Biologics

What does lot release protocol mean?

BLA approval letter reference lot release, manufacturer cannot distribute a lot of product until FDA issues the release for that lot; exemptions form lot release "placing lots on surveillance"

what type of expedited program is: A drug that is intended to treat a serious condition AND preliminary clinical evidence indicates that the drug may demonstrate substantial improvement on a clinically significant endpoint(s) over available therapies ?

Breakthrough therapy designation; submitted with IND no later than the end of phase 2 meeting; FDA response within 60 days of receipt of request; intensive guidance on efficient drug development, organizational commitment, rolling review, other actions to expedite review; designation may be rescinded if it no longer meets the qualifying criteria for breakthrough therapy

What is the definition of labeling?

FDA as written, printed or graphic material on the drug, on any of its containers or wrappers or on any material accompanying it. Includes: professional labeling (package insert), patient labeling (patient package insert), promotional labeling

What is animal rule?

FDA will consider the animal data to support the licensure of a product only when the following conditions are met: mechanism by which the product prevents disease or lessens effects of disease; efficacy is demonstrated in animal models; animal study endpoints are relate to outcome in humans; immunogenicity data in animals/human allow for selection of an effect dose.

What are the components of labeling?

Four types of labeling information submitted in a BLA: draft container and cartons labels, new package insert, annotated draft labeling text, and Structured product labeling (SPL), in addition, a Medication Guide or REMS if applicable is submitted for approval.

What are the requirements for carton label?

The carton label should contain: proper name of the product; manufacturer name, address, and license number; lot number or other lot identification; expiration date; preservatives if any; number of containers, if more than one; amount of product in container; recommended storage temperature; the words "shake well" or "do not freeze" as required; recommended individual dose, for mulit dose container; type and calculated amount of antibiotics added during manufacture; adjuvant if present; product source, when it is a factor in safety administration; minimum potency of product or the statement "No US standard of potency"; The statement "Rx only" for prescription biologics; reference statement to PI inside the package for other pertinent information

What is the definition of a biosimilar product?

The patient protection and affaordable care act (PPAC Act, 2010) created an abbreviated approval pathway for biological products. Section 351(i)(2) of the PHS act defines: "biosimilar or biosimilarity in reference to a biological product that is the subject of an application under suvsection (k) means: (a) that the biological product is highly similar to the reference product notwithstanding minor differences in clinically inactive components and (b) there are no clinically meaningful differences between the biological product and the reference product in terms of the safety, purity and potency of the product.

What are the requirements of 21 CFR 201.57(a)?

The requirements for all prescription drug/biologic labeling. Refer to print out

Toxicological assessments of biologics (ICH S 6) (in regard to IND)

Toxicity studies are expected to be performed in compliance with Good Laboratory Practice (GLP); however, it is recognized that some studies employing specialized test systems which are often needed for biopharmaceuticals, may not be able to comply fully with GLP. Areas of non-compliance should be identified and their significance evaluated relative to the overall safety assessment. In some cases, lack of full GLP compliance does not necessarily mean that the data from these studies cannot be used to support clinical trials and marketing authorizations.

What type of expedited program is : A drug that treats a serious condition AND generally provides a meaningful advantage over available therapies AND demonstrates an effect on a surrogate endpoint that is reasonably likely to predict clinical benefit or on a clinical endpoint that can be measured earlier than irreversible morbidity or mortality (IMM) that is reasonably likely to predict an effect on IMM or other clinical benefit (i.e., an intermediate clinical endpoint)

accelerated approval; The sponsor should ordinarily discuss the possibility of accelerated approval with the review division during development, supporting, for example, the use of the planned endpoint as a basis for approval and discussing the confirmatory trials, which should usually be already underway at the time of approval; no specified timelines; approval base on an effect on a surrogate endpoint or an intermediate clinical endpoint that is reasonably likely to predict a drug's clinical benefit; promotional materials must be submitted 120 days of marketing approval and then at least 30 days prior to the intended time of initial dissemination; confirmatory trials to verify and describe the anticipated effect on IMM or other clinical benefit; subject to expedited withdrawal.

What is the important of the Kefauver-Harris amendment of 1962?

added an efficacy requirement

How did FDASIA of 2012 impact biologics?

advances developemnt for drugs for rare disease, require electronic submissions for standardization of electronic data; establishes original BLA performace goals

What does the CBER advisory committee include?

allergenic products, blood products, cellular, tissues and gene therapies, transmissible spongiform encephalopathies, vaccines and related biological products

What is an emergency use IND?

allows the FDA to authorize use of an experimental drug in an emergency situation that does not allow time for submission of an IND in accordance with 21CFR , Sec. 312.23 or Sec. 312.34. It is also used for patients who do not meet the criteria of an existing study protocol, or if an approved study protocol does not exist.

What is the definition of an investigator?

an individual under whose immediate direction the study drug is administered or dispense, If a team is involved, the leader is the investigator; other team members are sub-investigators

What is the definition of sponsor-investigator?

an individual who both initiates and conducts a study and under whose immediate direction the study drug is administered or dispensed.

What is the definition of a sponsor?

an individual, company, institution or organization that takes responsibility for and initiates a clinical study

What is the definition of a clinical investigations?

any experiment in which a drug is: administered to, dispensed to, or used involving one or more human subjects

What constitutes a 7-day calendar report?

any fatal or life-threatening AE associated with use of drug.

What does Biologic mean?

any virus, therapeutical serum, toxin, antitoxin, or analogous product applicable to the prevention, treatment or cure of disease or injuries of man (21 CFR 600.3) virus, therapeutic serum, toxin, antitoxin, vaccine, blood, blood component or derivative, allergenic product, protein (except any chemcially synthesized polypeptide) or analogous product, or arsphenamine or derivative of arsphenamine ( or any other trivalent organic arsenic compound), applicable to the prevention, treatment, or cure of a disease or condition of human beings.

What is cooperative manufacturing?

applicable to biological products subject to licensure under the PHS act; strategies for meeting the increased nee for flexible manufacturing arrangements: short supply, divided, shared, contract

What is a medication guide?

applies primarily to human prescription products used on an outpatient basis without direct supervision by a healthcare profession; it is approved by FDA and distributed to patients when FDA determines it is necessary to patient's safety and effective use.

What is the review process for post-actions BLA?

approval: feedback/lessons learned meeting, PMCs, REMS, supplements; complete response, end of review conference

What does a withdrawal of an IND mean?

at any time a sponsor may withdraw an effective IND without prejudice.

What maintenance does the IND require?

average require 250-300 submissions during the development of a product; development safety update report, annual report, response to FDA request for information, general correspondence. F1571 should accompany all submission with IND

What is included in nonclinical studies?

biological activity/pharmacodynamics; toxicity testing; immunogenicity testing (if required); proposal for use of the "animal rule" (relevant animal models, challenge agents, correlate of protection, demonstration of efficacy; ICH S6 outlines the special consideration for toxicological assessments of biologics

What are types of products that would be submitted to the CBER?

cellular products and tissues, mAbs, growth factors or other proteins when used solely in manufacturing process; gene therapy products; vaccines and vaccine-associated products; allergenic extracts and allergen patch tests; antitoxins, antivenins and venoms; blood, blood componennts, plasma derived products, human cells, tissues and celllular and tissue-based products (HCT/Ps); medical devices involved in the collection, processingm testing manufacture and administration of licensed blood, blood components and cellular products.

How did the FD&C act of 1938 impact biologics?

drug definition encompasses biological products, safety requirement for new products, authorized factory inspections

Prescription drug user fee act of 1992 established what?

established user fees

what is the review process for review planning BLA?

first 60 days after receipt; two major tasks: determine fileability (filed, potential refusal to file (RTF), RTF; plan the review

When is an advisory committee convened?

first-of-a-kind, first-in-class product; novel product or use of new technology; risk/benefit ratio of a product or class of products is likely to be controversial; significant difference of scientific opinion within FDA on a complex matter; 9 months after submission (standard review) and 6 months after submission (priority review); the committee provides ADVICE, agency is not obligated to adopt the AC recommendations

Are genotoxicity and carcinogenicty studies needed for biologics? (in regard to IND)

genotoxicity no; carcinogencity yes (The need for a product-specific assessment of the carcinogenic potential for biopharmaceutical should be determined with regard to the intended clinical population and treatment duration (see ICH S1A Guideline). When an assessment is warranted, the sponsor should design a strategy to address the potential hazard. and The product-specific assessment of carcinogenic potential is used to communicate risk and provide input to the risk management plan along with labeling proposals, clinical monitoring, post-marketing surveillance, or a combination of these approaches.

What is an advisory committee?

independent expert advice on a range of complex scientific, technical and policy issues; each committee includes a chairperson, several members, a consumer, industry, and often a patient representative; members have recognized expertise and judgement in a specific field; governed by a number of federal laws and regulations (federal advisory committee act, 21 CFR part 14: public hearing before an advisory committee) FDA has 48 technical and scientific AC and panels

What is the review process for the review of the BLA?

information requests, meetings and/or teleconferences: mid-cycle meeting, late- cycle meeting, advisory committee meeting: lends credibility to the product review process and provides a forum for public discussion of certain controversial issues; status updates (mid cycle communication); discipline review letters, develop labeling, OMCs, REMS, agency performs establishment inspections (DMPQ), agency performs lot release testings (DMPQ)

What is needed in the CMC section of the IND?

information required to ensure identity, quality, purity,potency and strength based on phase of clinilca development; cells banks (pedigree, BSE studies, adventitous agent testing); manufacturing method (ciritcal process controls); testing methods (in process, characteriation, and lot release); stability; plans for future develpment of product

What is fast track program designation?

a drug intended for fast track product is intended for the treatment of serious or life-threatening conditions and demonstrates the potential to address unmet medical needs; the classification applies to the combination of the product and specific indication; a sponsor can submit a request for fast track designation at the time of the original (IND) submission or anytime thereafter prior to receiving marketing approval (BLA or NDA)

What are types of IND protocol amendments?

a new protocol, safety or design related changes to an exisiting protocol, new investigator (notification required within 30 days of being added); must submit to FDA before implemenation; IRB approval is needed prior to implementation

what is Bioresearch monitoring (BIMO)?

inspections and data audits to assure the quality and integrity of data; nonclinical testing laboratories in accordance with GLP, clinical investigators/monitors and institutional review boards in accordance with GCP, sponsors/contract research organizations (CRO) in accordance with good manufacturing practice (GMP), "cornerstone of preapproval process"

What was the purpose of the biologics price competition and innovation act of 2009?

introduced an abbreviated approval pathway for biosimilars

What is an investigator IND?

is submitted by a physician who both initiates and conducts an investigation, and under whose immediate direction the investigational drug is administered or dispensed. A physician might submit a research IND to propose studying an unapproved drug, or an approved product for a new indication or in a new patient population.

What is a treatment IND?

is submitted for experimental drugs showing promise in clinical testing for serious or immediately life-threatening conditions while the final clinical work is conducted and the FDA review takes place.

What are the requirements of clinicalTrials.gov?

it is a databank, sponsors of "applicable clinical trials" require to submit additional infiltration to NIH for inclusion in the clinical trial data bank and to certify to FDA that the requirements of Section 401(j) of the pHS act have been met (form FDA-3674:certification of compliance)

What are the requirements for container label?

label should contain: proper name of the product; manufacturer name, address, license number; lot number or other lot identification; expiration date; recommended individual dose; the statement :"rx only" for prescription biologics; special cases may justify the use of a partial label

What is contract manufacturing arrangements?

license manufacturer establishes a contract with another entity to perfom some or all of the manufacture of a product; contract facility engaged in significant manufacturing is NOT required to be separately licensed. License manufacturer must ensure the contract facility complies with applicable standards.

What is the pre-license inspections?

manufacturer does not hold license or manufacturing in new (unlicensed) area or a significantly different manufacturing process that other license products at that facilty. FDA has not inspected facitliy in last 2 years or significant GMP deficiencies noted in previous inspection

What types of biologics would be submitted to the CDER?

monoclonal antibodies for in vivo use, proteins intended for therapeutic use (including cytokines/interferons, enzymes/thromboytics) and other novel proteins extracted from animals, plants cell or microorganisms; immunomodulators; growth factors, cytokines and monoclonal antibodies intended to mobilize, stimulate, decrease or otherwise alter the product of cells in vivo

What are types of IND information amendments?

new toxicology or pharmacology information; final study reports for completed nonclinical or technical studies; new CMC or other technical information; notice of discontinuance of a clinical study; other important information, not within scope of protocol amendments, safety report or annual report.

What does inactive status for an IND mean?

no subjects entered into clinical studies for 2 years or a clinical hold in effect for more than one year. IND is still in effect but annual reports are not required. Resumptions occur 30 days after the FDA received a protocol amendment.

What is the review process for pre-submission activities for BLA?

outside the actual review time frame: proprietary name submission and review, establishment registration and NDC; applicants "strongly encouraged" to request a meeting: traditional pre-BLA meeting, other meeting types as necessary (electronic pre-submission meeting).

What are the different types of formats for INDs?

paper, eCTD to CDER, eCTD or eIND w/roadmap to CBER

What are the goals of lot release protocols?

prevents public distribution of substandard lotsl; allows for real-time monitoring of manufacturing, testing and product quality

What are the submission types for post licensing CMC changes?

prior approval supplement (PAS): substantial potential to have an adverse effect; changes being effected in 30 days (CBE-30) moderate potential to have an adverse effect; CBE: evidence that the proposed change has been validated in accordance with an approved protocol for such a change. Annual report: minimal potential to have an adverse effect

What type of supplement can you submit when you have to make a labeling change pursuant to a report on a pediatric study?

priority review;

What type of expedited program is : An application (original or efficacy supplement) for a drug that treats a serious condition AND, if approved, would provide a significant improvement in safety or effectiveness OR Any supplement that proposes a labeling change pursuant to a report on a pediatric study under 505A OR An application for a drug that has been designated as a qualified infectious disease product OR Any application or supplement for a drug submitted with a priority review voucher

priority review; submitted with original BLA, NDA, or efficacy supplement; FDA response within 60 calendar day of receipt; shorter clock for review of marketing application (6 months compared with the 10-month standard review); designation will be assigned at the time of original filing.

What was the purpose of PDUFA V?

promote transparency and improve communication between FDA review teams and applicant; established a review model for new molecular enitty NDAs and original BLAs; improve the efficiency and effectiveness of the first cycle review process; decrease number of review cycles necessary for approval

What is the Biologcs Control Act (Virus, Serum and Toxin Act of 1902?

prompted by the deaths of children, requires establishment license, labeling with proper name, identification of manufacturer, expiration date, revocation/suspension of license, penalties for violations

What is included in clinical research studies?

protocol design, dose and schedule, inclusion/exclusion criteria, stopping rules (safety), statistical considerations

What did the public health service act of 1944 do?

regulates biologics licensure, regulates biologics establishments

What goes into convening an advisory meeting?

required by statue (FDCA 505(i)(2)(A), 513(b)-©, 520(i)(2); FDA discretion: issues of significant public interest; controversial issues, issues that may require special expertise.

What was the most important outcome of FDAAA of 2007?

requires all biologics clinical trials (except phase 1) to be registered in clinical trials registry databank; REMS can be required at time of approval or after base on safety information; authorizes the review of DTC television ads before public dissemination of the ads and institues monetary penalitues for distributing a false or misleading DTC ad

What is the review process for official action for the BLA?

resolve any remaining issues (labeling, PMCs, REMs), complete response letter, includes deficiencies and recommendations for corrective action; approval letter

What did the FDA modernization act of 1997 complete?

revised PHS act and elminated the ELA dor all biologics (PLA/ELA replaced with BLA)

What is annotated labeling?

separate file, build on completed draft labeling text, annotated with relevant sections of the BLA

What is Structured Product labeling? (SPL)

separate file, extensible markup language format (XML), uses a standardized format to facilitate location information

What is the required content for a BLA?

specified under 21 CFR 601: application form, index, summary, financial disclosure or certification, CRFs and tabulations, patent information, technical sections, labeling

What does termination of an IND mean?

sponsor must end all clinical investigations, FDA may terminate an IND based on deficiencies in the IND or the conduct of studies or if the sponsor does not submit an accurate annual report. And IND that remains inactive for 5 years may be terminated.

What are the postlicensing Risk Evaluation and Mitigation Strategies (REMS)?

strategy to manager serious safety risks: medication guide, patient package insert, communication plans, elements to assure safety use (ETASU); assessments at 18 months, three and seven years after approval.

What are the requirements for IND annual reports?

submit within 60 days of the anniveray of "in effect" date for the IND; include enrollment, demographic and conduct status information for each study; adverse event summaries (safety reports, deaths, dropouts); drug action information; preclinical study status information; summary of significant manufacutirng changes; development safety update report (DSUR) standardizes reporting among ICH regions, meets the requirements for an annual report

What constitutes a 15-day calendar report for an IND?

suspected adverse reaction, serious, unexpected (notify FDA & all investigators in writing

What is the form 356(h) used for

the application form to market a new or abbreviated new drug or biologic for human use (NDA/ANDA/BLA)

What is the criteria for approval of a Biosimilar product?

the biological product and reference product must utilze the same mechanism or mechanisms of action; they use has been previously approved for the reference product; the route of administration, doage form and strength of the biological product are the same as those of the reference product; the facility in which the biological product is manufactured, processed, packed or held meets standards; the aprpvoal fo the biosimilar may not occur until 12 years after the reference product was approved.

What determines if a medication guide is required in the original BLA?

the drug product is the basis for determination; self injectiable drugs require medication guide; it if requires a health care professional to administer the drug a REMS is often required.

what is divided manufacturing arrangements?

two or more manufacturers are licensed and responsible for specific aspects of the manufacture of a product (none is licensed for all aspects for the manufacture of the product); each manufacturer is licensed under a separate BLA (21 CFR 601.2(a))

What are the types of regulatory action letters?

warning letters, notice if initiation of disqualification proceeding and opportunity to explain letters, untitled letters, administrative license action letters, license revocation: notice of intent to revoke license letter (10 day response with commitment to and plans for compliance/ 30 day submission of report with timelines; license suspension

What are the 3 most important offices of CBER?

Office of Blood Research and Review, Office of cellular (OBRR), tissue and gene therapies (OCTGT); Office of Vaccine Research and Review (OVRR)

What are the submission types for post licensing labeling changes?

PAS: any change to the package insert information required in 21 CFR 201.57(a); CBE: changes to reflect newly acquired information (unless its required under 21 CFR 201.57(a), Annual report: editorial or minor changes; advertisements and promotional labeling: at the time of initial dissemination of the labeling and at the time of initial publication of the advertisement.

What is REMS?

Risk Evaluation and Mitigation Strategy: FDA amendments act of 2007 gave FDA authority to require a risk evaluation and mitigation strategy from manufacturers to ensure that the benefits of a drug or biological product outweights its risks. Components of REMS may include: medication guide, patient package insert and/or communication plan

What must the IND application contain?

(1)Animal Pharmacology and Toxicology Studies - Preclinical data to permit an assessment as to whether the product is reasonably safe for initial testing in humans. Also included are any previous experience with the drug in humans (often foreign use). (2)Manufacturing Information - Information pertaining to the composition, manufacturer, stability, and controls used for manufacturing the drug substance and the drug product. This information is assessed to ensure that the company can adequately produce and supply consistent batches of the drug. (3) Clinical Protocols and Investigator Information - Detailed protocols for proposed clinical studies to assess whether the initial-phase trials will expose subjects to unnecessary risks. Also, information on the qualifications of clinical investigators--professionals (generally physicians) who oversee the administration of the experimental compound--to assess whether they are qualified to fulfill their clinical trial duties. Finally, commitments to obtain informed consent from the research subjects, to obtain review of the study by an institutional review board (IRB), and to adhere to the investigational new drug regulations. Once the IND is submitted, the sponsor must wait 30 calendar days before initiating any clinical trials. During this time, FDA has an opportunity to review the IND for safety to assure that research subjects will not be subjected to unreasonable risk.

IND safety reports

21 CFR 312.32©(1) IND safety reports: "sponsor must notify FDA... in an IND safety report of potential serious risks, from clinical trials or any other source, as soon as possible, but in no case later than 15 calendar days after the sponsor determines that the information qualified for reporting..."

Where are the GMPs located for Biologics?

21 CFR 600

What is biologic product deviation reporting?

21 CFR 600.14: any event and information relevant to the event, associated with the manufacturing, to include testing, processing, packaging, labeling, or storage, or with the holding or distribution, of a licensed biological product, if that event meets all the following criteria: represents a deviation from current good manufacturing practice, applicable regulations, applicable standards, or established specifications that may affect the safety, purity, or potency of that product or represents an unexpected or unforeseeable event that may affect the safety, purity or potency of that product and occurs in your facility or another facility under contract with you: must be submitted on form FDA 3486, and must be submitted within 45 days of the date the deviation occurred.

What is post licensing compliance?

21 CFR 601.12(d) changes to an approved application "an applicant must inform the FDA... about each change in the product, production process, quality controls, equipment, facilities, responsible personnel, or labeling established in the approved license application(s).

What are short supply manufacturing arrangements?

21 CFR 601.22: products in short supply; initial manufacturing at other than licensed location; provision allowing licensed biologic manufacturer to obtain the initial and partially manufactured version of the product from unlicensed facilities; generally used in unusual circumstances

What are the annual reporting requirements?

21 CFR 610.12(d):

What are the labeling regulations?

21 CFR 610.2: labeling information is required in BLA submissions to FDA for approval; 21 CFR 201.56-57 and 21 CFR 610.60-68: describe the content and format; 21 CFR 312.6-7: labeling and promotion for investigational new drugs "Caution: New Drug- Limited by Federal (or United States) law to investigate use"

What are lot release protocols?

21 CFR 610.2: requests for samples and protocols; official release; samples of any lot of any licensed product together with the protocols showing results of applicable tests; initiated during review (DMPQ); all products licensed under the PHS act may be subject to lot release

After you submit and IND, when can you start clinical trials?

30 days unless placed on clinical hold by FDA (FDA does not approved INDs); note: FDA communication on an IND is advise unless it is accompanied by a clinical hold order

What are examples of labeling changes requiring submission but may be distributed before FDA approval?

Addition of an adverse event due to information reported to applicant or FDA. Addition of a precaution arising out of a post-marketing study. Addition of strengthening a statement about abuse, dependence, psychological effect or over dosage. Clarification of the administration statement to ensure proper administration of the product.

What is considered preapproval compliance?

CMC change control: manufacturing changes are expected during the product development stage; keeping IND current with manufacturing information amendments; comparability studies: analytical, nonclinical/clinical studies

What are examples of labeling changes requiring FDA approval prior to product distribution?

Changes based on postmarketing study results, including, but not limited to, labeling changes associated with new indications and usage. Change in, or addition of, pharmacoeconomic claims based on clinical studies. Changes to the clinical pharmacology or the clinical study section reflecting new or modified data. Changes based on data from preclinical studies. Revision (expansion or contraction) of population based on data. Claims of superiority to another product. Change in container labels for licensed blood.

What are examples of labeling changes that would be reported in an annual report?

Changes in the layout of the package or container label without a change in content of the labeling. Editorial changes such as adding a distributor's name. changes in information about how the drug is supplied. Foreign language versions of the labeling, if no change is made to the content of the approved labeling and a certified translation is included.

What are the two categories of INDs?

Commercial (An IND for which the sponsor is usually either a corporate entity or one of the institutes of the National Institutes of Health (NIH). In addition, CDER may designate other INDs as commercial if it is clear the sponsor intends the product to be commercialized at a later date) and Research (LOOK UP/ASK)

What is the review process for submission process for BLA?

Complete at the time of original submission, under PDUFA V program, PDUFA time clock begins 60 days after receipt date, conformance to regulatory requirements, establish review team and distribute submission

What type of expedited program is: A drug that is intended to treat a serious condition AND nonclinical or clinical data demonstrate the potential to address unmet medical need OR A drug that has been designated as a qualified infectious disease products?

Fast track; submitted with the IND no later than the pre-BLA or pre-NDA meeting; FDA response within 60 calendars of receipt; actions to expedite development and review/ rolling review; designation may be rescinded if it no longer meets the qualifying criteria for fast track

In regards to REMS what are elements to ensure safe use?

Health care providers who prescribe the drug have particular training or experience or a specially certified; pharmacies, practioners or health care settings that dispense the drug are specially certified; the drug is dispensed to patients only in certain health care settings, such as hospitals; the drug is dispensed to patients with evidence or other documentation of safe use conditions, such as lab test results; each patient using the drug is subject to a certain monitoring; each patient using the drug is enrolled in a registry

Biolgical products are regulated by CBER except:

Monoclonal antibdies for in vivo use; they were transferred to CDER June 2003

What are the post-licensing safety reporting requirements?

Postmarketing 15 day alert report- serious and unexpected adverse events; Postmarketing 15 day alert report follow up: investigation of all adverse events submitted under the 15 day alert report; periodic adverse event reports: serious and unexpected as well as nonserious expected adverse events

What are the types of FDA enforcement actions?

Regulatory Action letters, product recalls, judicial enforcement

What is the draft package insert?

SPL formatted content of labeling (.XML file) and a Microsoft word formatted version (.doc file) should be submitted with original BLA submission, efficacy supplements, and all supplements that require review of labeling; an MS word version is not required for changes reported in an annual report. Subject to considerable negotiation with FDA

What are types of Judicial enforcement?

Seizure: remove product in violation of the law from distribution; injunction: civil action to stop production or distribution; prosecution: criminal action as results of acts prohibited in FD&C act