1	The IVD as a Tool in Patient Therapeutics Management Martha A. Feldman, RAC Drug & Device Development Co., Inc. AMDM Conference, San Jose CA September 14, 2006
2	Topics for Today Possible claims for IVD in managing patient therapeutics Types of clinical studies for demonstrating safety and effectiveness for each of the claims FDA Letter on Personalized Medicine Warning Letters to Manufacturers Marketing without FDA clearance or approval Marketing as an ASR, but exceeding regulations
3	Types of assays for managing therapeutics Drugs of Abuse Tumor markers Therapeutic levels Disease Detection Microbial Detection Detection of Genetic or Mutagenic Factors Clinical chemistries and hematological parameters Bioterrorism and Public Health
4	Drugs of Abuse Assays
5	Drugs of Abuse Assays Indication for Use: Determine drug levels of legal and illegal drugs Practical applications (i.e., management of patient therapeutics) Manage therapeutic levels of legally prescribed drugs that have potential for abuse Assess response to drug treatment programs
6	Drugs of Abuse Assays Risks Clinical Incorrect treatment (to counteract false high readings) Insufficient treatment given (false low readings) Social Inaccurate results which show use of illegal drug ingestion – loss of respect, loss of job, expelled from school, jail time
7	Examples of Drugs of Abuse Illegal marijuana, cocaine, opiates (including heroin), amphetamines (including Ecstasy or MDMA), and PCP (angel dust). Prescription codeine or other painkillers amphetamines NOTE: all amphetamine results should be considered carefully, even those from the laboratory. Some over-the-counter medications contain amphetamines that cannot be distinguished from illegally-abused amphetamines.
8	Relevant Guidance Documents Guidance for Labeling for Over-the Counter Sample Collection Systems for Drugs of Abuse Testing www.fda.gov/cdrh/ode/1359.pdf Draft Guidance for Industry and FDA Staff: Premarket Submission and Labeling recommendations for Drugs of Abuse Screening Tests www.fda.gov/cdrh/oivd/guidance/152.pdf
9	More Guidance Documents Home Use Test Kits (One Step Method) http://www.fda.gov/cdrh/oivd/homeuse-drug-collection.html Home Use Tests (Two-Step Method) http://www.fda.gov/cdrh/oivd/homeuse-drug-2step.html
10	IVDs for Tumor Markers
11	Tumor Marker IVDs Indications for use Screening Monitoring disease progression Monitoring disease recurrence Assessing efficacy of treatment Prognosing disease Practical applicability Timely intervention with medicine or surgery
12	Tumor Marker IVDs Examples Alpha feto-protein L 3% for hepatocarcinoma Bladder cancer antigen Breast cancer receptors HPV assays
13	Tumor marker IVDs Risks of inaccurate results Mismanagement of therapy: giving potentially toxic medicines, performing unnecessary surgery or not administering/intervening when needed Not detecting presence of antigen in detecting presence or recurrence of disease
14	References Class II Special Controls Guidance Document: AFP-L3% Immunological test systems, October 4, 2005
15	IVDs for Therapeutic Levels of Other Drugs or Biotechnology-Derived Therapeutics
16	IVDs for Drugs and BTD Therapeutics Indications for Use Ensuring drugs levels are in therapeutic range Assessing if adverse events may be due to over-dosage Practical applications Levels of anticoagulants prior to and during surgery
17	IVDs for Drugs and BTD Therapeutics Examples Coumadin Erthropoietin
18	References FDA Reminders For Falsely Elevated Glucose Readings From Use of Inappropriate Test Method http://www.fda.gov/cdrh/oivd/news/glucosefalse.html Guidance for Industry and FDA Staff 510(k) Submissions for Coagulation Instruments http://www.fda.gov/cdrh/oivd/guidance/1223.html
19	More References Guidance for Industry Document for Special Controls for Erythropoietin Assay Premarket Notifications [510(k)s] http://www.fda.gov/cdrh/ode/2241.html
20	IVDs for Disease Detection and Monitoring
21	Disease Detection and Monitoring Indications for use Aid in diagnosis Detection of disease Monitor progression Detect recurrence Differentiation between diseases Practical applications Congestive heart failure (CHF) Alzheimer’s disease Diabetes
22	Disease Detection and Monitoring Examples Alzheimer’s Disease: Nymox Urine NTP kit (Panel voted against approval 15 July 05) CHF: β-Type Natriuretic Peptide (30 Nov 2000) C-Reactive Protein Fibrin monomer paracoagulation test: Differential diagnosis between Disseminated intravascular coagulation (DIC) and primary fibrinolysis
23	Disease Detection and Monitoring Risks of poor performance False negative: inadequate or no treatment, or wrong treatment based upon erroneous results False positive: Unneeded treatment given May delay giving correct treatment for true cause of signs and symptoms Additional, unnecessary additional tests conducted
24	References FDA Approves New Laboratory Test To Detect Human Infections With Avian Influenza A/H5 Viruses http://www.hhs.gov/news/press/2006pres/20060203.html Draft Guidance for Industry and FDA Staff Class II Special Controls Guidance Document: Herpes Simplex Virus Types 1 and 2 Serological Assays http://www.fda.gov/cdrh/oivd/guidance/1305.html
25	More References Immunology Devices Panel Meeting - July 15, 2005 (NTP for Alzheimer’s Disease) http://www.fda.gov/cdrh/panel/summary/immun-071505.html Final Guidance for Industry and FDA Reviewers - Class II Special Control Guidance Document for B-Type Natriuretic Peptide Premarket Notifications (for CHF) http://www.fda.gov/cdrh/ode/guidance/1072.html
26	Even More References Class II Special Controls Guidance Document: AFP-L3% Immunological Test Systems http://www.fda.gov/cdrh/oivd/guidance/1570.html In Vitro Diagnostic Fibrin Monomer Paracoagulation Test http://www.fda.giv/cdrh/ode/2242.html Review Criteria for Assessment of Laboratory Tests for the Detection of Antibodies to Heliobacter pylori (17 Sept 92)
27	Still more references Guidance for Industry and FDA Staff - Review Criteria for Assessment of C Reactive Protein (CRP), High Sensitivity C-Reactive Protein (hsCRP) and Cardiac C-Reactive Protein (cCRP) Assays http://www.fda.gov/cdrh/oivd/guidance/1246.html
28	IVDs for Microbial Detection
29	Detection of Microbial Pathogens Indications for Use Described in 21 CFR 866, Subparts B, C, D Does not cover screening blood and plasma donors (covered by CBER) Practical Applications Specific recommendations for detection of particular microbial pathogens are not given in Guidance Document
30	Detection of Microbial Pathogens Risks of poor performance Failure to perform or error in interpretation of results can lead to improper patient management, or Inappropriate public health response False negative could lead to clinical misdiagnosis, withholding appropriate treatment and not instituting prevention and/or control efforts in the case of a transmissible disease. Missed diagnoses in pregnant women can lead to congenital infections in the newborn False positive can lead to potentially toxic treatment, social and psychological devastation, costly additional tests, quarantine, etc.
31	References Nucleic Acid Based In Vitro Diagnostic Devices for Detection of Microbial Pathogens - Draft Guidance for Industry and FDA Staff (8 Dec 05) http://www.fda.gov/cdrh/oivd/guidance/1560.html
32	IVDs for Genetic- or Mutation – based Diseases
33	Genetic- or Mutation-Based Diseases Indication for Use Detection of analytes in material or fetal media Detection of a mutation in patients Practical applications Risk assessment for developing fetus Managing therapeutic measurements in patients with known mutations
34	Genetic- or Mutation-Based Diseases Examples: Alpha-fetoprotein for detection of neural tube defect Cystic Fibrosis
35	Genetic- or Mutation-Based Diseases Risks of poor performance Genetic Unwarranted termination of pregnancy Inaccurate risk assessment for fetus Mutation Inappropriate therapeutic intervention Unaware of potential susceptibility; unprepared for adverse response to drug
36	References Draft Guidance for Industry and FDA Staff - Pharmacogenetic Tests and Genetic Tests for Heritable Markers (9 Feb 06) http://www.fda.gov/cdrh/oivd/guidance/1549.html FDA Approves First DNA-based Test to Detect Cystic Fibrosis (May 9, 2005) http://www.fda.gov/bbs/topics/NEWS/2005/NEW01178.html
37	More References Class II Special Controls Guidance Document: Drug Metabolizing Enzyme Genotyping System (10 Mar 05) http://www.fda.gov/cdrh/oivd/guidance/1551.html
38	Clinical Chemistries and Hematological Parameters
39	Clinical chemistries and hematological parameters Indications for use Determine levels of various biochemical parameters Detection of antibodies to viral agents Practical applications Assess level of hypoxia Diagnose acidosis Monitor electrolytes
40	Clinical chemistries and hematological parameters Examples Biocarbonate/Carbon dioxide test system Serum nitrogen levels Serum sodium levels Blood glucose levels Serum potassium levels
41	Clinical chemistries and hematological parameters Risks of poor performance False low and false high results could mean the administration of the wrong medicine, fluids, chemicals, etc. and/or the inappropriate amounts Failure to provide accurate results could mean missing a trend that, left untreated, would significantly affect patient outcome.
42	References Guidance for Industry – In Vitro Diagnostic Sodium Test System http://www.fda.gov/cdrh/ode/75.html Guidance for Industry – In Vitro Diagnostic Urea Nitrogen Test System http://www.fda.gov/cdrh/ode/72.html Guidance for Industry – In Vitro Diagnostic Chloride Test System http://www.fda.gov/cdrh/ode/73.html
43	More references Guidance for Industry – In Vitro Diagnostic Creatinine Test System http://www.fda.gov/cdrh/ode/74.html Guidance for Industry – In Vitro Diagnostic Glucose Test System http://www.fda.gov/cdrh/ode/76.html Guidance for Industry – In Vitro Diagnostic Potassium Test System http://www.fda.gov/cdrh/ode/77.html
44	Can there be more references – Yes! Guidance for Industry and FDA Staff: 510(k) Submissions for Coagulation Instruments http://www.fda.gov/cdrh/oivd/guidance/1223.html Review Criteria for In Vitro Diagnostic Devices for the Detection of IgM Antibodies to Viral Agents (August, 1992)
45	NEW CONCERNS: IVDs in Bioterrorism and Public Health
46	Bioterrorism and Public Health Indication for Use Detection of presence of noxious materials (pathogens, chemical or infectious agents) in blood, urine, other body fluids or tissues that may have a significant impact on public health Detection of sexually transmitted diseases Practical applications Isolating affected people to prevent spread Identifying noxious agents to be able to initiate therapy Rapid, accurate, identification of the source of a public health problem
47	Bioterrorism and Public Health Avian Flu A/H5 Viruses (3 Feb 06 notice) Hepatitis HIV Anthrax Mad Cow Disease (CJ Syndrome) Chlamydia, Syphilis, Gonorrhea Tuberculosis
48	Bioterrorism and Public Health Risks of poor performance Inaccurate results may results in no, inadequate or wrong treatment by misidentifying noxious agent or providing inaccurate levels False negative results may mean infected or contaminated persons may be unwittingly transmitting noxious agent to others False positive may cause panic, unnecessary treatment, additional testing
49	References Guidance for Industry and FDA Staff - In Vitro Diagnostic Devices to Detect Influenza A Viruses: Labeling and Regulatory Path http://www.fda.gov/cdrh/oivd/guidance/1594.html Guidance for Industry and FDA Staff - Class II Special Controls Guidance Document: Hepatitis A Virus Serological Assays http://www.fda.gov/cdrh/oivd/guidance/1536.html
50	More References Review Criteria for Assessment of In Vitro Diagnostic Devices for Direct Detection of Chlamydia in Clinical Specimens, Jan. 1992 Review Criteria for Devices Intended for the Detection of Hepatitis B “e” Antigen and Antibody to HBe (Dec., 1991) Review Criteria for Assessment of In Vitro Diagnostic Devices for Direct Detection of Mycobacterium SPP. (28 Deb 94)
51	Clinical Studies for IVDs
52	When Clinical Studies May be Required or Desired Required (may need an IDE) Guidance document says so Unresolved issues in preclinical studies Safety concerns Demonstration of clinical utility (FDA request) Predicate product submission contained clinical data Desired Feasibility; proof of concept Marketing evaluation; fundraising purposes
53	Overview of Classification of Medical Devices FD&C Act §513 (a)(1), (b) and (c) Class I - general controls Class II - general controls + special controls Class III - general controls + special controls + premarket approval
54	General Controls FD&C Act §513 (501, 502, 510, 516, 518, 519, and 520) Registration Device Listing Labeling Notification and Other Remedies Quality System Regulation
55	Study designs for different classes of medical devices Class I and II: The 510(k): demonstrate substantial equivalence - comparison study; no superiority Class III: Premarket Approval Application (PMA): demonstrate safety and effectiveness; rigorous study design, e.g., randomized, double-blinded, prospective, well-controlled Humanitarian Device Exemption (HDE): demonstrate safety only; £ 4000 cases/year (compare to drugs - £ 200,000)
56	Issues Unique to Studies on Medical Devices Risk level of device: SR or NSR Risk level of study: (e.g., NSR device in SR situation) IDE required or not Environment limitations for use of device Location where device is being used Ethical issues specific for devices Training in use of device (VERY IMPORTANT!)
57	Environmental Issues to Consider in planning IVD clinical studies Temperature Humidity Pressure (i.e., altitude) Electromagnetic Interference Sterility requirements Particulate matter in atmosphere Space (i.e., size for bedside, field use)
58	Location Issues to Consider in Clinical Studies on IVD Devices Hospital in-patient (including, OR, ER, hospital labs) Hospital - outpatient; clinician’s private office Field hospitals (e.g., battlefields, natural disasters) On-site medical care (e.g., accidents, sporting events, riots) Home use (OTC versus prescription; professional [e.g., visiting nurse], caregiver, patient self-testing)
59	Ethical Issues to Consider in IVD Device Clinical Studies - 1 Investigational diagnostic devices used for patient management Training clinical personnel in use of IVD; ongoing validation of training – new personnel, upgrades Prevention of, or delay in, giving standard treatment because of possible erroneous results from the IVD Giving unnecessary treatment because of possible erroneous results from the IVD Just because you can test for something does not mean that you should!
60	Ethical Issues - 2 Use of company’s own stored, leftover samples from a previous study for a new IVD study (different analyte) Use of a repository’s samples, i.e., long term storage, so no consent available or possible Informing subjects of results from an investigational IVD (i.e., if the company believes that the IVD is better than the gold standard)
61	References Guidance on Informed Consent for In Vitro Diagnostic Device Studies Using Leftover Human Specimens that are Not Individually Identifiable - Guidance for Sponsors, Institutional Review Boards, Clinical Investigators and FDA Staff http://www.fda.gov/cdrh/oivd/guidance/1588.html Points to Consider in the Collection of Data in Support of In Vitro Device Submissions for 510(k) Clearance http://www.fda/cdrh/ode/95.pdf
62	FDA News Release on Personalized Medicine http://www.fda.gov/cdrh/oivd/news.html
63	Personalized Medicine Examples: Third Wave technology: Invader UGTA1A Assay: detecting variations in a gene that affects how certain drugs are broken down and cleared by the body, e.g. irinotecan for treatment of colorectal cancer Roche AmpliChip: to individualize dosage of antidepressants, antipsychotics, beta-blockers and some chemotherapy drugs TRUGENE HIV-1 Genotyping Kit: detect variations in the genome of the HIV that make the virus resistant to some anti-retroviral drugs
64	Warning Letters
65	Selling IVDs without Clearance or Approval Warning Letter to Tepnel Diagnostics Ltd. http://www.fda.gov/cdrh/oivd/letters/092605-tepnel.html for detections of genetic-based diseases such as cystic fibrosis and cardiovascular diseases (26Aug 05) Warning Letter to Access Genetics http://www.fda.gov/cdrh/oivd/letters/080105-access.html for several tests, e.g., Thrombophilia Tests (Factor 5 Leiden, Factor 2 Prothrombin, MTHFR), Human Papillomavirus (HPV), Chlamydia & Gonorrhea PAP and Cystic Fibrosis
66	Selling ASR Products with Claims Letter to Nanogen Corporation http://www.fda.gov/cdrh/oivd/letters/081105-nanogen.html (11Aug 05)
67	QUESTIONS??? Martha A. Feldman (425)861-8262 mfeldman@druganddevice.com