Examine & Evaluate: Health Canada and FDA

Transcription

1 Examine & Evaluate: Health Canada and FDA Outsourcing in Clinical Trials Canada 2012 Nov. 14 Lubna Syed, Director Regulatory Affairs 1

2 Expectations for this Presentation? 2

3 Topics History: Chronicling evolution Health Canada and FDA so that we may better understand their current standing in the market. Regulations: Examining and evaluating the different ways that Health Canada compares with the FDA. Resources & Constraints: Analyzing the environment that both regulatory bodies are performing within and gain a strong understanding of how best to utilize these resources. Future: Anticipating and examining how the standards and protocols of the regulatory authorities will change in 3 years and how you can use that to your advantage. Future: investigating steps and measures necessary to gain support from authorities in order to jump start your trial. Developing solutions for transparency. 3

4 Introduction From the beginnings of civilization people have been concerned about diagnosing health, and about the quality and safety of foods and medicines. The evaluation of urine in order to aid in the diagnosis of a patient has been a part of medicine since ancient times. Babylonian and Sumerian physicians have inscribed their evaluations of urine into clay tablets as early as 4,000 B.C. Medieval doctors associated nearly every known disease with urinary characteristics, and some would diagnose patients without even meeting them, just by examining a bottle of their urine. Certain tests are still done today because they accurately indicate health problems; "malodorous urine is accurately classified as infected, red urine is still notable for the presence of blood, [and] brown urine for bilirubin or blood products, though diagnostic tests for the detection of biological substances in urine also exist. As a consequence of good intentions and of bad actions regulations and laws have been developed for food, drugs, and devices, and the conduct of clinical trials. 4

5 HISTORY FDA AND HEALTH CANADA 5

6 Milestones in History (US) 6

7 Federal Food and Drugs Act

8 Milestones in History USA 1883: Dr. Harvey W. Wiley becomes chief chemist, expanding the Bureau of Chemistry's food adulteration studies. Campaigning for a federal law, Dr. Wiley is called the "Crusading Chemist" and "Father of the Pure Food and Drugs Act." He retired from government service in 1912 and died in : Elixir of Sulfanilamide, containing the poisonous solvent diethylene glycol, kills 107 persons, many of whom are children, dramatizing the need to establish drug safety before marketing and to enact the pending food and drug law. 1938: The Federal Food, Drug, and Cosmetic (FDC) Act is passed by Congress, Extending control to cosmetics and therapeutic devices. Requiring new drugs to be shown safe before marketing-starting a new system of drug regulation. Eliminating the Sherley Amendment requirement to prove intent to defraud in drug misbranding cases. Providing that safe tolerances be set for unavoidable poisonous substances. Authorizing standards of identity, quality, and fill-of-container for foods. Authorizing factory inspections. Adding remedy of court injunctions to penalties seizures & prosecutions. 8

9 Milestones in History USA 1938: Wheeler-Lea Act, the Federal Trade Commission is charged with overseeing advertising associated with products otherwise regulated by FDA, with the exception of prescription drugs. 1962: Thalidomide, a new sleeping pill, is found to have caused birth defects in thousands of babies born in western Europe and Canada. News reports on the role of Dr. Frances Kelsey, FDA medical officer, in keeping the drug off the U.S. market, arouse public support for stronger drug regulation. Kefauver-Harris Drug Amendments passed to ensure drug efficacy and greater drug safety. For the first time, drug manufacturers are required to prove to FDA the effectiveness of their products before marketing them. Consumer Bill of Rights is proclaimed by President John F. Kennedy in a message to Congress. Included are the right to safety, the right to be informed, the right to choose, and the right to be heard. 1976: Medical Device Amendments passed to ensure safety and effectiveness of medical devices, including diagnostic products. The amendments require manufacturers to register with FDA and follow quality control procedures. Some products must have pre-market approval by FDA; others must meet performance standards before marketing. 9

10 Milestones in History USA 1988 Food and Drug Administration Act of 1988 officially establishes FDA as an agency of the Department of Health and Human Services with a Commissioner of Food and Drugs appointed by the President with the advice and consent of the Senate, and broadly spells out the responsibilities of the Secretary and the Commissioner for research, enforcement, education, and information. The Prescription Drug Marketing Act bans the diversion of prescription drugs from legitimate commercial channels. Congress finds that the resale of such drugs leads to the distribution of mislabeled, adulterated, sub-potent, and counterfeit drugs to the public. The new law requires drug wholesalers to be licensed by the states; restricts re-importation from other countries; and bans sale, trade or purchase of drug samples, and traffic or counterfeiting of redeemable drug coupons. Generic Animal Drug and Patent Term Restoration Act extends to veterinary products benefits given to human drugs under the 1984 Drug Price Competition and Patent Term Restoration Act. Companies can produce and sell generic versions of animal drugs approved after October 1962 without duplicating research done to prove them safe and effective. The act also authorizes extension of animal drug patents. 10

11 Milestones in History USA Recent 1992: Prescription Drug User Fee Act and renewed in 1997 (PDUFA II), 2002 (PDUFA III), 2007 (PDUFA IV), and 2012 (PDUFA V) 1997: Food Drug and Modernization Act (FDAMA) redefined 510(k) exemption criteria for class I devices, added class II exemption criteria, codified third-party review of 510(k)s, added substantial equivalence with Limitations, added Least Burdensome provision, Added evaluation of Automatic Class III designation (de novo), added recognition of standards, added class II petitions for exemptions. 2002: Medical Device Users Fee Modernization Act added user fees for medical devices, reauthorized in 2007 as part of FDAA Food and Drug Administration Amendments Act also including other fees and reauthorized in 2012 as MDUFMA III including Establishment fees. iceuserfeeandmodernizationactmdufma/ucm htm 2012: FDASIA Food and Drug Administration Safety and Innovation Act signed into law on July 9, 2012 and effective Oct. 1, 2012 many provisions. DCAct/SignificantAmendmentstotheFDCAct/FDASIA/ucm htm See references at back of presentation for more milestones in US History 11

12 Milestones in History Canada The federal oversight of food and drugs in Canada predates Confederation, but was initially confined to ensuring that food and drugs were not adulterated. The Proprietary or Patent Medicine Act (1909) was the first legislation to register medicines, which it limited to secret-formula, non-pharmacopoeial packaged medicines. The Act was the beginning of the protection of the public against drugs administered without medical supervision. Following the establishment of a federal Department of Health in 1919, the Food and Drugs Act was introduced in By the late 1920s, Regulations developed under the Act established specific requirements for licensing drugs. The Minister of Health had the authority to cancel or suspend a licence for violations of the requirements. A significant reworking of the Food and Drug Regulations did not begin until 1947, but it laid the foundation for the regulations in place today. By 1951, manufacturers were required to file new drug submissions prior to marketing their drugs. However, the regulations did not prevent the thalidomide tragedy of the early 1960s, which resulted in serious birth malformations and death to thousands of infants. The thalidomide tragedy prompted a complete revision of the regulations to strengthen the Department's regulatory abilities. The revision marked the first appearance of the requirement for manufacturers to submit evidence of efficacy in seeking a Notice of Compliance. 12

13 Milestones in History Canada The current system for the regulation of drugs in Canada focuses on pre-market activities and is characterized as point-in-time. A manufacturer can put its drug on the market once it has received a Notice of Compliance from Health Canada. The manufacturer must meet a number of obligations, but as long as the drug causes no adverse reactions or the manufacturer does not need to make changes to the drug, it may never be subject to review by Health Canada again. Medical and social trends, both domestic and international, are putting pressures on this system to evolve. The system for regulation of devices in Canada was updated significantly in Prior to that, notification of device distribution was required, except for products that remained in the body for longer than 30 days. Currently, regulation of devices in Canada is based on submission of product information based on a risk-based classification system. Natural Health Products (also known as complementary medicines or traditional remedies) are also subject to the Food and Drug Act and Regulations in Canada. The Natural Health Products Regulations came into force on January 1, 2004, with a transitional period: two years for site licensing and six years for licensing products with Drug Identification Numbers (DIN). 13

14 History of Cost Recovery Canada Fees were originally introduced to the Health Products and Food Branch (HPFB) in 1995 and were designed to recover a portion of the costs related to regulatory activities for human drugs. In 2000, a comprehensive review of the impact of the program was concluded. Fees were phased in for medical devices from 1995 to 2001, and its review completed in Fees for veterinary drugs were implemented in For , approximately 64% of all Health Canada user fee revenue originated in HPFB. The Branch is entitled to collect and spend revenues up to a maximum of $40.7 million. Once collected, these revenues are returned to the program areas to be applied towards the costs of those activities for which fees are charged. Revenue from cost recovery in 2005/06 made up approximately 20% of the overall HPFB operating budget. Some directorates are heavily reliant on cost recovery (such as the Therapeutic Products Directorate and the Health Products and Food Branch Inspectorate), others less so, and some directorates (such as the Natural Health Products Directorate) currently have no cost recovered funds factored into their allocations. 14

15 Krever Commission (1997) Canada s Tainted Blood Scandal Source: CBC News 15

16 Canada s Tainted Blood Scandal 1971 A test to detect hepatitis B is introduced. The Can. Red Cross (CRC) discontinues collecting blood from prisons, where hepatitis rates are higher than in general population First cases of what was then called non-a, non-b hepatitis (later identified as hepatitis C) to be transmitted through blood transfusions, are identified The American Red Cross inform CRC that non-a, non-b hepatitis is present in 4-9% of blood Compulsory reporting of non-a, non-b hepatitis begins. 134 cases are identified. November 1985 Canadian Red Cross starts testing blood products for the AIDS virus. December 1994 CRC recommends that anyone who received a blood transfusion in the 1980s be tested for hepatitis C. It s later learned that 95 per cent of hemophiliacs who used blood products before 1990 contracted hep-c. November 1997 Krever Commission report is released. March 27, 1998 Provincial and federal health ministers announce $1.2 billion in compensation Nov. 20, 1998 Ontario announces it will provide $200 million Ontario residents who were infected with hepatitis C before 1986 and after Jan. 28, 1999 A group of more than 1,000 hemophiliacs launched a $1-billion lawsuit against the government of Canada for using tainted blood obtained from U.S. jails. April 19, 2001 Supreme Court of Canada rules the CRC was negligent in managing the blood system in the early years of the AIDS crisis. April 11, 2003 CBS announces precautions to deter the spread of SARS. Sept. 3, 2003 CBS recalls all blood donated in Saskatchewan in August 2003 because of an epidemic of West Nile Virus. Sept. 22, 2004 The Canadian Standards Association announces Canada s first national standards for handling donated blood vein to vein. Oct. 1, 2007 Ontario Judge Mary Lou Benotto acquits former CRC Director Dr. Roger Perrault of charges of criminal negligence causing bodily harm. 16

17 Krever Commission (1997) The Krever Report (Justice Horace Krever) was tabled in the House of Commons on 26 November The Krever inquiry recommended the creation of Héma-Québec (HQ) for Quebec and Canadian Blood Services (CBS) for rest of the Canada, two agencies which would operate at arms-length from the federal government. It also made recommendations regarding compensation for persons who had received contaminated blood. Since the 1940s, the blood system had largely been the responsibility of the Canadian Red Cross Society. In the late 1970s a crisis emerged. Thousands of people were being infected with HIV and Hepatitis C. It became apparent that inadequately screened blood, often coming from high risk populations, was entering the system. Now as new viruses are identified, HQ and CBS take immediate precautions, recalling units when necessary, and screening with diagnostic testing. Further, blood is not taken from high-risk populations. 17

18 REGULATIONS As a consequence of good intentions and of bad actions regulations and laws have been developed for food, drugs, and devices, and the conduct of clinical trials. 18

19 What motivates regulations? In some cases, specific regulations are associated with serious health issues / outbreaks / potential outbreaks in the history of a country Sulfanilamide elixir, diethylene glycol (1937) Thalidomide (1967) Krever Commission (1997) DEHP (cancer causing) leaching from plastics Reuse of single use devices? (nosocomial infections) Silicone breast implants Novel Flu Virus (SARS, others?) Fungal Meningitis from non-sterile cardioplegia? (2012) 19

20 Medical Device Regulations Canadian Medical Devices Regulations (new classification regulations 1998) 4 Classes of medical devices (risk-based classification) Class I devices clinical trial results not required in device registration (listing) Class II devices clinical trial results not usually required as part of device application Class III devices clinical trial results may be required as part of device application Class IV devices clinical trial results often required as part of device application Food and Drug Administration (Code of Federal Regulations) 3 Classes of medical devices (risk-based classification) Class I, lowest risk class, rely on quality system regulations, device registration (listing) Class II, middle risk class, can require clinical trial results as part of device application, demonstrated equivalency to predicate device Class III, highest risk class, require clinical trial results demonstrate safety and effectiveness 20

21 Blood Bags are Class II and III in Can 21

22 Health Canada Regulations Trials Canadian Medical Devices Regulations - Part 3 of the Regulations covers Investigational Testing Involving Human Subjects Guidance on conducting clinical trials (Drugs and Health Products) Good Clinical Practices Declaration of Helsinki Investigational Testing Authorization from the Minister required prior to distribution of Class II, III or IV medical device 22 Drugs and Health Products Office of Clinical Trials for Clinical Trial Applications (CTAs) containing drug substances and their corresponding products of synthetic or semi-synthetic origin, excluding Biotechnological/Biological (Schedule D) and Radiopharmaceutical (Schedule C) drugs, that are filed with Health Canada pursuant to Division C.05 of the Food and Drug Regulations. ICH Guidances Clinical Trial Applications (CTAs) includes Phase I, II and III clinical trials Clinical Trial Manual:

23 Example Content Device Application If IVD and not used for patient management: Manufacturer Information: name, address, telephone number Device Information: name, class, catalog number, family/system/kit/group, copy of label Institution Information: name and address of clinical sites, written approval from institutions indicating investigational testing can occur there Protocol Information: protocol of testing, number of units of device to be used for testing, hypothesis and objectives of testing, period of time during which testing will be conducted, copy of patient consent form 23 Otherwise, also add the following: Description of Device: materials used in manufacture and packaging, description of features that permit it to be used for medical conditions Device History: list of countries other than Canada where device has been sold including total # units sold in each country and summary of reported problems / recalls Risk Assessment Investigator Information: names, qualifications, training, agreement to conduct testing according to protocol, inform patient and get written consent, report incidents

24 Example Content Drug CT Application 24

25 FDA Regulations Medical Devices Code of Federal Regulations (21CFR) Parts 312, 812, 54 and Good Clinical Practices Declaration of Helsinki Clinical Trials and IDE Guidance Documents ourdevice/investigationaldeviceexemptionide/ucm htm Guidance Documents (see references at back) Anonymized Specimen Collection IDE Clinical Investigations (BLA, PMA and 510(k)) Clinical Trials Withdrawn Subjects Electronic Source Documents Clinical Trials Guidance on Informed Consent for In Vitro Diagnostic Device Studies Using Leftover Human Specimens that are Not Individually Identifiable, 2006 Apr

26 Pre-submission process Formerly called pre-ide process (since 1995) New Guidance Document July 13, 2012 May or may not be followed by an IDE to provide the opportunity for an applicant to obtain FDA feedback (protocols, statistics, sample size, clinical trial design, submission type) prior to intended submission of an IDE or marketing application. egulationandguidance/guidancedocuments/ucm pdf 26

27 IDE Process (21 CFR Part 812) Investigational Device Exemptions (IDE) When a device is used for patient management or the study/device is significant risk, then a Pre-IDE is required Certain investigational IVD device studies are exempt from most of the provisions of 21 CFR Part 812 (21 CFR 812.2(c)(3)). Guidance document In Vitro Diagnostic (IVD) Device Studies -Frequently Asked Questions, 2010 June 25 development of IVD studies broad view of the regulatory framework pertaining to the development phase of IVD devices. onandguidance/guidancedocuments/ucm pdf 27

28 Good Clinical Practices (GCPs) Adherence to the principles of GCPs, including adequate human subject protection universally recognized as a critical requirement to the conduct of research involving human subjects. Many countries have adopted GCP principles as laws and/or regulations. The Food and Drug Administration s (FDA s) regulations for the conduct of clinical trials, which have been in effect since the 1970s, address both GCP and HSP. FDA regulations and guidance documents are accessible at Office of Good Clinical Practice page on FDA web site for the conduct of clinical trials, both nationally and internationally. 28

29 Bioresearch Monitoring FDA s bioresearch monitoring (BIMO) program conducts on-site inspections of both clinical and nonclinical studies performed to support research and marketing applications/submissions to the agency. Links to the compliance programs for each inspection type and contact information for each Center s BIMO program are also accessible from the Good Clinical Practice page of the FDA web site. 29

30 Office of Good Clinical Practice See the Office of Good Clinical Practice's (OGCP's) mission statement 1 on the OGCP's Web page. cs/runningclinicaltrials/default.htm 30

31 GHTF (now IMDRF) Final Documents Global Harmonization Task Force (GHTF), now become International Medical Devices Regulators Forum (IMDRF) for government agencies Next Meeting in France (Nice) 2013 March 19 to 21 Study group 5 (GHTF) published final Guidance Documents Clinical Investigations Clinical Evaluations Clinical Evidence and Definitions Reportable Events IMDRF for regulatory convergence. Members include representatives from authorities of Australia, Brazil, Canada, China, EU, India, Japan, Russia and the United States, (China, India, Russia invited but not confirmed). Also participating AHWG member 31

32 RESOURCES AND CONSTRAINTS 32

33 Constraints and Resources Budget for Health Canada for fiscal 2012 issued by parliament (Federal) blue book main estimates for coming fiscal year (statutory million) and users fees Budget for FDA for fiscal 2013 Issued by Federal (minus sequestration?) and User fees act (medical device users fees 595 million) Agency departmental responsibilities (food, drugs, cosmetics, biologics, radiology, etc.) Political Environment 33

34 Constraints and Resources FDA pre-submission process formally defined Health Canada, more informal process open to meetings with Sponsors and Teleconferences regarding novel products and unique clinical trials. Guidance Documents available from both agencies 34

35 Consequences of Clinical Trial Issues 35

36 Consequences False Data 36

37 2012 Fungal Meningitis Outbreak 37

38 APPLYING A PROGRESSIVE APPROACH & GAINING SUPPORT 38

39 How to Leverage What to Do Do your homework Guidance Documents Predicates / Comparator published information (FDA web site and Health Canada web site) Design your Studies (include medical research and input from physicians and users) Statistical Design of Study (sample size, data analysis, end points, surrogates appropriate?) Ethical Considerations News stories expect impact to your trials/submissions Communication is key Clinical studies are expensive ensure that you are measuring the right things in the right (intended use) population, using the right sample size to meet your end points Obtain clarity from regulatory agencies before hand 39

40 PREPARING FOR THE FUTURE 40

41 Preparing for Future Medical Devices Communicate clearly and frequently with your review division, and your team (including your CRO) Design your trial to suit as many geographies as possible (if possible for patient indication being evaluated) Obtain and follow device specific and clinical guidance documents Reduced budgets for regulatory authorities requiring process streamlining and further resource constraints (federally funded budgets are based on world economic factors) Pediatric Specific Clinical Trial Designs Expect and budget for post-market studies Use of clinical evaluation data from multi-country clinical trials User fees increases and mandatory post-market clinical costs need to be incorporated into your budget Unique Device Identifier Environmental legislation Standards harmonization and divergence MDUFA III Commitment Letter (FDA) IMDRF guidance to be incorporated directly into FDA and Health Canada regulations Auditing Unique Device Identifier Regulatory Product Submission (electronic format to be shared across agencies) Quality System recognition 41

42 US FDA Sequestration - Resources FDA is federally funded. This is how sequestration will work. If Congress can't decide on how to trim the federal deficit by $1.2 trillion over the next nine years by Jan. 1, automatic spending cuts that size, spread over nine years, will start then. Members of Congress loathe the idea because the cuts could indiscriminately hurt valuable programs. The cuts, estimated by the White House at $109 billion in 2013, are to be split evenly between defense spending and discretionary domestic spending, excluding wars, Social Security and Medicaid. BUT could and probably will include FDA budget. 42

43 Preparing for Unexpected Situations and Future Proposed Guidance Documents FDA FDA (CDRH) Plan of Action: acco/cdrh/cdrhreports/ucm htm FDA hot topics acco/cdrh/cdrhreports/ucm htm MDUFA III Commitment Letter ences/ucm pdf Proposed Guidance Documents Health Canada 2012 Guidance Documents: =search&s_s20rch.p1r1m3tr5cf53lds=hcyear%2chcsubject%2chctype%2 Chcsource%2Chccollection&S_S20RCH.p1r1m3tr5cS7rt=ReverseAlphabetica l&s_08d4t.s3rv5c3=basic&s_m5m3typ3.sp3c5f53r=index&s_m5m3typ3.t3 xt6p3r1t7r=or&s_m5m3typ3.v1l93=html%2fxhtml&s_s20rch.d7csp3rp1g 3=20&S_F8LLT2XT=Planned+Guidance+Documents&S_S20RCH.l1ng91g3= eng 43

44 Questions? Thank You! 44

45 Informed Consent USA FDA exercises enforcement discretion, with respect to its current regulations governing the requirement for informed consent when human specimens are used for FDA regulated in vitro diagnostic (IVD) device investigations For specimens left over from routine clinical care or analysis (that would otherwise have been discarded) or specimen repositories, or unrelated research. As long as subject privacy is protected by using only specimens that are not individually identifiable Applies only to IVD device investigations regulated by FDA that are exempt from most requirements of the IDE regulation (21 CFR 812) under 21 CFR 812.2(c)(3) Document your justification for why this guidance applies to the specimens you are using. 45

46 Documented Justification Points a) The investigation meets the IDE exemption criteria at 21 CFR 812.2(c) (3). b) The study uses leftover specimens, that is, remnants of specimens collected for routine clinical care or analysis that would have been discarded. The study may also use specimens obtained from specimen repositories or leftover specimens that were previously collected for other research purposes. c) The specimens are not individually identifiable, i.e., the identity of the subject is not known to and may not readily be ascertained by the investigator or any other individuals associated with the investigation, including the sponsor. If the specimen is coded, it will be considered to be not individually identifiable if neither the investigator(s) nor any other individuals associated with the investigation or the sponsor can link the specimen to the subject from whom the specimen was collected, either directly or indirectly through coding systems. d) The specimens may be accompanied by clinical information as long as this information does not make the specimen source identifiable to the investigator or any other individual associated with the investigation, including the sponsor. e) The individuals caring for the patients are different from and do not share information about the patient with those conducting the investigation. f) The specimens are provided to the investigator(s) without identifiers and the supplier of the specimens has established policies and procedures to prevent the release of personal information. g) The study has been reviewed by an IRB in accordance with 21 CFR Part 56. RECOMMENDATION: Put the justification right into the clinical plan or protocol for why informed consent is not required, so it can be reviewed by the IRB. 46

47 References USA CDC USDA-APHIS Fish & Wildlife Services US Department of Commerce Bureau of Industry and Security (BIS) 47

48 US FDA References 8/28/2011: Draft Guidance for Industry - Oversight of Clinical Investigations: A Risk-Based Approach to Monitoring 2 FDA is publishing this new draft guidance to assist sponsors of clinical investigations in developing risk-based monitoring strategies and plans for clinical investigations of human drug and biological products, medical devices, and combinations thereof. This guidance is intended to make clear that sponsors can use a variety of approaches to meet their monitoring responsibilities during clinical investigations. This guidance describes a modern, risk-based approach to monitoring that focuses on critical study parameters and relies on a combination of monitoring activities to effectively oversee a study. Comments were due by November 28, /15/2011: Draft Guidance for Industry, Clinical Investigators, and Food and Drug Administration Staff - Design Considerations for Pivotal Clinical Investigations for Medical Devices 3 This document is intended to provide guidance to those involved in designing clinical studies intended to support premarket submissions for medical devices and FDA staff who review those submissions. Comments were due by November 14, /26/ Advanced Notice of Proposed Rule Making - Human Subjects Research Protections: Enhancing Protections for Research Subjects and Reducing Burden, Delay, and Ambiguity for Investigators 4 - The Office of the Secretary of the Department of Health and Human Services (HHS) in coordination with the Office of Science and Technology Policy (OSTP) is issuing this advance notice of proposed rulemaking (ANPRM) to request comment on how current regulations for protecting human subjects who participate in research might be modernized and revised to be more effective. This ANPRM seeks comment on how to better protect human subjects who are involved in research, while facilitating valuable research and reducing burden, delay, and ambiguity for investigators. The comment period for the proposed rule published July 26, 2011, at 76 FR were due by October 26, /14/2011: Draft Guidance for Industry and Food and Drug Administration Staff - In Vitro Companion Diagnostic Devices 5 This draft guidance is intended to assist (1) sponsors who are planning to develop a therapeutic product that depends on the use of an in vitro companion diagnostic device (or test) for its safe and effective use and (2) sponsors planning to develop an in vitro companion diagnostic device that is intended to be used with a corresponding therapeutic product. Comments were due by September 12,

49 US FDA References Continued 8/15/2011: Draft Guidance for Industry and Food and Drug Administration Staff - Factors to Consider when Making Benefit-Risk Determinations in Medical Device Premarket Review 6 FDA has developed this draft guidance document to provide greater clarity for FDA reviewers and industry regarding the factors FDA considers when making benefit-risk determinations during the premarket review process for certain medical devices. Comments were due by November 14, /1/2011: Commercially Distributed In Vitro Diagnostic Products Labeled for Research Use Only or Investigational Use Only: Frequently Asked Questions, Draft Guidance for Industry and FDA Staff 7 This draft guidance document is intended to clarify the types of in vitro diagnostic (IVD) products that are properly labeled for research use only ("RUO") or for investigational use only ("IUO"), and provide the responses of the Center for Devices and Radiological Health (CDRH) and the Center for Biologics Evaluation and Research (CBER) to some frequently asked questions about how such products should and should not be marketed. This document is intended for manufacturers and distributors of RUO and IUO IVD products and any other entities who label IVD products. Comments were due by August 30, /24/2011: Financial Disclosure by Clinical Investigators, Guidance for Clinical Investigators, Industry, and FDA Staff (PDF - 151KB) 8 This guidance is intended to assist clinical investigators, industry, and FDA staff in interpreting and complying with the regulations governing financial disclosure by clinical investigators, 21 CFR part 54. This document is a revision of the Guidance for Industry: Financial Disclosure by Clinical Investigators dated March 20, The revised guidance addresses issues raised by the Office of the Inspector General (OIG), Department of Health and Human Services, in its report, OEI , The Food and Drug Administration s Oversight of Clinical Investigators Financial Information as well as questions FDA has received from industry and the public. Comments were due by July 25, /7/2011: Electronic Source Documentation in Clinical Investigations, Guidance for Industry (Draft) (PDF - 170KB) 9 This document provides guidance to sponsors, contract research organizations (CROs), data management centers, and clinical investigators on capturing, using, and archiving electronic data in FDA-regulated clinical investigations. This guidance is intended to ensure the reliability, quality, integrity, and traceability of electronic source data and source records maintained at the site for FDA inspection. Comments were due April 7,

50 US FDA References Continued 10/14/2010: Investigational New Drug Applications (INDs) - Determining Whether Human Research Studies Can Be Conducted Without an IND (PDF - 210KB) 10 This guidance is intended to assist clinical investigators, sponsors, and sponsor-investigators in determining whether human research studies must be conducted under an investigational new drug application (IND), as described in Title 21 of the Code of Federal Regulations, part 312 (21 CFR part 312) (the IND regulations). This guidance describes when an IND is required, specific situations in which an IND is not required, and a range of issues that, in FDA s experience, have been the source of confusion or misperceptions about the application of the IND regulations. Comments were due January 12, /29/2010: Safety Reporting Requirements for INDs and BA/BE Studies, Guidance for Industry and Investigators (Draft) (PDF - 688KB) 11 This document provides guidance to sponsors and investigators on safety reporting requirements for human drug and biological products that are being investigated under an investigational new drug application (IND) and for drugs that are the subjects of bioavailability (BA) and bioequivalence (BE) studies that are exempt from the IND requirements. This guidance contains definitions used for safety reporting, makes recommendations on when and how to submit a safety report, and provides advice on other safety reporting issues that have generated questions from sponsors and investigators. Comments were due December 28, /19/2010: Proposed rule - Reporting Information Regarding Falsification of Data 12 The proposed rule will require sponsors to report information indicating that any person has, or may have, engaged in the falsification of data involving studies including, but not limited to, clinical investigations, nonclinical laboratory studies, and clinical studies in animals. Comments were due May 20, /13/2010: IRB Continuing Review After Clinical Investigation Approval, Draft Guidance (PDF KB) 13 This guidance is intended to assist IRBs in carrying out their continuing review responsibility under 21 CFR (a) and (f) by providing recommendations regarding the criteria, process, and frequency of continuing review to assure the protection of the rights and welfare of subjects in clinical investigations. The draft guidance should also help clinical investigators and sponsors better understand their responsibilities related to continuing review. Comments were due March 15,

51 US FDA References Continued 11/28/06: FDA Extends the Comment Period on the Draft Guidance for Industry, Clinical Laboratories and FDA Staff on In Vitro Diagnostic Multivariate Index Assays [PDF107 KB] 14 Federal Register Notice. 15 Written or electronic comments on this draft guidance were due by March 5, /17/06: Withdrawal of the Advance Notice of Proposed Rulemaking entitled "Institutional Review Boards: Requiring Sponsors and Investigators to Inform Institutional Review Boards of Any Prior Institutional Review Boards Reviews" 16 After reviewing public comments on this ANPRM, FDA concluded that rulemaking on this matter was not warranted at this time. A notice withdrawing this ANPRM published in the Federal Register on Jan. 16, This notice can be found on FDA's Dockets Management Web site at The effective date for this withdrawal was February 16, /27/04--FDA published a Notice of Availability announcing the availability of a draft guidance entitled "Information Program on Clinical Trials for Seriousor Life-Threatening Diseases and Conditions" 18 PDF version of the draft guidance 19 FDA is revising its March 2002 guidance for industry of the same title to include guidance for sponsors who will be submitting information required by the Best Pharmaceuticals for Children Act. Written comments should be submitted to the Division of Dockets Management (HFA- 305), Food and Drug Administration, 5630 Fishers Lane, Room 1061, Rockville, MD Electronic comments for Docket No. 2004D-0014 were due by March 29,

52 Import/Export Permits Canada Import Permits for Animal Pathogens (Canada) path/animae.shtml Import Permits Lab Pathogens (Canada) 52

53 Helpful Links and Resources International Air Transport Association (IATA) Dangerous Goods Center for Disease Control (CDC) Transport of Infectious Substances Department of Transportation (DOT) Hazardous Materials: Infectious Substances (49 CFR Parts 171 et.al.) World Health Organization (WHO) Guidance on Regulations for the Transport of Infectious Substances 0.pdf US Dept of Treasury Office of Foreign Asset Control (OFAC). The link is provided here: Web based certification training from University of Wisconsin =100 53

54 History Year Milestone 1820 Eleven physicians meet in Washington, D.C., to establish the U.S. Pharmacopeia, the first compendium of standard drugs for the United States Drug Importation Act passed by Congress requires U.S. Customs Service inspection to stop entry of adulterated drugs from overseas President Lincoln appoints a chemist, Charles M. Wetherill, to serve in the new Department of Agriculture. This was the beginning of the Bureau of Chemistry, the predecessor of the Food and Drug Administration Peter Collier, chief chemist, U.S. Department of Agriculture, recommends passage of a national food and drug law, following his own food adulteration investigations. The bill was defeated, but during the next 25 years more than 100 food and drug bills were introduced in Congress Dr. Harvey W. Wiley becomes chief chemist, expanding the Bureau of Chemistry's food adulteration studies. Campaigning for a federal law, Dr. Wiley is called the "Crusading Chemist" and "Father of the Pure Food and Drugs Act." He retired from government service in 1912 and died in Tea Importation Act passed, providing for Customs inspection of all tea entering U.S. ports, at the expense of the importers Association of Official Agricultural Chemists (now AOAC International) establishes a Committee on Food Standards headed by Dr. Wiley. States begin incorporating these standards into their food statutes 1902 The Biologics Control Act is passed to ensure purity and safety of serums, vaccines, and similar products used to prevent or treat diseases in humans. Congress appropriates $5,000 to the Bureau of Chemistry to study chemical preservatives and colors and their effects on digestion and health. Dr. Wiley's studies draw widespread attention to the problem of food adulteration. Public support for passage of a federal food and drug law grows The original Food and Drugs Act is passed by Congress on June 30 and signed by President Theodore Roosevelt. It prohibits interstate commerce in misbranded and adulterated foods, drinks and drugs. The Meat Inspection Act is passed the same day. Shocking disclosures of insanitary conditions in meat-packing plants, the use of poisonous preservatives and dyes in foods, and cure-all claims for worthless and dangerous patent medicines were the major problems leading to the enactment of these laws First Certified Color Regulations, requested by manufacturers and users, list seven colors found suitable for use in foods 1911 In U.S. v. Johnson, the Supreme Court rules that the 1906 Food and Drugs Act does not prohibit false therapeutic claims but only false and misleading statements about the ingredients or identity of a drug Congress enacts to overcome the ruling in U.S. v. Johnson. It prohibits labeling medicines with false therapeutic claims Sherley Amendment to overcome the ruling in U.S. v. Johnson. It prohibits labeling medicines with false therapeutic intended to defraud the purchaser, a standard difficult to prove. 54

55 History Year Milestone 1913 Gould Amendment requires that food package contents be "plainly and conspicuously marked on the outside of the package in terms of weight, measure, or numerical count." 1914 In U.S. v. Lexington Mill and Elevator Company, the Supreme Court issues its first ruling on food additives. It ruled that in order for bleached flour with nitrite residues to be banned from foods, the government must show a relationship between the chemical additive and the harm it allegedly caused in humans. The court also noted that the mere presence of such an ingredient was not sufficient to render the food illegal. The Harrison Narcotic Act requires prescriptions for products exceeding the allowable limit of narcotics and mandates increased record-keeping for physicians and pharmacists who dispense narcotics In U.S. v. 95 Barrels Alleged Apple Cider Vinegar, the Supreme Court rules that the Food and Drugs Act condemns every statement, design, or device on a product's label that may mislead or deceive, even if technically true The Bureau of Chemistry is reorganized into two separate entities. Regulatory functions are located in the Food, Drug, and Insecticide Administration, and nonregulatory research is located in the Bureau of Chemistry and Soils McNary-Mapes Amendment authorizes FDA standards of quality and fill-of-container for canned food, excluding meat and milk products. The name of the Food, Drug, and Insecticide Administration is shortened to Food and Drug Administration (FDA) under an agricultural appropriations act FDA recommends a complete revision of the obsolete 1906 Food and Drugs Act. The first bill is introduced into the Senate, launching a five-year legislative battle Elixir of Sulfanilamide, containing the poisonous solvent diethylene glycol, kills 107 persons, many of whom are children, dramatizing the need to establish drug safety before marketing and to enact the pending food and drug law The Federal Food, Drug, and Cosmetic (FDC) Act of 1938 is passed by Congress, containing new provisions: Extending control to cosmetics and therapeutic devices. Requiring new drugs to be shown safe before marketing-starting a new system of drug regulation. Eliminating the Sherley Amendment requirement to prove intent to defraud in drug misbranding cases. Providing that safe tolerances be set for unavoidable poisonous substances. Authorizing standards of identity, quality, and fill-of-container for foods. Authorizing factory inspections. Adding the remedy of court injunctions to the previous penalties of seizures and prosecutions. Wheeler-Lea Act, the Federal Trade Commission is charged with overseeing advertising of products except prescription drugs. 55

56 History 56 Year Milestone 1939 First Food Standards issued (canned tomatoes, tomato purée, and tomato paste) FDA transferred from the Department of Agriculture to the Federal Security Agency, with Walter G. Campbell appointed as the first Commissioner of Food and Drugs Insulin Amendment requires FDA to test and certify purity and potency of this lifesaving drug for diabetes In U.S. v. Dotterweich, the Supreme Court rules that the responsible officials of a corporation, as well as the corporation itself, may be prosecuted for violations. It need not be proven that the officials intended, or even knew of, the violations Public Health Service Act is passed, covering a broad spectrum of health concerns, including regulation of biological products and control of communicable diseases Penicillin Amendment requires FDA testing and certification of safety and effectiveness of all penicillin products. Later amendments extended this requirement to all antibiotics. In 1983 such control was found no longer needed and was abolished Miller Amendment affirms that the Federal Food, Drug, and Cosmetic Act applies to goods regulated by the Agency that have been transported from one state to another and have reached the consumer FDA publishes guidance to industry for the first time. This guidance, "Procedures for the Appraisal of the Toxicity of Chemicals in Food," came to be known as the "black book." 1950 In Alberty Food Products Co. v. U.S., a court of appeals rules that the directions for use on a drug label must include the purpose for which the drug is offered. Therefore, a worthless remedy cannot escape the law by not stating the condition it is supposed to treat. Oleomargarine Act requires prominent labeling of colored oleomargarine, to distinguish it from butter. Delaney Committee starts congressional investigation of the safety of chemicals in foods and cosmetics, laying the foundation for the 1954 Miller Pesticide Amendment, the 1958 Food Additives Amendment, and the 1960 Color Additive Amendment Durham-Humphrey Amendment defines the kinds of drugs that cannot be safely used without medical supervision and restricts their sale to prescription by a licensed practitioner In U.S. v. Cardiff, the Supreme Court rules that the factory inspection provision of the 1938 FDC Act is too vague to be enforced as criminal law. FDA consumer consultants are appointed in each field district to maintain communications with consumers and ensure that FDA considers their needs and problems Federal Security Agency becomes the Department of Health, Education, and Welfare (HEW). Factory Inspection Amendment clarifies previous law and requires FDA to give manufacturers written reports of conditions observed during inspections and analyses of factory samples Miller Pesticide Amendment spells out procedures for setting safety limits for pesticide residues on raw agricultural commodities. First large-scale radiological examination of food carried out by FDA when it received reports that tuna suspected of being radioactive was being imported from Japan following atomic blasts in the Pacific. FDA begins monitoring around the clock to meet the emergency

57 History Year Milestone 1958 Food Additives Amendment enacted, requiring manufacturers of new food additives to establish safety. The Delaney proviso prohibits the approval of any food additive shown to induce cancer in humans or animals. FDA publishes in the Federal Register the first list of substances generally recognized as safe (GRAS). The list contains nearly 200 substances U.S. cranberry crop recalled three weeks before Thanksgiving for FDA tests to check for aminotriazole, a weedkiller found to cause cancer in laboratory animals. Cleared berries were allowed a label stating that they had been tested and had passed FDA inspection, the only such endorsement ever allowed by FDA on a food product Color Additive Amendment enacted, requiring manufacturers to establish the safety of color additives in foods, drugs and cosmetics. The Delaney proviso prohibits the approval of any color additive shown to induce cancer in humans or animals. Federal Hazardous Substances Labeling Act, enforced by FDA, requires prominent label warnings on hazardous household chemical products Thalidomide, a new sleeping pill, is found to have caused birth defects in thousands of babies born in western Europe. News reports on the role of Dr. Frances Kelsey, FDA medical officer, in keeping the drug off the U.S. market, arouse public support for stronger drug regulation. Kefauver-Harris Drug Amendments passed to ensure drug efficacy and greater drug safety. For the first time, drug manufacturers are required to prove to FDA the effectiveness of their products before marketing them. The new law also exempts from the Delaney proviso animal drugs and animal feed additives shown to induce cancer but which leave no detectable levels of residue in the human food supply. Consumer Bill of Rights is proclaimed by President John F. Kennedy in a message to Congress. Included are the right to safety, the right to be informed, the right to choose, and the right to be heard Drug Abuse Control Amendments are enacted to deal with problems caused by abuse of depressants, stimulants and hallucinogens FDA contracts with the National Academy of Sciences/National Research Council to evaluate the effectiveness of 4,000 drugs approved on the basis of safety alone between 1938 and Child Protection Act enlarges the scope of the Federal Hazardous Substances Labeling Act to ban hazardous toys and other articles so hazardous that adequate label warnings could not be written. Fair Packaging and Labeling Act requires all consumer products in interstate commerce to be honestly and informatively labeled, with FDA enforcing provisions on foods, drugs, cosmetics, and medical devices FDA Bureau of Drug Abuse Control and Treasury Department Bureau of Narcotics are transferred to the Department of Justice to form the Bureau of Narcotics and Dangerous Drugs (BNDD), consolidating efforts to police traffic in abused drugs. Reorganization of federal health programs places FDA in the Public Health Service. FDA forms the Drug Efficacy Study Implementation (DESI) to implement recommendations of the National Academy of Sciences investigation of effectiveness of drugs first marketed between 1938 and Animal Drug Amendments place all regulation of new animal drugs under one section of the Food, Drug, and Cosmetic Act-Section 512-making approval of animal drugs and medicated feeds more efficient. 57