RAC Exam

DRLS

Drug Registration and Listing System

Unexpected Adverse Drug Experience

not listed in drug labeling

PMA changes

notification and FDA involvement is outlined below. •PMA supplement (180 days) - §814.39(a) ◦for significant changes that affect the safety and effectiveness of the device ◦in-depth review and approval by FDA is required before implementation of the change ◦A full PMA review including a review by an outside advisory panel may be required. The criteria for a full PMA review includes changes in the device that may raise different types of safety and effectiveness questions or changes in which there may be no accepted test methods for evaluating the issues of safety or effectiveness. Some 180-day PMA supplements may be reviewed using the Real-Time Review process. In this process the supplement is reviewed during a meeting or conference call with the applicant. FDA will fax its decision to the applicant within five working days after the meeting or call. The change must meet certain criteria to be eligible for this type of review. Supplements with detailed clinical data are generally not considered for this program. The criteria and process for the Real Time Review program are outlined in Real-Time Premarket Approval Application (PMA) Supplements. •Special PMA Supplement -- Changes Being Effected - §814.39(d) ◦for any change that enhances the safety of the device or the safety in the use of the device ◦may be placed into effect by the applicant prior to the receipt of a written FDA order approving the PMA supplement. After FDA approves a PMA, any change described below that enhances the safety of the device or the safety in the use of the device [§814.39(d)(2)] may be placed into effect by the applicant prior to the receipt of a written FDA order approving the PMA supplement, but after the applicant receives specific acknowledgment that the application qualifies for review under §814.39(d)(2) provided that: ◾the PMA supplement and its mailing cover are plainly marked "Special PMA Supplement -- Changes Being Effected;" ◾the PMA supplement provides a full explanation of the basis for the changes; ◾the applicant has received acknowledgment that the application qualifies as a "Special PMA Supplement -- Changes Being Effected" from FDA for the supplement; ◾the PMA supplement specifically identifies the date that such changes are being effected; and ◾the change is made according to the good manufacturing practices regulation. The following changes are permitted [§814.39(d)(1)]: ◾labeling changes that add or strengthen a contraindication, warning, precaution, or information about an adverse reaction; ◾labeling changes that add or strengthen an instruction that is intended to enhance the safe use of the device; ◾labeling changes that delete misleading, false, or unsupported indications; and ◾changes in quality controls or the manufacturing process that add a new specification or test method, or otherwise provide additional assurance of purity, identity, strength, or reliability of the device. The applicant is encouraged to contact the PMA Staff to assist in determining if the change meets the requirements of §814.39(b). •30-day Notice and 135 PMA Supplement - §814.39(f) ◦Used for modifications to manufacturing procedures or methods of manufacture that affect the safety and effectiveness of the device. ◦Changes in a manufacturing/sterilization site or to design or performance specifications do not qualify ◦If the change qualifies as a 30day Notice, the change may be made 30 days after FDA receives the 30day notice unless FDA informs the PMA holder that the 30-day Notice is not adequate and describes the additional information or action required. If the 30-day Notice was not adequate, but contained data meeting appropriate content requirements for a PMA supplement, then the 30-day Notice will become a 135-day PMA Supplement. Additional guidance can be found in "30-Day Notices and 135-Day PMA Supplements for Manufacturing Method or Process Changes, Guidance for Industry and CDRH". Note: 30-day Notice is not the same as a 30-day Supplement. See below for information regarding the 30-day Supplement. •PMA Manufacturing Site Change Supplement ◦For moving the manufacturing site if certain conditions apply. ◦Manufacturing site must have received a Quality System/GMP inspection within the last two years. ◦If requirements are not met, 180-day PMA Supplement must be submitted. •Annual (periodic) Report or 30-day Supplements-§814.39(e) ◦FDA may allow certain changes to be reported in an annual report or 30-day supplement an instead of a PMA supplement submission. (If this method is utilized, FDA will typically request that the information be reported in the annual report and not as a 30-day supplement.) ◦FDA will notify applicants of this alternative through an advisory opinion to the affected industry or in correspondence with the applicant. FDA will identify a change to a device for which the applicant has an approved PMA and for which a PMA supplement is not required under 814.39(a). FDA will identify such a change in an advisory opinion under §10.85, if the change applies to a generic type of device. Such changes will be identified in written correspondence to each PMA holder who may be affected by FDA's decision. FDA will require that a change, for which a PMA supplement under §814.39(a) is not required, to be reported to FDA in a periodic (annual) report or a 30-day PMA supplement. In written correspondence, FDA will identify the type of information that is to be included in the report or 30-day PMA supplement. If FDA requires that the change be reported in a periodic report, the change may be made before it is reported to FDA. If FDA requires that the change be reported in a 30-day PMA supplement, the change may be made 30 days after FDA files the 30-day supplement, unless FDA informs the PMA holder that additional information is required, the supplement is not approvable, or the supplement is denied. The 30-day PMA supplement must follow the instructions in the correspondence or advisory opinion. Any 30-day PMA supplement that does not meet the requirements of the correspondence or advisory opinion will not be filed and, therefore, will not be deemed approved 30 days after receipt. The applicant is encouraged to contact the PMA staff to assist in determining if the change meets the requirements of §814.39(e). •Document to file ◦for changes that do not affect the safety or effectiveness of the device ◦very limited or no FDA involvement prior to implementation of the change Minor manufacturing changes and minor quality control changes can be documented to file. Examples of changes that can be documented to file include editorial changes to a Standard Operating Procedure (SOP) to make instructions clearer and combining two SOPs into one.

Type C meeting

other meetings that are not A or B; Scheduled within 75 days of request. FDA notifies Sponsor of the date within 21 days of request.

Equivalance testing (for changes in drug)

assess the identity, strength, quality, purity, or potency - test pre and post changes

eDRLS

electronic Drug Registration and Listing System

CFR

has 50 titles; official compilation of regulations; updated yearly

Moderate Change in NDA

moderate potential to have an adverse effect on the identity, strength, quality, purity, or potency of a drug - uses CBE-30

ANDA 505(j)

no clinical data necessary; demonstrate "sameness" to a registered drug- same: -conditions of use -active ingredient -route of administration -labeling Submitted to the Office of Generic Drugs

Best Pharmaceuticals for Children Act (BPCA)

part of FDAAA to incentive pediatric studies- voluntary program; prior to PREA - incentive was 6 months exclusivity

Type B meeting

pivotal meetings; End of Phase 1, End of phase 2, pre-IND, NDA, pre-BLA, post marketing and REMS. Scheduled within 60 days of request. FDA notifies Sponsor of the date within 21 days of request.

Section 351 of the Public Health Service Act

vaccines are regulated under this since it is for public health

Other miscellaneous changes - major

-changes requiring completion of studies to demonstrate eqiuvalence -addition of stability protocol or changes to approved stability protocol -extension of an expiration dating period based on data obtained under a revised protocol

4 Categories of Communication from FDA

1. Administrative meetings or communications 2. Product application meetings 3. regulatory communications (e.g., guidance docs, citizen petitions, etc.) 4. Public administrative proceedings.

Kefauver-Harris Amendments

1962 -in response to Thalidomide side effects; required companies to also demonstrate efficacy; also required informed consent in clinical studies, required drug advertising to disclose accurate information about side effects.

Medwatch forms

3500A - required reporting 3500 - voluntary reporting

Device User Facilities

A "device user facility" is a hospital, ambulatory surgical facility, nursing home, outpatient diagnostic facility, or outpatient treatment facility, which is not a physician's office. User facilities must report a suspected medical device-related death to both the FDA and the manufacturer. User facilities must report a medical device-related serious injury to the manufacturer, or to the FDA if the medical device manufacturer is unknown. A user facility is not required to report a device malfunction, but can voluntarily advise the FDA of such product problems using the voluntary MedWatch Form FDA 3500 under FDA's Safety Information and Adverse Event Reporting Program. Healthcare professionals within a user facility should familiarize themselves with their institution's procedures for reporting adverse events to the FDA. See "Medical Device Reporting for User Facilities", a guidance document issued by FDA.

medical device

An instrument, apparatus, implement, machine, contrivance, implant, in vitro reagent or similar or relate article, including any component, part or accessory intended for the use in diagnosis of disease or other conditions, or in the cure, mitigation, treatment or prevention of disease on man or other animals intended to affect the structure of any function of the body of man or other animals, and which does not achieve its primary intended purposes through chemical action within or on the body, and which is not dependent upon being metabolized for the achievement of its primary intended purposes (FD&C Act Section 201)

Dear Doctor Letter

A remedial communication required by the FDA when a drug company advertises a drug with incomplete/misleading information about its efficacy/safety

drug

Any article intended for use in the diagnosis, cure, mitigation, treatment or prevention of disease in man.

Importer

Any importer who furthers the marketing of a device from a foreign manufacturer to the person who makes final delivery or sale of the device to the ultimate consumer or user, but does not repackage, or otherwise change the container, wrapper, or labeling of the device or device package. The initial importer must have a physical address in the United States staffed by individuals responsible for ensuring the compliance of imported devices with all applicable FDA laws and regulations. Importers are required to report to the FDA and the manufacturer when they learn that one of their devices may have caused or contributed to a death or serious injury. The importer must report only to the manufacturer if their imported devices have malfunctioned and would be likely to cause or contribute to a death or serious injury if the malfunction were to recur.

Relabeler

Changes the content of the labeling from that supplied from the original manufacturer for distribution under the establishment's own name. A relabeler does not include establishments that do not change the original labeling but merely add their own name.

Drug Recall Classifications

Class I recall: a situation in which there is a reasonable probability that the use of or exposure to a violative product will cause serious adverse health consequences or death. Class II recall: a situation in which use of or exposure to a violative product may cause temporary or medically reversible adverse health consequences or where the probability of serious adverse health consequences is remote. Class III recall: a situation in which use of or exposure to a violative product is not likely to cause adverse health consequences.

Federal Register

Daily supplement to CFR

medical device safety reporting

During an investigation, report an ADE if unexpected and serious within 10 days to FDA, all IRBs and all investigators (this is working 10 days from when sponsor becomes aware of this). NO reporting for expected adverse events.

EIR

Establishment Inspection Report - FDA summarizes the inspection and classifies it as NAI, VAI, or OAI.

FAERS

FDA Stores Drug Safety Data in here

FURLS

FDA Unified Registration and Listing System for establishment registration of medical device operators and distrubutors).

Exclusivity

It depends on what type of exclusivity is granted. Orphan Drug (ODE) - 7 years New Chemical (NCE)- 5 years "Other" Exclusivity - 3 years for a "change" if criteria are met Pediatric Exclusivity (PED) - 6 months added to existing Patents/Exclusivity Patent Challenge - (PC) - 180 days (this exclusivity is for ANDAs only)

Pediatric Research Equity Act (PREA)

Mandatory Pediatric studies

MDUFMA

Medical Device User Fee and Modernization Act 2002. Required electronic medical device event reporting.

NAI

No Action Indicated

OAI

Official Action Indicated

Repackager

Packages finished devices from bulk or repackages devices made by a manufacturer into different containers (excluding shipping containers).

required medical device reporting - Medical Device User Facility

Report within 10 working days of becoming aware 1. suspected device-related death - to FDA and Mfg 2. Serious injury to FDA OR mfg 3. Submit form 3419 Annual User Facility REport 4 optional reporting through medwatch

RFD

Request for Designation - to request a center for a combo product; FDA responds within 60 days. If not response, then request is granted. Can dispute it within 1 days of receipt (Request for Reconsideration).

Reporting ADEs (post-market)

Sponsor must report all ADEs within 15 calendar days of information Report Periodic ADE Reports (PADERS) quarterly for first 3 years, every year thereafter

MDR

System used for event Reporting for device manufacturers and importers

Types of 510(k)

TRADITIONAL 510(k) submission - Most companies introducing a new Class 2 medical device must submit a traditional 510(k) Premarket Notification. This is a full 510(k) that includes all 21 sections. Read more about the sections and format of a Traditional 510(k). ABBREVIATED 510(k) submission - When you submit an Abbreviated 510(k), you are providing summary reports that demonstrate your use of guidance documents, special controls or Declarations of Conformity to recognized standards to expedite review of your submission. You might qualify to submit an Abbreviated 510(k) if: •FDA Guidance document(s) exists •Special controls have been established •The FDA has published a recognized Consensus Standard that you have followed SPECIAL 510(k) submission- The final type of FDA Premarket Notification is called the Special 510(k). This is used when a modification has been made to a medical device that already has 510(k) clearance. It allows the manufacturer to declare conformity with the Design Controls set out of 21 CFR Part 820 without providing the data.

Pediatrics Research Equity Act (PREA)

The law requires pediatric studies to: 1. assess the safety & effectiveness of the drug product for the claimed indications in all relevant ped subpopulation 2. to support dosing and administration for each pediatric subpopulation for which drug is safe and effective

VAI

Voluntary Action indicated

Financial Disclosure forms

1. FORM FDA 3455, Disclosure Statement,8 for each clinical investigator who, or whose spouse or dependent child, had disclosable financial interests in and/or arrangements with any sponsor of the covered clinical study. The form should include an attachment with detailed information about those financial interests and arrangements (for example, the nature of the contingent payment or the equity holdings of the investigator, or the investigator's spouse or dependent child, that exceeded the threshold) and a description of the steps taken to minimize the potential for bias resulting from the disclosed financial interests and arrangements (21 CFR § 54.4(a)(3)). See Section IV.C for additional information; 2. FORM FDA 3454, Certification, for any clinical investigator who has no disclosable financial interests in or arrangements with any sponsor of the covered clinical study (21 CFR § 54.4(a)(1)); the applicant may append a list of investigator names to a single FORM FDA 3454 for those investigators with no disclosable financial interests or arrangements; or 3. If the applicant was unable to obtain some or all of the financial information needed to disclose or certify for a clinical investigator, the applicant must identify any disclosable financial interests or arrangements of which it is aware, certify that it acted with due diligence to obtain the information (listed as option 3 on FORM FDA 3454), and include an attachment identifying the reason why any missing information could not be obtained (21 CFR § 54.4). FDA expects that in the vast majority of cases, applicants will be able to provide a complete financial Certification or Disclosure Statement and that the need to certify that they acted with due diligence will be rare.

Financial Disclosure

1. Any compensation made to the investigator by any sponsor of the covered clinical study in which the value of compensation could be affected by study outcome. 2. A proprietary interest in the tested product including, but not limited to, a patent, trademark, copyright or licensing agreement. 3. Any equity interest in any sponsor of the covered clinical study, i.e., any ownership interest, stock options, or other financial interest whose value cannot be readily determined through reference to public prices. The requirement applies to interests held during the time the clinical investigator is carrying out the study and for one year following completion of the study. 4. Any equity interest in any sponsor of the covered study if the sponsor is a publicly held company and the interest exceeds $50,000 in value. The requirement applies to interests held during the time the clinical investigator is carrying out the study and for one year following completion of the study. 5. Significant payments of other sorts (SPOOS) are payments that have a cumulative monetary value of $25,000 or more and are made by any sponsor of a covered study to the investigator or the investigator's institution during the time the clinical investigator is carrying out the study and for one year following completion of the study. This would include payments that support activities of the investigator (e.g., a grant to the investigator or to the institution to fund the investigator's ongoing research or compensation in the form of equipment), exclusive of the costs of conducting the clinical study or other clinical studies, or to provide other reimbursements such as retainers for ongoing consultation or honoraria.

What are the items included in a Supplemental amendment or annual report indicating a change?

1. Conformance to specifications: Assessment of the effects on a change in the identity, strength, quality, purity, or potency 2. Additional Testing: evaluation of any changes in the chemical, physical, microbiological, biological, bioavailability and/or stability. Examples: evaluate hardness or friability of a table, dissolution profiling or in vivo bioequivalence, evaluate extractables from new packing or moisture permeability, evaluate changes in impurity profile, toxicology tests if necessary.

Serious Adverse Drug Experience

1. Death 2. life-threatening event 3. in-patient hospitalization 4. persistent or significant disability 5. congenital anomaly/birth defect

labeling change - moderate

1. addition of adverse event info 2. addition of a precaution arising from postmarket study 3. clarification of drug administration

mfg process changes- major

1. affect the dose release or delivery 2. affect sterility (ex. changes in lyophilization equipment of different size, changes in terminal sterilization method, change in sterilization steps or method, change in filter types) 3. fundamental change in process or technology (e.g, dry to wet granulation, drying process, filtration vs centrifugation, synthesis route) 4. changes in natural product (e.g., removal of viral agent or inactivation, cell line source) 5. changes to drug substance (e.g. changes after final intermediate step, affect on impurity, physical or chemical, biological property) 6. addition of in code imprint or change to ink used if the ink is currently not used on a CDER-approved Drug. 7. new procedure for reprocessing a batch or drug substance or product that fails to meet the specifications

Changes in specifications - minor (annual report)

1. any changes made to comply with a FDA statutory 2. tightening of a criteria 3. addition or revision of an alaternative analytical procedure that provides the same or increased assurance 4. change in analytical procedure used for testing materials prior to final intermediate that provides same or increase assurance

Changes to container closure system - minor (annual report)

1. change in container closer for a nonsterile drug based on showing equivalency to an approved system 2. change in size/shape of container for a nonsterile solid dosage drug 3. change in change in labeled amount for nonsterile solid dosage drugs 4. changes in container closure system of nonsterile solid oral dosage forms or nonsterile liquies as long as new package involves the same or better protective properties

labeling change - minor

1. change in layout of package labeling 2. editorial changes such as distributor name 3. foreign language versions 4. changes made to comply with requirements

labeling change - major

1. changes based on postmarketing studies, including changes associated with new indications and usages 2. changes in pharmacoeconomic claims 3. changes in clin pharm or clinical study section 3. changes in preclinical study data 4. Revisions to population based on data 5. claims of superiority 6. changes in labeled storage conditions

mfg process changes- moderate

1. changes that are not major CBE-30 1. changes not listed as major 2. for natural protein products: increase or decrease in production scale during finishing steps that involved different equipment, or replacement of equipment with different design that doe not affect process methodology 3. changes in dry heat depyrogenation process for glass containers, filtration process changes that go from single to dual filters, changes to another sterilization chamber that results in a change in validation CBE-0: 1. changes that provide increased assurance that the drug will have the charactistics of identity, strength, quality, purity and potentency 2. elimination of a in-process filtration performed as part of the mfg of a terminally sterilized drug product

mfg process changes- minor (annual report)

1. changes to equipment of the same design and operating principle 2. minor change in code imprint 3. change in ink when currently used on approved drug 4. addition or deletion of a code imprint on a solid drug other than a modified release form 5. change in order of addition of ingredients 6. changes in scale of mfg for terminally sterilized drugs that increase the bulk solution storage by no more than 50% beyond the validated limits 7. Natural protein drug products: change in scale that does not involve equipment change, replacement of equipment with the same design

required medical device reporting - Medical Device IMporter

1. device may have resulted in death - 30 days of becoming aware 2. if likely the device may cause death or serious injury - 30 days

Changes to container closure system - major change

1. for liquid or semi-solid (creams), change in primary packaging that has not been previously approved 2. when primary package controls the dosage delivery 3. change in ink or adhesive when package is semi-permeable 4. any change that may affect drug sterility (e.g., glass ampule to vial, from single unit dose to multi-dose unit, container size or shape, etc. ) 5. deletion of secondary packaging component that provides addl protection to the drug 6. new container closure if doesn't provide the same protective properties

Mfg site - minor changes

1. move to 2ndary site for 2ndary packaging - (does not contact the drug) 2. labeling site change 3. different mfg site for intermediate mfg or processing 4. change in contract sterilization of PACKAGING components if the process is not materially different 5. transfer of mfg of finished product sterilized by terminal processes to a newly constructed building or existing bldg. at the same mfg site 6. move to different site for ink imprinting on oral tablets

Manufacturing site Moderate Changes

1. move to different mfg site that is not mentioned in major changes 2. change in aseptic site that is not new or is used on similar approved drugs 3. modified-release solid oral dosage 4. move to a different mfg site fro TESTING if the SOPs approved in NDA or via annual report are used, all post-approval commitments have been fulfilled such as methods validation and the new site has the capability to perform the intended testing 5. move to a different mfg site for the mfg or processing of the final intermediate - CBE-0 can be submitted

Changes in specifications - Major

1. relaxing a criteria 2. Deleting any specification or a part of 3. establishing a new regulatory analytical procedure (ex. the standard abiding by, such as USP) 4. change in analytical procedure used for testing components, packaging components, the final intermediate, after final intermediate, or starting materials introduced after the final intermediate. 5. change in testing of raw materials for viruses

Manufacturing site Changes - Major

1. sites that do NOT have satisfactory GMP inspection history require a PAS 2. new site never been inspected (except if it is for mfg of an intermediate) 3. when dose delivery in-process materials is changing (ex. liposomal drug, transdermal systems, oral and nasal inhalers, 4. Transfer to a new aseptic processing facility or new lyophilization processing site/area 5. newly constructed sterilization site (once this change is approved, subsequent changes to this facility would be a CBE-30)

REview time NDA vs ANDA

10mos for NDA vs 22 months for ANDA (GDUFA 2012 trying to reduce this timeframe to 10 months for 90% of applications).

Virus-Toxin Law

1901; 13 children died from contaminated tetanus antitoxin. Required licensing, vaccine mfg inspections and premarket approval of vaccines, serums and antitoxins.

Food, Drug and Cosmetic (FD&C) Act

1938 and subsequent Acts; basic Food & Drug Law. Came about after the sulfanilamide contamination that killed a bunch of kids. Strengthened safety and labeling. Still only focused on safety (not yet efficacy).

Biologic

Biological products, or biologics, are medical products. Many biologics are made from a variety of natural sources (human, animal or microorganism). Like drugs, some biologics are intended to treat diseases and medical conditions. Other biologics are used to prevent or diagnose diseases. Examples of biological products include •vaccines •blood and blood products for transfusion and/or manufacturing into other products •allergenic extracts, which are used for both diagnosis and treatment (for example, allergy shots) •human cells and tissues used for transplantation (for example, tendons, ligaments and bone) •gene therapies •cellular therapies •tests to screen potential blood donors for infectious agents such as HIV

Examples of Biologics

Botox: has both dermatologic and neurologic uses Herceptin: for a certain type of breast cancer Vaccines, for example: the Shingles vaccine and the flu vaccines Enbrel: for rheumatoid arthritis and psoriasis

Changes in specifications - moderate

CBE-30 1. changes in regulatory analytical procedures those not identified as major 2. relaxing an acceptance criteria or deleting a raw material test when used prior to final intermediate 3. relaxing an in-process acceptance criterion associated with microbial monitoring of the production environment. 4. relaxing acceptance criteria or deleting a test to comply FDA statutory CBE-0 1. addition to a spec that provides increase assurance (e.g., adding a new test and acceptance criteria) 2. other changes that provide increases assurance

Changes to container closure system - Moderate change

CBE-30 1. changes in size or shape of container for a sterile drug 2. change in no. of units or amount of a nonsterile drug 3. change in container closure system that are not considered major changes CBE-0 1. changes in size or shape of container for a nonsterile drug, except for solid dosage (minor change - annual report) 2. change in labeled amount for nonsterile drug, except for solid dosage forms 3. change in or addition or deletion of a desiccant

CBER vs CDER Biologics Reviews

CBER Allergenics Patch tests used to diagnose the causes of contact dermatitis. Extracts used to diagnose and treat rhinitis ("hay fever"), allergic sinusitis and conjunctivitis, and bee stings. •Blood Blood and blood components used for transfusion, such as red blood cells, plasma, and platelets. Pharmaceutical products made from blood, such as clotting factors and immunoglobuilns. •Devices - in vitro diagnostics Medical devices and tests used to safeguard blood, blood components, and cellular products from HIV, hepatitis, syphilis, and other infectious agents. Reagents used to type blood. Machines and related software used to collect blood and blood components. •Gene Therapy •Human Tissues and Cellular Products Human tissues for transplantation, such as skin, tendons, ligaments, and cartilage. Cellular products, such as human stem cells and pancreatic islets. Tissue and cellular products have the potential to treat cancer, Parkinson's disease, hemophilia, anemia, diabetes, and other serious conditions. •Vaccines •Xenotransplantation Products Xenotransplantation products use live animal cells, tissues, or organs to treat human diseases such as liver failure and diabetes, where human materials are not always available. CDER ◦Monoclonal antibodies for in vivo use. ◦Most proteins intended for therapeutic use, including cytokines (e.g., interferons), enzymes (e.g. thrombolytics), and other novel proteins, except for those that are specifically assigned to the Center for Biologics Evaluation and Research (CBER) (e.g., vaccines and blood products). This category includes therapeutic proteins derived from plants, animals, humans, or microorganisms, and recombinant versions of these products. Exceptions to this rule are coagulation factors (both recombinant and human-plasma derived). ◦Immunomodulators (non-vaccine and non-allergenic products intended to treat disease by inhibiting or down-regulating a pre-existing, pathological immune response). ◦Growth factors, cytokines, and monoclonal antibodies intended to mobilize, stimulate, decrease or otherwise alter the production of hematopoietic cells in vivo. ◦other non-vaccine therapeutics

medical device recall categories

Class III - not likely to cause advers health consequences class II - may cause temporarty consequences class I - can or will cause serious adverse health consequences or death Report to FDA within 10 days of a class I or II recall This classification is similar to Drug Recall classification in terms of severity,

482 Form

FDA gives for official inspection notice

Medical Device registration and listing

Facilities that produce or distribute product must register. Depending on the activities, many of these will also have to list the devices and associated activities. Example: Importers have to register but do not list the product (importers do not change the product at all - just distribute it as is). Registration is electronic - payment is through Device Facility User Fee (DFUF) website - use payment confirmation to register on FURLS. examples of those who need to register: - contract mfg (includes contract packagers) -Remanufacturer - importer -domestic or wholesale distributor who does not import the device -contract sterilizer -Specification developer

Field Copy Certification

Field Copy Certification (that it is a true copy of the CMC technical section) included? Field Copy Certification is not needed if there is no CMC technical section or if this is an electronic submission (the Field Office has access to the EDR)

Pediatric clinical trials

In addition to regular protections, these risk/benefit ratios must apply: 1. No greater than minimal risk 2. greater than minimal risk but presents prospect of direct benefit to the child participating 3. a minor increase over minimal risk but likely to yield generalizable knowledge about the child's disorder

Registration & listing of BLA products

Must use SPL electronic format -register annually on or before Dec 31st each year -list all products, with bi-annual updates to listings in Jun & Dec

Review times

NDA/BLA -10 months for standard review -6 months for priority review

Time and Extent Application (TEA)

The purpose of a TEA is to request that FDA determines whether a condition is eligible for inclusion in the OTC drug monograph system. A TEA should be submitted only for conditions that the applicant believes have been marketed OTC to a material extent and for a material time (67 FR 3060). Under 21 CFR 330.14, a TEA may be submitted for: •Conditions initially marketed (under an approved application under section 505 of the FD&C Act) in the United States after the OTC drug review began in 19727 •Conditions marketed only outside the United States (and that would be regulated as OTC drugs in the United States) FDA typically makes an eligibility determination within 1 year of receiving a TEA, and a fee is not required.

Biologic

a virus, therapeutic serum, toxin, antitoxin, vaccine, blood, blood component or derivative, allergenic product, protein (except any chemically 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.

Device Master File

a way to preserve trade secrets of medical device companies and their suppliers.

Device Master Record

compilation of all the instructions, drawings and other records, that must be used to produce a product.

Manufacturer and User Facility Device Experience (MAUDE) database

contains mandatory reports filed by manufacturers and importers from August 1996 to present, all mandatory user facility reports from 1991 to present, and voluntary reports filed after June 1993. The MAUDE database houses MDRs submitted to the FDA by mandatory reporters (manufacturers, importers and device user facilities) and voluntary reporters such as health care professionals, patients and consumers.

Type A meeting

critical meeting (For drug approval) to address a stalled development (e.x, SPA mtg, post-action meeting, dispute resolution). Held within 30 days of FDA's receipt of written request from Sponsor. FDA notifies Sponsor of the date within 14 days of request.

Other miscellaneous changes - annual report

extension of expiration dating period based on full shelf life data on production batches obtained under an approved stability protocol -addition of time points in stabtility protocol or deletion of time points

Suitability petition

for a generic drug that has a different route of administration, dosage form, strength or inactive ingredients

Major Change in NDA

substantial potential to have an adverse effect on the identity, strength, quality, purity, or potency of a drug - uses Prior Approval Supplement

Component and composition changes

includes inactive ingredients as well; ALL changes except deletion or reduction of an ingredient that affects color only (annual report change) require a PAS

483 Form

inspection findings; have 15 days to respond with correction plan

citizens petition

may be used to request the amendment or repeal of conditions covered by proposed or final OTC drug monographs (21 CFR 10.30 and 21 CFR 330.10(a)(12)). The citizen petition process should not be used to make an initial request to include in the OTC drug monograph system conditions marketed in the United States after the beginning of the OTC drug review in 1972 or those without any U.S. marketing experience; these must first be determined to be eligible for potential inclusion through submission of a TEA in accordance with 21 CFR 330.14.6

Device History Record

means a compilation of records containing the production history of a finished device.

Minor Change in NDA

minimal potential to have an adverse effect on the identity, strength, quality, purity, or potency of a drug - uses annual report to report the change

1906 Food & Drug Act

prohibited the marketing of adulterated (contaminated) and misbranded food and drugs. Did NOT require product standards and gov't did not have much authority. In response to Upton Sinclair's writings of unsafe conditions in meat packing facilities.

Other miscellaneous changes - moderate

reduction in expiration dating to provide increase assurance

Durham-Humphrey Amendment 1951

required certain medications that could be habit forming or dangerous to be dispensed only with a prescription. Until this law, there was no requirement that any drug be labeled for sale by prescription only. This was the first time there was an OTC vs prescription category.

Field Alert

submit within 3 days of discovering a significant problem with a distributed drug product 1. incidents causing the drug product or labeling to be mistaken for or applied to another article 2. bacterial contamination 3. significant chemical, physical or other change, deterioriation in distributed drug product 4. failure of one or more distributed drug product batches to meet the specs established

pharmacokinetics

what the body does to the drug (how metabolized). is currently defined as the study of the time course of drug absorption, distribution, metabo-lism, and excretion.

pharmacodynamics

what the drug does to the body (e.g. lowers blood pressure, etc. ). is the study of the biochemical and physiological effects of drugs on the body or on microorganisms or parasites within or on the body and the mechanisms of drug action and the relationship between drug concentration and effect.

Special Mfg circumstances for biologics mfg

when short supply of a product, various scenarios can occur: 1. can use an unlicensed, but registered facility to mfg initial component, but not final product 2. Divided mfg: use two registered and licensed sites to mfg the product in its entirety 3. Shared mfg: each site is registered and listed for various steps in the process - neither does the whole process

Manufacturer

within 30 days - 1. report to FDA if the learn device has contributed to death or serious injury 2. report to FDA if likely it would cause death or seriuor injury within 5 days 1. becoming aware of event requiring immediate remediation to prevent substantial harm to public health

Bioequivalence for ANDA

~25 normal health subjects - measure the active ingredients in bloodstream; no significant difference in the absorption rate and extent of absorption when the same dose is used (as compared to RLD)