Warning Letters Issued for Unlicensed Biological Products
Dr. Gray’s Smallpox Shield
Firm With No Biologics License Warned for Promoting Product to Prevent Smallpox
On April 4, 2003, FDA's Center for Biologics Evaluation and Research (CBER) issued a Warning Letter to Dr. Bill Gray of Saratoga, California. The Warning Letter was issued following a review by FDA of the firm's website. The review determined that "Dr. Gray's Smallpox Shield," a preparation of Variolinum in sugar pellets, was being promoted for conditions that caused it to be a drug and further, that it was purported to prevent smallpox and compared extensively to the smallpox vaccine. The Homeopathic Pharmacopoeia does not recognize Variolinum.
The Warning Letter also noted that the product appeared to be for sale to customers in the United States. The website stated that, “the remedy is available only by prescription,” however, the prescription was free of charge from the website. Once the prescription was obtained, the remedy could be purchased directly from the website.
The Warning Letter advised the firm that in order to introduce or deliver for introduction a biologic into interstate commerce, a valid biologics license must be in effect. The Warning Letter stated that based on a review of FDA files, “your product is not the subject of an approved biologics license application (BLA) or an investigational new drug application (IND). Therefore, your shipments of product for which a valid license or IND is not in effect represent violations of the Act and the Public Health Service Act and may result in the FDA seeking such relief as provided by law.”
Target Your Health, Inc.
Firm Warned for Promoting Live Cells from Sheep and Cattle Embryos to Heal Organs
On September 26, 2003, the FDA's Center for Biologics Evaluation and Research (CBER) issued a Warning Letter to the CEO of Target Your Health, Inc., Wildomar, California. The Warning Letter was issued following a review by FDA of the firm's website. The review determined that the firm's "Live Cell Growth Factors" were being promoted for conditions that caused the products to be drugs. In describing the Live Cell Growth Factors, the firm's website stated that ".live cells from sheep or cattle embryos have the potential to adapt and heal organs or body tissue in need of repair."
FDA also raised concerns in the Warning Letter regarding the statement on the firm's website that, "The Live Cells are removed from animals in approved slaughterhouses that have passed all health controls. The veterinary controls certify that the animals are healthy, suitable for human consumption and free of any spongiform encephalitis."
FDA advised the firm that in December 1997, the U.S. Department of Agriculture (USDA) established restrictions on the importation of certain ruminant products, including meat and meat products from ruminants, due to Bovine Spongiform Encephalopathy (BSE). The regulations specifically prohibit the importation of ruminant products used in many of the commercial medias, extracts, reagents, antisera, etc., for in vivo or in vitro use. In addition, the FDA issued a guidance document (September 1997) requesting that materials derived from ruminants that have resided in or originated from countries where BSE has been diagnosed not be used in the manufacture of FDA-regulated products intended for administration to humans.
The Warning Letter also noted that a "Personal Orders" page of the website provided for payment and shipment of the firm's products to U.S. addresses. The products appear to be available to anyone who orders the products from this website, notwithstanding the website's statement, "Take Live Cell Growth Factors as prescribed by your health professional."
The Warning Letter advised the firm that in order to introduce or deliver for introduction a biologic into interstate commerce, a valid biologics license must be in effect. The Warning Letter stated that based on a review of FDA files, "your product is not the subject of an approved biologics license application (BLA) or an investigational new drug application (IND). Therefore, your shipments of product for which a valid license or IND is not in effect represent violations of the Act and the Public Health Service Act and may result in the FDA seeking such relief as provided by law."
Internet Promotion of Anti-THRAX and Homeovax
Firm Warned for Internet Promotion of Anti-ANTHRAX As Alternative to Anthrax Vaccine
On September 30, 2003, the FDA issued a Warning Letter to Dr. Gordon Josephs, Chelationcare Centers, Scottsdale, Arizona. The Warning Letter was issued for the promotion of products advertised on the firm's websites at Internet addresses: http://www.anti-thrax.com and http://homeovax.com. The Warning Letter advised the firm that FDA had determined that the firm's Anti-THRAX anthrax vaccine alternative and Viral Immune alternative immunizations and vaccinations were being promoted for conditions that caused the products to be drugs under the Federal Food, Drug, and Cosmetic Act (Act) and biologics, as defined in the Public Health Service Act.
The Warning Letter stated that the Anti-THRAX anthrax vaccine alternative and Viral Immune alternative immunizations and vaccinations are drugs because the therapeutic claims as shown on the firm's websites establish their intended use as drugs and because the components of these products are recognized in the Homeopathic Pharmacopeia of the United States (HPUS).
The claims on the firm's Anti-THRAX website included: ". . .a way to stimulate the immune system to resist anthrax (like a vaccine does);" ". . .rapidly cause the body to stimulate its immune system to resist anthrax;" ". . stimulate your immune system to resist anthrax with advanced bio-energetics;" and "We've added some homeopathic ingredients to Anti-THRAX to help boost the immune system and provide for cutaneous anthrax."
Likewise, the firm's Viral Immune website made therapeutic claims such as: "Viral Immune No-Shot Flu Shots!" "Our Alternative Immunization Kit contains nosodes which cover viral, bacterial, and even fungal childhood diseases;" " . . .stimulate the virus-fighting side of the immune system."
The Warning Letter also noted that the Anti-THRAX website stated that the product is "Available only to our patients (Ask how you can become a patient)" with a link provided including a registration form and a short medical history form. The link stated: "AFTER REGISTERING AS A PATIENT, If you desire any preventive, homeopathic products that we offer to our patients, you are able to request them. We ship anywhere within the USA."
The Warning Letter advised the firm that it had failed to register their drug establishment pursuant to section 510 of the Act. Consequently, the firm's products were being marketed in violation of the Act.
The Warning Letter advised the firm that they should immediately discontinue website offers to sell the Anti-THRAX anthrax vaccine alternative and Viral Immune alternative immunizations and vaccinations, and remove from all websites all other promotional materials for products that contain the same or similar violative presentations.
Firm Warned for Promoting Product for Unapproved Use
On June 23, 2003, the FDA’s Center for Biologics Evaluation and Research (CBER) issued a Warning Letter to Allergen, Inc., (Allergen), Irvin, California. The Warning Letter objected to Allergen’s dissemination of promotional materials for the marketing of BOTOX® COSMETIC Botulinum Toxin Type A. Botulinum Toxin Type A is a drug under the Food, Drug, and Cosmetic Act (the Act) and a biologic, as defined in the Public Health Service Act (PHS Act).
CBER’s Advertising and Promotional Labeling Branch (APLB) reviewed three journal advertisements for BOTOX® COSMETIC and concluded that the advertisements were in violation of the Act and its implementing regulations.
The Warning Letter stated that FDA “…has concluded that your journal advertisements are false and/or misleading because they falsely identify your product as a cosmetic treatment, fail to reveal material facts about the product's use, and minimize the risk information presented.”
The Warning Letter advised Allergen that their advertisements “…misleadingly suggest that this drug is effective, for conditions beyond those that have been approved by FDA. The advertisements included the claims, ‘FDA-approved for the temporary treatment of frown line in people aged 18 to 65.’”
The approved indication for use is: “BOTOX® COSMETIC is indicated for the temporary improvement in the appearance of moderate to severe glabellar lines associated with corrugator and/or procerus muscle activity in adult patients…65 years of age.”
FDA requested that Allergen immediately cease dissemination of all promotional materials containing the same or similar violations outlined in the Warning Letter.
On December 17, 2002, CBER informed Thomas R. Theodore of its proposal to debar him from providing services in any capacity to a person that has an approved or pending drug product application, including but not limited to a biologics license application. Mr. Theodore was informed that his debarment would be permanent.
In accordance with section 306 of the Federal Food, Drug, and Cosmetic Act, CBER based its decision to debar Mr. Theodore on the finding that he was convicted in a Federal Court for conduct relating to the regulation of a drug product. A jury found him guilty of nine felony and three misdemeanor violations of Federal law.
Mr. Theodore was part owner and operator of Private Biologicals Corporation (PBC). PBC was in the business of producing an unapproved drug product named LK-200. The product was a supernatant of white blood cell material, and was distributed for use in treating cancer as well as other diseases. PBC adulterated LK-200 in that the facilities and controls used in manufacture did not conform with current good manufacturing practice to assure that the product met the requirements of the Act as to safety and that LK-200 had the identity, strength, and quality it was represented to possess. In addition, the PBC manufacturing facility, located in Woburn, Massachusetts, was not registered with FDA. Moreover, Mr. Theodore never sought approval to distribute the LK-200 product, and did not request an investigational exemption to distribute the product.
On December 17, 2002, a letter offered Mr. Theodore an opportunity to request a hearing to dispute CBER's proposed debarment. Mr. Theodore did not request a hearing and on August 5, 2003, Mr. Theodore's final debarment order was published in the Federal Register.
Warning Letters Issued to Five Clinical Investigators
The FDA’s Center for Biologics Evaluation and Research issued Warning Letters to the following clinical investigators conducting research using investigational biologic products in human subjects:
- Gary Frenette, M.D., Ph.D., Carolinas Medical Center, Charlotte, NC (October 4, 2002).
- Juan L. Tellez, M.D., Illinois Center for Clinical Trials, Chicago, IL (October 23, 2002).
- Roberta Luskin-Hawk, M.D., AIDS Research Alliance, Chicago, IL (December 20, 2002).
- Douglas C. Wolf, M.D., Atlanta Gastroenterology Associates, Atlanta, GA. (April 8, 2003).
- Jacqueline M. Halton, M.D., Children’s Hospital of Eastern Ontario, Ottawa, Ontario (April 13, 2003).
These inspections were conducted as part of the FDA’s Bioresearch Monitoring Program that includes inspections designed to review the conduct of clinical research involving investigational drugs.
- Each of the Warning Letters to the clinical investigators included at least one of the following violations: (1) Failure to protect the rights, safety, and welfare of subjects under the investigator’s care; (2) Failure to ensure that the investigation was conducted according to the investigational plan; (3) Failure to obtain informed consent; (4) Failure to maintain adequate records of the disposition of the investigational drug; (5) Failure to assure Institutional Review Board (IRB) review by not promptly reporting changes in the research activity; (6) Failure to prepare and maintain adequate and accurate case histories; and (7) Failure to furnish accurate reports to the sponsor.
Each Warning Letter advised the clinical investigator that the failure to effectively implement corrective actions and/or the commission of other violations may warrant the initiation of enforcement actions without further notice. These actions could include initiation of clinical investigator disqualification proceedings, which may render a clinical investigator ineligible to receive investigational new drugs, and/or injunction. Each clinical investigator provided corrective actions plans to prevent the recurrence of the violations.
Warning Letters Issued to Two Institutional Review Boards
On December 9, 2002, the Center for Biologics Evaluation and Research issued a Warning Letter to the Catholic Health Partners Institutional Review Board (IRB), Chicago, Illinois. On April 14, 2003, the Office of Compliance and Biologics Quality, Center for Biologics Evaluation and Research issued a Warning Letter to the North Texas Institutional Review Board, c/o Terry Fredeking, President, Antibody Systems, Inc., Hurst, Texas.
The purpose of the inspections that formed the basis for each Warning Letter was to determine if the IRB’s procedures for the protection of human subjects complied with FDA regulations. The Warning Letter to Catholic Health Partners included the following violations: (1) Failure to prepare, maintain, and follow written procedures for conducting the review of research, including periodic review; (2) Failure to review proposed research at convened meetings at which a majority of the members of the IRB are present, including at least one nonscientific member; (3) Failure to conduct continuing review of research at intervals appropriate to the degree of risk; (4) Failure to ensure that research is reviewed free from conflict of interest; (5) Failure to fulfill requirements for expedited review; (6) Failure to fulfill membership requirements; (7) Failure to require that information given to subjects as part of informed consent is in accordance with the provisions of 21 CFR 50.20, 50.25, and 50.27; and, (8) Failure to prepare and maintain adequate documentation of IRB activities.
The violations noted in the Warning Letter to North Texas IRB included: (1) Failure to prepare, maintain, and follow written procedures for conducting the review of research, including periodic review; (2) Failure to determine that risks to subjects are minimized; (3) Failure to conduct continuing review of research at intervals appropriate to the degree of risk; (4) Failure to require that information given to subjects as part of informed consent is in accordance with the provisions of 21 CFR 50.25; (5) Failure to ensure that research is reviewed free from conflict of interest; (6) Failure to review proposed research at convened meetings at which a majority of the members of the IRB are present; and (7) Failure to prepare and maintain adequate documentation of IRB activities.
Based on the deficiencies found during the inspections, the IRBs did not meet the requirements of 21 CFR Part 56. Therefore, effective immediately, the Catholic Health Partners IRB was prohibited from admitting new subjects from ongoing studies, and the North Texas IRB was prohibited from approving new studies that are subject to Parts 50 and 56 of the FDA regulations. These restrictions would remain in effect until FDA determined that the IRBs’ corrective actions were satisfactory, that the IRB met the requirements of Part 56, and that the restrictions had been removed.
Clinical Investigator Disqualified
Disqualification Based on Violations of Regulations Governing Clinical Investigations and Human Subject Protections
On April 4, 2003, Dr. Roy C. Page, of Memphis, Tennessee, signed a Disqualification Agreement with CBER in which he agreed to be permanently disqualified as a clinical investigator. Dr. Page is no longer eligible to receive investigational new drugs, animal drugs, biologics, devices, or food additives, and shall not be entitled to conduct any further studies of investigational products regulated by FDA. Dr. Page was involved in the study of investigational drugs involving supernatants from culturing blood cells with tumor cells, for use in the treatment of cancer.
CBER initiated formal disqualification proceedings against Dr. Page based upon his repeated and deliberate violations of the clinical investigation and human subject protection regulations. Regulatory violations included: (1) administering the cell supernatants when no IND was in effect, (2) enrollment of an ineligible subject, (3) failure to obtain informed consent, (4) administration of prohibited concurrent investigational treatments, (5) failure to account for the all subjects in the studies, (6) failure to obtain IRB approval of protocol amendments, (7) failure to maintain case histories, (8) failure to document the administration of investigational drugs to subjects, (9) failure to document concurrent medications, and (10) failure to retain records.
Clinical Investigator Disqualification Proceedings
On rare occasions, careful evaluation of the evidence concerning the conduct of a clinical trial shows that a clinical investigator appears to have repeatedly or deliberately violated regulations governing the conduct of clinical studies involving investigational biologics. In such situations, CBER sends the clinical investigator a written notice detailing the alleged violations (primarily 21 CFR Parts 50 and 312) and initiates an administrative proceeding to determine if the clinical investigator should be disqualified from receiving, in the future, any investigational products regulated by FDA. The letters are titled Notice of Initiation of Disqualification Proceeding and Opportunity to Explain (NIDPOE). In FY 2003 CBER issued NIDPOE letters to Alfred E. Chang, M.D., Ann Arbor, Michigan, and Patrick J. Daley, M.D., Tulsa, Oklahoma. The NIDPOE letters are available in redacted form on the FDA website at http://www.fda.gov/foi/nidpoe.
After the clinical investigator has an opportunity to respond to the allegations, CBER evaluates all of the available evidence and may prepare a Notice of Opportunity for Hearing (NOOH) letter to be issued to the clinical investigator. The NOOH letter informs the clinical investigator of his/her right to a regulatory hearing under 21 CFR 16.22 and 312.70(a), the next step in the process of determining whether he/she should be disqualified. No final FDA decision has been made at the time of issuance of the NOOH letter regarding eligibility to continue to receive investigational products. FDA issued an NOOH letter to Peter K. Law, Ph.D., Memphis Tennessee, during FY 2003. The NOOH letter is available in redacted for on the FDA website at http://www.fda.gov/foi/nooh.
Warning Letter Issued to Blood Bank’s President and CEO
FDA Inspection Discloses Blood Bank Shipping Blood Without Approved License
On December 18, 2002, the FDA’s Kansas City District issued a Warning Letter to Joyce M. Eisel, President and CEO, Gateway Blood Association, St. Louis, Missouri. An FDA inspection of Gateway Blood conducted on November 18-22 and 26, 2002, revealed that the blood bank was collecting units of platelets and pheresis, for transfusion and was shipping some of these units in interstate commerce. The units distributed in interstate commerce were not covered by an approved license.
During the period of January 1, 2002 to October 31, 2002, the firm’s records indicated that units of unlicensed platelets, pheresis were collected for transfusion and shipped to hospitals in Illinois. Shipment of unlicenced blood products in interstate commerce is a violation of the Public Health Service Act.
The Warning Letter advised the blood bank that these are serious violations of the law that may result in FDA taking regulatory action without further notice. These actions include, but are not limited to, seizing product inventory, obtaining a court injunction against further marketing of the product, or assessing civil money penalties. The Warning Letter noted that FDA was in receipt of a November 26, 2002 letter, which outlined the firm’s corrective action plan. Based upon an initial review, FDA stated that the Agency had no objections concerning the proposed corrective actions.
Warning Letter Issued to Blood Bank
On November 1, 2002, the FDA’s Denver District issued a Warning Letter to James H. Hinton, President and CEO, Presbyterian Healthcare Services, Albuquerque, New Mexico. An FDA inspection of this blood bank from June 7 through July 2, 2002, documented deviations from the Current Good Manufacturing Practice Regulations, Title 21, Code of Federal Regulations (21 CFR) Parts 600 - 680, for blood and blood products. These deviations included the following:
- Failure to review all records pertinent to the lot or unit maintained pursuant to FDA regulations before the release or distribution of a lot or unit of final product;
- Failure to document the performance of each significant step in the collection, processing, compatibility testing, storage, and distribution of each unit of blood and blood components so that all steps can be clearly traced;
- Failure to document that Fresh Frozen Plasma ("FFP") has been processed and placed in a freezer within 8 hours of collecting, or within the time frame specified for use for the blood collecting, processing, and storage system;
- Failure to maintain adequate processing records to demonstrate all steps in blood processing;
- Failure to assure that the irradiator performed in the manner for which it was designed; and,
- Failure to maintain standard operating procedures to ensure the proper collection, processing, compatibility testing, quarantine, storage, handling, and disposition of blood and blood components.
In the Warning Letter, the FDA acknowledged receipt of the firm’s July 18, 2002 correspondence responding to the Form FDA-483. FDA’s review of the firm’s response found it to be inadequate. The proposed corrective actions did not include an effective quality control system to assure that future deviations could be detected and corrected.
An FDA investigator also noted that the position of the Quality Assurance Coordinator had been vacant for approximately one year and that employees had been conducting the quality control of each others' work. In order to assure objectivity, an independent review of the records should be performed. The Warning Letter advised that the firm should take prompt action to correct these violations.
Revised Consent Decree for the American Red Cross
ARC Agrees to Revisions in Consent Decree Including Financial Penalties for Failure to Comply with Regulations
United States v. American National Red Cross. On April 15, 2003, the American Red Cross (ARC) agreed to substantial revisions in its consent decree with the FDA. The revised consent decree includes financial penalties that will apply if, in the future, ARC fails to comply with the laws and regulations that are aimed at ensuring the safety of the nation’s blood supply.
In the original 1993 consent decree, ARC agreed to establish clear lines of managerial control over a newly established comprehensive quality assurance system; to enhance training programs; and to improve computer systems, records management, and policies for investigating and reporting problems, including adverse reactions.
The revised consent decree includes many of the same substantive provisions, updated to provide a series of deadlines for completing specific requirements of the decree and addressing additional types of violations observed since the 1993 consent decree was entered. It also includes a comprehensive penalty scheme to address potential future violations. If ARC fails to comply with blood safety rules and revised decree requirements, FDA can assess penalties up to the following maximum amounts:
- $10,000 per event (and $10,000 per day) for any violation of an ARC standard operating procedure (SOP), the law, a consent decree requirement or time line;
- $50,000 for the preventable release of each unit of blood for which FDA determines that there is a reasonable probability that the product may cause serious adverse health consequences or death, as well as $5,000 for the release of each unit that may cause temporary problems, up to a maximum of $500,000 per event;
- $50,000 for the improper re-release of each unsuitable blood unit that was returned to ARC inventory; and
- $10,000 for each donor inappropriately omitted from the National Donor Deferral Registry.
During the first year of the decree, penalties will be capped at one percent of the gross annual revenues generated by ARC’s Biomedical Products and Services (ARC’s blood operation). These gross annual revenues are currently $1.924 billion. The cap increases to two percent in the second year, three percent in the third year, and reaches the maximum of four percent in following years.
As in the 1993 consent decree, ARC agreed to retain the services of outside consultants to assure quality control. In addition, ARC must reimburse FDA for the costs of all FDA inspections that FDA considers necessary to evaluate ARC’s compliance with the decree. FDA decisions under the revised decree will be reviewed under the arbitrary and capricious standard.
Blood Systems, Inc. (BSI) Consent Decree Vacated
In a letter dated November 20, 2002, Blood Systems, Inc. (BSI), through its counsel, noted its intentions to pursue the possibility of vacating the Consent Decree of Permanent Injunction that was entered into by BSI and the Food and Drug Administration (FDA) on April 22, 1996. Since entry of the Consent Decree, BSI has made approximately 79 submissions to the FDA and the FDA has reviewed all submissions and has responded in writing to BSI for the majority of these submissions. All of the requirements listed in the Consent Decree have been satisfied. The BSI Consent Decree of Permanent Injunction was vacated on July 30, 2003. FDA joined with the firm’s motion to vacate the injunction, as BSI was able to satisfactorily meet the conditions of the Consent Decree.
License Revocation Proceedings
FDA Inspection Revealed that Plasmapheresis Center Engaged in Violative Record Keeping
FDA conducted an inspection from May 29 through June 3, 2002, of Universal Reagents, Inc. (URI), Indianapolis, Indiana. The firm operates as a small plasmapheresis facility. Additionally, on June 7, 2002, FDA inspected Central Indiana Regional Blood Center, Inc. (CIRBC), Indianapolis, Indiana, which performs infectious disease testing for URI under a contract agreement. FDA determined, through its investigation and inspections of both URI and CIRBC that URI had significant deviations from the standards established in its license as well as in the applicable regulations.
FDA also documented that URI had willfully engaged in violative record keeping practices and falsified records. As a result of the inspectional findings, FDA issued a letter to URI on October 23, 2002, to notify the firm of the Agency’s intent to revoke their U.S. license, and to issue a notice of opportunity for a hearing. On July 10, 2003, FDA published a Notice for Opportunity for Hearing in the Federal Register. On August 11, 2003, URI formally requested a hearing on the proposed revocation. FDA is currently reviewing URI’s hearing request.
OvImmune, Inc. (OvImmune), was engaged in the manufacture and distribution of “hyperimmune eggs” and powdered egg antibody products that were used to purportedly treat and cure a variety of diseases including yeast infections, autism, cancer, chronic fatigue syndrome and AIDS without an approved application or investigational new drug application (IND) in effect.
On July 23, 2003, Marilyn A. Coleman of Richwood, Ohio, and Mitchell V. Kaminski of Niles, Illinois, and their company Ovimmune Inc., were convicted of food and drug-related misdemeanors for manufacturing and distributing egg powders they claimed could cure a wide range of diseases. The jury convicted them of four counts of introducing unapproved new drugs into interstate commerce, three counts of introducing misbranded drugs into interstate commerce, failure to register a drug manufacturing facility, three counts of misbranding drugs while held for sale after shipment in interstate commerce, and two counts of producing adulterated drugs. Each count against the individuals carries a maximum penalty of one-year imprisonment, one year of unsupervised release and a $100,000 fine. The corporation is subject to a $200,000 fine for each count.