Proove's Corporate Response

to STAT journalists alegations

June 8, 2017

 

OFFICIAL CORPORATE RESPONSE: STAT News Hit Pieces Were the Farthest Things from the Truth

 

For the past six months, the Company has chosen not to dignify these erroneous statements, but due to the “sensational” nature of these falsehoods being spread by terminated employees and consultants, the situation is spiraling out of control and Proove is forced to respond and set the record straight.  On Friday, June 2, Proove representatives delivered a forceful request to the Managing Editor of STAT News for a correction of two erroneous stories written by Charles Piller and published online in December 2016 and February 2017.  These inaccurate stories have caused damages to Proove®’s reputation, our ordering physicians, research collaborators, and patients.  These stories contained many errors and misstatements about Proove®’s technology, science, business practices, and leadership.  Even more disturbing was Mr. Piller’s overall approach and obvious bias. In an age where anyone can post “fake news” online, both pieces contained errors of omission, lacked context and/or perspective in key areas (all of which portrayed Proove® in a negative light), featured some sources that have no knowledge of our company or our emerging industry, and relied on information – much of it incorrect and/or misleading – provided by disgruntled and discredited former employees.   In contrast, Proove® would like to share with you the facts with verifiable and reliable sources to restore its otherwise unblemished reputation.

 

Technology

 

False Claims: In both stories, Mr. Piller suggests that Proove® markets 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 [sic 2017] in the Journal of Psychiatric Research.”

 

Truth: In 2005, NIH began funding the largest prospective study in chronic pain. NIHfunded scientists, based at the UNC 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].  UNC Chapel Hill submitted patent protections for this unique algorithm, and then licensed it exclusively to Proove.[5]  Based on this algorithm, Proove® launched Proove Pain Perception® in 2014 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]

 

                 

STAT News Response

June 8, 2017

Page 2

 

Contrary to Piller’s assertions, Proove® technology is the product of substantial monetary investments and supported by numerous published studies (see table on Page 4).  The Company has not only published its studies in peer-reviewed journals, but has also received recognitions for its research presented at major medical meetings, including the

American Academy of Neurology (2014),[7] American Society of Interventional Pain Physicians (2014),[8] and American Society of Regional Anesthesia (2015).[9]

 

False Claims: In both stories, Mr. Piller alleges that Proove® technology does not help patients. To support his erroneous claims, he relies 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. 

 

Truth: This “audit” doesn’t exist. 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, quantitative improvement in pain when using Proove® technology to guide treatment.[10] M.O.S.A.I.C. is a 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 has been approved and listed on the U.S. National Library of Medicine’s website, www.ClinicalTrials.gov (NCT Identifier: NCT02485795).[11]  NSPC physician and researcher, Dr. Daniel Kendall, served as the initial principal investigator 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®. Over 73% of NSPC patients had a favorable treatment response following changes based on Proove® reports.  The average numerical pain rating score (NRS) before Proove® testing was 7.7 and the average NRS after treatment guided by Proove® information was 4.6.  This reduction of 3.1 points on a 1 to 10 scale or 40% exceeds the FDA’s requirement of 2.1 points or 30% to have an indication of analgesia approved.  In fact, 26.5% of the NSPC patients reported a greater than 50% reduction in pain.

 

  • Proove® technology also resulted in appropriate reduction in opioid utilization for high risk patients. 15% of patients reported taking less opioid medication after treatment guided by Proove information.  Interestingly enough, for those patients switched to a non-opioid analgesic, there was no significant difference in the average medication efficacy rating of opioids medication in visit 2 (p=0.87),

 

                 

STAT News Response

June 8, 2017

Page 3

 

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.

 

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

 

Truth:  First, Mr. Piller was informed repeatedly during the reporting process that Proove®’s technology is based on both genetics and non-genetic factors (environmental, lifestyle, behavioral). Specifically, Proove Opioid Risk® 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 (see table on next page).

 

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 care 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 Proove Opioid Risk® have been accepted for publication in peer-reviewed publications so far[12],[13],[14], with 6 additional studies currently under review.   This data directly opposes Piller’s false allegations. Rather than 93% being an exaggeration as suggested by Piller, the accuracy of Proove® Opioid Risk is shown in published peerreviewed studies to be as high as almost 97%.

 

Concerning the role of genetics in the profile, Proove® data supports the National Institutes of Drug Abuse and the American Society of Addiction Medicine15 estimations that genetic factors account for up to half of the risk of substance abuse.  Taking these factors into account during clinical examinations is necessary to effectively combat the opioid abuse epidemic currently sweeping the nation. However, genetic factors alone are not enough.  That’s why Proove Opioid Risk® profile balances genetic and non-genetic factors in its proprietary algorithm.

 

The following is a table outlining all of those individual factors and some of the associated peer-reviewed scientific publications:

Protein Name                                       Gene                  SNP Marker                Associated Neuro-Psychiatric Disorders

Catechol-O-Methyltransferase COMT rs4680 Drug Abuse16; Anxiety17; Depression18
Dopamine Beta-Hydroxylase DBH rs1611115 Cocaine Addiction19; ADHD20; Schizophrenia21
Dopamine D1 Receptor DRD1 rs4532 Depression22; Heroin Addiction[15][16]
Dopamine Receptor D2 ANKK1/DRD2 rs1800497 Alcohol & Cocaine Dependence[17]
Dopamine D4 Receptor DRD4 rs3758653 Anxiety[18]
Dopamine Transporter SLC6A3 DAT rs27072 Methamphetamine Addiction[19]
GABA Receptor A, gamma2 subunit GABRG2 rs211014 Alcohol Abuse[20]
Opioid Receptor, Kappa 1 OPRK1 rs1051660 Mood Disorders[21][22]; Alcoholism[23]
Methylenetetrahydrofolate Reductase MTHFR rs1801133 Bipolar Disorder, Depression[24]
Opioid Receptor, Mu 1 OPRM1 rs1799971 Heroin Addiction[25]
Serotonin Receptor 2A HTR2A rs7997012 Drug Abuse,7 Depression[26][27][28][29][30][31]

Risk Factors

Age                                        16-45 years old33

Personal history                       Mental disorders34; Depression35,; Alcoholism27; Drug use36; Rx drug abuse37

16 Tassin, J.P., Uncoupling between noradrenergic and serotonergic neurons as a molecular basis of stable changes in behavior induced by repeated drugs of abuse. Biochem Pharmaco, 2008. 75(1): p. 85-97. 17 Koks, S. and E. Vasar, Deramciclane (Egis). Curr Opin Investig Drugs 2002. 3(2): p. 289-94.

  • Wade, A.G., et al., Citalopram plus low-dose pipamperone versus citalopram plus placebo in patients with major depressive disorder: an 8-week, double-blind, randomized study on magnitude and timing of clinical response. Psychol Med, 2011. 41(10): p. 2089-97.
  • Fernandez-Castillo, N., et al., Association study between the DAT1, DBH and DRD2 genes and cocaine dependence in a Spanish sample. Psychiatr Genet, 2010. 20(6): p. 317-20.
  • Ji, N., et al., Dopamine beta-hydroxylase gene associates with stroop color-word task performance in Han Chinese children with attention deficit/hyperactivity disorder. Am J Med Genet B Neuropsychiatr Genet, 2011. 156B(6): p. 730-6. 21 Cubells, J.F., et al., Linkage analysis of plasma dopamine beta-hydroxylase activity in families of patients with schizophrenia. Hum Genet, 2011. 130(5): p. 635-43.

22 Nyman, E.S., et al., Interaction of early environment, gender and genes of monoamine neurotransmission in the aetiology of depression in a large population-based Finnish birth cohort. BMJ Open, 2011. 1(1): p. e000087.

STAT News Response

June 12, 2017

Page 5

 

Business Practices

 

False Claims: Mr. Piller wrote that Proove® is using their 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 $144,000 a year for enrolling their patients and ordering tests.

 

Truth: Proove® reimburses participating investigators only for the time they spend providing research services.  No research or payment is tied to the number of tests ordered, patients referred, or the size or prestige of an institution or medical practice. Investigators are required to submit completed and signed time records, as well as the original source research documents to support an audit of their time records. Only after documents are audited and approved based on time-study standards does Proove® issue a payment based on the fair market value of the service as determined by an independent third party. The “source” for the amount alleged by Mr. Piller was an unauthorized and inaccurate draft document developed by a subcontractor that was immediately rejected as wildly inaccurate and removed from circulation as soon as Proove® learned of it.  Mr. Piller did not ask Proove® about the authenticity of this document prior to his reporting. In fact, Proove®’s records show that the Company paid study investigators an average of $6,400 in 2016 or less than $550 per month. This represents less than 2% of the average annual salary for a pain management[32] or orthopedic surgeon[33].

 

False Claims: Mr. Piller also wrote that Patient Engagement Representatives (PE Reps) inflate 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.

 

Truth: Clinicians, not PE Reps, determine 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 includes relevant ICD codes.  In addition, ordering clinicians often submit a letter of medical necessity, and a patient must sign a HIPAA consent form and assignment of benefits to Proove®. On average, clinicians order Proove® profiles on 1.67 patients a day, out of an average of between 25 and 40 patients seen per day by a clinician, and these orders are restricted by written standing orders and a clinician’s request.  These facts stand in stark contrast to Piller’s erroneous allegations that Proove® “is in it for the money… to swab as many people as possible… test every single soul who walked in.” 

 

In addition to medically-necessary testing, any patients who volunteer as a study participant must sign an informed consent, and complete extensive paperwork on every visit, which can take as long as 20 minutes per visit to complete.   The average patient will complete and sign 90 forms over a three to six month period to track his/her outcomes.  PE Reps conduct these patient outcome interviews, and only fill out paperwork based on the study protocol. This process intentionally separates the medical care provided by the doctor and office staff, from the clinical research services performed by the PE Rep.  The clinician, if they are a study investigator, also may spend time outside of providing medical care to complete assessments.  PE Rep activities are restricted by inclusion and exclusion

 

STAT News Response

June 8, 2017

Page 6

 

criteria for the various research studies as to who they will collect information from on a given clinic day.

 

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

 

Truth: Like other providers of laboratory-developed tests (LDTs), Proove® is subject to the FDA’s Clinical Laboratory Improvement Amendments of 1988.[34]  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 undergoes inspections and has received accreditation by the nation’s most scientifically rigorous laboratory standards through the College of American Pathologists (CAP).[35]  These accreditations and quality standards underscore 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® welcomes FDA review and is prepared with the commensurate data.  However, the FDA has not created a pathway for companies like Proove® to achieve regulatory and reimbursement approval for an LDT at this time.

 

Leadership

 

Finally, both of these articles inaccurately, unfairly, and maliciously attack Proove®’s leadership. Proove®’s founder and CEO, Brian Meshkin, has a track record of innovation and helping solve public health problems.42  Meshkin’s award-winning injury prevention efforts started when he was just a teenager lobbying for the nation’s first bicycle helmet law for children and subsequent related laws. His social entrepreneurship efforts continue today, 30 years later, with Proove as it tackles the opioid abuse epidemic which is the leading cause of injury death for adults and teenagers in America.  However, due to Piller’s apparent personal animosity, these articles falsely suggest dissension.

 

False Claims: 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, is taking a “wait-and-see” approach about Proove and its technology.

 

Truth:  Governor Leavitt, who has served a two-year term on Proove’s board, remains firmly committed to the company and its future.  Leavitt Equity Partners (LEP) invested $3.5 million into the company because it has great promise. LEP continues to feel this way and invested in the process to drive that science forward on behalf of patients who deserve safe and informed relief for chronic pain.”  Proove® is proud of our association with Leavitt Equity Partners, honored to have been its first investment, and looks forward to continued successful collaborations with their team.

 

 

 

 

STAT News Response

June 8, 2017

Page 7

 

Conclusion

 

Proove®, through its in-house legal counsel and external law firms, is pursuing all possible legal actions to recover damages and protect itself from further harm from these defamatory allegations from a variety of sources.  Proove® firmly asserts that its practices are within the confines of the law and consistent with OIG guidance.  In fact, Proove®’s solutions are aligned with the public health priorities of the Department of Justice and Department of Health and Human Services, as its technology platform is clinically-proven to reduce pain and accurately identify patients at risk for opioid misuse.

 

Proove® categorically denies all of the allegations embedded in these stories, the false source documents used, as well as unsubstantiated quotes by disgruntled, terminated former employee sources.   This isolated, outlier false stories stand in contrast to the objective, “glowing” news coverage previously published about Proove® and its CEO in other publications.    This story has created a “snowball” effect which must be addressed.

 

Ironically, the very issues raised in these articles are not weaknesses, but rather strengths.  Proove® welcomes the opportunity to share the facts and the truth.  Proove® is proud of its research, technology and business practices.  But most importantly, Proove® is proud of the outcomes that it achieves for patients dealing with chronic pain.

 

Proove® offers the only solution in the market that is proven to help clinicians achieve clinicallysignificant reductions in patient pain and accurately identify patients at risk for opioid abuse.  These false stories did a disservice to the cause of helping patients.  Rather than embarrassing Proove®, these stories are filled with holes and embarrassing for those who took part in it.

 

We are confident that truth always prevails and the facts are on our side.

 

[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. Science 314, 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] https://www.aan.com/PressRoom/Home/PressRelease/1269  

[8] https://www.benzinga.com/pressreleases/14/04/p4471862/proove–biosciences–receives–first–place–in–the–americansociety–of–inte 

[9] https://www.asra.com/page/166/best–of–meeting–awards

[10] http://www.kswo.com/story/35555782/90–of–patients–achieve–40–pain–reduction–within–60–days–in–large–precisionmedicine–clinical–trial

[11] https://clinicaltrials.gov/ct2/show/NCT02485795  

[12] 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.

[13] 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

[14] 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. 15 ASAM Long Definition of Addiction, April 2014

[15] Le Foll, B., et al., Genetics of dopamine receptors and drug addiction: a comprehensive review. Behav Pharmacol, 2009.

[16] (1): p. 1-17.

[17] Noble, E.P., D2 dopamine receptor gene in psychiatric and neurologic disorders and its phenotypes. Am J Med Genet B Neuropsychiatr Genet, 2003. 116b(1): p. 103-25.

[18] Navarro, J.F., et al., Effects of L-741,741, a selective dopamine receptor antagonist, on anxiety tested in the elevated plusmaze in mice. Methods Find Exp Clin Pharmacol 2003. 25(1): p. 45-7.

[19] Gross, N.B., P.C. Duncker, and J.F. Marshall, Striatal dopamine D1 and D2 receptors: widespread influences on methamphetamine-induced dopamine and serotonin neurotoxicity. Synapse, 2011. 65(11): p. 1144-55.

[20] Han, D.H., et al., Craving for alcohol and food during treatment for alcohol dependence: modulation by T allele of 1519T>C GABAAalpha6. Alcohol Clin Exp Res, 2008. 32(9): p. 1593-9.

[21] Carlezon, W.A., Jr., et al., Kappa-opioid ligands in the study and treatment of mood disorders. Pharmacol Ther, 2009.

[22] (3): p. 334-43.

[23] Gelernter, J., et al., Opioid receptor gene (OPRM1, OPRK1, and OPRD1) variants and response to naltrexone treatment for alcohol dependence: results from the VA Cooperative Study. Alcohol Clin Exp Res, 2007. 31(4): p. 555-63.

[24] Peerbooms, O.L., et al., Meta-analysis of MTHFR gene variants in schizophrenia, bipolar disorder and unipolar depressive disorder: evidence for a common genetic vulnerability? Brain Behav Immun, 2011. 25(8): p. 1530-43.

[25] Nelson, E.C., et al., Association of OPRD1 polymorphisms with heroin dependence in a large case-control series. Addict Biol, 2014. 19(1): p. 111-21.

[26] Celada, P., et al., The therapeutic role of 5-HT1A and 5-HT2A receptors in depression. J Psychiatry Neurosci, 2004. 29(4): p. 252-65.

[27] Lauschke, V.M. and M. Ingelman-Sundberg, Requirements for comprehensive pharmacogenetic genotyping platforms.

Pharmacogenomics, 2016. 17(8): p. 917-24.

[28] Compton, W.M. and N.D. Volkow, Abuse of prescription drugs and the risk of addiction. Drug Alcohol Depend, 2006. 83 Suppl 1: p. S4-7.

[29] Manchikanti, L., et al., Psychological factors as predictors of opioid abuse and illicit drug use in chronic pain patients. J Opioid Manag, 2007. 3(2): p. 89-100.

[30] Sproule, B., et al., Changing patterns in opioid addiction: characterizing users of oxycodone and other opioids. Can Fam Physician, 2009. 55(1): p. 68-69.

[31] Institute of Medicine Committee on Advancing Pain Research, C.a.E., The National Academies Collection: Reports funded by National Institutes of Health, in Relieving Pain in America: A Blueprint for Transforming Prevention, Care, Education, and Research. National Academies Press (US), 2011.

[32] https://www.glassdoor.com/Salaries/pain–management–physician–salary–SRCH_KO0,25.htm 

[33] https://www.glassdoor.com/Salaries/orthopedic–surgeon–salary–SRCH_KO0,18.htm 

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

[35] http://www.cap.org/web/home/lab/accreditation/laboratory–accreditationprogram?_afrLoop=136253709004664#!%40%40%3F_afrLoop%3D136253709004664%26_adf.ctrl–state%3Dd487t48ze_4  42 http://www.brianmeshkin.com/about–2/vision/