RAC Sample Test

A key pharmaceutical product parameter has a specification range of 90-100. Which of the following postmarketing specification changes would require FDA notification prior to making the change? A. 89-100 B. 90-99 C. 95 +/- 5 D. 95-100

A. 89-100 Question Feedback: Notification is required when the specification range is widened. VIII. Specifications: B. Major Changes (Prior Approval Supplement) The following are examples of changes in specifications considered to have a substantial potential to have an adverse effect on the identity, strength, quality, purity, or potency of a drug product as these factors may relate to the safety or effectiveness of the drug product. C. Moderate Changes (Supplement—Changes Being Effected) Supplement—Changes Being Effected in 30 Days b. Relaxing an acceptance criterion

A company has a 510(k) device and wants to expand its indications for use. The device can be used for the new indication, which includes a new and distinguishable patient population, with only minor changes to the device's specifications. Which actions need to take place before marketing the device for the new indication: A. A new 510k needs to be submitted with appropriate testing for the new indication B. Since the device specification changes are minor, a special 510k can be submitted C. The device can be marketed right away and the change described in the Annual Report D. The device can be marketed after submission of labeling change

A. A new 510k needs to be submitted with appropriate testing for the new indication Question Feedback: A new indication for use requires a new 510(k) clearance.

Which of the following does NOT describe requirements for reserve samples? A. A reserve sample representative of one lot of shipped product per year must be retained B. The reserve sample should be at least twice the amount required for all tests required to determine whether the active ingredient meets established specifications except for sterility and pyrogen testing C. Reserve samples should be stored under conditions in line with those on the product labeling D. Any evidence of reserve sample deterioration should be investigated and documented

A. A reserve sample representative of one lot of shipped product per year must be retained Question Feedback: A reserve sample representative of each lot of each shipment of each active ingredient shall be retained—NOT one lot of shipped product per year.

How should an NDA holder report a change to aseptic processing filtration parameters (including flow rate, pressure, time or volume, but not filter material or pore size rating). A. Changes Being Effected in 30-Days B. Changes Being Effected in 0-Days C. Prior Approval Supplement D. Annual Report

A. Changes Being Effected in 30-Days Question Feedback: The holder of an approved application under section 505 of the act must assess the effects of the change before distributing a drug product made with a manufacturing change. Examples from Guidance for Industry: Changes to an Approved NDA or ANDA 2004: The following are examples of changes considered to have a moderate potential to have an adverse effect on a drug product's identity, strength, quality, purity or potency as these factors may relate to the product's safety or effectiveness. Additional validation studies for new parameters should be performed for changes to filtration parameters for aseptic processing (including flow rate, pressure, time or volume, but not filter materials or pore size rating).

FDA has issued a Complete Response Letter to a company. The company views many of the deficiencies as minor. The regulatory professional should meet with the team to: A. Devise a strategy for responding to all deficiencies identified by FDA B. Devise a strategy to respond to any minor deficiencies in order to restart the review clock C. Inform the team a Class 1 resubmission has a six-month review clock D. Inform the team a Class 2 resubmission has a three-month review clock

A. Devise a strategy for responding to all deficiencies identified by FDA Question Feedback: Resubmissions purport to answer all of the deficiencies needing to be addressed by the applicant prior to the original application's approval as set forth in a previous action letter.

FDA currently requires all medical device registration and listing information (annual, initial or updates) to be submitted via: A. FDA's Unified Registration and Listing System (FURLS) B. FDA Forms 2891 and 2892 C. FDA Forms 2656 and 2657 D. FDA Form 3356

A. FDA's Unified Registration and Listing System (FURLS) Question Feedback: According to FDA's website, the Food and Drug Administration Amendments Act of 2007 requires all registration and listing information (annual, initial or updates) to be submitted electronically unless FDA grants a waiver. Further, registration and listing information needs to be submitted via FDA's Unified Registration and Listing System (FURLS)/Device Registration and Listing Module (DRLM).

A customer complains he or she received your company's biological product but the primary label was not on the container. As the regulatory professional, what is the best course of action to take to address this incident? A. First, verify the complaint; second, investigate the manufacturing process; third, file a Biological Product Deviation report B. First, verify the complaint; second, investigate the manufacturing process; third, recall the entire lot C. First, verify the complaint; second, file the Biological Product Deviation report; third, issue the customer a credit/replace for the product D. First, verify the complaint; second, investigate the manufacturing process; third, issue a press release regarding the event

A. First, verify the complaint; second, investigate the manufacturing process; third, file a Biological Product Deviation report Question Feedback: Depending on the type of biologic being manufactured, a recall may or may not be required. At minimum, the regulatory professional must verify the complaint, investigate the manufacturing process and file the Biological Product Deviation report.

An investigator wishing to begin a clinical investigation using xenotransplantation must submit the following: A. IND B. 505(b)(2) C. BLA D. INAD

A. IND Question Feedback: The use of xenotransplantation products (cells, tissue and organs derived from animals) in clinical trials in the US is regulated by FDA under both the PHS Act (42 U.S.C. 262) and the FD&C Act (21 U.S.C. 321(g), Sec. 201(g). Before use in clinical trials, xenotransplantation products must be reviewed by FDA either as Investigational New Drug (IND) applications for biologics or Investigational Device Exemptions (IDEs) for certain xenotransplantation products that may be regulated as devices. Development of investigational xenotransplantation products must be in compliance with 21 CFR Part 312 for INDs or 21 CFR Part 812 for IDEs. Xenotransplants are biological products regulated by CBER. Xenotransplantation is any procedure that involves the transplantation, implantation or infusion into a human recipient of either (a) live cells, tissues or organs from a nonhuman animal source, or (b) human body fluids, cells, tissues or organs that have had ex vivo contact with live nonhuman animal cells, tissues or organs.

A serious adverse event of Grade 4, life-threatening hallucinations is reported by an investigator for an investigational drug in a Phase 3 clinical trial for patients with advanced stage malignant melanoma. Grade 1-3 (mild, moderate, severe) hallucinations have been reported previously in the Investigator's Brochure. You advise the medical monitor to confirm the severity grade for this AE is reported correctly by the investigator. What subsequent reporting should follow? A. If AE is confirmed to be Grade 4, report as a serious and unexpected AE associated with the investigational drug to FDA via phone or facsimile within 7 calendar days, followed by a written report within 8 additional calendar days B. If AE is clarified as Grade 3 not Grade 4, report as a serious and unexpected adverse event to FDA in writing within 15 calendar days C. Regardless of AE severity grade, report as a serious and unexpected AE associated with the investigational drug to FDA in writing within 15 calendar days D. If AE is clarified to be Grade 3 not Grade 4, report as a serious adverse event in the IND annual safety report

A. If AE is confirmed to be Grade 4, report as a serious and unexpected AE associated with the investigational drug to FDA via phone or facsimile within 7 calendar days, followed by a written report within 8 additional calendar days Question Feedback: Reporting criteria for drug AEs is serious AND unexpected, whereas the reporting criteria for device is only serious.

Which of the following is NOT required for compliance under 21 CFR Part 11 (electronic records and electronic signatures)? A. Manually generated, time-stamped audit trails to record the date and time of operator entries and actions that create, modify or delete electronic records B. Validation of systems to ensure accuracy, reliability, consistent intended performance and the ability to discern invalid or altered records C. Authority checks to ensure that only authorized individuals can use the system, electronically sign a record, access the operation or computer system input or output device, alter a record or perform the operation at hand D. Establishment of, and adherence to, written policies holding individuals accountable and responsible for actions initiated under their electronic signatures, in order to deter record and signature falsification

A. Manually generated, time-stamped audit trails to record the date and time of operator entries and actions that create, modify or delete electronic records Question Feedback: Time-stamped audit trails must be secure, computer-generated records that independently record the date and time of operator entries and actions that create, modify, or delete electronic records. Manually generated records are NOT acceptable.

Which federal law made it illegal for physicians reimbursed by federally funded programs to prescribe or recommend a patient use a particular manufacturer's medical products when the doctor receives payment from that manufacturer? A. Medicare and Medicaid Patient Protection Act of 1987 B. Food, Drug, and Cosmetic Act of 1938 (FD&C Act) C. Food and Drug Administration Modernization Act of 1997 (FDAMA) D. Food and Drug Administration Amendments Act of 2007 (FDAAA)

A. Medicare and Medicaid Patient Protection Act of 1987 Question Feedback: The Medicare and Medicaid Patient Protection Act of 1987 is also known as the Federal Anti-Kickback Statute and makes it illegal for any person—e.g., healthcare provider, office manager or sales agent—to knowingly and willingly solicit, offer, pay or receive "remuneration" (including kickbacks, bribes, rebates or anything of value) directly or indirectly in cash or in kind to any person to induce or cause that person to prescribe a product for which payment may be made in whole or in part under a federal or federally funded healthcare plan.

A medical device company allows its sales force to maintain a product inventory in the field. The device has an expiration date indicated on its labeling. A sales person notes one of his products has expired and contacts headquarters for instructions on what to do. He is told to return the product to headquarters for replacement. The return of this product is considered as what type of recall? A. Not a recall—it is considered normal stock rotation B. Class I recall C. Class II recall D. Class III recall

A. Not a recall—it is considered normal stock rotation Question Feedback: This action will be considered as market withdrawal; involves no violation of the FD&C Act. It is considered normal stock rotation (the device is considered under the company's inventory and quality system.)

An NDA holder wants to extend the drug product shelf life from two to three years. What is the best course of action to pursue? A. Present three years of real-time stability data on three consecutive batches following an approved stability protocol in the NDA Annual Report B. Present 18 months of accelerated stability data on three consecutive batches in the NDA Annual Report C. Present three years of real-time stability data on three consecutive batches in an NDA Changes Being Effected in 30-Days supplement D. Present 18 months of accelerated stability data on three consecutive batches in a NDA Changes Being Effected in 0-Days supplement

A. Present three years of real-time stability data on three consecutive batches following an approved stability protocol in the NDA Annual Report Question Feedback: §314.70(d)(2)(vi), Data from stability studies should be provided on at least three consecutive batches of the drug product. An extension of an expiration dating period based on full shelf life data on production batches obtained under a protocol approved in the application. In the absence of an approved/agreed stability protocol with FDA, if the sponsor chose to provide real time stability data on three batches, the change should be submitted as a prior approval supplement.

A blood center has discovered a unit of packed red blood cells for commercial use previously shipped to a local hospital was stored inappropriately for four days during the manufacturing process. The blood center should: A. Recall the blood product and initiate a blood product deviation report to CBER within 45 calendar days of discovery of the deviation. B. Recall the blood product and initiate a blood product deviation report to CDRH within 45 calendar days of discovery of the deviation. C. Recall the blood product and initiate a blood product deviation report to CBER within 15 calendar days of discovery of the deviation D. Recall the blood product and initiate a blood product deviation report to CDRH within 15 calendar days of discovery of the deviation.

A. Recall the blood product and initiate a blood product deviation report to CBER within 45 calendar days of discovery of the deviation. Question Feedback: CBER is the FDA branch handling biologic products and the appropriate reporting period is 45 days from discovery of the manufacturing deviation. Under 21 CFR 606.171, a manufacturer is required to report certain events associated with the manufacturing, to include testing, processing, packing, labeling or storage, or with blood or blood component holding or distribution, which may affect the a distributed product's safety, purity or potency. Safety, purity and potency are defined in 21 CFR 600.3(p), (r) and (s). Under 21 CFR 606.171(c), a manufacturer should submit reports as soon as possible, but is required to submit reports at a date not to exceed 45 calendar days from the date of discovery of information reasonably suggesting a reportable event has occurred.

Blood Center ABC has just opened in a Midwestern state. It plans to manufacture blood and blood products from volunteer blood donors and offer these products for sale to local dialysis clinics and hospitals in other states. Blood Center ABC must: A. Register with FDA within five days after beginning operations and provide a current list of all products manufactured, prepared and processed that are in commercial distribution B. Wait to distribute any blood products until an FDA GMP inspection is completed successfully. C. Submit a BLA to FDA prior to distributing any blood products in interstate commerce D. Submit a label supplement to FDA prior to distributing any blood products in interstate commerce

A. Register with FDA within five days after beginning operations and provide a current list of all products manufactured, prepared and processed that are in commercial distribution Question Feedback: 21 CFR 607.21 "The owner or operator of an establishment entering into an operation defined in §607.3(d) shall register such establishment within 5 days after the beginning of such operation and submit a list of every blood product in commercial distribution at the time. If the owner or operator of the establishment has not previously entered into such operation (defined in 607.3(d) of this chapter) for which a license is required, registration shall follow within 5 days after the submission of a biologics license application in order to manufacture blood products."

Your company recently had a successful End-of-Phase 2 meeting for a novel drug and would like your regulatory advice on designing the pivotal Phase 3 study. The clinical compound team wants to use a primary endpoint and unusual design never utilized before in the therapeutic area you are studying. Which type of meeting would be the best choice for getting FDA alignment with your pivotal Phase 3 study? A. Request a Special Protocol Assessment Meeting B. Request a Pre-NDA Meeting C. Request a Type C Meeting D. Request a Type A Meeting

A. Request a Special Protocol Assessment Meeting Question Feedback: Based on guidance documents, FDA encouraged the use of the SPA process for trials in which the proposed study design or endpoints are unusual, or for studies that involve an indication or disease for which the FDA has not previously approved a drug or biologic product. Pre-NDA is later, after you would need to discuss the Phase 3 trial design. A Type C Meeting would be better used for general drug development questions. Type A meetings generally are used for dispute resolution; they also are used if a sponsor wants a meeting after receiving comments from FDA on the SPA.

FDA is authorized to regulate advertising for what type(s) of medical devices? A. Restricted Devices B. Non-Restricted Devices C. All medical devices D. None, as this is the responsibility of the FTC

A. Restricted Devices Question Feedback: "Under the FD&C Act, FDA has regulatory authority over the labeling of all medical devices. However, FDA's regulation of medical device advertising is limited to a subset of medical devices. The Federal Trade Commission (FTC) regulates the advertising, as opposed to the labeling, of most medical devices under sections 12-15 of the Federal Trade Commission Act, which prohibit false or misleading advertising of certain products that FDA regulates. (Title 15, United States Code [U.S.C.] section 52-55). Sections 502(q) and 502(r) of the FD&C Act authorize FDA to regulate the advertising of certain devices, which are known as restricted devices (discussed below). Section 502(r) also states that restricted devices are not subject to sections 12-15 of the Federal Trade Commission Act. Thus, FDA regulates the advertising of restricted medical devices while the FTC regulates the advertising of non-restricted devices."

Which of the following statements is NOT true for Phase I Investigational New Drug (IND) Applications and Investigational Device Exemptions (IDEs) for significant-risk products? A. The investigational product must be manufactured in full compliance with CGMP B. Clinical study protocols must be reviewed and approved by an Institutional Review Board C. The IND or IDE goes into effect 30 days after FDA receives the application, unless FDA notifies the sponsor otherwise D. The application must include an environmental impact statement that contains a claim for categorical exclusion or an environmental assessment

A. The investigational product must be manufactured in full compliance with CGMP Question Feedback: According to CFR 210, 2(c), "An investigational drug for use in a phase 1 study, as described in 312.21(a) of this chapter, is subject to the statutory requirements set forth in 21 U.S.C. 351(a)(2)(B). The production of such drug is exempt from compliance with the regulations in part 211 of this chapter." However, based on FDA guidance, Phase 1 investigational drugs should be manufactured with the application of some (not full) CGMP.

A company is developing a combination product consisting of a device that injects a specially formulated small molecule drug for pain into the muscle tissue. Which of the following describes the best US regulatory path: A. The product is regulated as a drug B. The product is regulated under CDRH C. The company should file a BLA to obtain US marketing approval D. The company should submit a request for designation to OCP

A. The product is regulated as a drug Question Feedback: Primary mode of action is the pain drug and the device is a delivery system

A firm submitted a protocol and received IRB approval for a clinical trial involving children in which there would be no prospect of direct benefit to the individual subjects. On what basis could this study be approved by the IRB? A. The trial was likely to yield generalizable knowledge about the subject's disorder or condition and all other regulatory requirements were met B. Parental consent was included in the IRB submission C. The clinical investigation involved a less than minimal risk to the subjects D. This trial should not have been approved.

A. The trial was likely to yield generalizable knowledge about the subject's disorder or condition and all other regulatory requirements were met Question Feedback: Clinical investigations involving greater than minimal risk and no prospect of direct benefit to individual subjects, but likely to yield generalizable

While reviewing product complaint files for MDR reportability, you notice a complaint regarding a common failure mode of an implantable screw. No patient involvement or adverse consequences were reported in the complaint. Your firm has initiated a Class I recall for this implantable screw due to safety issues associated with this failure mode. As a regulatory professional your decision is: A. This complaint is reportable; an MDR will be filed with FDA within 30 days B. A review of the complaint history is needed to see whether such failure mode likely will cause or contribute to death or serious injury C. No MDR is needed as there is no patient involvement and no adverse consequences were reported D. No MDR is needed but you will file this complaint in the recall file

A. This complaint is reportable; an MDR will be filed with FDA within 30 days Question Feedback: When a recall is initiated for a particular product failure mode, such failure mode automatically is MDR-reportable to FDA. Additionally, while the complaint did not report an adverse event, the manufacturer should evaluate the potential to cause an adverse event if the failure mode was to re-occur

Which of the following is NOT stipulated by FDA to support product postapproval stability requirements? A. Three batches per year per container/closure system in the stability program B. An adequate number of batches C. An amount compliant with the postapproval stability commitment D. Reliable, meaningful and specific test methods

A. Three batches per year per container/closure system in the stability program Question Feedback: Items 2 and 4 are directly from 21 CFR 211.166 Stability testing. Item 3 is supported by 21 CFR 314.81, A status report is to be included for any chemistry, manufacturing and controls studies the applicant has agreed to perform and for all product stability studies. Sec. 211.166 Stability testing (a) There shall be a written testing program designed to assess the stability characteristics of drug products. The results of such stability testing shall be used in determining appropriate storage conditions and expiration dates. The written program shall be followed and shall include: (1) Sample size and test intervals based on statistical criteria for each attribute examined to assure valid estimates of stability;(2) Storage conditions for samples retained for testing;(3) Reliable, meaningful, and specific test methods;(4) Testing of the drug product in the same container-closure system as that in which the drug product is marketed;(5) Testing of drug products for reconstitution at the time of dispensing (as directed in the labeling) as well as after they are reconstituted.(b) An adequate number of batches of each drug product shall be tested to determine an appropriate expiration date and a record of such data shall be maintained. Accelerated studies, combined with basic stability information on the components, drug products, and container-closure system, may be used to support tentative expiration dates provided full shelf life studies are not available and are being conducted. Where data from accelerated studies are used to project a tentative expiration date that is beyond a date supported by actual shelf life studies, there must be stability studies conducted, including drug product testing at appropriate intervals, until the tentative expiration date is verified or the appropriate expiration date determined.

A company plans to develop a new anemia treatment. The product is a polypeptide fragment of the human protein erythropoietin that has not been approved previously. The company plans to produce the polypeptide by chemical synthesis. To date, FDA has approved other erythropoietins, but not the fragment. What is the appropriate pathway by which to seek approval? A. Under FD&C Act Section 505(b)(1) B. Under FD&C Act Section 505(b)(2) C. Under PHS Act Section 351(a) D. Under PHS Act Section 351(k)

A. Under FD&C Act Section 505(b)(1) Question Feedback: Although the product is a fragment of a human protein, it will be a chemically synthesized polypeptide and, therefore, will be regulated under the FD&C Act (not the PHS Act). Because the treatment is a new active ingredient, the sponsor should seek approval via 505(b)(1).

When can modified labeling format be used for an OTC product? A. When the required Drug Facts and other FDA required information exceed 60% of the total surface area available for labeling B. When the required Drug Facts and other FDA required information exceed 90% of the total surface area available for labeling C. When the manufacturer determines the required Drug Facts and FDA required information do not fit within its label design D. When recommended by FDA after review of information to be included in the label

A. When the required Drug Facts and other FDA required information exceed 60% of the total surface area available for labeling Question Feedback: Answers 1, 2 and 4 are reasons to issue Notice of Intent to Revoke license. Answer 3 is a postapproval reporting issue (21 CFR 606.170(b)).

From a subsidiary in Ireland, you are forwarded a report saying a patient taking your company's drug was hospitalized with a case of Stevens-Johnson syndrome. This hypersensitivity reaction is not listed on your label. You should report this case to FDA: A. Within 15 calendar days of receipt of the report B. Within 15 business days of receipt of the report C. Within 10 business days of receipt of the report D. With the next periodic adverse drug experience report

A. Within 15 calendar days of receipt of the report Question Feedback: All serious and unexpected adverse drug experiences, whether foreign or domestic, should be reported to FDA within 15 calendar days. 21 CFR 314.80(c)(1)(i) Postmarketing 15-day "Alert reports." The applicant shall report each adverse drug experience that is both serious and unexpected, whether foreign or domestic, as soon as possible but in no case later than 15 calendar days of initial receipt of the information by the applicant.

A company is developing an (unapproved) drug-device combination product but is not sure to which center it should submit its marketing application. The company should first submit: A. A Request for Determination to the appropriate review division based on the product's primary mode of action B. A Request for Designation to the Office of Combination Products C. A Request for Determination to the Office of Pharmaceutical Science D. A Request for Designation to the Office of New Drug Quality Assessment

B. A Request for Designation to the Office of Combination Products Question Feedback: The Office of Combination Products assigns review responsibility for combination products based on the product's primary mode of action. By submitting a "Request for Designation," a company may obtain a formal agency determination of a combination product's primary mode of action and the lead agency center for the product's premarket review and regulation.

Company X has conducted clinical studies to support drug A's safety and effectiveness. Company X is planning to develop a new drug A dosage formulation and route of administration. This new formulation will rely on previously conducted clinical studies to support drug A's safety and effectiveness. Which of the following should be submitted by Company X? A. A 505(b)(2) application B. An NDA containing full reports of investigations of safety and effectiveness C. A 505(j) application D. An efficacy supplement

B. An NDA containing full reports of investigations of safety and effectiveness Question Feedback: The applicant conducted the clinical studies. A new dosage formulation and route of administration will require an NDA.

Company ABC is planning to move its manufacturing process to a new clinical manufacturing site. The product is a biologic and currently in a Phase 2 clinical study. Once the manufacturing site is validated, it will produce material for the planned Phase 3 pivotal study. What sort of comparability data would be required for the manufacturing site change? A. Analytical data and a small clinical trial to prove equivalence B. Analytical data and a nonclinical toxicology study C. Analytical data only D. Comparability is not required as the process is exactly the same.

B. Analytical data and a nonclinical toxicology study Question Feedback: Bioanalytical data, stability studies and a nonclinical toxicology study are suggested to prove the two processes are comparable prior to starting the Phase 3 studies at the new manufacturing site.

The Quality System Regulation calls for finished device manufacturers to carry out all of the following EXCEPT: A. Quality audits conducted by individuals who do not have direct responsibility for the operation being audited B. Annual audits of operations C. Documenting the dates and results of quality audits and re-audits D. Having findings reviewed by management responsible for the matters audited

B. Annual audits of operations Question Feedback: FDA recommends periodic audits and does not specify a time.

A firm is preparing a 510(k), premarket notification to FDA for an in vitro diagnostic test, a microhematocrit analyzer that, among other intended uses, can determine a blood donor's hematocrit prior to donation. The firm should address the 510(k) submission to: A. CDER B. CBER C. CDRH D. OCP

B. CBER Question Feedback: This agreement describes those product characteristics or medical indications requiring a collaborative review effort by the two centers and the regulatory jurisdiction for biologic product and medical devices is clearly stated. Intercenter Agreement between CBER and CDRH. VI. Medical Devices for which CBER will have lead responsibility. CBER also has the responsibility for regulating all in vitro tests (including diagnostic tests which are not performed in association with blood bank practices).

Which FDA center should have primary jurisdiction for the premarket review and regulation of a nasal spray single-entity combination product that uses a drug as its primary mode of action (PMOA) A. CDRH B. CDER C. CBER D. CDRH and CDER

B. CDER Question Feedback: Under FD&C Act Section 503(g)(1), assignment to lead center is based on the combination product's primary mode of action (PMOA). In this product, the drug has the (PMOA

What type of communication will FDA send an applicant when the review division concludes an NDA or ANDA cannot be approved in its present form and certain additional information or clarifications are needed? A. Non-approvable letter B. Complete response letter C. Non-approval letter D. Approvable letter

B. Complete response letter Question Feedback: All deficiencies identified by FDA will be in the complete response letter. The letter also will reflect the review of the entire application and/or amendments submitted.

All of the following choices are examples of Type B meetings with FDA EXCEPT: A. Certain End-of-Phase 1 meetings B. Dispute resolution meetings C. End-of-Phase 2 meetings D. Pre-NDA meetings

B. Dispute resolution meetings Question Feedback: Dispute resolution meetings are Type A meetings.

The drug substance manufacturing plant proposes widening a critical in-process test limit associated with the final intermediate manufacturing process. What will need to be done for the plant to implement the change? A. File the change as an annual reportable change and implement the change immediately B. File a Prior Approval Supplement and wait for agency approval before implementation C. File a Prior Approval Supplement and wait for agency approval before implementation D. File a Changes Being Effected in 30 days and implement after day 30 if the agency has not contacted the company

B. File a Prior Approval Supplement and wait for agency approval before implementation Question Feedback: Widening acceptance criteria for an in process test performed on the final intermediate would be classified as a Prior Approval Supplement. Therefore, the change would need to be filed with and approved by FDA before implementation.

You are the regulatory expert in a small start-up medical device company. A clinical investigation is required for your Class II medical device's 510(k) submission. One of the investigators conducting the study also has received 1,000 stock options from your company as part of his consulting agreement. What information related to this investigator must be included with your 510k submission? A. Form 3454, certifying lack of financial interests and arrangements B. Form 3455, disclosing the stock options for the specific investigator C. Form 3455, disclosing proprietary interest in the tested product D. No additional forms are required

B. Form 3455, disclosing the stock options for the specific investigator Question Feedback: The guidance states, if the stock options' value cannot be determined through public prices, it needs to be disclosed.

At the completion of a Preapproval Inspection where a deficiency was noted, a meeting is convened to discuss what document? A. Form FDA 482 B. Form FDA 483 C. Form FDA 1572 D. EIR

B. Form FDA 483 Question Feedback: Form FDA 483 is the most correct because an EIR is not written by FDA until the investigators return to their office. An FDA Form 483 is issued to firm management at the conclusion of an inspection if an investigator(s) has observed any conditions that in his or her judgment may constitute violations of the Food, Drug, and Cosmetic Act (FD&C Act) and related acts. FDA Form 483s are discussed with a company's management at the inspection's conclusion. Each observation is read and discussed so there is a full understanding of what the observations are and what they mean. EIRs should be completed and submitted for final classification within a timely manner commensurate with the current regulatory action timeframes for the anticipated regulatory action, but generally not to exceed 30 working days when no further action is expected. Sec. 20.101 Administrative enforcement records.

A company has submitted its NDA for review. When must additional safety information be submitted to FDA in a safety update report to avoid triggering an extension of the review clock? A. Six months after the initial NDA submission (180 day safety update) B. Four months after the initial NDA submission (120 day safety update) C. Upon initial NDA submission D. After NDA approval

B. Four months after the initial NDA submission (120 day safety update) Question Feedback: "(vi) A summary and updates of safety information, as follows: (b) The applicant shall, under section 505(i) of the act, update periodically its pending application with new safety information learned about the drug that may reasonably affect the statement of contraindications, warnings, precautions, and adverse reactions in the draft labeling. These "safety update reports" are required to include the same kinds of information (from clinical studies, animal studies, and other sources) and are required to be submitted in the same format as the integrated summary in paragraph (d)(5)(vi)(a) of this section. In addition, the reports are required to include the case report forms for each patient who died during a clinical study or who did not complete the study because of an adverse event (unless this requirement is waived). The applicant shall submit these reports (1) 4 months after the initial submission; (2) following receipt of an approvable letter; and (3) at other times as requested by FDA. Prior to the submission of the first such report, applicants are encouraged to consult with FDA regarding further details on its form and content."

With regard to NDA applications, all the following are true EXCEPT: A. Labeling and promotional material must be submitted during the preapproval period B. Labeling changes are reported in the quarterly report to an approved NDA C. Fees may be waived if the designated drug is for orphan products D. NDAs may be submitted in the traditional format on paper or electronically

B. Labeling changes are reported in the quarterly report to an approved NDA Question Feedback: Depending on the type of change, labeling changes are reported in either the Annual Report or in a supplement. (a) Changes to an approved application. (1)(i) Except as provided in paragraph (a)(1)(ii) of this section, the applicant must notify FDA about each change in each condition established in an approved application beyond the variations already provided for in the application. The notice is required to describe the change fully. Depending on the type of change, the applicant must notify FDA about the change in a supplement under paragraph (b) or (c) of this section or by inclusion of the information in the annual report.

Which of the following is considered part of the Device Master Record? A. Employee training record B. Labeling specifications C. Design reviews D. Calibration records

B. Labeling specifications Question Feedback: Labeling specifications are part of the DMR

Your company is developing a new drug to be developed and used in combination with a cystoscopic light device for the early detection of bladder cancer. You are asked to develop an overall regulatory strategy. The first step you undertake is: A. Submit a Request for Designation to FDA Office of Combination Products for determination of the lead center for primary jurisdiction for the combination product. B. Make a preliminary internal company determination of the combination product's primary mode of action. C. Submit an IND along with a Request for Designation to FDA CDER Office of Oncology Drug Products (OODP). D. Submit a request for designation to FDA CDRH and notify the Office of Combination Products

B. Make a preliminary internal company determination of the combination product's primary mode of action. Question Feedback: It is important to determine the primary mode of action first to be able to make a recommendation as to which agency component should have primary jurisdiction, to be followed by a request for designation to FDA OCP if deemed necessary when the product's classification or the agency center to which it should be assigned in unclear or in dispute.

You are the regulatory representative for a product currently available by prescription only that comes in several different strengths. Due to the nature of the symptoms the lower doses treat, the drug is considered a candidate for a partial switch to an OTC medication. What type of marketing application would you file to support the partial switch of your product? A. NDA supplement B. NDA C. NDA Deviation D. ANDA

B. NDA Question Feedback: As the product is not a candidate for a full switch to OTC status, the product in an OTC status is considered to be a "new drug." Therefore, a new NDA under Section 505(b)(1) of the FD&C Act must be submitted by the sponsor.

What market exclusivity type confers seven years of protection from competitor product marketing application approval? A. New Chemical Entity (NCE) exclusivity B. Orphan Drug Exclusivity C. Pediatric Exclusivity D. Exclusivity granted for an ANDA with Paragraph IV certification

B. Orphan Drug Exclusivity Question Feedback: Orphan drug exclusivity prevents FDA from approving an application for the same drug for the same condition for seven years. NCE confers five years of exclusivity (does not apply to ANDA/generics). Pediatric exclusivity extends all other exclusivity by six months. Paragraph IV (non-infringement of patent) exclusivity provides 180-day exclusivity to any "first applicant" if all other conditions are met

Due to mechanical failure, a product line has remained in process for five days beyond the time limit established in the company's SOPs. Which of the following should be done first? A. Reject all products in this one line since the time limit has been exceeded B. Proceed with processing and quarantine the product until QA/QC completes a deviation report and investigation C. Complete the manufacturing process and proceed to ship the product D. Review the SOP to determine if the time limitation is appropriate.

B. Proceed with processing and quarantine the product until QA/QC completes a deviation report and investigation Question Feedback: Quarantine would give the company time to conduct an investigation and determine suitability for release.

Which of the following are NOT required to be included in a combination product Request for Designation (RFD)? A. The product's proprietary name B. Process validation protocols and reports C. Chemical, physical or biological composition D. The sponsor's identity

B. Process validation protocols and reports Question Feedback: Process validation protocols and reports are not required to be submitted as part of the RFD.

The following applies to autologous chondrocytes expanded in vitro for the repair of cartilage defects: A. Regulated under PHS Act Section 351 and no premarket approval required B. Regulated under PHS Act Section 351 and premarket approval required C. Regulated under PHS Act Section 361 and no premarket approval required D. Regulated under PHS Act Section 361 and premarket approval required

B. Regulated under PHS Act Section 351 and premarket approval required Question Feedback: The product is a HCT/P (human cells, tissues and cellular and tissue-based products). In vitro expansion of cells is considered more than minimal manipulation. The product, therefore, does not meet the criteria to be regulated under PHS Act Section 361 (criteria: minimal manipulation; homologous use; not combined with another article; no systemic effect and not dependent on metabolic activity of living cells except if for autologous use, use in a first-degree or second-degree blood relative or for reproductive use) and is regulated under PHS Act Section 351 and requires a Biologics License Application (BLA).

A pharmaceutical company decides to collaborate with a diagnostic device manufacturer to develop a new therapeutic drug. The diagnostic device is intended to identify patients most likely to benefit from the use of the therapeutic product. The device previously has been cleared for a different intended use. What should the diagnostic device manufacturer do prior to commercial distribution of the device for the new intended use? A. Define the patient population identified by the diagnostic device B. Submit a new premarket submission for the device for use with the novel therapeutic product C. Revise the labeling to specify the therapeutic product for which the device has been approved or cleared for use D. Identify the therapeutic product class in which the diagnostic device may be applicable for use

B. Submit a new premarket submission for the device for use with the novel therapeutic product Question Feedback: The best choice is 2. 1 and 3 alone are insufficient to market a device legally. A therapeutic class, instead of a specific therapeutic product, should not be claimed unless there is sufficient evidence to support this.

Which of the following is required for a sponsor to advertise that a prescription drug is safer or more effective than another prescription drug? A. The representation must have been approved as part of the labeling in an initial new drug application or biologic license B. The representation is supported by substantial evidence derived from adequate and well-controlled studies as defined by applicable regulation C. The requirement for adequate and well-controlled studies is waived by regulation D. Peer-reviewed scientific literature in support of the claim must be submitted in a preapproval supplement

B. The representation is supported by substantial evidence derived from adequate and well-controlled studies as defined by applicable regulation Question Feedback: Peer-reviewed scientific literature in support of the claim is not required to be submitted in a preapproval supplement but should be supplied to the Food and Drug Administration, if requested. Sec. 202.1 Prescription-drug advertisements (6) An advertisement for a prescription drug is false, lacking in fair balance, or otherwise misleading, or otherwise violative of section 502(n) of the act, among other reasons, if it: (i) Contains a representation or suggestion, not approved or permitted for use in the labeling, that a drug is better, more effective, useful in a broader range of conditions or patients (as used in this section patients means humans and in the case of veterinary drugs, other animals), safer, has fewer, or less incidence of, or less serious side effects or contraindications than has been demonstrated by substantial evidence or substantial clinical experience (as described in paragraphs (e)(4)(ii) (b) and (c) of this section) whether or not such representations are made by comparison with other drugs or treatments, and whether or not such a representation or suggestion is made directly or through use of published or unpublished literature, quotations, or other references.

A company has a new blood pressure medication, NOSTRESS. Clinical trials are completed and demonstrate similar safety and efficacy to drugs currently on the market. Clinical data are ready for submission to FDA. Chemistry, manufacturing and controls data are not ready, but will be in two months. What is the fastest NDA filing method? A. Submit NDA as a rolling review B. Wait until CMC data are ready to submit C. File the NDA with the clinical data and update the CMC data in the four-month update D. Request Fast Track designation

B. Wait until CMC data are ready to submit Question Feedback: Rolling review and Fast Track are only for drugs treating serious disease and meeting an unmet medical need; the four-month safety report is for clinical safety only.

In the original application for drug "X," your company submitted a comparability protocol outlining a series of proposed, repetitive container closure system changes, the tests and studies that would be used to evaluate the changes and the acceptance criteria that would be met. The application since has been approved. Subsequent comparability test results did not meet some of the predefined acceptance criteria. What regulatory option does your company have in this situation? A. Your company may implement the change(s), but an explanation as to why some of the acceptance criteria were not met must be included within the next Annual Report B. Your company may still pursue the change(s) and should submit a Prior Approval Supplement providing supporting data to justify why the change will not affect the specific drug product's identity, strength, quality, purity and potency adversely as related to the product's safety and effectiveness C. Your company may still pursue the change(s) and should submit a CBE-30 providing supporting data to justify why the change will not affect the specific drug product's identity, strength, quality, purity and potency adversely as related to the product's safety and effectiveness D. There is no further regulatory option; the proposed change(s) cannot be implemented since the predefined acceptance criteria were not met.

B. Your company may still pursue the change(s) and should submit a Prior Approval Supplement providing supporting data to justify why the change will not affect the specific drug product's identity, strength, quality, purity and potency adversely as related to the product's safety and effectiveness Question Feedback: If test results do not meet the acceptance criteria, the company may elect not to implement the change. However, it still has the option to pursue the change(s) by submitting a Prior Approval Supplement to provide supporting data to justify why the change will not affect the drug product adversely.

A company has a new oral drug, GOODDRUG, it wishes to market in the US. Studies on intravenous GOODDRUG have been conducted by several academic centers demonstrating safety and efficacy and have been published in peer-reviewed journals. The most-appropriate method to gain approval would be by filing a: A. ANDA B. SNDA C. 505(b)2 D. 505(b)1

C. 505(b)2 Question Feedback: Since the drug has been studied and those results published, a comparability study between IV and oral dosage forms is acceptable under a 505(b)2

If a company is planning to market a medical device that is substantially equivalent to a device marketed before 1976, which regulatory path would be most appropriate: A. IDE B. PMA C. 510(k) D. Special Assessment Protocol

C. 510(k) Question Feedback: A device legally marketed prior to 28 May 1976 (pre-amendment device) can be used as a predicate device to demonstrate substantial equivalence as part of the Premarket Notification (510(k)).

How many days does FDA have to review an Abbreviated 510(k)? A. 30 days B. 60 days C. 90 days D. 180 days

C. 90 days Question Feedback: Because both Special 510(k)s and Abbreviated 510(k)s are alternate approaches to the Traditional 510(k), with the goal of streamlining application evaluation, the Special 510(k) review clock is 30 days. Many people often think the review clock for an Abbreviated 510(k) is also 30 days, but it actually is 90.

A Class II device with electrical components was subjected to extensive standardized testing such as the International Electrotechnical Commission (IEC) series (recognized conformance standard). The tests were conducted by a third party. Which route of submission is the most suitable for this device? A. Traditional 510(k) B. Special 510(k) C. Abbreviated 510(k) D. PMA

C. Abbreviated 510(k) Question Feedback: A manufacturer has the option to submit an Abbreviated 510(k) when FDA has recognized relevant consensus standards applicable to the device. This Abbreviated 510(k) will include a declaration of conformity to the recognized consensus standards, and this declaration, in many cases, should eliminate the need to review actual test data for those aspects of the device addressed by the standards, thus the review will be more efficient.

A pharmaceutical manufacturer has a high-volume tablet product that requires the production of about 600 batches per year to meet demand. The batch records are generated from the same Master Production (Batch) Record. Each batch record calls for yield calculation to be recorded three ways: theoretical yield, actual yield and percentage of theoretical yield. Which of these calculations would be impacted most by the amount of waste accumulated during the granulation process? A. All three yield calculations B. Theoretical yield C. Actual yield and percentage of theoretical yield D. None of the three yield calculations

C. Actual yield and percentage of theoretical yield Question Feedback: To make the correct selection, it is necessary to understand anything affecting the actual yield, e.g., waste, samples pulled, etc., in any part of the process affects the percentage of theoretical yield calculation because the percentage of theoretical yield is a ratio of the actual yield expressed as a percentage (see Part 210.3 (19)). Sec. 210.3 Definitions. (17) Theoretical yield is the quantity that would be produced at any appropriate manufacturing, processing or packing stage of a particular drug product, based on the quantity of components to be used, in the absence of any loss or error in actual production. (18) Actual yield is the quantity actually produced at any appropriate manufacturing, processing or packing phase of a particular drug product. (19) Percentage of theoretical yield is the ratio of the actual yield (at any appropriate manufacturing, processing or packing phase of a particular drug product) to the theoretical yield (at the same phase), stated as a percentage Sec. 211.103 Calculation of yield. Actual yields and percentages of theoretical yield shall be determined at the conclusion of each appropriate phase of manufacturing, processing, packaging, or holding of the drug product.

Your company is developing an autologous cellular therapy product. FDA informed the company its product will be regulated as an HCT/P (Human Cells, Tissues and Cellular and Tissue-Based Product). Based on this information, with which of the following regulatory requirements will your company need to be compliant when manufacturing the product? A. 21 CFR 210 / 211 (CGMP requirements for pharmaceuticals) B. 21 CFR 2171 and 21 CFR 820 C. All Subparts of 21 CFR 1271 except Subpart C (Donor Eligibility) D. All Subparts of 21 CFR 1271

C. All Subparts of 21 CFR 1271 except Subpart C (Donor Eligibility) Question Feedback: The correct answer is 3. Since the product is regulated under PHS Act Section 361, it is subject only to the requirements in 21 CFR 1271, with the exception of Subpart C, as autologous products are not subject to donor eligibility requirements.

Your company's commercial product is manufactured by a third-party manufacturer (TPM). The manufacturing site undercharges one of the excipients. Without contacting your company, the TPM decides to rework the batch and now would like the product to be released upon completion of the investigation. Your technical team contacts you for regulatory advice on whether the lot can be released upon approval of the investigation. As a regulatory professional, as a first step you: A. Recommend the lot be released B. Recommend the lot not be released C. Assess whether the rework steps are within the regulatory filing and whether there is a potential regulatory impact D. If the rework steps are not in the current filing, submit a post-approval change to include the rework steps in order to release the material

C. Assess whether the rework steps are within the regulatory filing and whether there is a potential regulatory impact Question Feedback: Product release and disposition is a quality responsibility, not regulatory. The regulatory professional is responsible for reviewing the event and assessing whether the additional steps performed in the manufacturing process are allowed within the regulatory filing. The team may decide to include the rework procedure; however, additional data may be needed for the submission. Therefore the recommended first step is response 3.

Pharmacogenomic testing data results must be submitted to an IND in all the following circumstances EXCEPT : A. Test results will be used to determine clinical trial dosing schedule selection B. Test results will be used to make decisions in an animal trial used to support safety C. Data were derived from general gene-expression analysis of trial participants D. Test results constitute a known valid biomarker for toxicologic outcomes in humans

C. Data were derived from general gene-expression analysis of trial participants Question Feedback: Exploratory or research data are not required to be submitted, but are welcomed as a voluntary submission of the data in a VGDS (voluntary genomic data submission).

The responsibilities of an investigator of a clinical study include all of the following EXCEPT: A. Ensures compliant IRB reviews and approves study B. Provides current and updated financial disclosure information C. Disposes of unused study medication D. Obtains informed consent

C. Disposes of unused study medication Question Feedback: The investigator is responsible for controlling the study medication during the study, but the sponsor is required to dispose of the unused medication in a well-documented way.

Drug Master File may be used for any of the following purposes EXCEPT: A. Supplemental information on the drug product or drug substance B. Supplemental information for any type of submission to the agency C. FDA approval of the Drug Master File D. Incorporation by reference of all or part of any Drug Master File's contents to support a submission when the holder has authorized the incorporation in writing

C. FDA approval of the Drug Master File Question Feedback: FDA does not approve or disapprove Drug Master Files; it only reviews them as supplemental information. FDA ordinarily neither independently reviews Drug Master Files nor approves or disapproves submissions to a drug master file.

Notice of Intent to Revoke license can be issued by CBER for the following reasons, EXCEPT: A. Unable to gain access to the manufacturing facility after reasonable efforts for an inspection B. Licensed products are no longer safe and effective for intended use C. Failure to report serious adverse event D. Manufacturer fails to conform to applicable standards to ensure product safety, potency and purity

C. Failure to report serious adverse event Question Feedback: Answers 1, 2 and 4 are reasons to issue Notice of Intent to Revoke License. Answer 3 is a postapproval reporting issue (21 CFR 606.170(b)).

During the open-label extension phase of a clinical trial for NEWDRUG, some new and different adverse events occurred that could affect final labeling. NEWDRUG's NDA was submitted six weeks ago. What is the best way to notify FDA of these adverse events? A. Medwatch form 3500A B. 100 day review C. Four-month update D. Response to FDA request for information

C. Four-month update Question Feedback: Section 505(i) requires an NDA update four months after the initial submission—entitled "safety update report" by the code—which would affect the draft label's contraindication, warnings, precautions and adverse reactions sections.

To be approved by FDA, a generic drug must be therapeutically equivalent to the branded product with the exception of: A. Dosage Form B. Route of Administration C. Inactive Ingredient(s) D. Labeling

C. Inactive Ingredient(s) Question Feedback: The law requires generic drugs approved by FDA TO have the same active ingredient(s), dosage form, strength, route of administration, labeling, and conditions for use as the branded product, and that the generic and branded drug be bioequivalent. The inactive ingredients can be different. Sec. 314.92 Drug products for which abbreviated applications may be submitted. For determining the suitability of an abbreviated new drug application, the term "same as" means identical in active ingredient(s), dosage form, strength, route of administration, and conditions of use, except that conditions of use for which approval cannot be granted because of exclusivity or an existing patent may be omitted.

The basic elements of an IRB-approved Informed Consent Form include the following EXCEPT: A. Description of the foreseeable risks of the study B. Disclosure about the alternative procedures or treatments available C. Information about the treatment group to which the patient is assigned D. Explanation of conditions for any compensation offered

C. Information about the treatment group to which the patient is assigned Question Feedback: For studies subject to FDA regulations, the Informed Consent documents should meet the requirements of 21 CFR 50.20 and contain the information required by each of the eight basic elements of 21 CFR 50.25(a), and each of the six elements of 21 CFR 50.25(b) appropriate to the study. IRBs have the final authority for ensuring the adequacy of the information in the Informed Consent Form.

FDA may refuse to file a PMA for all of the following reasons EXCEPT: A. The application does not contain all the information required under Section 515(c)(1)(A)-(G) of the FD&C Act B. The PMA contains a false statement of material fact C. Major or minor deficiencies are identified with the clinical data after substantive FDA review D. The PMA is not accompanied by a statement of either certification or disclosure as required by 21 CFR 54 Financial Disclosure by Clinical Investigators

C. Major or minor deficiencies are identified with the clinical data after substantive FDA review Question Feedback: Substantive review of the PMA submission will begin once FDA determines the submission will not be refused

In a medical device company, which of the following units has ultimate responsibility for data integrity and product quality: A. Quality Assurance B. Quality Control C. Management D. Regulatory Compliance

C. Management Question Feedback: Management has the ultimate responsibility of ensuring quality systems are effective and a quality policy is implemented and followed as intended, which ensures data integrity and product quality

Postapproval pharmacovigilance for an adverse drug experience is: A. Mandatory for both product license holder and healthcare professionals B. Voluntary for both product license holder and healthcare professionals C. Mandatory for product license holder but voluntary for healthcare professionals D. Voluntary for product license holder but mandatory for healthcare professionals

C. Mandatory for product license holder but voluntary for healthcare professionals Question Feedback: "(c)(1)(i) The applicant shall report each adverse drug experience that is both serious and unexpected whether foreign or domestic, as soon as possible but in no case later than 15 calendar days of initial receipt of the information by the applicant."(iii) The requirements of paragraphs (c)(1)(i) and (c)(1)(ii) of this section, concerning the submission of postmarketing 15-day Alert reports, shall also apply to any person other than the applicant (nonapplicant) whose name appears on the label of an approved drug product as a manufacturer, packer, or distributor." Sec. 314.80 Postmarketing reporting of adverse drug experiences.(c) Reporting requirements. The applicant shall report to FDA adverse drug experience information, as described in this section. (1)(i) Postmarketing 15-day "Alert reports." The applicant shall report each adverse drug experience that is both serious and unexpected, whether foreign or domestic, as soon as possible but in no case later than 15 calendar days of initial receipt of the information by the applicant.(ii) Postmarketing 15-day "Alert reports"—follow up. The applicant shall promptly investigate all adverse drug experiences that are the subject of these postmarketing 15-day Alert reports and shall submit follow up reports within 15 calendar days of receipt of new information or as requested by FDA. If additional information is not obtainable, records should be maintained of the unsuccessful steps taken to seek additional information. Postmarketing 15-day Alert reports and follow ups to them shall be submitted under separate cover.(iii) Submission of reports. The requirements of paragraphs (c)(1)(i) and (c)(1)(ii) of this section, concerning the submission of postmarketing 15-day Alert reports, shall also apply to any person other than the applicant (nonapplicant) whose name appears on the label of an approved drug product as a manufacturer, packer, or distributor. To avoid unnecessary duplication in the submission to FDA of reports required by paragraphs (c)(1)(i) and (c)(1)(ii) of this section, obligations of a nonapplicant may be met by submission of all reports of serious adverse drug experiences to the applicant. If a nonapplicant elects to submit adverse drug experience reports to the applicant rather than to FDA, the nonapplicant shall submit each report to the applicant within 5 calendar days of receipt of the report by the nonapplicant, and the applicant shall then comply with the requirements of this section.

The following biological products are regulated by CBER EXCEPT: A. Immunizing toxoids B. Monoclonal antibodies for in vitro use C. Monoclonal antibodies for in vivo use D. Infusion of animal sourced cells into a human

C. Monoclonal antibodies for in vivo use Question Feedback: Monoclonal antibodies for in vivo use were transferred to CDER's Office of New Drugs (OND) effective 30 June 2003.

An Investigational New Drug Application (IND) goes to the "Inactive Status" when: A. No subjects are entered into clinical trials for a period of one year B. IND is on clinical hold for six months C. No subjects are entered into clinical trials for a period of two years or the IND is on clinical hold for one year D. No subjects are entered into clinical trials for a period of one year or IND is on clinical hold for six months

C. No subjects are entered into clinical trials for a period of two years or the IND is on clinical hold for one year Question Feedback: If no subjects are entered into clinical studies for a period of two years or more under an IND, or if all investigations under an IND remain on clinical hold for one year or more, FDA may place the IND on inactive status. Sec. 312.45 Inactive status. (a) If no subjects are entered into clinical studies for a period of 2 years or more under an IND, or if all investigations under an IND remain on clinical hold for 1 year or more, the IND may be placed by FDA on inactive status. This action may be taken by FDA either on request of the sponsor or on FDA's own initiative. If FDA seeks to act on its own initiative under this section, it shall first notify the sponsor in writing of the proposed inactive status. Upon receipt of such notification, the sponsor shall have 30 days to respond as to why the IND should continue to remain active

Advertising and promotional materials are required to be submitted to FDA at the time of initial dissemination or publication for all products EXCEPT: A. Prescription Drugs B. Biologics C. Non-restricted devices and OTC drugs D. None, all products require submission of advertising and promotional material.

C. Non-restricted devices and OTC drugs Question Feedback: Non-restricted medical device and OTC drug advertising is regulated by the Federal Trade Commission (FTC) under the FTC Act.

During a clinical study, which is NOT the role of the sponsor? A. Control distribution of drugs B. Monitor studies C. Obtain informed consent D. Submit IND/Protocol to FDA if required

C. Obtain informed consent Question Feedback: It is the investigator's responsibility to obtain the informed consent.

73. The Medical Device User Fee and Modernization Act of 2002 (MDUFMA) enacted all the following EXCEPT: A. User fees for premarket reviews B. Office of Combination Products C. PDUFA renewal for five additional years D. New regulatory requirements for reprocessing single-use devices

C. PDUFA renewal for five additional years Question Feedback: PDUFA was initiated/reauthorized under FDAMA.; Also, the Prescription Drug User Fee Act would not be renewed under an act written to regulate medical devices.

For which device below does the Quality System Regulation require the same procedures for identifying the control number for each unit, lot or batch of finished devices as those mandated by the new UDI Rule? A. Surgical gloves B. X-ray machines C. Pacemakers D. Syringes

C. Pacemakers Question Feedback: According to 21 CFR 820.65,"Each manufacturer of a device that is intended for surgical implant into the body or to support or sustain life and whose failure to perform when properly used in accordance with instructions for use provided in the labeling can be reasonably expected to result in a significant injury to the user shall establish and maintain procedures for identifying with a control number each unit, lot, or batch of finished devices and where appropriate components." The Pacemaker is a Class III implantable device and subject to 21 CFR 820.65. (Sec. 820.65 Traceability- Each manufacturer of a device that is intended for surgical implant into the body or to support or sustain life and whose failure to perform when properly used in accordance with instructions for use provided in the labeling can be reasonably expected to result in a significant injury to the user shall establish and maintain procedures for identifying with a control number each unit, lot, or batch of finished devices and where appropriate components. The procedures shall facilitate corrective action. Such identification shall be documented in the DHR.)

In a company's originally approved application for drug product Y, the finished product specification for a noncompendial impurity had an acceptance criterion of 0.1 %. In a subsequent Annual Report, this noncompendial impurity's acceptance criterion was tightened to 0.08%. Now, the company wants to relax the specification back to 0.1%. What reporting category is appropriate for this change? A. Changes Being Effected (CBE) 0-days B. Changes Being Effected in 30 days (CBE-30) C. Prior Approval Supplement D. Annual Report

C. Prior Approval Supplement Question Feedback: Prior FDA approval is required for relaxing a noncompendial impurity's release specification limit. (Relaxing or deleting specifications to comply with USP is reportable in a Changes Being Effected-30 Supplement.)

When should the manufacturer of a Class III medical device expect to have an FDA Premarket Approval Inspection? A. Within an IDE application B. After IDE study Phase II C. Prior to PMA approval D. Within two years following PMA approval

C. Prior to PMA approval Question Feedback: As a condition of approval, FDA may require an inspection to ensure the manufacturing facilities, methods and controls are in compliance with Part 820 and, if applicable, to verify documents pertinent to the pending PMA

During a Class II product recall, additional complaint reports of the same product problem involved in the recall were received for products not in the date range of the product lots being recalled. What action should the regulatory professional recommend to the company? A. Discontinue the recall until they can determine the actual range of affected product B. Revise the recall scope and notify FDA within two business days about the additional reports and the revised recall scope C. Reassess the root cause analysis, traceability data and rationale for the original recall range to determine why original assumptions were incorrect and notify FDA within 10 working days of the extended recall range D. Provide FDA with a second correction and removal report

C. Reassess the root cause analysis, traceability data and rationale for the original recall range to determine why original assumptions were incorrect and notify FDA within 10 working days of the extended recall range Question Feedback: Reports regarding the extension of the recall range are required to be filed within 10 working days of receiving the additional reports. The manufacturer amends the originally filed report and does not file a new report. 21 CFR 806.10(d): If, after submitting a report under this part, a manufacturer or importer determines that the same correction or removal should be extended to additional lots or batches of the same device, the manufacturer or importer shall within 10-working days of initiating the extension of the correction or removal, amend the report by submitting an amendment citing the original report number assigned according to paragraph (c)(1) of this section, all of the information required by paragraph (c)(2), and any information required by paragraphs (c)(3) through (c)(12) of this section that is different from the information submitted in the original report. The manufacturer or importer shall also provide a statement in accordance with paragraph (c)(13) of this section for any required information that is not readily available.

A company's Phase 3 investigational drug product, available in three different tablet strengths, is a rapidly dissolving, immediate release, white, film-coated tablet. For the commercial drug product, the marketing division proposed distinguishing different strengths by using three different colors. What needs to be done to support this change in the drug product appearance? A. A bioequivalence study B. Multi-point in vitro dissolution profiles C. Release and stability testing of the proposed formulation against the specification established for white tablets D. Formulation changes are not acceptable after Phase 3 studies

C. Release and stability testing of the proposed formulation against the specification established for white tablets Question Feedback: Adding a colorant to the tablet film coat is considered a minor drug product formulation change. Release and stability data for the proposed formulation meeting a specification established for the current formulation will be sufficient. However, the company should evaluate HPLC method specificity for impurities and ensure colorants do not interfere with impurity separation

A pharmaceutical company received approval of a drug that contains a boxed warning on its labeling. What type(s) of advertisements are NOT permitted? A. Published journals and newspapers B. Radio and television C. Reminder advertisements D. Internet advertisements

C. Reminder advertisements Question Feedback: Answer 3 is correct because reminder advertising is not permitted for drugs with boxed warnings since the boxed warning must be present on all advertising. Reminder ads are not appropriate for drugs whose labeling has a "boxed warning" about certain very serious drug risks."

Good Manufacturing Practices (GMPs) are NOT applied to the chemical synthesis of an Active Pharmaceutical Ingredient (API) manufacturing process during: A. Intermediate compound drying B. Introduction of the starting material into the process C. Starting material synthesis D. API Packaging

C. Starting material synthesis Question Feedback: For synthetic processes, the introduction of the starting material into the manufacturing process is known as the point at which GMPs are applied in API manufacture. Starting materials synthesis does not have to be completed under GMPs.

A sponsor wishes to obtain permission from FDA to submit an ANDA for a drug product that varies from the Reference Listed Drug (RLD) in route of administration, dosage form or strength. What process should be used to apply for that permission from FDA? A. Citizen Petition B. Pre-NDA Meeting C. Suitability Petition D. Notice of Opportunity for Hearing

C. Suitability Petition Question Feedback: A Suitability Petition is a request for permission to submit an ANDA. Sec. 314.93 Petition to request a change from a listed drug. (b) A person who wants to submit an abbreviated new drug application for a drug product which is not identical to a listed drug in route of administration, dosage form, and strength, or in which one active ingredient is substituted for one of the active ingredients in a listed combination drug, must first obtain permission from FDA to submit such an abbreviated application.

A firm received a raw material for one of its drug products. The raw material was placed in quarantine and sampled appropriately. Sample containers should be identified so the following information can be determined: A. The manufacturer name, lot number, name of person who collected the sample and the date on which the sample was taken B. The manufacturer name, lot number, the sample attributes, name of person who collected the sample and the date on which the sample was taken C. The material name, lot number, the container from which the sample was taken, name of person who collected the sample and the date on which the sample was taken D. The material name, lot number, sample attributes and the date on which the sample was taken

C. The material name, lot number, the container from which the sample was taken, name of person who collected the sample and the date on which the sample was taken Question Feedback: Sample containers shall be identified so the following information can be determined: material name, lot number, the container from which the sample was taken, name of person who collected the sample and the date on which the sample was taken.

During a periodic visit to a clinical investigator, the study monitor should ensure all of the following EXCEPT: A. Informed Consent has been documented in subject records B. The study protocol is being followed C. The subjects are satisfied with the treatment they receive D. Changes to the protocol have been approved by the Institutional Review Board

C. The subjects are satisfied with the treatment they receive Question Feedback: Guidance for Industry—Oversight of Clinical Investigations—A Risk-Based Approach to Monitoring

Company ABC has requested Orphan Drug Designation (ODD) for its product. The product currently is in clinical trials for a rare blood disease with a prevalence of approximately 100,000 individuals. The product previously was approved for another indication for which the prevalence is approximately one million individuals. Would the company be eligible for orphan drug designation for the rare blood disease and why? A. No, ODD cannot be granted on products previously approved B. Yes, ODD can be granted because the product is approved C. Yes, ODD can be granted because it is for a different indication than the indication currently marketed D. No, ODD cannot be granted because the product is currently approved

C. Yes, ODD can be granted because it is for a different indication than the indication currently marketed Question Feedback: A sponsor may request ODD for a previously unapproved drug or a new orphan indication for an already marketed drug. In addition, a sponsor of a drug otherwise the same as an already approved orphan drug, may seek and obtain ODD for the subsequent drug for the same rare disease or condition if it can present a plausible hypothesis that its drug may be clinically superior to the first drug.

Five-year exclusivity for a chemical compound, sometimes called New Chemical Entity (NCE) exclusivity, prevents the approval of all of the following for five years EXCEPT: A. A generic application for the approved active ingredient B. A generic application for a salt of the approved active ingredient C. A generic application for an ester of the approved active ingredient D. A Section 505(b)(1) New Drug Application (NDA) for the same drug

D. A Section 505(b)(1) New Drug Application (NDA) for the same drug Question Feedback: NCE exclusivity prevents the approval of a generic application for the approved active ingredient or any salt or ester of the approved active ingredient for five years. However, five-year exclusivity does not prevent FDA from approving, or a company from submitting, a full Section 505(b)(1) NDA for the same drug. Small Business Assistance: Frequently Asked Questions for New Drug Product Exclusivity (FDA website) 1. What is new drug product exclusivity? New Drug Product Exclusivity is provided by the Federal Food, Drug, and Cosmetic Act under section 505(c)(3)(E) and 505(j)(5)(F). Exclusivity provides the holder of an approved new drug application limited protection from new competition in the marketplace for the innovation represented by its approved drug product. This limited protection precludes approval of certain 505(b)(2) applications or certain abbreviated new drug applications (ANDAs) for prescribed periods of time. Some exclusivity provisions also provide protection from competition by delaying the submission of 505(b)(2) applications and ANDAs for certain periods of time. Full new drug applications under 505(b)(1) and 505(b)(2) can receive 5 years of exclusivity for a new chemical entity drug product. A 505(b)(1), 505(b)(2) application or a supplement to a new drug application can receive 3 years of exclusivity. 21 CFR 314.108—New drug product exclusivity. (b) Submission of and effective date of approval of an abbreviated new drug application submitted under section 505(j) of the act or a 505(b)(2) application. (1) [Reserved](2) If a drug product that contains a new chemical entity was approved after September 24, 1984, in an application submitted under section 505(b) of the act, no person may submit a 505(b)(2) application or abbreviated new drug application under section 505(j) of the act for a drug product that contains the same active moiety as in the new chemical entity for a period of 5 years from the date of approval of the first approved new drug application, except that the 505(b)(2) application or abbreviated application may be submitted after 4 years if it contains a certification of patent invalidity or noninfringement described in § 314.50(i)(1)(i)(A)(4) or § 314.94(a)(12)(i)(A)(4).

In routine stability testing of an NDA drug, a firm discovers a previously unidentified impurity at the 24-month checkpoint. The firm performs a laboratory investigation and the impurity results are confirmed. The drug product has a 36-month shelf life. What should happen next? A. A full investigation into the identification and safety of the impurity should commence. B. A full investigation into the source of the impurity should commence C. CDER should be notified within 15 working days and a Class III recall should be initiated. D. A field alert report should be submitted to the FDA District Office within three working days of confirmation of the impurity.

D. A field alert report should be submitted to the FDA District Office within three working days of confirmation of the impurity. Question Feedback: A field alert report form must be submitted within three working days to the "NDA-Field Alert Report" coordinator in the firm's jurisdictional FDA District Office, who also be available to answer any questions a firm may have regarding the reports.

A sponsor intends to submit a Special Protocol Assessment (SPA) request for a clinical trial that will form the primary basis of an NDA efficacy claim. Which of the following is TRUE? A. The sponsor should submit the SPA request within 30 days after the trial's start to expedite FDA feedback B. An SPA provides an opportunity to focus on general drug development issues C. The SPA request will be handled as a request for a Type B meeting D. A sponsor can submit a revised protocol while the agency is reviewing an earlier version of the same protocol

D. A sponsor can submit a revised protocol while the agency is reviewing an earlier version of the same protocol Question Feedback: The agency can communicate with the sponsor regarding the protocol before issuing a Special Protocol Assessment letter. In such cases, the sponsor can choose to submit a revised protocol. If a sponsor submits a revised protocol, for any reason, while the agency is reviewing an earlier version of the same protocol, FDA ordinarily will not respond to the questions posed about the earlier version of the protocol and will consider the original request withdrawn. The agency will consider a request for a Special Protocol Assessment of a revised protocol to be a new request and will act on the revised protocol within 45 days

The difference between advertising and professional labeling for prescription drugs is: A. Advertising can be directed only to consumers and professional labeling can be directed only to professionals B. Advertising must be accompanied by a package insert while professional labeling must be accompanied by a brief summary C. Advertising can be directed to either consumers or professionals while professional labeling can be directed only to consumers D. Advertising must be accompanied by a brief summary and professional labeling must be accompanied by a package insert.

D. Advertising must be accompanied by a brief summary and professional labeling must be accompanied by a package insert. Question Feedback: Per 21 CFR 202.1, prescription drug advertisements include true statement of information in brief summary relating to side effects, contraindications and effectiveness.

A manufacturer changes the size and shape of a container for a nonsterile solid dosage form drug already approved by FDA. What would be the most appropriate postapproval vehicle for this potential action? A. Postapproval Supplement: Changes Being Effected - Immediate (CBE 0) B. Postapproval Supplement: Changes Being Effected in 30 days (CBE 30) C. Prior Approval Supplement (PAS) D. Annual Report

D. Annual Report Question Feedback: This type of change is considered to have minimal potential to have an adverse effect on a drug product's identity, strength, quality, purity or potency as these factors may relate to the drug product's safety or effectiveness. Therefore, an Annual Report is the most appropriate course of action to report this type of minor change. Sec. 314.70 Supplements other changes to an approved application. (d) Changes described in an annual report (minor changes). (1) Changes drug substance, drug product, production process, quality controls, equipment, or facilities that have a minimal potential to have an adverse effect on the identity, strength, quality, purity, or potency of the drug product as these factors may relate to the safety or effectiveness of the drug product must be documented by the applicant in the next annual report in accordance with 314.81(b)(2). (2) These changes include, but are not limited to: (iv) A change in the size and/or shape of a container containing the same number of dosage units for a nonsterile solid dosage form drug product, without a change from one container closure system to another

All of the following are considered raw data in a preclinical study EXCEPT: A. Final Pathology Report B. Records of quarantine and animal receipt C. Animal data entered into the animal chart D. Computer printout derived from data transferred to computer media from lab data sheets

D. Computer printout derived from data transferred to computer media from lab data sheets Question Feedback: Raw data are defined as "any laboratory worksheets, records, memorandum, notes that are the result of original observations and activities" and are necessary for the reconstruction and evaluation of the report of that study."

What is a major difference between an HDE application and a PMA application? A. Application form and content B. Labeling requirements C. Supplemental applications D. Effectiveness requirements

D. Effectiveness requirements Question Feedback: Effectiveness requirements are not included in an HDE application. Sec. 814.3 Definitions. m) HDE means a premarket approval application submitted pursuant to this subpart seeking a humanitarian device exemption from the effectiveness requirements of sections 514 and 515 of the act as authorized by section 520(m)(2) of the act. (e) PMA means any premarket approval application for a class III medical device, including all information submitted with or incorporated by reference therein. "PMA" includes a new drug application for a device under section 520(1) of the act.

Your company is considering a new drug product. It has been on the market for more than 30 years in a foreign country, but has never been approved in the US. To sell this product in the US, you may do the following immediately EXCEPT: A. Determine monograph or NDA status of the product B. Initiate clinical studies in the foreign country to support the claims since the clinical data are old and would not meet current requirements C. Determine whether this is a New Chemical Entity D. Import the product and use new labeling

D. Import the product and use new labeling Question Feedback: The importation of a drug product to be distributed in the US must meet US regulations, regardless of its approved status in another country, therefore answer 4 is correct.

While reviewing data for an upcoming New Drug Application (NDA) submission, the in-house monitor found the investigator's Curriculum Vitae (CV) has not been updated since it was submitted with the Investigational New Drug (IND) application. According to FDA guidance on Form 1572, how often should the investigator's CV updated? A. Annually B. Every two years C. Every three years D. It does not need to be updated

D. It does not need to be updated Question Feedback: FDA regulations do not require a CV or other statement of qualifications to be updated during a clinical study

A drug manufacturer creates a game-based simulation to assist diabetes patients with management of their blood glucose levels and to motivate them to adhere to their medication schedules. The game will be based on a password protected website that will be made available to patients when an FDA-approved drug is prescribed to them. How will the game most likely be regulated by FDA? A. It should be included as part of the NDA submission B. It will be regulated as a Class I medical device C. It will be regulated as an in vitro diagnostic product D. It will not be an FDA regulated product

D. It will not be an FDA regulated product Question Feedback: This type of "advertising" would fall under the category of a "help-seeking" advertisement because the product is not named, although it likely makes recommendations about actions that might be taken based on a particular symptom, i.e., low or elevated glucose levels. Unlike drug and device promotional labeling and prescription drug and restricted device advertising, disease awareness communications are not subject to the requirements of the FD&C Act and FDA regulations.

A drug clinical trial subject is involved in an automobile accident. As a result, an exploratory laparotomy is performed, that identifies a ruptured spleen. A splenectomy is performed, resulting in patient hospitalization. What, if any, reporting is required? A. The splenectomy should be reported as an adverse event B. The splenectomy and automobile accident should be reported as an adverse event. C. The hospitalization should be reported D. No expedited reporting is required and the subject can continue in the study when recovered

D. No expedited reporting is required and the subject can continue in the study when recovered Question Feedback: The splenectomy is related to the automobile accident, not the drug product being studied. Therefore, no report is required. However, the event resulted in hospitalization (meeting seriousness criteria) and would be captured and reported both within the eventual Clinical Study Report (CSR), and in an annual report summarizing serious adverse events.

A company is planning to develop a sunscreen containing an ingredient consistent with its published monograph for marketing within the US. What type of filing does the company have to submit? A. No action is required by the sponsor as it is a cosmetic B. ANDA C. 505(b)(1) D. No premarket approval is required

D. No premarket approval is required The active ingredients allowed for use in sunscreens are published in the final monograph 21 CFR 352. A product including a codified sunscreen ingredient does not require FDA premarket approval provided the full monograph conditions are met.

Your company is developing a New Chemical Entity (NCE) to treat Glioblastoma multiforme, which is the deadliest and most common form of malignant brain tumor. The compound team has designed a pivotal study protocol with a clinically meaningful and well-established primary endpoint. To increase the likelihood FDA will agree with the study design, which of the following regulatory strategies has to occur prior to initiating the pivotal study? A. Request Fast Track designation B. Request priority review C. Request approval under Subpart H, Accelerated Approval of New Drugs for Serious or Life Threatening Illness D. Request Special Protocol Assessment

D. Request Special Protocol Assessment Question Feedback: A Special Protocol Assessment applies to a Phase 3 study and must be requested prior to initiating the study, so answer 4 is correct. Fast Track designation can be requested at any time. Priority review is requested prior to filing an NDA, not prior to clinical studies. Answer 3 is not applicable to this case, as Subpart H applies to utilization of surrogate, not well-established endpoints

A company is developing an unapproved drug-device combination product in which the primary mode of action is the drug. What application type and to which center should the company submit its application for marketing approval? A. Submit a Premarket Application to CDRH B. Submit an Investigational New Drug Application to CDER C. Submit a Premarket Notification application to CDRH D. Submit a New Drug Application to CDER

D. Submit a New Drug Application to CDER Question Feedback: The primary mode of action determines the center to which a company should submit its application. Because the primary mode of action in this case is a drug, a new drug application should be submitted to CDER.

When multiple facilities are involved in a Class III device's design, assembly or processing, the PMA holder should do all of the following EXCEPT: A. Ensure the quality systems in all facilities are in compliance with 21 CFR 820 regulations, as applicable B. Include in the PMA submission a complete description of the device's manufacturing, processing, packing, storage and installation methods C. Provide written authorization to reference the Device Master File information from a contracted facility D. Submit quality system information only for the facility involved in the design of the device

D. Submit quality system information only for the facility involved in the design of the device Question Feedback: When multiple facilities are involved in device design, assembly or processing, the PMA holder should submit applicable quality system information for each facility in separate volumes, clearly identifying the facilities to which they apply.

A company is sponsoring a Phase 2 clinical study investigating a new drug for treatment of Disease X, which currently affects 190,000 people in the US. Which of the following may a regulatory professional take into consideration if senior management asks about requesting Orphan Drug Designation (ODD)? A. The new drug would not be eligible for ODD given the number of people currently affected by Disease X in the US B. The company must demonstrate Disease X is life-threatening for the new drug to be eligible for ODD C. Obtaining ODD is not possible since an IND has already been submitted D. The company must request ODD before submitting a marketing application for the new drug

D. The company must request ODD before submitting a marketing application for the new drug Question Feedback: According to 21 CFR 316.23, "A sponsor may request orphan-drug designation at any time in the drug development process prior to the submission of a marketing application for the drug product for the orphan indication."

You have modified your 510(k) cleared device with a special 510(k). In which of the following cases would you need to create a new device listing for the device? A. You have added new sizes and shapes in the product portfolio B. You have changed the material composition of the device C. You have changed the package of the device D. You have added an additional device under a different name with the same intended use and indication for use but with a minor change to its physical characteristics

D. You have added an additional device under a different name with the same intended use and indication for use but with a minor change to its physical characteristics Question Feedback: From 21 CFR 807.22(b): (b) Registration and listing updates. Owners or operators shall review and update all of their establishment registration and device listing information that is on file at FDA, documenting any changes that were not previously reported as follows: (1) Annual registration for each fiscal year is required for all establishments. Annual registration shall take place during the period beginning on October 1 and ending on December 31 of each fiscal year; (2) Updates to the registration information as described in 807.25(b) shall be made within 30 days of any change to such information; (3) Every fiscal year, during the period beginning on October 1 and ending on December 31, owners or operators shall review and update all of their device listing information that is on file at FDA, reporting any changes or deletions to listings and any new listings that were not previously reported. The accuracy of all information on file must be confirmed each year regardless of whether any changes were made to the owner or operator's list of devices; and 4) Changes to listing information may also be made at other times, such as when a device is introduced into commercial distribution, when a change is made to a previously-listed device, or when a previously-listed device is removed from commercial distribution.

. Your company is the initial importer of a medical device. Which of the following must be true? A. You must maintain quality assurance files B. You share responsibility for submission with the other distributors C. You must report device malfunctions in an Annual Report D. You must register your company's establishment with FDA

D. You must register your company's establishment with FDA Question Feedback: 21 CFR 807.20(a)(4)—Acts as an initial importer as defined in § 807.3(g), except that initial importers may fulfill their listing obligation for any device for which they did not initiate or develop the specifications for the device or repackage or relabel the device by submitting the name and address of the manufacturer. Initial importers shall also be prepared to submit, when requested by FDA, the proprietary name, if any, and the common or usual name of each device for which they are the initial importer. (Amendment published at 77 FR 45941 Aug 2, 2012.)