered that pharmacists generally don’t have experience with using a laboratory micro-pipette to prepare a sub-microgram per milliliter dilution. It seems pointless to further mention that the original contract research organization had no idea how to train the small army of shift-working pharmacists in the typical hospital pharmacy.

Once the drug was mixed, it had to be rushed to the operating room to be immediately administered by a surgeon using multiple injections directly into the cancerous organ of a patient under general anesthesia. Here again, this CRO failed to anticipate all the complications such a situation would present.

needle used in clinical research study

First, it required as many as a dozen needles. Not standard needles mind you, these were 9-inch needles normally only used only by anesthesiologist to deliver anesthetics to the spinal cord. Unfortunately, the ill-prepared CRO left it to each of the participating investigators to source and purchase these needles. No one had considered that the hub size and internal diameter of a needle will vary by manufacturer (the air volume of the needle needed to be considered in determining the dose) or that the supplied large-barrel syringes were not graduated to accurately measure a one-tenth of a milliliter dose. No one even considered that surgeons, without explicit guidance, would employ individual surgical techniques that might alter the actual dosage of drug delivered.

During a surgery, one cannot expect a busy surgeon to collect the various data required for a clinical trial. A well trained study coordinator that can “gown-up” for the surgery is essential, albeit very hard to find. Compared to other specialties, surgeons participant in clinical trials far less frequently and thus are less likely to have experienced study coordinators on their staffs.

As a final example, this CRO was located in a different country from the study sites. The contracted medical monitor was a freelancer working from his home. The pharmacists, surgeons, treating physicians, monitoring staff, sponsor staff, and statistician were all in different locations, and all needed near-immediate access to the phase 1 safety data as it was being collected in the field. Despite this glaring team communication problem, the original CRO had attempted to implement a paper-based case report form that required more than 100 forms per patient and thus couldn't be easily faxed between the stakeholders.

It was a disaster waiting to happen! Luckily, this sponsor recognized their mistake fairly early on in the study and called upon Emissary to step in and salvage their critically-important safety study.

Emissary quickly analyzed the problems and took immediate steps to get the trial back on track. The first was to establish workable communication processes, including replacing the paper case report form with a sophisticated electronic data capture (EDC) system. This allowed the medical monitor and the lead investigator to carefully monitor the safety parameters on a near real-time basis from their geographically-dispersed locations. It allowed Emissary staff to know exactly when a patient would be dosed so that staff could be on-site to ensure each procedure went smoothly.

Emissary’s services went far beyond what might be expected from the typical CRO. To eliminate any problems with drug reconstitution and dosage calculation, Emissary sent a licensed pharmacist into the hospital to oversee this critical step. To help ensure standardization and to assist with data collection, Emissary medical staff went into the operating suite to observe each procedure.

As most of the coordinators were inexperienced, Emissary incorporated extensive checks into the EDC software and carefully re-designed the source data worksheets to help the coordinators compile valid and reliable data. This system was so sophisticated that it even automatically alerted the medical monitor if certain conditions arose that might indicate a safety issue.

Thru Emissary’s efforts, the study ended up a major success! The data showed the drug was well tolerated and provided early evidence that it might someday dramatically improve the way this type of cancer is treated.