Good Laboratory Practices for Biotechnology Research BIOE 470/570, Regulation of Drugs and Medical Devices Oregon State University February 19, 2014 Carol A. Pratt, Ph. D. , JD K&L Gates LLP Portland, Oregon 503 -226 -5762 carol. pratt@klgates. com copyright 2014 Carol A. Pratt
Good Laboratory Practices (GLPs) § A quality system of management controls for research laboratories and organizations to try to ensure the uniformity, consistency, reliability, reproducibility, quality, and integrity of non-clinical safety tests. § An international set of principles Good Laboratory Practice (GLP) embodies a set of principles that provides a framework within which laboratory studies are planned, performed, monitored, recorded, reported and archived. These studies are undertaken to generate data by which the hazards and risks to users, consumers and third parties, including the environment, can be assessed. . . GLP helps assure regulatory authorities that the data submitted are a true reflection of the results obtained during the study and can therefore be relied upon when making risk/safety assessments. [Medicines and Healthcare Products Regulatory Agency - UK (MHRA)] 2
FDA’s Good Laboratory Practices (GLPs) § Initiated in 1978 § Response to high profile fraud in pharmaceutical and chemical industries § Statutory requirements § Federal Food Drug & Cosmetic Act (multiple sections) § Regulatory requirements § 21 CFR Part 58: Good Laboratory Practices for Nonclinical Laboratory Studies § http: //www. accessdata. fda. gov/scripts/cdrh/cfdocs/cfcfr/CFRSearch. cfm 3
FDA GLP Requirements: 21 CFR Part 58 § Applies to: § Nonclinical laboratory studies § Intended to support applications to FDA for marketing or research permits § For products that require approval/clearance by the FDA § Purpose: § Assure the quality and integrity of safety data submitted to the FDA (which is used by FDA to make product approval decisions) 4
Nonclinical studies: 21 CFR Part 58. 3(d) § Nonclinical laboratory study § prospective in vitro or in vivo experiments § on “test articles” (products subject to FDA premarket approval) § Drugs, biologics, medical devices, food additives, food colors § in “test systems” § Any animal, plant, microorganism, or subparts thereof to which the test article is administered or added § under laboratory conditions § to determine safety § Why are GLPs limited to safety studies? § Products must be safe and effective for their intended purpose § In the US, safety has priority over efficacy § Historically related to drug development cycle 5
Drug Development Cycle In vitro and in vivo (animal) studies to screen compounds, determine physical/chemical characteristics and test safety. Preclinical GLPs Larger, multi-site study – initial test of efficacy in patients based on doses from Phase 1. Determine sample size. Phase 1 Phase 2 FIRST IN HUMAN Study – Small, tightly controlled study in healthy subjects to determine safety and dose ranging (pharmacokinetics). Phase 3 Large, multisite study in patients to test efficacy. 6
Drug Development Cycle Safe for Human Use? GLPs – 21 CFR Part 58 Preclinical Cell and Animal Studies GCPs: Human subjects: 21 CFR Part 50, 56 Investigational Drugs/Biologics: 21 CFR Part 312 Investigational Devices: 21 CFR Part 812 Phase 1 Phase 2 Phase 3 Clinical Trials – Human Subjects 7
Nonclinical Laboratory Studies § “Do not include: § Studies using human subjects or human specimens § Exploratory studies to determine: § If a test article has any potential utility (efficacy), or § Physical/chemical characteristics of test article § Medical devices* § Bench tests involving chemical or physical testing § GLPs n/a if there is no “test system” (animal, plant or microorganism) § Early feasibility studies of potential utility *FDA Draft Guidance, The Applicability of Good Laboratory Practice in Premarket Device Submissions: Questions and Answers (8/28/13) 8
GLPs - 21 CFR Part 58 TITLE 21 --FOOD AND DRUGS CHAPTER I--FOOD AND DRUG ADMINISTRATION DEPARTMENT OF HEALTH AND HUMAN SERVICES SUBCHAPTER A--GENERAL PART 58 GOOD LABORATORY PRACTICE FOR NONCLINICAL LABORATORY STUDIES § § § § § Subpart A--General Provisions Subpart B--Organization and Personnel Subpart C--Facilities Subpart D--Equipment Subpart F--Test and Control Articles Subpart G--Protocol for and Conduct of a Nonclinical Laboratory Study Subparts H-I [Reserved] Subpart J--Records and Reports Subpart K--Disqualification of Testing Facilities http: //www. accessdata. fda. gov/scripts/cdrh/cfdocs/cfcfr/CFRSearch. cfm 9
GLPs - 21 CFR Part 58 § Personnel § Must have adequate education, training, and experience § Each study must have a designated study director § Study protocol § Study must be conducted according to a written, approved protocol § Any changes to protocol must be pre-approved and signed by study director § Testing facilities – must: § § § Comply with animal care facility requirements Have separate areas for performing laboratory tests Have separate areas for receipt, storage and use of test articles Have written SOPs to comply with GLP requirements Must have a quality assurance unit (QAU) 10
GLPs - 21 CFR Part 58 § Data records § All data must be recorded directly, promptly and legibly in ink § Data entries must be: § Dated on the date of entry, and § Signed or initialed by the person making the entry § Any change in an entry must be dated, signed or initialed at the time of the change and explained. Practice Tip #1 Document, Document 11
FDA Proposed Expansion of GLPs § FDA’s GLPs are less comprehensive than international standards § ISO – 9000: Quality Management * § International Organization for Standardization (ISO) § ISO-9001 Certification: certification of compliance with ISO-9000 family of requirements § Requires certification (unlike the FDA) § More comprehensive than FDA’s GLPs § Proposed new rule (Federal Register, 75, 80012, 12/21/10) § Change GLP regulations to be more similar to ISO 9001 § Pressure on the FDA for international harmonization of regulatory requirements to accommodate global companies / markets *http: //www. iso. org/iso_catalogue/management_and_leadership_standards/quality_management. htm 12
FDA Proposed Expansion of GLPs § Would apply to all studies conducted by nonclinical laboratory facilities § Studies of efficacy and of physical/chemical characteristics § Multisite studies § Modify personnel, study director roles § Electronic and computerized systems § Specify additional sponsor responsibilities § Development/approval of the study protocol § Compliance with Animal Welfare Act § More detailed records of inspectional findings by the Quality Assurance Unit § More detailed records about test article characteristics (strength, purity, stability, etc. ) 13
Enforcement of GLPs § Rejection of data § FDA may reject the data supporting the marketing or research application § Angry sponsor! § Breach of contract lawsuit, damages § Inspections § FDA’s Bioresearch Monitoring Program § Inspection of nonclinical and clinical studies and facilities § Inspection findings – Form 483 § Must respond with a written corrective action plan within 15 days § Pass re-inspection § Not public § Warning Letters § Disqualification of testing facility 14
Enforcement of GLPs – Warning Letters § Are public – published on FDA website § Usually issued only if facility has inadequate response to a Form 483 § Must respond in writing within 15 days § Address current violations § Corrective action plan (CAP) – revise/add procedures to ensure violation do not occur in the future § The CAP is most important § 20/80 Rule (20% backward looking; 80% forward looking) § Inadequate response can lead to shut down or legal action without further notice 15
GLP Warning Letter - Example 16
Isis Services Warning Letter § Isis Services is a preclinical contract research organization (CRO) § Involved medical device nonclinical laboratory studies § Result of an FDA inspection § “This inspection is a part of FDA’s Bioresearch Monitoring Program, which includes inspections designed to verify compliance with Title 21 of the Code of Federal Regulations (21 CFR), Part 58 - Good Laboratory Practice (GLP) for Nonclinical Laboratory Studies. ” § Form FDA 483 was issued § Company’s written response to the Form 483 was “inadequate” Isis warning letter: http: //www. fda. gov/ICECI/Enforcement. Actions/Warning. Letters/2011/ucm 263814. htm 17
Isis Warning Letter § Failure to ensure that each individual engaged in the conduct of or responsible for supervision of a nonclinical laboratory study has education, training, and experience, and failure to ensure that the testing facility maintains a current summary of training and experience. [21 CFR 58. 29(a) and (b)] § No evaluations for employees on xxxx dates § No record that employees attended required training sessions § Failure of testing facility and study directors to fulfill their responsibilities. [21 CFR 58. 31, 58. 33] § The testing facility failed to designate a study director before the study was initiated § The testing facility let the sponsor designate study directors § The testing facility failed to provide documentation that study directors were trained on the SOP for Study Directorship 18
Isis Warning Letter § Failure of the quality assurance unit to determine that no deviations from approved protocols or SOPs were made without proper authorization and documentation, and to review the final study report to assure that such report accurately describes the methods and SOPs. [21 CFR 58. 35(b)(5) and (6)] § There is no documentation to show that final study reports for xxx studies were reviewed § XX wrote the contributing scientist reports for studies xxx; however, there is no documentation of him participating in the studies, nor were there any amendments adding him to the studies. § Failure to retain the final study reports. [21 CFR 58. 190] § Final reports were provided with company’s response to the Form 483 but were not available during the inspection 19
Isis Warning Letter § “You must address these violations and establish procedures to ensure that any ongoing or future studies are conducted in compliance with the Act and applicable FDA regulations. § Within fifteen working days of receipt of this letter, you must provide written documentation of the specific additional corrective actions that you have taken or will take to address all of the violations noted above and to prevent recurrence of similar violations in current or future nonclinical laboratory studies conducted by your facility. Any submitted corrective action plan must include projected completion dates for each action to be accomplished. In addition, please provide a complete list of all nonclinical laboratory research of FDA‑regulated devices for the last five years, including the name of the study and the test article, the names of the study director and sponsor, and the current status of the studies. § We will review your company’s response and determine whether it is adequate. Failure to respond to this letter and take appropriate corrective action could result in FDA taking regulatory action without further notice to you, including disqualification proceedings in accordance with 21 CFR 58. 202. ” 20
IIT Warning Letter 21
IIT Warning Letter § Failure of testing facility management to assure that test articles or mixtures were appropriately tested for identity, strength, purity, stability, and uniformity, as applicable [21 CFR 58. 31(d)]. § The protocol stated that the sponsor would test the dose formulations prior to shipment and samples of the dose formulation would be sent to the sponsor for xx analysis during study weeks 5, 13, 26, 52, 78 and 103. § You subsequently amended the protocol, approximately one year after dosing ended and two weeks before the final report was signed by the study director, to indicate that the dose formulation results would be submitted separately by the sponsor. § Although the sponsor did submit the results to the agency after the inspection, the testing facility failed to assure that the appropriate testing was conducted in order for the study director to include the necessary information in the final report. § Take Home Message – the testing facility is responsible for complying with GLPs regardless of the sponsor’s actions/non-actions http: //www. fda. gov/ICECI/Enforcement. Actions/Warning. Letters/2005/ucm 075728. htm 22
IIT Warning Letter § Failure to include a description of all circumstances that may have affected the quality or integrity of the data in final study reports [21 CFR 58. 185(a)(9)]. § As described, the study director lacked critical information regarding the dose formulation administered to animals in study xx. Characteristics of the dose formation are essential to the study director's assessment of study outcomes, and the absence of this information limits the quality and the integrity of the data for study xx. § In your. . . final report you did not communicate that you lacked the critical data, or that you had reservations about drawing study conclusions without knowing the actual doses of xx administered to the animals. § We acknowledge your February 4, 2005 response that the sponsor instructed you to finalize the final report using the data that were available at the time. Since your attempts to obtain required information from the sponsor were unsuccessful, your final report conclusions should have communicated such critical limitations as circumstances that affected the quality and integrity of the data; because you did not know whether the intended doses of xx were actually administered to the animals, the study director could not provide a meaningful assessment of study outcome. § Thus, your conclusion in the final report summary that there was no evidence of a carcinogenic effect in any organ. . . could not be reached in light of the missing information and should have conveyed that you lacked critical data to draw study conclusions. 23
IIT Warning Letter § Not all nonclinical laboratory studies were conducted in accordance with the protocol [21 CFR 58. 130(a)]. § The protocol for study xx required the consent of the study director or study pathologist prior to sacrificing moribund animals. Five study animals were sacrificed without documentation of the required consent. § Failure to have an approved written protocol for each study [21 CFR 58. 120(a)] § You conducted study-specific activities for studies xx before the protocol was approved. § In particular, animals were randomized into study specific dosing groups before the study was initiated. § In your response dated February 4, 2005, you suggested that animal randomization is considered "pre-start" data collection, similar to the acquisition of a test article's certificate of analysis. § Because animal randomization depends upon a protocol-defined group number and size, FDA considers such activities to be part of conducting the study. Thus, you conducted specific study-related activities without an approved protocol 24
Practice Tip #2 Follow The Protocol Practice Tip #1 Document Deviations From the Protocol 25
GLPs: Laboratory Notebooks § Provide detailed, accurate, dated record of experimental plans, results, conclusions and ideas § Provides details to allow replication of results § Scientific integrity § Reliability of results § Basis for invention disclosures (is a result patentable? ) § Provides information for patents (specifications, claims) § Used as corroborating evidence of inventorship, if disputed § Who knew what when? 26
Laboratory Notebooks § Industrial § Notebooks are owned by the company § Inventions are owned by the company § Employee is the inventor § Company owns the patent rights § Employee must assign IP rights to employer as a condition of employment § Employment Agreement requires employees to maintain notebooks and records § Company SOPs set out procedures for maintaining notebooks and records § Notebooks are stored by the company § No copies kept by the employee 27
Laboratory Notebooks § Academia § Notebooks are owned by the faculty member § University owns the invention (IP) and patent rights § Faculty must assign IP rights to university as a condition of employment § Faculty member is inventor § University typically gives some percentage of income from patents to faculty scientist § Notebooks (usually) are not required § Discretion of faculty § Recommended by technology transfer office § Leaves academics vulnerable to inventorship/patent disputes § May not be able to provide corroborating evidence of contribution to invention or the date of invention 28
Industrial Laboratory Notebooks § Assigned to employee researcher § Notebook assigned a company number and assigned to an individual scientist § Bound notebooks § § Secured pages (unlike 3 -ring notebook) Commercially available Usually ~ 300 pages Page 1: sign-out page § Name of scientist § Date issued and date completed § Purpose/projects § Page 2: Instructions for record keeping § Table of Contents § Entry pages § Format provides structure for important record keeping 29
Industrial Laboratory Notebooks § Page format § § Subject or Project: From page: To page: Identity of person entering data: § Recorded by: § Date: § Witness § Read & Understood By: § Date: § Witness should be technically competent to understand be unbiased (not involved in the study) § No witness = no corroboration § Some courts have used witness signing date as the effective date 30
GLPs for Laboratory Notebooks § Entry should be made immediately after work is done (must be “contemporaneous”) § Enter time § Individual page should not be used for more than one date § If have empty space on page, draw a “X” through empty space. § Write legibly and in ink § Each section should have a clear, descriptive heading § § § Introduction Experimental Plan Observations and Data Discussion of Results Conclusions 31
GLPs for Laboratory Notebooks, cont’d § Entries § Level of detail § Provide sufficient detail such that an independent person could replicate experiment based on the notebook § Related loose material should be taped onto the notebook page § Printouts, graphs § Gels § Statistical analyses § Related information stored elsewhere should be referenced in notebook § Example: “Photographs of cells stored in Binder # __. ” § Corrections/changes § Do not write over original entry § Explain reason for correction § Initial and date 32
GLPs for Laboratory Notebooks, cont’d § Maintenance of notebooks § Should not be allowed off company site § Should be kept in a locked place overnight § Photocopies § Strictly regulated by company policy to protect IP § May not be allowed at all § Storage of notebooks § Completed notebooks should be copied to microfilm or microfiche § Original notebook should be archived indefinitely § May be needed for evidence in litigation that could take place years later 33
Role of Laboratory Notebooks in Protecting IP § Determine inventorship § Correct inventorship § Valid patents must include all rightful inventors § Protect patents from challenge § First to invent system – interference proceedings § First to file system – derivation proceedings § Determine ownership § Flows from assignment by inventors § Basis for allocation of royalties § Commercialization of IP rights 34
Inventorship § Key = conception § “The threshold question in determining inventorship is who conceived the invention. ” § The formation in the mind of the inventor of a “definite and permanent idea” of the “complete and operative invention” § A mental act § Inventor need not know the invention will work (that = reduction to practice) § Reduction to practice § Actual: carrying out of the invention (make/test the invention) § Constructive: file a patent application § Provides corroborating evidence of conception § Research records, patent application 35
Role of GLPs in Protecting Intellectual Property § How to prove conception (a “mental act”)? § Key issue: who knew what when? § “Inventor must prove conception by corroborating evidence of oral testimony, preferably by showing a contemporaneous disclosure. ” ([Burroughs v. Barr Labs (1994), AZT dispute] § Laboratory notebooks § Are the industry standard for contemporaneous documentation § It is critical to document what you know and when you knew it § An evidentiary record of: § Conception § Reduction to practice § Compliance with GLP requirements help document IP rights 36
Role of Laboratory Notebooks in Protecting IP § First-to-invent system § Previous U. S. patent system (prior to March 2013) § Key to determining inventorship was date of conception § Laboratory notebooks were key evidentiary record used in high profile lawsuits § Outcome of cases hinged on records that had been kept 3 – 5 years previously (before the trial) § Employees may no longer at the company § Witnesses may be gone § Employees/witnesses may work for competitor (plaintiff) 37
First-to-File System § Leahy-Smith America Invents Act (“AIA”) § Based on first to file patent application § Effective March 16, 2013 § Harmonizes the US and most other countries § Reflects acceptance of a global marketplace for goods and IP § Provides bright-line rule for IP rights § Don’t have to prove conception (what the inventor ‘knew’) by corroborating evidence § Race to the PTO § Resolving inventorship disputes § Laboratory notebooks will still play a key role in resolving inventorship disputes 38
First-to-File System § Impact of first-to-file system § Will encourage earlier filing of patent applications § Provisionals filed to establish priority date § Need to be followed with non-provisional within 1 year § Pressure to file early may result in inadequate enablement of patent claims § May make patents vulnerable to later invalidity claims § Correct identity of inventors § Each inventor has right to patent § Failure to name all inventors can result in invalid patent § Inventorship disputes will involve derivation proceedings § Petitioner must show by substantial evidence: § Petitioner = the inventor (= conception) § Petitioner communicated the invention to the first applicant (invention derived from the communication) § Laboratory notebooks should document conception and communication with collaborators and colleagues 39
Example of Role of Laboratory Notebooks in Inventorship Litigation § OHSU v. XYZ Pharmaceuticals (Sponsor) § Academic – industry preclinical research collaboration § Research agreement § “Joint inventions will be jointly owned” § Facts § Sponsor gave compounds to Dr. OHSU to test in cell culture assay § There was an unexpected finding from Dr. OHSU’s experiment § 3 months later, Sponsor filed 3 patent applications related to the unexpected finding. Sponsor was sole inventor § OHSU claimed that Dr. OHSU was a co-inventor and should be added to the patents § Sponsor claimed they had expected the finding based on in-house experiments they conducted prior to Dr. OHSU’s experiment § OHSU sued Sponsor to have inventorship corrected by adding Dr. OHSU to the patents 40
OHSU v. XYZ Pharmaceuticals § Key issues § Who conceived the invention? § Could Sponsor produce corroborating evidence of their claim that they had conceived the invention prior to receiving results from Dr. OHSU? § Evidence § Dr. OHSU’s laboratory records corroborated the content and date of Dr. OHSU’s alleged findings § Sponsor’s laboratory notebooks did not corroborate their assertion that they knew before Dr. OHSU which compounds would work § 3 weeks prior to Dr. OHSU’s experiment, Sponsor’s scientist’s notebook contained statement of experimental plan but no results or data § Page was witnessed 2 months after page date (which was after OHSU experiment) § Outcome: case settled 41
Practice Tip #3 Look Ahead – Today’s Record is Tomorrow’s Evidence 42
Summary § Compliance with GLP requirements is important for: § FDA compliance § Assuring safety of products for first use in human clinical trials § Getting products approved by the FDA § Protection of IP 43
Good Laboratory Practices for Biotechnology Research Questions? 44
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