FDA and Valor

Lessons Learned from the Valor Medical Case

by DeeAnn Visk

On Thursday, April 17^th, the San Diego Clinical Research Network (SDCRN) and the San Diego Regulatory Affairs Network (SDRAN) held a joint meeting at CareFusion entitled “Increased Focus on Enforcement in Clinical Research – Lessons from Recent Cases.”

Clinical research activities are currently subject to unprecedented government scrutiny, as evidenced by many recent settlements between the U.S. Department of Justice (DOJ) and both medical device and pharmaceutical companies. Typically, government investigations focus sales and marketing practices; they have now expanded to include research and development activities.

Thomas W. McNamara, a white-collar defense attorney from Ballard Spahr LLP in San Diego, presented the case of “Valor Medical: A Local Prosecution with Universal Lessons.”  McNamara, a former federal prosecutor, discussed the case against the San Diego biomedical device maker Valor Medical.  They have been prosecuted for not including two negative lab test results in their 2008 Investigational Device Exemption (IDE) application.

Word Cloud from McNamara talk

The case began with the company filing their IDE in 2008, and ended with the U.S. Attorney’s Office filing criminal charges against the company and its officials in 2014.  McNamara concluded that the company’s lack of transparency, and failure to grasp the seriousness of the FDA’s inquiry, combined with Murphy’s Law to produce “a perfect storm” of events, ending with criminal charges against the company and four of its leaders. How did they get into this mess?

In 2007, the company began seeking pre-market approval for their product Neucrylate, which was implanted via catheter to treat aneurysms.  Upon its contact with blood, Neucrylate becomes sponge-like, thereby stopping life-threatening hemorrhages. Chromosomal assay (CAA) and mouse lymphoma assay (MLA) tests were done, and indicated that Neucrylate was cytotoxic and mutagenic.

The company decided did not include these tests in Valor’s IDE application to the FDA in 2008. FDA regulations require that all results of any animal tests be included in IDE's.  The IDE was rejected.  In 2009, Valor's regulatory consultant left the company with hard feelings—he had also been a member of the Board and was removed from this position.  Unbeknownst to Valor, he reported to the FDA the company’s failure to include the CAA and MLA tests in their application to conduct clinical testing.

In 2010, the company filed a new IDE for Neucrylate, again omitting the CAA and MLA test reports. The FDA then inspected their site for two days, during which the company’s leaders were not forthcoming about the tests.  Meanwhile, a lower-level employee told the FDA that there was an intentional decision to not include these test results.

In 2011, FDA sent Valor a warning letter indicating their failure to include reports of all prior clinical, animal, and laboratory testing of the device in their IDE.  Valor’s management responded that the omission of the animal tests was “inadvertent”, blamed it on the change in regulatory personnel, and claimed the tests only came to their attention in February 2011.

“Remember,” warned McNamara, “the ‘e’ in email stands for evidence.”

The FDA then turned to the U.S. Attorney General’s Office, which issued a search warrant that was executed in 2012.  Imagine the work disruption when armed, bullet-proofed vested, federal agents enter your company and order you to step away from your computers.  Every scrap of paper is removed, along with any computers (that they cannot make a mirror image of on a hard drive).  Email messages found on the company’s computers indicated that Valor was aware of the negative test results long before 2011.

Valor’s presidents (past and present), Chief Scientific Officer, and clinical research consultant were charged with misdemeanor violations, and the company pled guilty to a felony charge.  Two of Valor's executive team entered into a deferred prosecution agreement.  The other two plead guilty to a misdemeanor.

So what lessons can be gleamed from this tale?

1) If a decision is made to not include a test in a regulatory filing, ensure this is reviewed by a regulatory attorney.

2) Take FDA warning letters and inspections seriously. If possible, include a management representative on all employee interviews during an inspection.

3) If given notice of an FDA audit, come up with a plan to comply with their requests.

4) Beware of the possible repercussions of parting ways on bad terms with employees. 

Whistleblower and Evidence

In listening to an NPR report on tax evaders, the author realized that law enforcement likes to give people to opportunity to “come clean”, especially to non-violent crimes.  Officials at Valor choose not to admit their knowledge of the CAA and MLA reports when given the opportunity by the FDA.

Another reason for the mess may be the different sense of time perception between nimble startup companies and the government bureaucracy.  The gears of the federal government turn much more slowly.  What Valor perceived as ancient history, was still an ongoing investigation for the federal government.

McNamara believes that by following the above suggestions, companies can avoid the outcomes like Valor’s when dealing with the FDA.

DeeAnn Visk, Ph.D., is a freelance science writer, editor, and blogger.  Her specialties include molecular biology, genetics, immunohistochemistry, and microscopy.  DeeAnn lives in the San Diego, California area with family which includes two spoiled hens.

 

interactions between clinical trials and "-omics" revolution

 Report on November 2013 meeting of SDCRN

by DeeAnn Visk

On November 25, 2013, the San Diego Clinical Research Network held a meeting at the Sanford Consortium for Regenerative Medicine, with a reception at Bella Vista Cafe.  Three speakers talked about innovations in clinical trials.  J. Summer Rogers, Chief Executive Officer of nPruv, Inc., a company which acts like a “match.com” to match up patients and clinical trials, moderated the event.

The first speaker, Marcos Milla, Ph.D., Scientific Director and Fellow at Janssen, spoke from the pre-clinical research perspective about the search for drugs and patients by phenotypes.  New thinking about entire systems within a cell versus a specific target, allows complex cellular systems as a whole to be targeted.  Given the intricacies of problems with the immune system, this way of thinking will simplify a complex milieu.

Executing these experiments is the simple part.  A more difficult question is interpreting them.  One approach employs phenotypic read outs:  proliferation, migration, contact, differentiation, and activation.  These phenotypes can be read with automated systems, enabling high throughput screens.  Next, gross readouts of cell behaviors must be correlated with molecular readouts to permit determination of structural activity relationships.  To accomplish this, functional readouts need to be deconvoluted to concrete “hits”.  Harnessing knowledge of the human interactome will facilitate this goal.

Clinical trials can target complex pathways in the human interactome.

An example of this workcan be found in the eicosanoid biosynthetic pathway.  High throughput and high-sensitivity liquid chromatography mass spectroscopy is utilized to acquire data from three different phenotypically-normal, healthy patients exposed to prostaglandin inhibitors.   All three displayed remarkably different profiles.   Differences in these profiles suggest different drugs would be most effective for each patient.

One method to optimize these interactions is to bring together the wide variety of “-omics” (genomics, metabolomics, proteomics, etc.) to build a drug profile for each individual patient.  This information could then be used to optimize individual treatments for specific patients.

The next speaker, Andreas Koester, M.D., Ph.D., VP Clinical Trial Innovation & External Alliances, Janssen, spoke about clinical trial innovations spawned by collaborations between large pharmaceutical companies, and a patient-centric approach to designing trials. As a leader in clinical trial operations, he offered a different perspective.

As a potential drug journeys through the research and development process, out of 10,000 compounds, 1 new drug will be approved by the FDA.  Presently this process costs about 2 billion dollars and takes 10 years.  How can we better spend our time and money?

A collage of words from Andreas Koester’s talk on improving clinical trials.

We need to change how we design clinical studies.  Patients should be first in mind in designing trials.  Collaboration between drug companies will streamline this process.  TransCelerate BioPharma, Inc., a non-profit organization established by leading pharmaceutical companies to advance innovation and tackle inefficiencies in R&D, is an example of this.  TransCelerate has developed guidelines for risk-based monitoring to reduce the cost of clinical trials, and established criteria for the qualifications and training of clinical research sites.

A Blue Button™ Initiative begun by the Veterans Administration to allow patients the opportunity to access and download their health records is being extended to clinical trials.  Pfizer is piloting the use of Blue Button™ technology to enable participants in Pfizer trials to download their own electronic clinical data collected in the trial.  Patients sign up after the study to get data results through a third party.  Normally  patients  receive no information about the results of a clinical trial in which they participate.  By allowing patients access to this information, patients are more engaged with the process.

Novartis is partnering with Walgreens to bring clinical trials to the patient.  Ninety percent of all Americans live within three miles of a Walgreens pharmacy.  No longer must patients interested in participating in clinical trials travel scores of miles to participate.  Novartis is currently doing a novel trial, allowing study participants to have their follow-up visits at Walgreens rather than hospitals, in an attempt to run the trial more efficiently and scale more widely.

Recently, the FDA allowed a trial for a investigational new drug (IND) with a clinical trial protocol developed using crowdsourcing.  The open innovation drug developer, Transparency Life Sciences, gained FDA clearance to proceed with a phase II trial of the antihypertensive drug lisinopril as adjunctive therapy in multiple sclerosis.  This groundbreaking, crowdsourced protocol also eliminated most study visits by using telemonitoring to assess outcomes.

The final speaker of the evening, Steven Steinhubl, M.D., Director of Digital Medicine at Scripps Clinic and Scripps Translational Science Institute, spoke about using mobile health technologies (mHealth) to conduct patient-centered clinical trials.  The change he advocates in clinical trials is to “move the mountain,” by bringing clinical trials to patients.  Presently healthcare is designed around the physician and not the patient.  Clinical trials are also designed around physician investigators.

The biggest driver of cost for clinical trials is Phase III testing.  Ninety percent of the cost is associated with this step.  Mobile health technologies can allow us to do studies more efficiently, and reduce costs.  However, there are cultural and regulatory barriers to implementing mobile health technologies into clinical trials.

Translational medicine employs clinical trials to move ideas from research to the bedside.

Another area needing change is the average lag time between a definitive clinical trial and changing the majority of clinical practice.  Currently it is 17 years.  Although 17 years is unacceptable, from a historical standpoint we are improving rather dramatically.  For example, it took 264 years for vitamin C use (via citrus fruits) on ships to prevent scurvy to become common practice after a definitive study.

During discussion, the panel agreed that the device and pharma industry need to be integrated from invention through clinical trials.  Perverse financial incentives for reimbursement on devices encourages the creation of a new device to accompany every new test.  This needs to be fixed.  Ironically, medicine is the only industry where more technology increases costs.

This entry was originally posted on www.deeannvisk.com on January 12, 2014.