Legal Requirements For Labeling Of Biological Drug Products

I. FDA REGULATIONS AND REQUIREMENTS

A. Background

1.	The FDA is an agency within the Public Health Service, which in turn is a part of the Department of Health and Human Services. It regulates the pharmaceutical, biological and medical device industries pursuant to the Food, Drug and Cosmetic Act. The FDA is now organized into five major program centers: the Center for Biologics Evaluation and Research ("CBER"), the Center for Drug Evaluation and Research, the Center for Devices and Radiological Health, the Center for Food Safety and Applied Nutrition, and the Center for Veterinary Medicine.
2.	The FDA regulates food products, cosmetics, medicines and medical devices, as well as radiation-emitting products such as microwave ovens. Feed and drugs for pets and farm animals also come under FDA scrutiny.
3.	The FDA is one of the nation's oldest protection agencies. Its approximately 9,000 employees monitor the manufacturer, import, transport, storage and sale of about $1 trillion work of products each year.
4.	The FDA has over 1,100 investigators and inspectors who cover the country's almost 95,000 FDA-related businesses.

1.

Biological products are regulated under 42 USC §262, et seq. a. "Biological Product": As used in 42 USC §262, et al., the term "biological product" means the virus, therapeutic serum, toxins, anti- toxin, vaccine, blood, blood component or derivative, allergenic product, or arsphenamine or derivative of arsphenamine ( or any other trivalent organic arsenic compound), applicable to the prevention, treatment or cure of a disease of human beings. (42 USC §262(i).) b. similarly, the Code of Federal Regulations defines "biological product" to mean any virus, therapeutic serum, toxin, or analgesic product applicable to the prevention, treatment or cure of diseases or injuries of man. (21 CFR §6003(h).) c. Biologic License Application ("BLA") - 42 USC §262(A) provides that no person shall introduce or deliver for an introduction into interstate commerce any biological product unless: (1) A biologics license is in effect for the biological product; and (2) each package of the biological product is plainly marked with: 1. The proper name of the biological product contained in the package; and 2. The name , address, and applicable license of the manufacturer of the biological and; 3. The expiration date on the biological product. d. A BLA is approved after the manufacturer shows to the satisfaction of the FDA's Center for Biological Evaluation and Research that: 1. The biological product that is the subject of the application is safe, pure and potent and; 2. The facility in which the biological product is manufactured, possessed, packaged or held meets standards designed to ensure that the biological continues to be safe, pure and potent. (42 USC §262(a).) e. Not surprisingly, false labeling of a biological product is prohibited: No person shall falsely label or mark any package or container of any biological product or alter any label or mark on the package or container of the biological product so as to falsify the label or the mark. (42 USC §262(b).) f. "Container", also referred to as " final container", is the immediate unit, bottle, vial, ampule, tube or other receptacle containing the product as distributed for sale, barter or exchange. (21 CFR §600.3(bb).) g. "Package" is the immediate carton, receptacle or wrapper, including all labeling materials therein and thereon, and the contents of the one or more enclosed containers. If no package, as defined in the proceeding sentence, is used, the container shall be deemed to be the package. (21 CFR §600.3(cc).) h. "Label" means any written, printed or graphic material on the container or packet or any such name clearly visible through the immediate carton, receptacle or wrapper. (21 CFR §600.3(dd).)

C. Regulation Governing the Contents of a Package Insert

1.

General Labeling Requirements a. In the Food, Drug and Cosmetic Act, Congress enacted statutes for the labeling of all drugs. The labeling requirements for prescription drugs are found at 21 CFR §§201.50 to 201.59. b. Specific Requirements of a Package Insert (1) Section 201.57 governs "the specific requirements on content and format of labeling for human prescription drugs." Section 201.57 also dictates the order of the headings which should be included in the labeling of a drug: i) Description ii) Clinical Pharmacology iii) Indications and Usage iv) Contraindications v) Warnings vi) Precautions a) General b) Information for Patients c) Laboratory Tests d) Drug Interactions e) Carginogensis, Mutagenesis, Impairment of Fertility f) Pregnancy g) Labor and Delivery h) Nursing Mothers I) Pediatric Use vii) Adverse Reactions viii) Drug Abuse and Dependence ix) Overdosage x) Dosage and Administration xi) How Supplied xii) Animal Pharmacology and/or Animal Testing xiii) Clinical Studies and References a) The labeling for a prescription drug shall contain a section which corresponds with the above headings, unless the section or sub-section is "clearly inapplicable." (21 CFR §201.56(d(3).)

D.	Modifying a Package Insert: Regulations Governing Changes to Approved Labeling

1.

General provisions regarding changes a. 21 CFR §314.70 governs changes to a product's labeling. b. These are specific subparts governing changes to labeling in different circumstances. (1) §314.70(b)(3) governs changes requiring FDA approval before change is made. (2) §314.70(c) governs changes to (among other things) labeling, that may be made before FDA approval. The manufacturer must submit a supplement to its BLA to "add or strengthen" labeling information including information concerning: i) Contraindications ii) Warnings iii) Precautions iv) Adverse Reactions v) Drug Abuse vi) Dependence vii) Overdose viii) Instruction Dosage and Administration ix) Correction of False, Misleading or Unsupported Indications for Use (3) §314.70(d) governs changes which may be made without prior FDA approval and may be instead described in the manufacturer's annual report to the FDA.

E. Post-Marketing Factors That Can Affect Product Labeling

1.

Adverse Experience Reports a. Post marketing reporting of adverse experiences in biological products (21 CFR §600.80.) b. Medwatch Form 3500 report c. Definition of Adverse Experience: An "adverse event associated with the use of a biological product in humans, whether or not considered product related." (21 CFR §600.80.(a). d. Reporting Requirements (1) " Serious and unexpected" events must be reported, regardless of the source. i) A serious adverse experience is fatal or life-threatening, is permanently disabling, requires inpatient hospitalization or is a congenital anomaly, cancer or overdose (accidental or intentional). This includes adverse event from drug abuse. (21 CFR §600.80(c). ii) An unexpected adverse experience is one that is not listed in the current labeling for the product and includes an event that may be symptomatically and pathophysiologically related to an event listed in the labeling, but differs from the event because of greater severity or specificity. (2) Report using Medwatch Form 3500 must be made as soon as possible or within 15 working days of receipt of the information. All such reports must be investigated and any information obtained from the investigation must be reported within 15 days of its receipt. (21 CFR §600.80(c). (3) On a periodic basis, the manufacturer must view all adverse experiences that are the subject of a post-marketing 15-day alert report and submit follow-up reports within 15 calendar days of its receipt of new information or as requested by FDA. (4) All other adverse events which are not serious or are serious but expected must be reported on a quarterly basis. Reports must include a narrative summary and analysis for all such events which were not reported as a serious and unexpected event, and a history of actions taken since the last report because of adverse product experiences.

2.

In summary, information obtained through mandated post-marketing reporting can lead to additional labeling or changes in existing labeling. While a manufacturer of a biological product is not allowed to warn of every potential risk (because that would dilute the warning), it is required to both report serious and unexpected events, and to ensure that its product labeling fully and clearly imparts warning of those events and significant risks to the prescribing physician.

F. Food and Drug Modernization Act of 1997 (November 21, 1997)

1.	On November 9, 1997, the House and Senate both unanimously accepted the conference report and statement on the Senate bill that amends the Federal Food, Drug and Cosmetic Act. The Food and Drug Modernization Act of 1997 was signed into law by President Clinton on November 21, 1997. The following provisions apply equally to New Drug Applications (NDAs) and Biological License Applications (BLAs).
2.	Dissemination of information on new use of drugs: Section 401: a. §401 allows the dissemination of information on new uses of drugs under specific conditions. b. Known as the "Mack-Frist provision" this change responds to complaints that the FDA regulation of timely new medical information has been too restrictive. c. Sponsors can now disseminate to health care practitioners, pharmacy benefit managers, insurers, group health plans and government agencies. Such information cannot be sent directly to patients. d. Criteria: (1) The product must be approved and the information must comply with the regulations applicable to approved product use information; (2) The information must not be derived from research conducted by another manufacturer, except with its permission; (3) The manufacturer must submit the information to the FDA 60 days before beginning distribution, together with safety and effectiveness information from clinical trials and safety information from reports of clinical experience; (4) The manufacturer must comply with section 554, relating to the submission of a supplement covering the use in question; (5) The manufacturer must include with the information to be disseminated a prominent statement that the use has not been approved, a copy of the approved labeling, and disclosures related to authorship and funding, as well as a bibliography. e. The information is restricted to a copy of a peer-reviewed article from a scientific or medical journal or a reference textbook that includes information about a clinical investigation of a product. The information may not be false or misleading and may not pose a significant risk to the public health. f. Manufacturers must submit, on a biannual basis, a list of articles and reference publications disseminated under section 551 and list the categories of persons that received them. This report shall cover only distributions of the previous six months. g. The FDA may order a manufacturer to cease dissemination of information if: i) a supplement does not contain adequate information for approval of the new use; ii) the manufacturer is not acting with due diligence to file a supplement; or iii) the information being disseminated does not comply with statutory requirements.
3.	The FDA is issuing a guidance document on how manufacturers are to implement their plans to disseminate information on new uses of their product. The document is anticipated to be released in early June, 1998.

II. JUDICIAL REQUIREMENTS

A. Warnings in Labeling of an "Unavoidably Dangerous Product"

1.	Prescription drugs are viewed by courts as being "unavoidably dangerous." They are "dangerous" by virtue of the fact that they inevitably produce some side effects, many of which can be extremely serious. But since they also confer a benefit upon the patient in controlling an illness or condition in the first place, and in many instances are life-sustaining, they are treated somewhat differently under the law, and held to be "unavoidably" dangerous.
2.	Courts generally require that a manufacturer warn the prescribing physician (the "learned intermediary") about significant risks inherit in the product.
3.	Since these warnings are required by the FDA to be contained in the product labeling (repeated in the Physician's Desk Reference - "PDR") courts primarily focus in product liability cases on the appropriateness and accuracy of the product's labeling in the package insert.
4.	One court summarized the manufacturer's labeling obligations as follows; a. The warning must adequately indicate the scope of the danger; b. the warning must reasonably communicate the extent or seriousness of the harm that could result from misuse; c. The physical aspects of the warning must be adequate to alert a reasonably prudent person to the danger; d. the warning must indicate the consequences that might result from failure to follow it; e. The means to convey the warning must be adequate, i.e., the manufacturer must bring the warning home to the doctor.

B. Interplay of FDA Requirements and Judicially-Created Standards

1.	The mere fact that a product's labeling complies with the FDA's requirements does not insulate the manufacturer from liability.
2.	In legal terms, federal regulation of the product by FDA does not give rise to "preemption." (Medtronic v. Lohr 116 S.Ct. 2240, 135 L.Ed.2d (1996).
3.	States are free to impose their own common law requirements that may go beyond what FDA requires.
4.	However, many courts will refuse to impose strict liability on a manufacturer who was not permitted by the FDA to warn of a specific risk, under the theory that in such a case, compliance with both federal and state requirements is impossible. (Feldman v. Lederle Laboratories 125 N.J. at 135; Carlin v. Superior Court (Upjohn Co.) (1996) 13 Cal. 4th 1104, 1115, 56 Cal. Rptr. 162.) This concept is sometimes referred to as "conflict preemption."

C.	The Labeling Must Warn of "Actually Known or Reasonably Scientifically Knowledgeable" Risks.

1.	Standard now followed by California and various other states.
2.	Not every "conceivable" or "theoretical" risk must be warned about, but only those risks for which there is "significant" medical evidence of a health hazard.
3.	The manufacturer also need not warn of adverse reactions where significant differences of opinion exist within the medical community with regard to potential adverse reactions.
4.	Whether a risk is "known or knowable" as to a particular product is determined on a case by case basis. As one court put it, the inquiry is what " a reasonable scientist operating in good faith should have known under the circumstances of the evidence." (Carlin, supra.)
5.	Although proof of compliance with FDA requirements is not controlling, it is admissible, and may be considered by the jury in determining whether the risk was known or scientifically knowable.
6.	In general, if a biological product manufacturer can demonstrate that its label contains FDA-required information regarding dosage, usage, contraindications, adverse reactions, etc., and keeps the FDA informed of any significant new information in the medical literature which might prompt a labeling change, it will usually be able to successfully defend itself against claims that its product label failed to contain adequate warnings. It should be equally vigilant, however, to track other sources of information disseminated about its product in advertising, promotion and other avenues.