Y ou want to treat reflux of blood draining from a patient’s brain?

1. You want to treat reflux of blood draining from a patient’s brain? • Are you using any device FDA has already approved, cleared or allowed for that indication and use so that it is a standard of care? • Do you need to talk to the FDA about an IDE? • Do you need to get an FDA consultant to review special controls or pre-market approvals? https://www.federalregister.gov/articles/2010/09/08/2010-22303/guidance-for-industry-and-food-and-drug-administration-staff-class-ii-special-controls-guidance BioMed IRB presented at Hubbard Foundation Conference May 12, 2012

2. Open with Q&A, but close with unanswered questions • Might endovascular surgical devices for increasing the flow of blood out of the brain be of interest to the FDA? • Who can testify as to the standard of care? • What influences the on label (FDA-approved, cleared) or FDA-allowed use? • Risk from off label use falls on who? • Promoting? Making/importing? Practice of Medicine? BioMed IRB presented at Hubbard Foundation Conference May 12, 2012

3. Promoting an unapproved use for a medical device -- a crime against the patient and a regulatory violation? • If the data was not collected in a study, retroactive approval for looking at files to develop a hypothesis and design a study might be approvable, is this the REGISTRY study? • When did the off label use cross the line to promoted and illegal use? • Practice of medicine • Investigational Device Exemption BioMed IRB presented at Hubbard Foundation Conference May 12, 2012

4. Links for FDA info about CCSVI or IDE • FDA warning about MS and CCSVI http://www.fda.gov/NewsEvents/Newsroom/PressAnnouncements/ucm303538.htm • More on IDE specifically http://www.fda.gov/MedicalDevices/DeviceRegulationandGuidance/HowtoMarketYourDevice/InvestigationalDeviceExemptionIDE/ucm162453.htm • http://www.fda.gov/MedicalDevices/DeviceRegulationandGuidance/HowtoMarketYourDevice/InvestigationalDeviceExemptionIDE/ucm046164.htm BioMed IRB presented at Hubbard Foundation Conference May 12, 2012

5. Obsoletebut informative reads • 2001: CMS (Medicare) will cover with FDA IDE for PercutaneousTransluminal Angioplasty (PTA) of the Carotid Artery concurrent with stenting • http://www.cmms.hhs.gov/medicare-coverage-database/details/nca-decision-memo.aspx?NCAId=62&ver=9&NcaName=Percutaneous+Transluminal+Angioplasty+(PTA)+of+the+Carotid+Artery+Concurrent+with+Stenting&NCDId=201&ncdver=5&IsPopup=y&bc=AAAAAAAAEAAA& • 2008: off label use of biliary stents in peripheral arterial disease is associated with most adverse events http://www.sciencedaily.com/releases/2008/01/080121080347.htm BioMed IRB presented at Hubbard Foundation Conference May 12, 2012

6. An IRB perspectiveDATA QUALITY & INTEGRITY Contrast GMP to GCP GMP = Good Manufacturing Practice Fear is “dry-lab” (fabricated data) BioMed IRB presented at Hubbard Foundation Conference May 12, 2012

7. (obsolete but historically instructive) http://www.fda.gov/MedicalDevices/DeviceRegulationandGuidance/GuidanceDocuments/ucm081362.htm • “… encourage reviewers to be sensitive to the possibly of inaccurate, withheld or otherwise false data in submissions…. For example, the data may appear to be fabricated or the device design may suggest that the performance data are not feasible. “ • Integrity Memorandum G91-2 BioMed IRB presented at Hubbard Foundation Conference May 12, 2012

8. Obsolete but still informing us about Data Integrity is the AIP “The term “data integrity” is not just casual language. It is a direct reference to the FDA Application Integrity Policy (AIP) that the FDA invokes when there is evidence of fraud, bribery, or other acts that impact the validity of data used to support marketing applications.” http://www.fda.gov/ICECI/EnforcementActions/ApplicationIntegrityPolicy/ucm134453.htm BioMed IRB presented at Hubbard Foundation Conference May 12, 2012

9. GCP = Good Clinical Practice • Goal is that data is useful for scientific & regulatory purposes • Is it ethical to do this experiment, at this time, with this population? IRB decides • Is quality sampling and statistical control applied only to GMP? FDA decides • Joseph Moses Juran (December 24, 1904 – February 28, 2008) inspect process statistically • Vilfredo Federico Damaso Pareto (15 July 1848 – 19 August 1923) cycles of FOXES (speculators) and LIONS (post bubble return to conservatives) BioMed IRB presented at Hubbard Foundation Conference May 12, 2012

10. What NOT to do under GCP • Mehta warned by FDA • http://www.fda.gov/ICECI/EnforcementActions/WarningLetters/2012/ucm295027.htm • If you run an internet search, is any study that you find ALSO on http://clinicaltrials.gov and if not, why not? • If you search MS or maybe MS CCSVI on line, do you get recruited for study or off label? BioMed IRB presented at Hubbard Foundation Conference May 12, 2012

11. How do you develop data to develop hypotheses? • Looks to be about half a dozen makers of stents (what about balloons?), maybe only a couple suitable for the indication, if it exists, of CCSVI • If maker/importer should know that higher sales are because of off-label uses, that should lead to contacting FDA to design protocol for data collection to expand indication on label • Maker/importer OR MD can • ask for IDE from FDA, and • Apply for IRB approval BioMed IRB presented at Hubbard Foundation Conference May 12, 2012

12. liability for Clinical Investigation • clinical data is generated during research phases, and therefore cannot be specified. This type of data is generated to inform, rather than to confirm. The regulations concerning the management of clinical data were designed to focus on confirmation of accuracy, and not on integrity. It is critical to note that the regulators were aware of the inability to predict data at this point in research and therefore regulations designed to associate legal responsibility for the integrity of clinical data were developed and are contained within 21 CFR 312.70.The scope of 312.70 is limited to Clinical Investigators, formally assigning legal responsibility to those individuals most directly responsible for the generation and protection of clinical data. BioMed IRB presented at Hubbard Foundation Conference May 12, 2012

13. Disclosing investigator COI is Reqd • the clinical regulations were supplemented by new regulations in 1999 that were intended to ensure that any financial interests of clinical investigators that might have the ability to affect the reliability of data were classified and fully disclosed to the government.This expansion of the regulations was considered necessary as many forms of compensation provided to clinical investigators at that time created a situation that could incentivize the falsification of data. These types of situations included:• Compensation made to the clinical investigator in which the value of the- compensation could be affected by the study outcome• a proprietary interest by the investigator in the tested product, such as a patent• a significant equity interest in the sponsor of the covered study• significant payments by the sponsor of the covered study of other sorts, such as- a grant to fund ongoing research, compensation in the form of equipment, or- retainers for ongoing consultation or honoraria BioMed IRB presented at Hubbard Foundation Conference May 12, 2012

14. Investigator initiated studies • If the device maker/marketer/importer does not start a study, the MD can (maybe should?) • The FDA can second-guess the MD, so coming to the IRB without going to the FDA is an invitation to disaster • The IRB comfort level is probably “retrospective file review” and nothing more • But, is a registry just that, or, is it more? • How do you protect consults with others? PSO? BioMed IRB presented at Hubbard Foundation Conference May 12, 2012

15. Practice of medicine? Off label? • Between a doctor and a patient, if the device is already available for a different use and the best available treatment for the patient at the time is off label, then under STATE LAW does that fit as PRACTICE OF MEDICINE? • If doctor promotes off label to land another patient, is that now an FDA violation? • What if prospective patients contact MD? BioMed IRB presented at Hubbard Foundation Conference May 12, 2012

16. FDA regulated • The Food, Drug and Cosmetic Act (FDCA) states that if a device is labeled, promoted or used in the US, it will be regulated by the FDA and is subject to pre-marketing and post-marketing regulatory controls to assure safety and effectiveness. BioMed IRB presented at Hubbard Foundation Conference May 12, 2012

17. CRIMES OF INTEREST • A 69-year-old San Diego man who was convicted of selling more than 9,000 unapproved medical devices over 12 years has been sentenced to 51 months in federal prison, according to 10news.com. In addition, James Folsom must pay a $250,000 fine. He was convicted in 2010 in federal court on 26 felony counts including conspiracy, misbranding devices and failing to register devices, according to the report. • Folsom claimed that his devices, which were never approved by the U.S. Food and Drug Administration, used electrical frequencies to destroy diseased cells in the body, including cancer and AIDS.Folsom sold the devices under the names NatureTronics, AstroPulse, BioSolutions, Energy Wellness and Global Wellness for $1,000 to $2,000 each. His business reportedly generated more than $8 million in revenue. BioMed IRB presented at Hubbard Foundation Conference May 12, 2012

18. Rife -- Internet; Lyme; FDA • http://www.fourwinds10.net/siterun_data/government/judicial_and_courts/news.php?q=1265313651 • http://www.rifeforum.com/forum/printthread.php?t=3019 BioMed IRB presented at Hubbard Foundation Conference May 12, 2012

19. Stents triggering fda visit DURING clinical trials • http://online.wsj.com/article/SB10001424052748704243904575630724192380594.html BioMed IRB presented at Hubbard Foundation Conference May 12, 2012

20. http://www.attorneyatlaw.com/2009/06/swiss-company-u-s-affiliate-charged-with-unapproved-marketing-of-spinal-cement-products/http://www.attorneyatlaw.com/2009/06/swiss-company-u-s-affiliate-charged-with-unapproved-marketing-of-spinal-cement-products/ • Norian Corp. unit conducted unauthorized clinical trials of the products, called SRS and CRS, from May 2002 to 2004, during which time at least three of about 200 patients involved in the trials died, according to Michael Levy, the U.S. Attorney for the Eastern District of Pennsylvania. • Norian is based in West Chester, Pennsylvania. • The bone cement products were designed to prevent compression following spinal fractures. The illegal clinical trials were conducted at undisclosed U.S. Veterans Affairs facilities and other hospitals across the United States, officials said. • Illegal Promotion Alleged • Synthes and Norian officials are accused of encouraging surgeons to use the cement in patients, even though the products were not approved by the Food and Drug Administration. BioMed IRB presented at Hubbard Foundation Conference May 12, 2012

21. Rogues Gallery or Patients’ Hopes? • http://www.utsandiego.com/news/2009/feb/18/bn18convict-medical-scam/?zIndex=55119 • Royal Raymond Rife, in the 1930’s, radio frequencies as therapy? • Kimberly Bailey, Fallbrook, in prison for plotting to kill partner in Rife marketing, 2002 • James Folsom, carrying on after Bailey jailed for crimes unrelated to Rife marketing, convicted 2009 BioMed IRB presented at Hubbard Foundation Conference May 12, 2012