On May 25, 2005, the Food and Drug Administration (FDA) will issue its Current Good Tissue Practice (CGTP) for Human Cells, Tissues, and Cellular and Tissue-Based Products (HCT/Ps), representing the last of three FDA rules* that have been developed to improve the safety of HCT/Ps by preventing the introduction, transmission, and spread of communicable disease. The CGTP regulations will require HCT/P establishments to recover, process, store, label, package, and distribute HCT/Ps in a way that prevents the introduction, transmission, or spread of communicable diseases. HCT/P establishments must also maintain complaint files and evaluate each complaint relating to core CGTP requirements. Such establishments will also be required to 1) investigate any adverse reaction involving a communicable disease related to an HCT/P they made available for distribution and 2) report to FDA any serious adverse reactions involving a communicable disease. Serious adverse reactions are defined by FDA as fatal, life-threatening, resulting in permanent impairment of a body function or permanent damage to body structure, or necessitating medical or surgical intervention, including hospitalization. The establishments will be required to use the FDA MedWatch mandatory reporting form (Form FDA-3500A) and submit each report to FDA within 15 days of initial receipt of the information. This will be the first federal requirement for reporting of adverse reactions from transplanted HCT/Ps. Nearly simultaneously with the CGTP rule, the Joint Commission on Accreditation of Healthcare Organizations (JCAHO) revised its standards for the Laboratory Accreditation Program (revised standards QC.5.300, QC.5.310, and QC.5.320) and adopted these standards for the Ambulatory Care, Office-Based Surgery, Critical Access Hospital, and Hospital Accreditation programs (new standards PC.17.10, PC.17.20, and PC.17.30) ( 1,2 ). Effective July 1, 2005, these standards will apply to accredited organizations that store or issue tissue. These new standards will require that organizations assign oversight responsibility for a tissue program, use standardized procedures in all tissue handling, maintain traceability of all tissues, and have a process for investigating and reporting adverse events. All adverse events involving tissues, including disease transmission or other complications suspected of being directly related to tissue use, are to be investigated and reported to the HCT/P establishment from which the tissue was received. Improved HCT/P adverse event surveillance from these two mandatory reporting rules is anticipated to improve the overall safety of HCT/Ps and reduce risk to HCT/P recipients. A successful surveillance system will be contingent upon reporting by physicians, infection-control practitioners, risk managers, and others who identify adverse events. Along with receiving mandatory reports from establishments, FDA continues to encourage direct voluntary reports through its MedWatch program by using MedWatch Form FDA-3500, available at http://www.fda.gov/medwatch . Additional information about FDA and HCT/Ps is available at http://www.fda.gov/cber/tiss.htm . References Joint Commission on Accreditation of Healthcare Organizations. Revised laboratory standards: QC.5.300, QC.5.310, and QC.5.320. Oakbrook Terrace, IL: Joint Commission on Accreditation of Healthcare Organizations; 2005. Available at http://www.jcrinc.com/subscribers/perspectives.asp?durki=9162&site=10&return=6066 . Joint Commission on Accreditation of Healthcare Organizations. Standards for tissue storage and issuance: PC.17.10, PC.17.20, and PC.17.30. Oakbrook Terrace, IL: Joint Commission on Accreditation of Healthcare Organizations; 2005. Available at http://www.jcrinc.com/subscribers/perspectives.asp?durki=9160&site=10&return=6065 . * Federal Register 66 FR 5447, January 19, 2001; 66 FR 29786, May 25, 2004; and 69 FR 68612, November 24, 2004.
What is the Center for Biologics Evaluation and Research (CBER)? CBER is the Center within FDA that regulates biological products for human use under applicable federal laws, including the Public Health Service Act and the Federal Food, Drug and Cosmetic Act. CBER protects and advances the public health by ensuring that biological products are safe and effective and available to those who need them. CBER also provides the public with information to promote the safe and appropriate use of biological products. The Center for Drug Evaluation and Research ( CDER ), which assures that safe and effective drugs are available to the American people, has gone through a functional and organizational metamorphosis since it began as a one-man operation to assess significant drug problems in the marketplace on the eve of the 1906 Pure Food and Drugs Act
Tremendous pressure to obtain and distribute a vaccine.
Previously, vaccine associated polio had been indicated in earlier vaccine studies (20 years earlier) when paralysis was initiated in the vaccination arm.
Concerns about residual live virus had been raised. Concerns raised about consistency of manufacturing and inactivation.
Good Manufacturing Practices (GMP), Good Laboratory Practices (GLP) and Good Tissue Practices (GTP) Richard E. Giles, Ph.D. Associate Professor Regulatory Affairs Institutional Compliance Office
GLPs describe good laboratory practices for conducting non-clinical laboratory studies that support or are intended to support applications for research or marketing permits for products regulated by the FDA. 21 CFR Part 58.
Compliance with GLPs is intended to assure the quality and integrity of the safety data filed pursuant to the Food, Drug and Cosmetic Act and sections of the Public Health Service Act.
Applicable to drugs, biologicals, devices, INDs (Investigational New Drug application) & IDEs (Investigational Device Exemption).
Compliance with GLPs not required for research outside the regulatory scope of the FDA.
Requirements for CLIA ( Clinical Laboratory Improvement Act ) Compliance, CAP ( College of America Pathologist ) Compliance and FACT ( Foundation for the Accreditation of Cellular Therapies ) Accreditation are similar in many aspects to GLPs.
Good Manufacturing Practices are defined in 21 CFR for Drugs and Pharmaceuticals in parts 210 & 211 and for Biologicals in parts 600-680.
Overlapping requirements occur.
GMPs pertain to the minimum current good manufacturing practice for preparation of drug products for administration to humans or animals or for preparation of biological products for administration to humans.
There are overlaps between GMPs, GTPs and FACT requirements.
#1 The FDA is responsible for protecting the public health by assuring the safety, efficacy, and security of human and veterinary drugs, biological products, medical devices, our nation’s food supply, cosmetics, and products that emit radiation.
#2 The FDA is also responsible for advancing the public health by helping to speed innovations that make medicines and foods more effective, safer, and more affordable; and helping the public get the accurate, science-based information they need to use medicines and foods to improve their health.
FDA Critical Path for Medical Product Development FDA: Challenge and Opportunity on the Critical Path to New Medical Products, March 2004 Modified
Adventitious Microbial Agents : Agents such as bacteria, fungi, mycoplasma, or viruses not an integral part of a material that may be present as chance contaminants; extrinsic.
Gene Transfer Vector (used herein as “vector”): A vehicle composed of DNA (or RNA) for transferring a gene or other nucleic acid sequence of interest; frequently based on viruses, bacteriophage or bacterial plasmids. May be replication defective or competent.
Gene Therapy : Transfer of a gene or other nucleic acid sequence by means of a “vector” into a patient to obtain a therapeutic effect.
Transduce/Transduction : Transfer of a gene or nucleic acid sequence into a target cell or organism.
Monoclonal Antibody : An antibody preparation of uniform composition and specificity produced from a single cell origin “clone” of an antibody producing cell.
Polio Disease Incidence ~ 0.03%, 1953 National Foundation Field Trial: Largest and Most Comprehensive Test of a Medical Product "The Cutter Incident", Paul A. Offit, M.D., Yale Univ. Press, 2005
Polio Epidemics "The Cutter Incident", Paul A. Offit, M.D., Yale Univ. Press, 2005
Mahoney Strain of Type 1 Polio (Highly pathogenic)
Good representative of a “hot” virus strain for a protective immune response.
Bad if inactivation is incomplete.
Seitz vs. Porous Glass.
Change in Quality of Porous Glass Filters. Due to change in staff (one key retirement).
Cell Culture. Sample volume (0.1% of final vaccine).
Monkey. Subsequent studies revealed that cortisone treated monkeys demonstrated live virus in Cutter samples previously tested in monkeys without steroid. Inoculation into the spinal cord found to be 500 fold more sensitive for detecting live virus.
Bulk Intermediate Storage
Salk’s lab treated with formaldehyde within days of filtration.
Cutter often stored for weeks or sometimes months before inactivation.
Viral particle clumping over time.
Salk recommended at least four sampling time points, with the last negative for virus. Total time of formaldehyde exposure = 3 x the time to reach the no detectable virus level.
Eli Lilly & Parke-Davis, six time points.
Cutter never determined when live virus FIRST eliminated. Disregard of Salk’s inactivation theory.
Cutter never acknowledge difficulties in obtaining consistent inactivation (9 of 27 lots failed).
National Foundation selected Eli Lilly & Parke-Davis because they were the only companies to make at least 11 consecutive lots passing safety tests.
"The Cutter Incident", Paul A. Offit, M.D., Yale Univ. Press, 2005
Inactivation Kinetics Four Point Linearity In the Observable Region + Linear Extrapolation. Four Point Linearity In the Observable Region Requirement Not Followed by Cutter "The Cutter Incident", Paul A. Offit, M.D., Yale Univ. Press, 2005
An “adventitious viral agent”. Was present in monkey kidney cells used to grow polio virus.
Found in both Salk & Sabin Vaccines, 1955-1963.
SV40 is more resistant to formaldehyde inactivation.
IOM Report 10/22/02.
Studies of groups of people who received polio vaccine during 1955-1963 provide evidence of no increased cancer risk.
However, because these epidemiologic studies are sufficiently flawed, the committee concluded in this report that the evidence was inadequate to conclude whether or not the contaminated polio vaccine caused cancer. In light of the biological evidence supporting the theory that SV40-contamination of polio vaccines could contribute to human cancers, the committee recommends continued public health attention in the form of policy analysis, communication, and targeted biological research.
Over 98 million Americans received one or more doses of polio vaccine during the period (1955-1963) when some of the vaccine was contaminated with SV40. SV40 has been found in certain types of human cancers, but it has not been determined that SV40 causes these cancers. The majority of evidence suggests there is no causal relationship between receipt of SV40-contaminated vaccine and cancer; however, some research results are conflicting and more studies are needed.
Revisions & New Regulations Published in the Federal Register in draft version for comments before a Final Rule is Issued.
Guidance Documents .
Published initially on CBER & CDER web page for comments.
“… draft guidance, when finalized, will represent the Food and Drug Administration’s (FDA’s) current thinking on this topic. It does not create or confer any rights for or on any person and does not operate to bind FDA or the public. You can use an alternative approach if the approach satisfies the requirements of the applicable statutes and regulations. If you want to discuss an alternative approach, contact the appropriate FDA staff.”
Do not establish legally enforceable responsibilities.
Viewed as recommendation unless regulatory or statutory requirement cited.
Points to Consider.
Replaced by Guidance Documents.
Still relevant for understanding FDA/CBER positions.
Quality Control is the process, procedures and authority used to accept or reject all components, drug product containers, closures, in-process materials, packaging material, labeling and drug products and the authority to review production records to assure that no errors have occurred, or if errors have occurred, that they have been fully investigated.
Challenge & Opportunity on the Critical Path to New Medical Products. http://www.fda.gov/oc/initiatives/criticalpath/whitepaper.html
GMP for Phase I.
“ Science is rapidly coming to understandings of the genetic and molecular mechanisms of not just a disease like cancer, but diabetes, cardiovascular disease, and on and on. As that rapid scientific discovery is occurring, the FDA is committed to facilitating the rapid translation and the development of that knowledge into the development of new drugs or treatments that are going to alleviate those diseases. But rapid does not mean reckless. There is no compromise in the rigor of the clinical trials process, no compromise in the rigor of laboratory testing and animal testing, or on the standards that will be applied.” Remarks by Andrew C. von Eschenbach, M.D., Acting Commissioner of Food and Drugs, Thursday, January 12, 2006