Reevaluating Studies: A CRO & A Coincidence?
21 CommentsBy Ed Silverman // August 1st, 2011 // 8:30 am
Last week, the FDA announced that any clinical tests conducted between April 2005 and June 2010 by a contract research organization called Cetero Research may have to be reevaluated because two FDA inspections and an outside audit found falsified data and manipulated samples. In explaining its move, the agency maintained there were “significant instances” of misconduct.
The agency says Cetero failed to conduct an adequate internal investigation to determine the extent and impact of the violations, and did not take sufficient steps to assure data integrity during those five years. And so drugmakers must check their databases for trials that were used to support New Drug Applications and Abbreviated New Drug Applications - and may have to repeat or confirm results (back story).
For its part, Cetero subsequently issued a statement saying the CRO initiated its own internal investigation of its Houston bioanalytical laboratory in 2009 after discovering six chemists had misreported the date that samples were extracted prior to analysis. They did this to seek overtime pay for hours when they did not actually work. But the CRO insists reports were filed with the FDA and agency feedback was sought, although none was received. Cetero clients were also contacted.
“We leaned in roughly June 2009 and that’s the time at which we self reported the findings to the FDA,” Cetero ceo Troy McCall tells us. “We requested a meeting at the time that we originally provided them with our preliminary findings and during the course of our 18 month investigation. We were providing them with regular updates…They received all the information we provided to them on an interim basis.
“We took these issues so seriously that we not only terminated the employees who were responsible for these actions, but we also replaced management and ultimately the site leadership,” McCalls continues. “…That was probably another half dozen or so people.” He reiterated that all of the terminated employees were based in the Houston facility.
There is, however, an interesting tidbit concerning some other former and current Cetero employees - several of them have had experience suitable for dealing with the recent troubles. How so? They also once worked for MDS Pharma Services, another CRO that is now owned by INC Research and, notably, had rather similar problems with the validity and accuracy of test results. In fact, in January 2007, the FDA notified drugmakers to reevaluate pharmacokinetic studies that were conducted for them by MDS from 2000 through 2004 (read here). UPDATE: MDS Pharma early and late-stage operations, by the way, were subsequently sold to INC Research and Ricera Biosciences, respectively (see here and here).
Which former and current Cetero employees worked at MDS? And when? Well, there was Jerry Merritt, who was MDS senior vice president and general manager from 2000 to 2006, when he left to run Cetero, although he was succeeded as ceo early last year by McCall. And Murray Ducharme, the chief scientific officer at Cetero, was previously an MDS vice president from 2000 to 2006, although his Cetera bio neglects to mention this (look here).
Then there was John Capicchioni, who was the MDS senior vice president of business development from 1994 to 2006, when he joined Cetero as vice president of business development, although his bio also overlooks time spent at MDS (see this).
There was also Herb Smith, who was MDS senior director of quality assurance from 1999 to 2007, when he became vp of quality assurance at Cetero, although he retired in April. Finally, there is April Johnson, who worked at MDS as a marketing manager from 1999 to 2005 and as a marketing director of early clinical research and bioanalysis from 2005 to 2007, when she joined Cetero as vp, business relationship management (see this). And, yes, her bio fails to mention MDS.
In other words, several current and former members of the Cetero managerial team arrived from another CRO that experienced similar breakdowns affecting the validity of bioequivalence data, which caused regulators to question the ability to conduct a proper audit (read a sample letter the FDA sent to drugmakers with pending ANDAs).
The problems at MDS, by the way, factored into growing concern a few years ago about oversight of CROs. The rise in the number of clinical trials prompted a corresponding growth in the number of such companies, along with complaints about quality and competency. In February 2007, for instance, Gilead reported that the FDA had found “certain irregularities” in studies conducted by MDS (read this).
We asked Cetero for comment about the experience some of their executives brought with them from MDS. Johnson, who also acts as the Cetero spokesperson, declined to comment.
Observer
This is quite a good piece of reporting, Ed. It’s also worth noting that the ceo spoke to you directly as part of his response strategy - a wise move on his part.
The follow-on question is - will he speak to you again after this post? “Just askin’ “
original industry insider
This is why any experienced sponsor’s Phase I Director will ALWAYS insist that all plasma samples from pk or other types of BA/BE studies be retained frozen until the NDA/ANDA is approved. We had some data irregularities from several pk studies from a CRO bioanalytical lab a few years back, and traced it to a problem with the method validation. With today’s micromethods there should be sufficient volume for repeat testing.
Because we had insisted on retained samples, we instructed the CRO with the suspect data to ship all of the frozen samples to another lab, and this time we made sure to check the method validation of that second beforehand. Samples were shipped, assays were performed (at the first CRO’s expense), the data passed muster with internal QC and the data were saved. We even brought in an outside pk consultant to review the data. We sent every last scrap of information we had to FDA so that their clinpharm folks could reconstruct exactly what happened, and they gave the ok to the data.
Like Pasteur said, “chance favors the prepared mind”.
GCP expert
“Falsus in uno, Falsus in omnibus”
So the fab five is Merritt, Ducharme, Cappichioni, Smith and Johnson. as for the remaining mischief, well many of them are on the Cetero webpage.
Lessons learned: Stay away from this CRO~
original industry insider
Most Medical Directors give no more thought as to which bioanalytical lab to use than they do as to what flavor jelly to put on their morning english muffin. Moreover, most of them don’t know what they don’t know, which is an understanding of assay validation and statistics. Collection of validations to them is mostly a checkbox exercise which results in large binders collecting dust somewhere in centra file.
If you are using a new CRO bio lab for the first time step aside and let your QA/QC people do their due diligence. Don’t rely on reputation. Lab reputations are nototious for changing. Best example is MDSPS. Make sure your QA/QC negotiates the specifics of the Agreement, right down to brand quality of the reagants. If you think this is trivial I can cite many cases where methods needed to be revalidated in such cases.
Don’t be fooled by an Ivy League biolab that doesn’t do GLP’s and instead dumps a truckload of supersexy looking clean HPLC chromatograms in your face. My QA/QC folks can tear those things down faster than a NY minute.
Leverage
What should be replaced is the entire chain of top level management in Cetero. The hiding won’t cease until they are gone including the just as frivolous local management across the sites. The clinical books are even easier to fudge. Bring on the lawsuits pharma world, litigate to the max. Looks like the FDA has already provided you with ammo as well as precedence, aka MDS.
25whitestone
So Leverage on what do you base your accusations against Cetero? What else do you know and can you share?
Leverage
The FDA findings and approach is already a telltale sign of what lurks underneath this monster CRO so I’ll leave it at that. They have only scratched the surface. Cetero’s challenge letter is merely a PR tactic to attempt to minimize damage but turth be told the bottom line is this CRO cannot and should not be trusted.
phoenix sun
Well this CRO was caught redhanded with thousands of cases of manipulation, falsification and fraud. A bioanalytical lab is usually run by highly educated and experienced chemists and lab rats. Poor management control was likely prevalent and folks that usually starts at the very top. The Chiefs and VPs are fully accountable from a regulatory and litigious standpoint and I cannot fathom how tightship their clinical research centers are managed if their lab cannot even be trusted? After all, this is a story of pure FRAUD. The worst case scenario in any research setting.
Discredit the lab but keep in mind many if not most of those data were study trial results conducted at their clinical research centers. I’m not a betting woman but I’d drop a hefty sum on this one.
Perhaps it’s time to look beyond the cover of this book. Start thinking outside the box, if you will.
original industry insider
Good call, Phoenix. If you think about it this is even a better argument NOT to use the same CRO for Phase I-III. Companies used to be reluctant to mix and match CRO’s in a singler development project due to data transfer problems, but the global nature of clinical studies has allowed that problem to be overcome.
What I was blessed to have, and what seems to be lacking today are STRONG project managers working on the sponsor side, who are accountable straight to the top and who have broad authority to “manage the managers” of the trials. They are also former medical directors who have a high index for suspicion. A project manager usually suspects something when things appear to be going to well with a particular CRO, since that’s not how things go in reality.
Looking back on whom I’ve worked with I would say with reasonable certainty that these project managers would NEVER have let a series of studies get to the point as they did with Cetero.
original industry insider
Just to reinforce that crime does indeed pay, below is reference to Dr. Lisa Krinski, former director of the notorious South Florida Bioavailability Clinic, who walked away with nearly a $4,000,000 golden parachute in 2006.
http://www.bizjournals.com/southflorida/stories/2006/01/02/daily1.html?jst=t3_ln_hl
Industry Veteran
Do you guys work for industry competitors or are you just angry guys and gals with too much time on your hands?
I have never seen so much speculation without facts or reason.
The “facts” in this article are that 5 senior people from Cetero also worked at MDS, and MDS had issues in their labs, and now Cetero is having issues too. The implication is that the two are linked.
The writer notes that MDS is now part of INC Research - true, but not the relevant part - INC bought the phase 2-3 operations. However, the former MDS Phase 1 and bioanalytical are now called Celerion - as they have more former MDS employees than Cetero, are they also evil?
MDS was never accused of “bad intent or fraud” - merely scientific error. Not sure how scientific error from one firm can lead to fraud at another.
However, if it can, it is important to note that MDS was once one of the top 5 CROs in the world by staff number, and there are former senior MDS people at virtually every major CRO - does that make every CRO with senior MDS people into criminals?
If so, you can include Covance, Quintiles, ICON, PRA, Kendle, etc, Some of these CROs have also had 483s, so does that mean their is a causal link?
If you want to look at fraud, look at SFBC - they were accused of fraud, rooted out the bad actors, put new clean management in charge, and changed their name to Pharmanet, to highlight the change of leaders (who ran the Pharmanet division of SFBC). That firm is led by some of the most respected people in the industry, and when they merged with inventiv to form the 5 largest CRO in the world, they chose the executives of pharmanet to lead the combined CRO - clearly fraud doesn’t get transmitted to good people simply by working at the same global CRO.
The author noted that the website for Cetero doesn’t highlight the past experience of several people specifically at MDS. There are a dozen bios on the Cetero website, and only one of them mentions a prior employer by name - these are not their CVs, these are marketing pieces that talk about their years of experience and education. He implies that they are hiding MDS affiliation, but clearly they have taken the approach of focusing on their current employer, without naming former employers - a classic marketing approach, not a nefarious attempt to hide the past.
The site also says the CEO of Cetero joined last year, about a year after the issue was reported to the FDA by Cetero, yet the “lynch mob” of industry experts on this blog are already to kill this guy - If you have something accurate to say, or some facts to add, then add them. But if you are merely hyenas trying to jump onto the FDA bandwagon, why don’t you wait until the story before you go jumping to conclusions.
I suspect that some of these people are like you - dedicated scientists who take their jobs seriously. I hope you never find yourself in a situation where your honestly is impugned but an errant junior government official.
original industry insider
Industry Veteran, why don’t you have a few dozen conversations, as I did with sponsors who had to redo ANDA’s and lost tens of millions of dollars because of the screw-ups running MDSPS. Then asked them how forthcoming MDSPS was in admitting their problems.
Pressures to cut corners in Phase I are now greater than ever with industry cutbacks. That is why I still site visit Phase I units when practically nobody else does.
Jeff McMullen at Pharmanet cleaned house at SFBC when he took over. How come we haven’t seen a similar move at Cetero? As a Senior Director, I was able to play judge, jury and executioner, because all I had to go on was my company’s integrity. Anybody with the slightest whiff of suspicion was usually shown the door because I wanted everybody to be squeaky clean and beyond reporach.
As an Industry Veteran you know that we are a small commmunity and have to maintain the highest standards even if it means sometimes giving someone the boot who we may have cut a break in more forgiving times.
You should also know that more and more CRO’s are being taken private–more opportunity to hide their stains from the public view.
morning glory
The FACT is this CRO, Cetero, was exposed and branded by the FDA as fraudulent and manipulative. Granted it was for the Houston location however that lab analyzes many clinical trial samples, to provide data to various drug sponsors, for many different trials conducted at its five sister clinical research centers. Every Cetero site is affected in a negative way due to the egregious misconduct of their central bioanalytical lab. Furthermore it will likely be a severe financial disaster for this company. This CRO’s rep has bit the dust.
original industry insider
Maybe we should go back to the way things used to be before all this outsourcing began. When I was at Abbott in the mid 1980’s we were cranking out new formulations of erythromycin every quarter, or so it seemed, so we needed a full time bioavailability unit. We contracted with the University of Utah Medical Center for them to run our BA/BE studies in a highly rigorous manner. We had a full time dedicated CRA to monitor the site biweekly. We developed and validated all bioanalytical methods at our home labs at Abbott Park, IL. The study director had only to walk to the next building if he/she wanted to review the assay data with the analytical chemists.
Everything was done to the highest level GLP’s and GCP’s, with no issues from the FDA.
Thus, there IS a way to do these studies properly, but I’m afraid we have to live with the monster we’ve created otherwise know as outscourcing.
fargoboy
all good points but I think you have to read the FDA letter. It seems that there were several violations and Cetero wanted to address only 2. It took them over a year to write a sop that addressed one. The individual responsible for that left today, maybe he can get a job blogging or at the very least a firm that needs publicity. I guess the strategy of waiting for the FDA to put it in writing didn’t work out
Points to ponder: When you pay peanuts, all you attract is elephants and monkeys. And suprise, suprise when the monkeys and elephants learn new ways to get more peanuts. Who would have thought that they would get creative in charging overtime hours for normal work. Its funny when supposedly very smart people PHD’s try to explain away their mismangement of simple accounting. Pay industry standards, demand excellant work, and hold people accountable. Do you honestly believe that this won’t happen again.
Outsourcing will not be any better than the expectations of the sponsor. Why do sponsor assume that everyone is doing a good job. You just farm it out and never check to see how they do the work. Whats scary is when you work at a CRO and see the differences in auditors. You would be suprised that a lot of auditors don’t like to look for problems, it screws up their lifestyle. I agree that strong project management is one of the core ingredients to good outsourcing.
Sometimes you are meant to be a good example to everyone else for the wrong reasons. No matter how good you are, how big your company is, how much money you have, or how good your product is, you can be brought down by one person, one group who is untrained, underpaid, unsupervised, and unappreciated. Somehow the industry will forget this and do it again. After all it isn’t rocket science but we could kill people anyway
Canadianite speaks out
I personally observed and am aware of the mischief all over Cetero. I also resigned since I did not want to be involved and mainly because my moral character is too good to serve them. The common theme amongst them is they protect their alliances and waste company funds on a monthly basis to benefit only themselves. If many of their own employees cannot trust them then why should drug companies also trust them with their clinical trials?
Weekender
Lashing back against the FDA? Good luck with that Cetero boys & girls! Answering the previous question, hell to the no would I trust this CRO!
a phd and a mba
FDA did their part so now it’s pharmas turn. Doubt this is just a coincidence.
Cetero’s response to FDA ends with “What is most important is that the processes being used today at Cetero are state‐of‐the‐art. They are in full compliance with FDA regulations and bioanalytical industry standards.” Suuuuure.
These execs appear to be dazed and confused. Because what is most important is that the processes used YESTERDAY, TODAY, and TOMORROW should be robust, ethical, factual, reliable, and 100% credible. Cetero even has the audacity (a.k.a. balls) to claim they’re in full compliance with regs & standards? So they presume they are in full compliance albeit with fake fraudulent data and serious misconduct? Pharma companies are supposed to believe this? Get real.
MTL knoledge
I Do not know if they were directly implicated in the Cetero event, but I do know lots of people who were directly involved in the MDS event at the MTL site. This artical is just trying to make links where there might not be any. I don’t think there was a link.
First Hand Knowledge
The vast majority of the comments are absolutely absurd. I am a former CCRC of Cetero in Fargo and worked there during this entire process (I left for completely different reasons). I was there the day it was dicovered and Dr. Alan Copa brought the entire facility in to a meeting and said, “Hey, this is what’s going on. This is what we know. This is what we are doing about it. We are conducting an investigation. We are contacting the FDA and all of our sponsor companies to let them know what’s going on.”
This was an incident where scientists in the bioanalytical lab in HOUSTON were lying on their timesheets. Period. They clocked in, left, came back and clocked out and said they were there working on samples. This was an isolated incident in one facility involving, if I’m not mistaken, six scientists. That’s six people in a company that employs hundreds.
I take extreme offense to comments like the one from pheonix sun that come out of left field and aim to do nothing but condemn the company as a whole. I worked on these studies. I was project lead for these studies. I entered the data. I did the corrections after QC/QA. I worked face to face with every single person involved in running these studies at the Fargo site and I would put my reputation on the line in a heart beat to say that not a single one of them would intentionally manipulate data, or do anything that would jeapordize a study for the very reason that if we did, we would lose our job instantly. Cetero is not the best company in the world, but I have never worked for another company that pounded GCP in to our heads so often.
On another note, to say that these previous MDS employees are in some way responsible for for the validation issues or in some way connected to these scientests who took it upon themselves to falsify their timecards is no more true than saying I, myself, am responsible for these scientists. They acted independently and thought they could cheat toget more money. Cetero took the iniciative and fired all those involved when it was discovered.
I am truly saddened by the stigma that this has and most certainly will leave on Cetero as it may effect employees on all levels. Needless to say that “blah blah blah” comments made by those who just want to hear themselves talk and have no real knowledge of what happened certainly don’t help the situation.
the inside connection
Cetero’s ‘distinguished’ Chief Scientific Officer recently left the company.
Things that make you go hmmm.