For a development-stage therapeutics company, business success or failure ultimately hinges on the outcome of its clinical trials: the lengthy and expensive series of experimental studies testing a company's candidate therapeutic, in statistically meaningful numbers of human patients, to attempt to demonstrate the candidate's safety and efficacy (for an introduction to clinical trials see this discussion from the U.S. National Institutes of Health). Government agencies charged with regulating the sale and use of therapeutics and medical devices, such as the Food and Drug Administration in the U.S., largely rely on the results of these trials to guide their decisions regarding whether or not to permit the marketing of new therapeutics.
And, just as the hopeful young company's business prospects hang in the balance of its clinical trials, so to do the fortunes of its investors, the hopes of patients eager to receive the new therapy, and (at least in the case of entirely novel therapeutics such as stem cells) the prospects of the industry as a whole. With so much money and so many lives on the line, it's easy to understand why the progress of a clinical trial is the object of intense scrutiny among members of all these interest groups.
Unfortunately, clinical trial data are guarded as jealously as state secrets by the companies sponsoring such trials, and for a compelling reason: with so much on the line, a company's share price can and will swing wildly in response to the least speculation regarding its trial's ultimate outcome. Fortunately for interested outsiders, however, some more-or-less reliable (albeit limited) sources of trial information do exist. In the U.S., one such source is the U.S. National Institutes of Health’s ClinicalTrials.gov web site, a publicly accessible online clinical trials registry. Mandated by law (Section 801 of the Food and Drug Administration Amendments Act of 2007, or FDAAA), ClinicalTrials is a repository of basic trial information required to be published (and regularly updated) by each sponsor of a Phase 2 or 3 clinical trial under U.S. jurisdiction. Phase 1 trials are excluded from the law’s requirements, but most trial sponsors register them at ClinicalTrials anyway.
Outsiders can glean quite a bit of useful information from a careful reading of these records, provided they know what to look for, and even more insight can be gained by monitoring these records’ changes with time (i.e., updates). For example, a trial whose anticipated Primary Completion Date keeps slipping further and further off into the future with each new record update is a trial that may well be in some trouble (frequently due to an unexpectedly slow rate of patient recruitment, but other types of problems might generate this signal, too). Whatever its cause, repeated slips in the Primary Completion Date indicate that the trial will be slower, and almost certainly more costly, than the company originally planned for.
But keeping up with ClinicalTrials records may be beyond the average reader’s ability. First there’s the sheer numbers problem: you’d need to visit, review, and analyze many tens of quite complex web pages daily merely to stay on top of the 33 current clinical trials registered by SCSI component companies. Then too there’s the problem that gleaning important signals from these records requires a fair amount of expert knowledge. For example, if it takes six months for a trial to add a third site to its list of participating locations is that fast, or slow? Is it a problem, or no big deal?
That’s where our newest tool, the SCSI Clinical Trials Monitor, comes to our readers’ aid. We’ve created a set of computerized algorithms for the systematic and automated analysis of ClinicalTrials.org records, and we’ve validated the rules these algorithms employ through discussions with clinical trial experts. Our system scans ClinicalTrials daily, searching for updates to the records of trials sponsored by SCSI component companies, and analyzes those changes to distinguish between those that are probably insignificant and those that might signal trouble ahead. These analyses are then summarized in what we hope you’ll find to be an easy-to-digest tabular format. Finally, our algorithm assigns a color-coded flag to each such record change, as well as a summary flag to the trial itself, as aids to help you quickly scan these tables. A green flag () indicates that no obviously worrisome sign was detected, while a yellow flag () indicates one or more potentially minor problems, and a red flag () indicates potentially significant problems. Again, the judgments these flags reflect are made from an investor’s perspective, not a medical perspective; flag assignments are nothing more than a quick heads-up for readers, not predictions regarding the ultimate success or failure of a trial. We encourage you to draw your own conclusions from the data.
Here follows a quick example, based on real-world data, to illustrate how the SCSI Clinical Trials Monitor works in practice.
1. Accessing the SCSI Clinical Trials Monitor Main Page
From any page on this site just click the "Clinical Trials" link near the top of the page:
2. Summary of All Trials
This main page presents a summary table of all trials currently being tracked by our system (each trial registered with ClinicalTrials listing a SCSI component company as either its sponsor or collaborator). The table presents one-line summaries of some key information for each such trial, and provides you with a link to drill down to more detailed information for each trial.
- Company: The name of the sponsoring or collaborating SCSI component company. A second company name in parentheses indicates either a co-sponsor under whose name the trial is registered, or else a division of the sponsoring company under whose name it is registered.
- Brief Title: A summary title indicating the cell type and the disease the trial addresses.
- Phase: The trial's phase (see here for a definition of clinical trial phases)
- End Date: The trial's most currently updated anticipated or actual "Primary Completion Date", the date on which the last patient will have been treated and the last data collected. In practice this is the earliest date on which the sponsor might publicly announce the trial's results, usually via a press release
- FDA Info: The trial's unique NCT number (assigned by ClinicalTrials.gov), linked to the trial's main page on the ClinicalTrials web site
- Last Update: The date of the most recent change to this trial's record detected by our system
- Summary Flag: A green, yellow, or red flag summarizing the level of the most significant problem for this trial that has been detected by our system. Clicking this flag will take you to a detail page for that individual trial (described below).
Trial Detail Page
Clicking on a trial's Summary Flag in the table discussed above will take you to a new page, detailing a wealth of data our system has collected regarding that trial.
Listed by order of appearance, the information presented on this page includes:
- The trial's full title
- Issues Summary: This is the same summary flag as the one you clicked on to reach this page
- Trial-Related Publications: A list of links to press releases and/or technical publications dealing with either the status or the results of this trial (if any). This is an intentionally sparse list; it includes only the most material publications, and specifically excludes the myriad of immaterial press releases some sponsors like to issue frequently in an effort to keep investors excited
- Timeline and Analysis of Changes to This Trial's Record: This table is the heart and soul of the SCSI Clinical Trials Monitor. Each line in the table lists important information extracted from each change to this trial's record over time. The table's fields include:
- Change Date: The date this update was submitted by the sponsor to ClinicalTrials
- Estimated Completion: The trial's recorded Primary Completion Date as of the Change Date
- Status: The trial's recorded Status as of the Change Date. Possible values include:
- NYR: Not yet recruiting (The trial has not yet begun)
- Rec: Recruiting (Patient recruitment is underway; treatment and data collection may also be underway)
- ANR: Active, not recruiting (The trial's full complement of patients has been recruited; treatment and/or data collection are underway)
- Com: Completed (The trial has ended according to plan)
- Sus: Suspended (Trial activity has been temporarily halted. This could be due to any of several - usually negative - causes, the most serious of which would be a 'clinical hold' ordered by the FDA in response to the occurrence of severe adverse events
- Ter: Terminated (The trial has ended early and not according to plan. Typical reasons can include 'futility' - interim data demonstrate that the therapeutic does not work - or the sponsor's inability or unwillingness to continue funding the trial
- Unk: Unknown (Our system was unable to determine the trial's status)
- Total sites: The total number of clinical trial locations recorded as of the Change Date
- Not Yet Recruiting; Recruiting; Active, not recruiting; Completed; Terminated; Withdrawn/Suspended: The total numbers of trial locations with these individual statuses. A 'terminated' site was removed from the trial by the sponsor. A 'withdrawn' site has removed itself from the trial. A 'suspended' site has temporarily suspended trial activities.
- Note: Miscellaneous information regarding this update. Statements in bold font briefly indicate why a negative (yellow or red) flag was assigned to this update.
- Flag: The flag assigned by our system to this update. A green flag indicates that no negative implications were detected. A yellow flag indicates potentially minor negative implications. A red flag indicates potentially significant negative implications. Again, these judgments are offered from an investor's perspective, not a medical perspective, and do not constitute predictions regarding the ultimate success or failure of the trial
Finally, let's look at what you might be able to learn about a trial using this tool - specifically focusing on actionable information that might influence your investment decisions. We'll take as our example the Trial Details for Osiris Therapeutics' ongoing Phase 3 trial of its Prochymal stem cells for Crohn's Disease.
As the figure above illustrates, this trial's first update dates back to June 2007, with no Primary Completion Date listed (there was no legal requirement to supply a Primary Completion Date prior to 2008). The trial began with a status of 'recruiting' and with just one trial site, whose status was also 'recruiting'. This first record thus earns a green flag, indicating that our system found nothing unusual about it. Further updates to this trial's record, through August of 2007, documented nice progress as additional trial locations came on board, reaching a total of 8 sites by August 28th, all of them recruiting. As the Note column shows, on August 28th the trial's anticipated enrollment was increased from its original value of 258 patients to 270, but our algorithm did not penalize this change, again awarding that update a green flag.
This trial continued uneventfully, earning an unbroken series of green flags from our algorithm, through September of 2008, by which time (as shown in the first row of the figure above) it had accumulated a total of 60 trial locations, all of them with a status of 'recruiting.' But the update dated November 10, 2008 offered a first sign of potential difficulty for this trial, when one trial location's status changed from 'recruiting' to 'suspended,' earning this update a yellow flag. This worrisome trend continued through the December 30, 2008 and February 3, 2009 updates, reaching a total of five sites withdrawn, suspended, or terminated and earning these updates red flags, indicating a possibly significant degree of concern. Further, as noted in the fourth row, by the February 3 update the trial had exceeded its previously anticipated Primary Completion Date.
Meanwhile, back at the NASDAQ stock exchange, the price of Osiris shares was steadily climbing, approaching a new 2-year high of $20.71 on February 6th, despite these worrisome signs of possible trouble ahead publicly available - yet buried - within the ClinicalTrials.gov web site.
The bottom finally fell out of the bucket on March 27, 2009, when Osiris issued a press release announcing its suspension of this clinical trial due to a significant flaw in the trial's design, triggering a massive sell-off driving OSIR's share price down to $14.40. It would continue to fall through October of that year (after a total of 10 sites had been withdrawn, terminated, or suspended from the trial, as shown in the last row of the figure above), reaching an ultimate low of just $6.35.
With the wisdom of hindsight, today we know that the problems detected and flagged by our algorithm in record updates dating back as far as November of 2008 were indeed directly related to the design flaw that ultimately led to the trial's suspension and the subsequent collapse of OSIR's share price. Had the SCSI Clinical Trials Monitor existed back then, and had you heeded its early warning, you might either have closed your position in OSIR near its top, thereby avoiding a bloodletting, or you might even have made a tidy sum shorting OSIR shares (if that's your style).
We must close by emphasizing that there is no guarantee that a red flag assigned by our algorithm necessarily signals a trial's failure or the impending collapse of its sponsor's share price. Indeed, as you browse through today's SCSI Clinical Trials Monitor you'll find a few examples of red flags assigned to trials that are proving, as far as anyone currently knows, to be quite successful. The Monitor is a current awareness tool, nothing more. We hope you find it useful.
The SCSI Clinical Trials Monitor is currently in beta; its design, data, and flag assignments may change without notice as we continue to work to further improve it. We welcome your comments, corrections, and feedback. Please address these to trials (at) BusaConsultingLLC (dot) com.Tweet