The History of Proove from 2009 until 2017

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Proove's Response Issued to Piller Claims on June 8, 2017

Piller Claims: In stories published in December 2016 and February 2017, Piller and STAT News suggested that Proove marketed an “unproven” technology that “lacks a firm scientific basis” and “peer-review”, and that “Proove’s first clinical study subjected to peer review, based on data from 134 patients, wasn’t published until late January in the Journal of Psychiatric Research.”

Empirical Evidence: This is false. In 2005, NIH began funding the largest prospective study in chronic pain. NIH-funded scientists, based at the University of North Carolina at Chapel Hill, discovered an algorithm or what is called a haplotype of genetic variants associated with pain sensitivity and chronic pain risk.[1] That work, along with clinical trials showing the impact on patient care, was published in 2005, 2006, and 2010 by respected peer-reviewed journals, including Science[2], Human Molecular Genetics[3], and Pain[4]. It was for this algorithm that UNC Chapel Hill submitted patent protections for this unique algorithm, and then licensed it exclusively to Proove.[5] Based on this algorithm, Proove launched the Proove Pain Perception profile to help clinicians objectively assess a patient’s sensitivity to pain and guide appropriate treatment. In addition, Proove acquired the commercial rights to the data and discoveries associated with that algorithm when it acquired a company formed by the UNC researchers in 2016.[6] 

Contrary to Piller’s assertions, Proove’s technology was supported by numerous published studies and is the product of substantial monetary investments. The Company has not only published its studies in peer-reviewed journals but has also received recognitions and awards for its research presented at major medical meetings, including the American Academy of Neurology (2014), American Society of Interventional Pain Physicians (2014), and American Society of Regional Anesthesia and Pain Medicine (2015). 

Piller Claims: In both the initial December and February stories, Mr. Piller alleged that Proove’s technology does not help patients. To support his erroneous claims, he relied on the anecdotal evidence of a single doctor who said he ordered “two tests” and didn’t see much value. Mr. Piller also referenced an “audit of 1,500 patient charts” at National Spine and Pain Centers (NSPC), which was supplied by an unnamed “former executive” to support this false assertion. This “audit” doesn’t exist. What does exist is an interim study report that was provided to NSPC in May 2016. It demonstrated positive patient outcomes. 

Empirical Evidence: Both of these claims are false. The findings of a Multicenter Longitudinal Observational Study Evaluating Genotypic Association with Clinical Outcomes in Interventional Pain Management Modalities (M.O.S.A.I.C.) showed significant improvement in pain when using Proove technology to guide treatment decisions. M.O.S.A.I.C. is a multi-center clinical trial, reviewed and approved by an institutional review board (IRB) licensed by the Office of Human Research Protections (OHRP) at the U.S. Department of Health & Human Services (HHS). The study had been approved and listed on the U.S. National Library of Medicine’s website, www.ClinicalTrials.gov (NCT Identifier: NCT02485795). NSPC physician and researcher, Dr. Daniel Kendall, served as the principal investigator of the trial where 11,605 study participants were enrolled at 32 NSPC locations. Among the study findings at NSPC:

· 92% of NSPC patients receiving Proove testing reported an average pain reduction of 40% following the treatment decisions informed by Proove.

· The average numerical pain rating score (NRS) before Proove was 7.7 and the average NRS after treatment guided by Proove information was 4.6. This reduction of 3.1 or 40% exceeds the FDA’s requirement of 2.1 or 30% on a 0 to 10 scale to have an indication of analgesia approved. In fact, 26.5% of the NSPC patients reported a greater than 50% reduction in pain.

· Over 73% of NSPC patients had a favorable response to medications following changes to their medications based on Proove reports between visit 2 and 3 in the M.O.S.A.I.C. trial. 

· Proove technology also resulted in appropriate reduction in opioid utilization for high risk patients. 15% of patients reported taking less opioid medication at visit 3 versus visit 2. Interestingly enough, for those patients switched to a non-opioid analgesic, there was no significant difference in the average medication efficacy rating in visit 3 versus the opioid medication in visit 2 (p=0.87), suggesting that these patients did just as well on non-opioids as they previously did on opioids. 

These facts are diametrically opposed to what Mr. Piller alleged. These strong outcomes – a 40% to 50% reduction in pain – are consistent across various types of clinicians, specialties, and treatment centers. 

Piller Claims: In both the December and February stories, Mr. Piller suggested that Proove marketed an “unproven” test that is “unsupported by hard data”, and “backed by little or no credible scientific data showing their reliability.” He went onto to misstate that “Proove’s predictive abilities rely on a 12-gene profile” suggesting that the test relied solely on genetics, and that Proove’s claims of up to 93% testing accuracy were “sales hype.”

Empirical Evidence: These claims are false. First, Mr. Piller was informed repeatedly during the reporting process that Proove’s technology is based on both genetics and non-genetic factors. Specifically, the Proove Opioid Risk profile contains 17 component factors – 11 DNA markers and six family and behavioral characteristics. Each one of these component factors have been established through independent, peer-reviewed published studies as contributing to narcotic addiction and related behaviors. 

There are five clinical studies demonstrating the high accuracy with which the Proove Opioid Risk profile performs. These studies were conducted in 126 clinics throughout the United States, which specialize in orthopedics, pain management, psychiatry, primary health and addiction treatment. The accuracy of the test, as measured by the gold-standard of statistical methods, ranged from 76.7% to as high as 96.7%. Three of these studies supporting the algorithm in the Proove Opioid Risk Profile have been accepted for publication in peer-reviewed publications so far[7],[8],[9], with 6 additional studies currently under review. Therefore, it’s the exact opposite of what Piller falsely alleges. Rather than 93% being an exaggeration as suggested by Piller, the accuracy of Proove Opioid Risk is shown in published peer-reviewed studies to be as high as almost 97%. 

Concerning the role of genetics in the profile, Proove consistently agrees with the National Institutes of Drug Abuse and the American Society of Addiction Medicine[10] that genetic factors account for half of the risk of substance abuse. Ignoring half of the equation is a mistake which has led to the current epidemic. In short, genetics alone are not enough. That’s why Proove Opioid Risk profile balances genetic and non-genetic factors in its proprietary algorithm. Genetics account for 42% of the result, while family, lifestyle, environmental, and behavioral factors account for 58%.

Business Practices

Piller Claims: Mr. Piller wrote that Proove was using this ongoing research effort as “largely a ploy to boost…revenues” by paying doctors to order “unnecessary tests on patients”. He asserts that Proove promises doctors they can make $144,000 a year for enrolling their patients and ordering the opioid risk tests.

Empirical Evidence: These claims are also false. Proove reimbursed participating investigators only for the time they spend with patients provided research services. No research or payment was tied to the number of tests or patients, the volume of referrals or the size or prestige of an institution or medical practice. The “source” in the article for this amount was a draft document developed by a subcontractor and immediately rejected as wildly inaccurate and removed from circulation by Proove as soon as Proove learned of it. Mr. Piller did not ask Proove about that as part of his reporting. In fact, Proove’s records showed that the company paid participating study investigators an average of $6,400 in 2016, compared to an average salary for a pain management physician or orthopedic surgeon ranging from $305,000 to $444,000 a year. This money – less than $600 per month - represents less than 2% of their annual income. Investigators were required to submit completed and signed time sheets, as well as the original source research documents, to Proove. The documents were audited and then compared with time-study standards before Proove issued a payment based on the fair market value of the service as determined by an independent third party. 

Piller Claims: Mr. Piller also wrote that Patient Engagement Representatives (PE Reps) inflated test orders by enrolling patients without their knowledge, pressuring doctors to order the Proove Opioid Risk Profile and falsifying paperwork for test orders, diagnoses, and outcomes.

Empirical Evidence: These are also false. Clinicians, not Proove PE Reps, determined the medical necessity of all clinical testing on a patient. Each profile ordered must have a testing agreement signed by both the physician and patient, which include relevant ICD diagnostic codes for each panel. In addition, an ordering clinician was required to submit a letter of medical necessity with the testing agreement, and a patient was required to submit a HIPAA consent form and assignment of benefits to Proove. In addition to agreements related to any medically-necessary testing, any patients who volunteered to be a study participant were required to sign an informed consent to do so, and had to complete extensive paperwork on every visit, which could take as long as 20 minutes per visit to complete. Clinicians ordered Proove profiles on an average 1.67 patients a day for each clinic, out of a total of between 20 and 30 patients a day seen by a clinician. 

These facts stand in stark contrast to the erroneous allegations in the story that Proove “is in it for the money… to swab as many people as possible… test every single soul who walked in.” The average patient completed 90 forms over a three to six-month period to track his/her outcomes and signed those forms. PE Reps conducted those patient interviews related to the patient outcomes studies, and only filled out paperwork based on their interviews with patients. This process intentionally separated the medical care provided by the doctor and office staff from the clinical research services performed by the PE Rep. The clinician, if they were a study investigator, also could spend time outside of providing medical care to complete assessments. Patients were more than aware of the testing ordered. Profiles that were ordered were restricted by written standing orders and a clinician’s request, and PER activities were restricted by inclusion and exclusion criteria for the various research studies as to who they could collect information from on a given clinic day. 

Piller Claims: Mr. Piller wrote that Proove exploited a “loophole” in FDA guidelines to “operate without any oversight on whether or not their products work as advertised” and delivered “spurious test results”. 

Empirical Evidence: This allegation is again false. Like other providers of laboratory-developed tests (LDTs), Proove was subject to the FDA’s Clinical Laboratory Improvement Amendments of 1988.[11] This federal law requires the California Department of Health to inspect Proove’s laboratory every two years for validity. As an added measure of quality, Proove voluntarily underwent inspections and received accreditation by the nation’s most scientifically rigorous laboratory standards through the College of American Pathologists (CAP).[12] In its inspections from CLIA and CAP over the last 2 years of its operations prior to the summer of 2017, Proove’s laboratory passed with a 100% rating without any corrective actions. Those accreditations and quality standards underscored Proove’s track record of accuracy and high-quality. 

Furthermore, twice over the last decade, the FDA has proposed draft guidance on how to regulate LDTs; however, the agency has been reticent to move forward and each of these proposals has glaringly ignored the reimbursement implications. Proove welcomed FDA review and was prepared with the commensurate data to submit either a 510(K) or de novo Class II medical device submission once the FDA created a pathway to allow such testing to be approved. 

Leadership

Finally, both of those articles inaccurately, unfairly, and maliciously attacked Proove’s leadership. Proove’s founder and CEO, Brian Meshkin, has a thirty-year track record of innovation and helping solve public health problems.[13] However, due to Piller’s apparent personal animosity, these articles falsely suggested dissension. 

Piller Claim: Mr. Piller wrote that Proove’s major investor, Leavitt Equity Partners, the private equity fund of former Utah Governor and former U.S. Department of Health and Human Services Secretary Michael Leavitt, was taking a “wait-and-see” approach about Proove and its technology.

Empirical Evidence: This is false. Governor Leavitt served a two-year term on Proove’s board. Governor Leavitt stated: “We invested $3.5 million into the company because it has great promise. We continue to feel that way. I believe in Proove. The science is developing. And we invested in the process to drive that science forward on behalf of patients who deserve safe and informed relief for chronic pain.”
   

[1] NIH Research Portfolio Online Reporting Tools: Pain Management https://report.nih.gov/nihfactsheets/ViewFactSheet.aspx?csid=57 

[2] Nackley, A.G. et al. Human catechol-O-methyltransferase haplotypes modulate protein expression by altering mRNA secondary structure. Science314, 1930-3 (2006).

[3] Diatchenko, L. et al. Genetic basis for individual variations in pain perception and the development of a chronic pain condition. Hum Mol Genet 14, 135-43 (2005)

[4] Diatchenko, L. et al. Catechol-O-methyltransferase gene polymorphisms are associated with multiple pain-evoking stimuli. Pain 125, 216-24 (2006).

[5] https://www.genomeweb.com/business-news/proove-bio-inks-exclusive-licensing-deal-unc-pain-dx 

[6] https://www.genomeweb.com/business-news/proove-biosciences-acquires-algynomics 

[7]Brenton et al. A Pilot Study to Evaluate a Predictive Algorithm of Genetic and Clinical Data for Opioid Use Disorder. Pharmacogenomics and Personalized Medicine, 2 March 2017.

[8]Farah et al. Evaluation of a Predictive Algorithm that Detects Aberrant Use of Opioids in an Addiction Treatment Centre. J Addict Res Ther 2017, 8:2

[9]Brenton et al. Validation Study of a Predictive Algorithm to Evaluate Opioid Use Disorder in a Primary Care Setting. Health Services Research & Managerial Epidemiology, May 2017.

[10]ASAM Long Definition of Addiction, April 2014 

[11] https://wwwn.cdc.gov/CLIA/Regulatory/default.aspx 

[12] http://www.cap.org/web/home/lab/accreditation/laboratory-accreditation-program?_afrLoop=136253709004664#!%40%40%3F_afrLoop%3D136253709004664%26_adf.ctrl-state%3Dd487t48ze_4 

[13] http://www.brianmeshkin.com/about-2/vision/ 

In December 2016, Charles Piller of STAT News publishes his first article full of unsubstantiated lies.

In February 2017, he publishes in STAT News an even more egregiously inaccurate and defamatory article.

During this time, Proove reaches out to the U.S. Attorney's offices and FBI and invites discussion and meetings.

In late May 2017, the U.S. Attorney's Office in the Southern District of California accidentally violates the Federal Whistleblower law and publishes sealed documents about Proove's whistleblower lawsuits on the public database called PACER. Law firms like Mintz Levin publish blog posts suggesting that the government took the cases - which they did not.  Proove informs the US Attorney's office of their folly and the government corrects their legal violation.

Proove sends STAT News a legal demand to correct its story or Proove will sue.

In early June 2017, the U.S. Attorney's office serves Proove with a subpoena and search warrant, and calls in local television station camera crews to film FBI agents taking boxes out of Proove's offices.

Piller publishes "victory dance" article in early June 2017 suggesting that the FBI's action validates his false articles.

Proove's revenue dropped by >90% due to insurance companies putting Proove on hold due to negative media attention around the government investigation. 

In August 2017, Proove enters a receivership to restructure.  Mid-August, Receiver informs CEO Brian Meshkin that he abandoning restructuring plan and liquidating the business owned by Meshkin. Meshkin resigns and sues the Receiver to stop liquidation.  Both parties mutually walk away, as the Receiver shuts down the business in a matter of months, and liquidates all assets against the will of the 96% shareholder, Meshkin. 

Proove's operations are placed on hold until the governmental inquiry ends. 

The governmental inquiry ends in April 2018, when the grand jury expired.  

Three years later in August 2020, a former independent sales distributor of Proove's, Donald Joe Matthews plead guilty to charges of conspiracy to defraud Medicare - without an indictment - and no evidence of wrongdoing.  

In June 2021, Matthews turns on Proove and one of its largest clients, National Spine & Pain Center (NSPC), and falsely implicates the Company.  Five former employees from Proove and four doctors from NSPC are indicted on the same charges as Matthews's plea.

In July 2021, all Defendants plea Not Guilty and begin defense.

Someone leaks to the Baltimore Sun (where the Proove founder is originally from) and OC Register (where the Proove founder lives) inaccurate representations of the indictment and they both publish stories filled with inaccurate information.

The trial is unfortunately postponed due to Covid from October 2021 until October 2022.

Again, the trial is unfortunately postponed again from October 2022 until January 2023 at the request of the government.

In the fall of 2022, two former execs from Proove receive Non-Prosecution Agreements (NPAs) to testify.  Instead of testifying for the government, they agree to testify for the defense. Another exec, one of the relators in the whistleblower lawsuits, agrees to testify for the government.

In December 2022, the united defense submits many pre-trial motions to challenge the facts of the government's case which lacks any evidence.  The judge demands prosecution, including FBI agents and Assistant U.S. Attorneys to provide written declarations under penalty of perjury to justify "something she has never seen before in her career".  In late December 2022, the U.S. Attorney's office for the Southern District of California is unwilling to justify their behavior and lack of evidence in written declarations, and agrees to dismiss all charges "in the interests of justice."