Pharmaceuticals

What are the primary sources for cGMP?

21 CFR 211 and ICH Q7

Withdrawal of an approved application?

21 CFR 314. 150, an approved application may be withdrawn voluntarily by the sponsor or involuntarily by the FDA. Voluntary: sponsor is no longer marketing the drug. FDA will notify all generics that NDA is being pulled, so they can no longer manufacture with that NDA referenced. Involuntary: safety in question, untrue statements of material fact.

What are Drug Master Files?

21 CFR 314.420: Voluntary submission to FDA intended to protect the confidentiality of the information submitted. A DMF provides FDA with details regarding proprietary information such as the chemistry, manufacturing and controls for drug substances, drug products, excipients, or packaging materials. Type I DMFs have been eliminated by FDA; Four types of DMFs Type II: Chemistry, manufacturer and control information for drug substances, intermediates and materials used in their preparation or similar information for drug products. Fee with GDUFA that relate specifically to APIs (b)Type III: component, composition, controls for release and intended uses of packaging materials (c) Type IV: excipients, controls, flavors, essences or materials used in their preparation (d)Type V: FDA-accepted reference information (2) DMF can be submitted in hard copy (duplicate) using either the CTD or traditional format or eCTD. (3) Contains: statement of commitment (all information is accurate and any changes will be submitted to FDA), list of firms authorized to reference it in other regulatory applications; DMF holder can restrict use (will need to be stated in the DMF with a list of firms their product and NDA # to use and a copy of DMF is sent to each firm (4) Used for DMF: support an IND/NDA/ANDA; amendment or supplement; another DMF. (5)DMFs are not approved by FDA, they are ONLY reviewed (6)Maintenance: annual reports are required on the anniversary date of original submission (1)Include update of firms, list of any changes that have taken place and have been reported as an amendment since the last annual report. (7) DMF holder can close a DMF by submitting a request to the Drug Master File staff stating the reason for the closure. Include statement that holders obligations are fulfilled. The agency may close a DMF that has not submitted their annual report/amendments- holder will be notified of closure of DMF and will have 90 days to update DMF to prevent closure (8)Changes to DMF affecting approved applications amendment as PAS, CBE-30, CBE, annual report- sponsors responsibility to submit with their NDA and will reference the DMF amendment.

Explain the formal meeting process with FDA

"Sponsor Actions: meeting request, meeting information package, preparation for meetings (contingency planning), Meeting conduct, Meeting Follow-up (issuance of minutes) (*never add new mater during the meeting). FDA Actions: Review meeting request & notify sponsor of outcome (grant denial), pre-meeting/internal meeting in advance of sponsor meeting, issue preliminary answers to questions to the sponsor 24-48 hours before the meeting, Issue official meeting minutes issued within 30 days"

What are examples of drug development tools?

"animal modles, ii. biological markers: a characteristic that is objectively measured and evaluated as an indicator of normal biologic processes, pathogenic processes or biological responses to a therapeutic intervention. Thus, a change to a biomarker following treatment with the drug product can predict or identify safety problems related to the drug or reveal a pharmacological activity expected to predict an eventual benefit from treatment. They may reduce uncertainty in drug development and evaluation by producing quantitative predications about drug performance. iii. clinical outcome assessments: (PRO: patient reported outcome) 1) PRO: an instrument that captures the outcomes of drug intervention during a clinical trial from the patient's perspective (change in pain or depression from before the therapy compared to over time after therapy). This is a questionnaire that is self-administered by the patient or through interview but other parties that report on patient perspectives. The questionnaires measure characteristics or constructs that should have a sound theoretical basis and be relevant to the patient group in which they are to be used. Must be thoroughly tested for its use; reports from validated PRO instruments can be used to support drug approval and claims in approved medical product labeling. iv. Clinician rating scales/caregiver rating scales

Drug development tools

"i. animal models, ii. biological markers: a characteristic that is objectively measured and evaluated as an indicator of normal biologic processes, pathogenic processes or biological responses to a therapeutic intervention. Thus, a change to a biomarker following treatment with the drug product can predict or identify safety problems related to the drug or reveal a pharmacological activity expected to predict an eventual benefit from treatment. They may reduce uncertainty in drug development and evaluation by producing quantitative predications about drug performance. iii. clinical outcome assessments: (PRO: patient reported outcome); 1. PRO: an instrument that captures the outcomes of drug intervention during a clinical trial from the patient's perspective (change in pain or depression from before the therapy compared to over time after therapy). This is a questionnaire that is self-administered by the patient or through interview but other parties that report on patient perspectives. The questionnaires measure characteristics or constructs that should have a sound theoretical basis and be relevant to the patient group in which they are to be used. Must be thoroughly tested for its use; reports from validated PRO instruments can be used to support drug approval and claims in approved medical product labeling. iv. Clinician rating scales/caregiver rating scales"

What is the intial review process when FDA receives an NDA?

(1)Once received, FDA has 60 days to determine whether the application is sufficiently complete to allow for a substantive review. If it is complete it will be filed on day 60, if not FDA can "refuse to file" (RTF) and will issue a formal RTF letter by Day 60 that will proved the reasons for the decision. FDA can also RTF sections of the NDA. If an applicant strongly disagrees with FDA's decision to RTF an application, the applicant has 30 days to request a meeting with FDA - following the meeting then the applicant can request that the agency file the application "over protest". The date of filing for "over protest" will be 60 days from the date the applicant requested the meeting. (2)For applications that are file: FDA performs an "initial filing review" by day 60 to identify filing review issues which are substantive deficiencies or concerns that may have significant impact on FDA's ability to review or approve the application. (3) Then applicant will receive the day 74 letter (mandated by PDUFA). This states the date FDA received the application (date the review clock begins); provides the review time line and includes an action date, when FDA will provide a decision on the application as well as dates when the applicant can expect or receive feedback from the review division on proposed labeling and Postmarketing requirements/commitments; also identifies the review classification granted by FDA. (under PDUFA V "program" will also state whether the division is considering convening an advisory committee meeting; (4)During the review FDA may ask the applicant for additional information "solicited information" or the applicant may submit additional information on its own initiative "unsolicited information". If the new information constitutes an amendment FDA may determine that an extension of the review PDUFA action date is needed to review the information. Only 1 three month extension can be given per review cycle. For solicited information that requires an amendment, FDA will also provide a new timeline for feedback on proposed labeling and postmarketing requirements or commitments.

what are the 4 elements of individual case safety reports?

(postmarketing) 1)an identifiable patient 2) and identifiable reporter 3) a suspected drug or biologicals product 4)an adverse experience or fatal outcome believed to be due to the suspect drug or product.

What is a serious adverse drug experience?

(postmarketing) any adverse drug experience occurring at any dose that results in any of the following outcomes: death, a life threatening adverse drug experience, inpatient hospitalization or prolongation of existing hospitalization, a persistent or significant disability/incapacity or congenital anomaly/birth defect. Important medical events that may not result in death, be life-threatening or require hospitalization may be considered a serious adverse drug experience when base on appropriate medical judgment, they may jeopardize the patient or subject and may require medical or surgical intervention to prevent one of the outcomes listed in this definition.

What is a life threatening adverse drug experience?

(postmarketing) any adverse drug experience that places the patient, in the view of the initial reporter, at immediate risk for death from the adverse drug experience as it occurred

What is an adverse drug experience?

(postmarketing) any adverse event associated with the use of a drug, whether or not considered drug related, including the following: 1)an adverse event occurring in the course of the use of a drug product in professional practice; 2) and adverse event occurring from drug overdose whether accidental or intentional; 3)an adverse event occurring from drug abuse; 4) an adverse event occurring from drug withdrawal; 5)any failure of expected pharmacologic action.

what is an unexpected adverse drug experience?

(postmarketing) any drug experience that is not listed in the current labeling for the drug product. If listed but occurs in great severity then its unexpected.

Reporting ADEs?

(postmarketing) non-sponsor who is not reporting ADEs to FDA directly has to report ADEs to the sponsor within 5 days. All serious and unexpected ADEs need to be reported to the FDA within 15 calendar days of initials receipt (all others are reported in PSURs)

What is a Suitabiliy Petition?

(specific type of citizen's petition): formal request to FDA to submit an ANDA with a change in: Route of administration, Dosage form, Strength, Active ingredient in same pharmacological class in a combination product. PREA: is applicable for all changes except strength. The suitability petition will be denied if pediatric studies are required. FDA has 90 days to approve or deny the petition; This can get approval as long as FDA does not require clinical investigations.; The requirement to conduct PREA studies triggers the requirement to deny a suitability petition.

How long should ADE files be maintained?

10 years and includes all raw data and any correspondence relating to the ADE

What are the requirements for IND safety reporting?

15 day report: serious unexpect adverse event, 7 day report: fatal or life-threatening event; follow up report: any new information; is there an equivalent to PM PSUR?

What is Orphan drug status?

21 CFR part 316: Congressional Action: Orphan drug act amendment to Federal Food, Drug, and Cosmetic Act: 01/04/83, Primarily to drugs and biologics, Designated office of orphan products, Same requirements as pharmaceuticals for approval; Definition: affecting less than 200,00 persons in the US or affecting more than 200,000 persons in the US but for which there is no reasonable expectation that the cost of developing and making available in the US a drug for such disease or condition will be recovered from sales (companies don't do this because they have to turn over financial information sales records, etc to FDA. Benefits:7 years of market exclusivity to the 1st sponsor to obtain approval for specified indications (example can have multiple indications where only 1 is Orphan status), Grants tax credits for clinical research undertaken by sponsor to generate data for marketing approval administered by IRS: up to 50% of expenses for clinical trials, Formal protocol assistance when requested by sponsors of orphan drugs from CDER or CBER, Research grants, through the OPD available for clinical trials of orphan drugs. (phase 1- 200k/year and phase 2/3 300-400k/year) Designation request: May be requested for: Previously unapproved drug. New orphan indication for an already marketed drug. A previously approved orphan drug indication if shown to be clinically superior to first drug. Required to submit annual report until approval, No time limits/review time for FDA- normally completed within 60-90 review, CAN BE REVOKED, Waives NDA/BLA application fee, requirements of PREA, greater safety profile, greater efficacy.

Patent submissions to the orange book? What types of patents can you have?

3542a submitted with application, 3542 submitted upon or after approval

What is rolling review?

: to qualify for rolling review, fast track designation must be granted . Sponsor should provide a schedule for submissions of the sections of the NDA. PDUFA goal date is determined when the last section of the NDA has been submitted- payment is due when the first section is submitted

What are evidenary hearings?

A formal evidentiary hearing is the administrative equivalent of a civil court hearing with comparable preparation and procedural controls. They occur when specifically provided by law, when mandated by congress or when ordered by FDA commissioner in order to discuss public health concerns for a product or review proposed guidances, such as Risk Evaluation and mitigation strategies (REMS).

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?

Adding a colorant to the tablet film coat is considered a minor change in the drug product formulation. Release and stability data for the proposed formulation meeting a specification established for the current formulation will be sufficient. However, the company should evaluate specificity of HPLC method for impurities and make sure colorants do not interfere with the separation of impurities.

When would you have a type C meeting?

All other development meetings (can also be granted as writing response only; FDA scheduling within 21 days, meeting within 75 days and briefing materials needed 1 month before)

What are the requirements of annual reports?

Annual Reports: Include: distribution data, labeling, CMC, Nonclinical, Clinical, PMR/PMC (Postmarketing requirements/commitments), other PMC, Log (optional): Summary: (21 CFR 314.81(b)(2)(i): summary of significant new information that might affect the drug products safety, effectiveness or labeling and a description of actions the sponsor has taken to intends to take as a result of this new information; indication whether labeling supplements for pediatric use have been submitted and whether new studies in the pediatric population have been initiated to support appropriate labeling for the pediatric population. Distribution Data (21 CFR 314.81(b)(2)(ii): Distribution data for the commercial drug product, including the national drug code number and the total number of dosage units of each strength or potency; quantities distributed for domestic and foreign use. Labeling (21 CFR 314.81(b)(2)(iii): Current professional labeling, patient brochures or package inserts and representative samples of the package labels; package insert or professional labeling including all text, tables and figures in electronic format; summary of any changes in the labeling that have been made since the last report, listed by date in the order in which they were implemented or if no changes, a statement of that fact. Chemistry, Manufacturing and Controls (21 CFR 314.81(b)(2)(iv): CMC changes: reports of experiences, investigations, studies or test involving physicochemical or any other properties if they affect the drug product's safety or effectiveness; full description of CMC changes not requiring supplemental application; Updated stability data obtained during the reporting period; List of outstanding regulatory business. Non-clinical laboratory studies (21 CFR 314.81(b)(2)(v): Copies of unpublished reports and summaries of published reports of new toxicological findings in animal studies and in vitro studies conducted by the sponsor of found in the public domain. Clinical Data (21 CFR 314.81(b)(2)(vi): Published clinical trials or abstracts of the drug, including clinical trials on safety and effectiveness; clinical trials on new uses; biopharmaceutics, pharmacology studies; and reports of clinical experience related to safety, conducted by the sponsor of found in the public domain; Summaries of complete unpublished clinical trials or prepublication manuscripts; Analysis of available safety and efficacy data in the pediatric population and changes in labeling based on this information. Status Reports of postmarketing study commitments (21 CFR 314.81(b)(2)(vii): Status report on each post marketing requirement/commitment concerning clinical safety, clinical efficacy, clinical pharmacology and nonclinical toxicology

What is the required content for the NDA?

Application forms: 356(h) (application to market a new drug), 3397 (user fee cover sheet), 3331 (new drug application field report) Index; Summary; Technical sections (at least 5 or 6): Chemistry, manufacturing, and controls (product quality): describe the composition, manufacturer and specifications of both the drug substance and the drug product as well as all the manufacturing controls and stability data; Nonclinical pharmacology and toxicology: any animal and in vitro drug studies that help to define the drug's pharmacologic properties and address toxicity related to its administration; Human pharmacokinetics and bioavailability; Microbiology, Clinical data: description of all clinical investigations completed in support of the drug's efficacy and safety, as well as the study protocols and copies of case reports forms for each patient who died during a clinical study or did not complete a study because of an adverse event regardless of the incident's relationship to the study drug, Statistical, Pediatric use; Case report tabulations and patient data; Case report forms; Financial disclosures/certification; Labeling: copies of labeling (including package insert, carton, and container labels and Medication Guide) should be provided in the application. Labeling must be submitted electronically in a formal that the agency can review and process (structured product labeling (SPL) format with an extensible markup language (XML) backbone.; Drug sample

What are some postmarketing requirements and commitments?

Approval letter will stipulate and postmarketing requirements/commitments. (1) Postmarketing requirement: study (observational epidemiological study, animal study or laboratory experiment) or clinical trial that the applicant must conduct after the application is approved. (2) Postmarketing commitment: written commitment by the applicant to FDA to provide additional information after approval of the application. 506B- reportable postmarketing commitments require annual status reports to be submitted by the applicant.

Phase 2 clinlca trials are being planned for a novel cancer drug. All of the following are appropraite factoring in this phase of the study, EXCEPT: a)Enrollment of cancer patient patients, b)Enrollment of healthy subjects, c)Study of one or more indications, d) Collection of safety data

B) enrollment of health subjects

A drug company's phase 3 trials will be concluding in six months. Members of the statistics team have questions pertaining to the pooling of studies for the statistical analysis in eCTD Module 2. As the regulatory professional, what is the best course of action: A)Submit a meeting request to FDA for a type A meeting. B) submit a meeting request to FDA for a type B meeting. C) submit a meeting request to FDA for a type C meeting. D) Submit a SPA to review the statistical analysis plan.

B, submit a meeting request to FDA for a type B meeting.

An investigation New Drug Application (NDA) 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 clincal trials for a period of two years of the IND is on clinical hold for one year. D) No subjects are entered into clinical trails for a period of one yar or IND is on clinical hold for 6 months.

C) * FDA or Sponsor can inactivate the IND

Your company is planning to submit an NDA to CDER. It was pulled together quickly and you are concerned it may not be complete. FDA's initial filing decision could be a refuse to file (RTF) for all of the following reasons EXCEPT: A) data tabulations (line listings or graphic displays cannot be interpreted. B) clear omission of required sections. C) an analysis was incorrectly carried out. D) technically definicent electronic submission

C, an analysis was incorrectly carried out

You receive an assignment to obtain a Special protocl assignment for a phase 3 clinical trial of an investigational anti-TNF biologic for inflammartory bowel disease. You advise the clinical team and senior management as follows: A) submit a request to FDA for a SPA as an amendment to the IND after the clinical trial has started. B) it is not possible to request a SPA for this clinical trial since it is not a phase 2 clinical trial, stability trial or cacinogenicity trial. C)submit a request to FDA for a SPAas a separate IND amendment at least 90 days before the clinical trial is scheduled to being. D) submit a request to FDA for a SPA as an amendeing to the IND and wait 45 days; if FDA does not raise objections, the SPA status is automatically granted.

C: submit a request to FDA for a SPAas a separate IND amendment at least 90 days before the clinical trial is scheduled to being.

What kind of submission would be used when a change in, addition or deletion of a desiccant (absorbant)?

CBE-0, may be distributed immediately following submission

what kind of submission would be used when adding or strengthening a contraindication, warning, precaution or adverse reaction?

CBE-0, may be distributed immediately following submission

What kind of submission would be used when changes are made in the size or shape of a container for a sterile drug?

CBE-30, may be distributed 30 days after submission if the sponsor is not informed otherwise by the FDA

Some cGMP information:

CGMPs for manufacturing, processing, packing or holding of drugs and for finished pharmaceuticals (21 CFR 210/211) (1) Concepts: building quality into the drug by using suitable equipment and employing appropriately qualified and trained personnel, establishing adequate written procedures and controls designed to ensure manufacturing processes are valid, establishing a system of in process material testing and final drug tests and ensuring stability of drugs for their intended period of use. (2) If sponsor is not compliant with 210/211 it renders the drug adulterated (3) Valid and applicable to API manufacturing (b) All drugs are to be manufactured in conformance with CGMPs- this act makes no distinction between an API and finished pharmaceutical.

What are comparabilty studies?

Comparability Studies: Submitted as a prior approval supplement or in an original application; Request to reduce the reporting category for a specified change includes: Tests, validation studies, and acceptance criteria to demonstrate absence of adverse effect. After approval of a comparability protocol, submit the results of the executed protocol per the agreed upon reporting category. Allows faster implementation for planned changes; *changing manufacturing sites is hard to use a comparability protocol.

what does the IND contain?

Cover letter, Form 1571,1572,3674, table of contents, introductory statement and general investigational plan, CMC information, Pharmacology Toxicology Information, Investigator's Brochure, Clinical Protocol(s), Summary of previous human experience with investigational new drug, additional information, if applicable (drug dependence, abuse potential, pediatric studies, etc.), other relevant information, if applicable or if request by FDA

A 505(b)(2) NDA is not an appropriate regulatory submission for the approval to market a: A) New chemical entity when FDA relies for approval on data not developed by the applicant. B) different route of administration for an approved product. C) Combination of two active ingredients that have been approved individually. D) New chemical entity when the sponsor has a right of reference to all applicable published studies.

D New chemical entity when the sponsor has a right of reference to all applicable published studies.

A company is planning to develop a sunscreen with 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)(2) D) No premarket approval is required

D, no premarket approval is required

A sponsor's drug development program has come to a standstill and is need of a meeting with FDA. The company decides to schedule a meeting through an IND amendment. Within how many days of FDA receipt should the meeting be schedule for? A) 180 B)75 C) 60 D)30

D: 30

What does NDC mean?

Designed to provide drugs in the US with a specific number that describes the product; NDC is limited to 10 digits (*11 now for billing); The first segment of the NDA is assigned by the FDA and identifies the vendor (or labeler) involved with the drugs manufacturer, packaging or distribution. The second segment conveys the product codes and comprises the entity, strength, dosage form and formulation. The third segment or package code indicates the package forms and sizes. The second and third segments of a given product's code are assigned by the manufacturer.

What is a DSUR?

Development safety update report (DSUR), Intended to be a common standard across ICH regions for pediatric reporting on investigational drug safety (including marketed drugs under going further study), Uses the "Development International Birth Date" (DIBD)

What are the requirements for Imports?

Drugs coming into US required to comply with 21 CFR 314.410. They must be the subject to an approved NDA or ANDA or an active IND (21 CFR 312.110) to be imported into the US- maybe imported if in compliance with the labeling exception (21 CFR201.122) and the drug substance is intended for further manufacturing, packaging or other processing operations. & import for export materials; companies must also file entry notices and entry bonds to customs at time of inspection. Foreign drug manufacturers/product must have a US agent and are required to register with FDA

Fast Track designation

FDA guidance June 2013 *; Usually utilized in the development of oncology and antiviral drugs; Purpose: Facilitate development and expedite review of new drugs that Intend to treat broad range of serious diseases, Potential to address an unmet medical need; Submission: Original IND or any time after original IND submission but prior to marketing approval, Should ordinary occur no later than pre-NDA conference, Submit request in writing to FDA, FDA has 60 days to respond; Noteworthy: Applies to a specific indication, Designation can be revoked/declassified; Benefits: Expedite development and review process, More frequent meetings, Rolling submission allows for early submission of complete sections of the application, Priority review designation with FDA's review goal of 6 months, Accelerated approval that allows for earlier approval of qualitied drugs base on surrogate endpoint, Can be revoked if product/indication is no longer showing potentially effective to treat disease during development lifecycle

What are ADE reports?

FDA has the authority to withdraw an application (NDA or ANDA) if a sponsor does not meet the reporting requirements for adverse drug experience (ADEs) reports, field events, annual reports and advertising and labeling as listed in 21 CFR 314.80 and 314. 81 within required timeframes (1) Field Events: Sponsor is required to report any of the following occurrence to the FDA within 3 working days of becoming aware of the event: Incidents causing the drug product or its labeling to be mistaken for, or applied to, another article; Any bacteriological contamination; any significant chemical physical or other change; or deterioration in the distributed drug product or any fail of one or more distributed drug product; or any failure of one or more distributed batches of the drug product to meet the specifications established for it in the application. (b)Can call FDA or email but followed by a written field alert report. Two hard copies of the report are required and the report and its mailing cover must be plainly marked "NDA-Field Alert Report" (2) Obtain ADE information from marketing experience (healthcare providers, patients, competitors); scientific literature (peer review and unpeered reviewed); unpublished reports; postmarketing clinical investigations; postmarketing epidemiological surveillance studies= must maintain all ADE reports for a period of 10 years, including raw data and correspondence. (3) If a non-sponsor elects to submit each report to the sponsor rather than the FDA, the non-sponsor shall submit each report to the sponsor within 5 calendar days of receipt and then the sponsor is required to submit these to the FDA. (4) 15 day alert reports/periodic reports

What is FDA's review process when the initial NDA has been review and no RTF was issued?

FDA review process: (A) When the application is validated and received it is routed to the regulatory project manager (RPM). The RMP will ask supervisory team leaders from appropriate disciplines to assign reviewers. The first review task is to determine from each specific discipline whether the application is fileable. Review team is made up of clinical, pharmacology and toxicology, chemistry, clinical pharmacology, etc. if clarification is needed the specialist can communicate to the sponsor through an information request (IR) or advice letter (AD) these are handled via email, telephone or direct mail. The RPM facilitates these communications. (B) DR letters can be issued "discipline review" after each discipline reviewed their section. They are used sparingly (C) For some applications outside experts are needed.(D) FDA then determines whether any bioresearch monitoring (BIMO) or current GMPs inspections are required prior to approval. (i) Preapproval inspection: FDA can inspect manufacturing facilities (CGMP inspection) and/or sites where the drug was tested in nonclinical or clinical studies (BIMO inspections). They are likely to occur: (a)NMEs or original BLAs (b) Priority reviews (c) The first application filed by an applicant (d) For-cause inspections (ie. one clinical trial site had a significantly better trial outcome than other sites) (e) Original or supplemental applications, if the cGMP status is unknown (ie. more than 2 years since the domestic facility was last inspected, or the establishment is new and has yet to be inspected by FDA or another global regulated authority. (E) FDA will then make a determination whether postmarketing requirements or commitments are necessary. If yes, this is communicated to the applicant to discuss and agree on specific studies. (F) FDA also review the labeling in parallel to the step above. FDA makes sure that the labeling reflects the product's safety and efficacy and allows physicians, healthcare providers and consumers to understand if the drug outweighs the risk. (G) Finally FDA will decide if they are ready to take action on the application. If it's a new molecular entity or an original BLA the office director must sign, all others the division director can sign. (H) FDA decision on an application: (1)Approval letters: issued when FDA has determined that the drug is safe and effective- can be acceptably manufactured and is appropriately labeled: this is the date you can start to market the drug for sale. (2)Complete response: lists all deficiencies identified by FDA and identifies the steps the applicant should take to address these deficiencies in a future submission before the application can be approved.

What is the timeline for the NDA review process?

Filing review is 1-2 months, Day 0 is the day FDA receives the NDA, Filing day + 30 complete application filed, Day 60 filing decision or RTF, Day 74 communicate filing review issues, Mid-cycle review meeting : 3 months and 5 months post receipt; Mid cycle communication 3 months and 5 months post receipt; Late cycle meeting 3 months or 2 months prior to action; Complete inspections: 2 months prior to action; between month 8-10 (roughly)PDUFA action letter

What is accelerated approval?

For serious or life threatening illnesses (21 CFR 314.500-314.460 [subpart H]) Purpose: Facilitate development and expedite review of new drugs that will Treat serious or life-threatening conditions, Provide meaningful therapeutic benefit over existing thereapies, Surrogate endpoint reasonably likely to predict clinical benefit; Criteria: Same as for fast track: demonstrates potential to address unmet medical need, *surrogate end points reasonably likely to predict a clinical benefits other than survival. Approval can be based on: Surrogate endpoint or an effect on clinical endpoint other than survival or irreversible morbidity, Restricted use or distribution (ie certain facility or physician with special training, performance of special medical procedure ); There is no formal process, sponsor can request upon submission of NDA; Requires post-approval study to demonstrate clinical benefit: can remove indication after approval if not demonstrating clinical benefit

What form is required when submitting promotional material? And when is it require to be submitted?

Form 2253 are required with each submission as well as a copy of the piece and PI/med guide (if applicable). Needs to be submitted at dissemination; For accelerated approval products promotional, advertisements etc. needs to be submitted 120 days; and after approval submit at least 30 days before dissemination

What is a 505(b)(2) NDA?

Full NDA but relies on data not owned by applicant, bridging data submitted to support changes, relies on data collected by another sponsor for some aspect of safety or efficacy for which there is not right of reference (ie. published literature); Reference listed drugs are listed in the orange book; Changes can include: Dosage form, strength, formulation, route of administration, dosing regimen, or indication; change in active ingredient; A new combination product where the active ingredients have been previously approved; Change to an active ingredient; Change from RX to OTC.

What is a 505(b)(1)?

Full tradition NDA, full reports of safety and efficacy, typically most substantial data package, this si the foundation for subsequent regulatory filiings

What is the advisory committee meeting?

Held by FDA to obtain recommendations and advice from subject matter experts on the safety and efficacy foods, drugs, biologics and medical devices. Comprised of independent experts and public representatives. Most commonly they provide medical expertise on product approvals, labeling conditions, scientific issues and research projects. Required for all new molecular chemical entities or provide a written explanation as to why one is not required.

What are the IND principles?

IND definition: an exemption from the law prohibiting unapproved drugs in interstate commerce. The IND is the process under which human trials of investigational drugs are conducted in the US. The IND phase of drug devleopment is a real partnership between sponsor and FDA. Goals of this process are: prompting early termination of a development program for an unsafe or ineffective drug, ensuring adequate study design, identifying critical path opportunities, increasing the likelihood of a successful first-cycle action for drugs that are safe and effective

What is the process of establishment registration?

Manufacturing facility must be registered before the marketing application can be approved; All drug establishments (not exempt under section 510(g) and subpart B of part 207, engage in manufacture, preparation, propagation, compounding, or processing of a drug or drugs shall register and submit a list of every drug in commercial distribution within 5 days after beginning to manufacture commercial products or within 5 days of submitting a marketing application; Foreign companies must comply as well.

What are the modules of the CTD?

Module 1: regional administrative information, Module 2: Summary of Quality, Non-clinical overview, clinical overview, non-clinical summaries, clinical summaries; Module 3: Quality, Module 4: Non-clinical study reports, Module 5: clinical study reports

Do phase 1 pharmacokinetic studies require financial disclosure forms?

No, they are not covered studies.

OTC approval through NDA?

Premarket approval, may require user fee if new clinical studies required, confidential filing, potential marketing exclusivity if new clinical studies required, drug product specific, mandated FDA review times, FDA approval of brand name required, FDA pre-approval required for moderate or major changes, and minor changes, may be required to support safety and efficacy label comprehension, label must conform to drug facts label requirements, content of labeling to be developed and approved by FDA base on the results of: clinical studies, label comprehension studies, self-selection studies, actual use studies

What are the different types of product recalls? And what is the process?

Product Recall: (1)Class I: when there is a reasonable probability that the use of or exposure to a suspected product will cause serious adverse event health consequences or death (2) Class II: when the use of or exposure to a suspected product may cause temporary or medically reversible adverse health consequences, or where the probability of serious adverse health consequences is remote (3) Class III: when use of or exposure to a suspected product is not likely to cause adverse health consequences but the product violates FDA labeling or manufacturing laws. (b)Process of recall: depth of recall (level of distribution chain to which the recall is to be extended- consumer level, retail level, wholesale); public warnings to alert affected parties in urgent situations; effectiveness checks to ensure that all affected parties have received the recall notification and have taken appropriate action- also, possible withdrawal from market (where sponsor removes product due to minor violation, medical device safety alert: issued in situations where a medical device may present an unreasonable risk of substantial harm

What is the difference between a protocol amendment and an information amendment?

Protocol amendment: New protocols, Changes in protocols, New investigator, Information amendment: New information- study reports (ie. clinical, clinical pharmacology, nonclinical, toxicology, chemistry), Discontinuance of a clinical investigation

What does REMS stand for and what is it?

REMS: Risk Evaluation and Mitigation Strategy: see REMS guidance (1) Sponsors can voluntary submits a REMS or FDA can request one (sponsor must submit within 120 days of FDA notification); can happen at any time during the products lifecycle (pre and post approval) (2)Helps determine if the drugs benefits outweigh the risks (3)Must include the following: (1)Timetable for the submission of strategy by 18 months, 3 years and 7 years after REMS is approved by FDA (2)A thorough explanation of the rationale for and supporting information about the content of the proposed REMS, as well as a time table by which the elements will be implemented. (3) May also include one or more of the following: (a) Medication guide (b) Patient package insert (c)Communication plan to healthcare professionals: and explanation of the strategy being employed to ensure that the benefits of the drug outweigh the risks (d)Elements to assure safe use (ETASU): may be required if a drug has been shown to be effective but is associated with a serious adverse event. The drug could only be approved with elements of the REMS to mitigate the specific serious risked listed on the product's labeling (ie a system or process to ensure that certain laboratory test result outcomes are obtained before a drug may be dispensed) (4)Applicants and FDA can proposed modifications. Applicant has 120 days to respond if requested by agency and agency has 180 days to act on the request and 60 days for minor modifications or modifications based on safety label changes.

what kind of submission would be used when there are changes based on postmarketing study results, including new indications and usage

Require a Prior Approval Supplement, 4-6 months before distribution

What kind of submission would be used when there is a a change in qualitative or quantiative formualtion? And what is the time frame?

Require a Prior Approval Supplement, 4-6 months before distribution

What is the content of an IND annual report?

Report of the progress of the investigation that includes: Individual study information, Summary information, General investigation plan for upcoming year, Revisions to the investigator brochure, Phase 1 study modifications not previously reported, Significant foreign marketing developments, Log of outstanding business (optional), important actions; Requirement may be fulfilled by submission of a DSUR: Development safety update report (DSUR), Intended to be a common standard across ICH regions for pediatric reporting on investigational drug safety (including marketed drugs under going further study), Uses the "Development International Birth Date" (DIBD)

What are the requirements for Postmarket Safety Reports?

Required to review ADE information obtained from all potential sources (foreign and domestic) including: Marketing experience, Scientific literature (peer-reviewed and non-peer reviewed), Unpublished reports, Postmarketing clinical investigations, Postmarketing epidemiological/surveillance studies; 15 day Alert Reports (serious and unexpected) ,Periodic Reporting (quarterly first 3 years (required to be filed within 30 days), annually after) (1) Types of reports: PADER: Periodic Adverse Drug Experience Report, PSUR: Periodic Safety Update Report, PBRER: Periodic Benefit-Risk Evaluation Report (new ICH format) (2) Regulations for periodic reporting: divided into 4 sections with clearly marked tabs. Section 1: narrative summary and analysis; & analysis for 15 day reports; Section 2: narrative discussion of actions taken (includes labeling changes and studies initiated since last periodic report); Section 3: index line listing of Form 3500A; Section 4 all form 3500As. Need a waiver to submit information in PSUR format or PBRER format.

What are the reporting requiremnts for clinical adverse events?

Sponsor must submit a written IND safety report if any experience associated with the use of the drug that is both serious and unexpected or any findings from tests in the laboratory animals that suggests a significant risk for human subjects, include reports of mutagenicity, teratogenicity or carcinogenicity. 15 day report: findings from clinical or epidemiological studies that suggest a significant risk to study participants; serious suspected adverse reactions that occur at a rate high than expected; serious adverse events from bioavailability studies and bioequivalence studies conducted without an IND. For clinical studies: an adverse experience or fatal outcome need not be submitted to FDA unless the applicant concludes there is a reasonable possibility that product caused the adverse experience or fatal outcome.; Each written notification must be submitted on a 3500A MedWatch Form or in narrative format (foreign events may be submitted either on a form3500A or if preferred a CIOMS (council for international organizations of medical sciences). *reports from animal or epidemiological should be submitted in narrative format. All reports should be labeled "IND safety Report"; The sponsor is required to notify FDA by phone or fax of any unexpected fatal or life-threatening experience associated with the use of the drug as soon as possible but not later than 7 calendar days. ; The sponsor must provide follow up information for each IND safety report submitted as soon as all available information has been gathered. If upon further investigation sponsor established that it is now reportable (when it previously wasn't) sponsor has 15 calendar days to submit to FDA; Bioavailability (BA) and Bioequivalence (BE) studies conducted without an IND, the person conducting the study (including CROs) is required to notify FDA of any serious adverse event within 15 days of occurrence, and if fatal or life threatening adverse event from study within 7 days. Follow up information must be submitted as soon as its available and identified as "Follow up BA/BE safety report".

What is SPL format?

Structure Product Labeling: based on XML language. SPL requires forms 2656, 2657, 2658 be submitted electronically in SPL format; also required to submit official contacts name, mailing address, telephone numbers, and email address; each registered establishments telephone number, type of operations performed at each registered establishment; b. Foreign establishments must follow this too

What is a Suitabiliy Petition?

Suitability Petition: formal request to FDA to submit an ANDA with a change in Route of administration; Dosage form; Strength; Active ingredient in same pharmacological class in a combination product; (2)PREA: is applicable for all changes except strength. The suitability petition will be denied if pediatric studies are required. FDA Guidance for Industry, How to Comply with the Pediatric Research Equity Act (September 2005) Pediatric Rule, approval actions taken or applications submitted on or after April 1, 1999, for: changes in active ingredient, indication, dosage form, dosing regimen, or, route of administration, Required to include pediatric assessments, unless: waived, or Deferred; (3)FDA Guidance for Industry, Pediatric Study Plans (July 2013); Can obtain additional exclusivity (6 months) for pediatric studies; Will add an extra 6 months in addition to other patents; Sponsors are required to develop a PEDS formulation: if comes in a tablet form, sponsor is required to make attempt a new form for PEDS.

What is a 505(j)?

The ANDA application: generic drug application, duplicate of reference listed drug (RLD), primary bioequivalence/CMC data; completely relies on innovator (RLD) for safety and efficacy data; same conditions of use/labeling as RLD; unless part of a suitability petition, must have the same as RLD for active ingredient, route of administration, dosage form, strength; Bioequivalence definition: rate and extent of absorption (same molar dose)= no significant difference from RLD and an intention difference in the extent of absorption can be different from the RLD when it's in proposed labeling; Must demonstrate bioequivalence: In vitro: in health volunteers; pharmacokinetic study; active moiety measured normally in plasma; In vivo: clinical comparison trial (unable to measure moiety); Inherently bioequivalent- parenterals: injection = bioequivalent as long as excipients are the same as the RLD; Excipients can be different for some (but not all) dosage forms; Tablets/capsules: active moiety is same as RLD but actual excipients/binders don't have to be the same only conform (*FYI: FDA frowns upon different excipients)

What is the HatchWatchman Act?

The Hatch-Waxman Act (Drug Price Competition and Patent Term Restoration Act of 1984) provides for patent term extensions. Under the amendment to the FD&C Act, a sponsor may qualify for three-year exclusivity if the following criteria are met: the active moiety must have been the subject of an approved application, the new application (defined as a full NDA, BLA, 505(b)(2) or a supplement to any application mentioned) must contain new clinical trial data that are essential to support the approval of the new application, and the clinical trials must be conducted by the applicant.

The sponsor has requested a Special Protocol Assessment. Can the sponsor submit a revised protocol after the request has been made?

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.

What are the goals of an NDA?

The drug is safe and effective for its proposed use(s), The benefits of the drug outweigh the risks, The proposed labeling is appropriate and adequate, The methods of manufacture and testing and the controls used to maintain the drug's quality are adequate to preserve the drug's identity, strength, quality, and purity

What type of submission would a change in qualitative or quanititative formulation require?

This is considered and major change and would require a PAS (prior approval supplement)

What type of submission would changes based on postmartketing study results, including a new indication and usage?

This would be a major change and would require a PAS

What type of submission would a change in the layout of the package (no content change)?

This would be a minor change, annual report

What type of submission would extending ther expiration date based on full shelf life data and an approved protocol?

This would be a minor change, annual report

What type of submission would changes in the size or shape of a container for a sterile drug substance be considered?

This would be a moderate change and would required a CBE-30

What happens when you transfer an approved drug to a new owner?

Transfer ownership 21 CFR 314.72: Former owner shall submit letter/document that states all rights to the application have been transferred to the new owner. New owner will submit signed application form and letter with the new owners agreements, commitments, promises and conditions made by the former owner. Labeling, brand and name of manufacturer are all considered annual report changes for this transaction.

When would you schedule a Pre-IND meeting?

When you have a life threating or dibilitating disease to required animal studies needed to initate human trials- (discuss and reach an agreement)

When would you schedule a EOP1 meeting?

When you have an accelerated approval drug to agree on phase 2 trials before starting

What is the orange book?

Where you can find all the RLDs and use RLD to submit and ANDA through a suitability petition. (2)The generic drugs list in the orange book are given two ratings "A" or "B". A rating: no in vivo bioequivalence issue is known; Active ingredients or dosage form present a potential bioequivalence problem but applicant's approved application contains scientific evidence (through in vivo and in vitro studies) establishing bioequivalence of the product to the selected RLD. B rating: FDA has documented bioequivalence problems or a significant potential for such problems and no adequate studies demonstrating bioequivalence have been submitted to the agency; FDA has an insufficient basis to determine therapeutic equivalence (quality standards are inadequate); the drug products are under regulatory review. (3)Pharmacist also use this to find generic drugs that are approved for the RLD so it's cheaper for the patient. This is regulated at the state level as to what/how this is determined (positive formulary, negative formulary, combined positive and negative, "non-formulary")

What is a treatment IND?

a means of providing eligible subjects with investigational drugs or Treatment INDs are issued biologics for the treatment of serious and life-threatening illnesses for which there are no suitable alternative treatments. (Allows limited use of unapproved drug for patients with serious, life-threatening disease.

What are the different types of studies?

a. Phase 1 studies: PK, DM (?), pharmacology and safety, healthy volunteers (20-80 subjects); b. Phase 2 studies: dose ranging, short-term side effects & risks, preliminary efficacy, pediatric study plans(?) (100's of patients affect with the disease/condition), (can submit proprietary name at completion); c. Phase 3 studies: special protocol assessment(?), pivotal efficacy, safety, benefit/risk relationship & labeling (1000s of patients); normally 2 separate adequate and well controlled trials (one investigation confirming the results obtained from a prior concurrent investigation are needed to establish effectiveness. (*occasionally one study can be efficient.); i. Special protocol assessment: mechanism to obtain FDA agreement to time line critical study protocols (within 45 days): 3 types of protocols: animal carcinogenicity protocols, finabl product stability protocols, clinical protocols for phase 3 trials forming the primary basis for an efficicay claim (typically used); Protocol amendments can restart the clock so discuss with FDA beforehand; FDA agreement is "binding"- unless there is a substantial scientific issue- comments are received normally within 45 days.

What is an adverse event in clinical setting?

an adverse event is any untoward medical occurrence associated with the use of a drug in humans whether or not considered drug-related.

What is Life threatening adverse event or life threatening suspected adverse reaction?

an adverse ever or suspected adverse reaction is considered "life-threatening" if, in the view of either the investigator or sponsor, its occurrence places the patient or subject at immediate risk of death. It does not include an adverse event or suspected adverse reaction that had it occurred in a more severe form, might have caused death.

What are types of Protocols that are SPAs?

animal carcinogenicity protocols, stability protocols, protocol for phase 3 trails related to efficacy claims (NOT dose ranging protocols)

What kind of submission changes in the layout of the package (no content change)?

annual report, maybe distributed prior to reporting in next annual report

What kind of submission is required to extent the expiration date bnased on full shelf-life data and approved protocol?

annual report, maybe distributed prior to reporting in next annual report

what is Suspect adverse reaction?

any adverse event for which there is a reasonable possibility that the drug caused the adverse event. For IND safety reporting: reasonable possibility means there is evidence to suggest a causal relationship between the drug and adverse event. Implies a lesser degree of certain about causality than adverse reaction.

What is breakthrough therapy designation?

brought on by FDASIA; to qualify the drug must be for a serious or life threatening disease, and preliminary clinical evidence shows the drug may offer substantial improvement over current therapies. Should be requested by sponsor prior to submitting application; FDA has 60 days to respond

Extra information regarding ADEs:

causality is not considered in postmarketing reports: If the adverse event is serious, unexpected, and associated with the use of the drug it must be submitted both as an IND safety report and a 15 day alert report; Sponsor should not use the patients information under the reporter; A sponsor can include a disclaimer statement in the report indicating that it is not admitting or denying that the ADE report submitted constitutes an admission that the drug cause or contributed to an adverse event; FDA monitors all adverse events on FAERS system; FDA posts potential signals on its website quarterly

What is Serious adverse event or Serious suspected adverse reaction?

considered serious if in the view of either the investigator or sponsor it results in any of the following outcomes: death, a life threatening adverse event, inpatient hospitalization or prolongation of existing hospitalization, a persistent or significant incapacity or substantial disruption of a the ability to conduct normal life functions, or a congenital anomaly/birth defect. Also: medical or surgical intervention

What is an Unexpected Adverse Event or Unexpected Suspected Adverse Reaction:?

considered unexpected if it is not listed in the investigator brochure (IB) or is not listed at the specificity or severity that has been observed; or if an IB is not required or available, is not consistent with the risk information described in the general investigation plan or elsewhere in the current application as amended. (greater severity of a list AE is considered unexpected

When would you have a type A meeting?

dispute resolution, Clinical Holds, Special Protocol Assignment, Post Action Meeting (held within 30 days, with FDA response in 14 to schedule, briefing materials are need at least two weeks before the meeting)

What are the requirements for exports?

exports must comply with the receiving countries regulations

What is a Citizen Petition?

formal written request to FDA asking the agency to take or refrain from taking an administrative action.; FDA has 180 days to respond: Must contain the following: Action requested, Statement of grounds, Environmental impact, Economic impact, A certification by the submitter

What is priority review

given to drugs that offer major advances in treatment or provide a treatment where no adequate therapy exists. (8 vs 10 months; 10 vs 12 in the program). Requires at least one to submit for priority review: Provide evidence of increased effectiveness in treatment, prevention or diagnosis of disease. Eliminate or substantially reduce a treatment limiting drug reaction. Provide documented evidence of enhanced patient compliance to treatment schedule and dose. Provide evidence of safety and effectiveness in a new subpopulation such as children.

Target product profile

i. It is organized according to the key sections of the drug's intended labeling. Its prepared by the sponsor and submission is voluntary. It is a dynamic summary that will change as knowledge of the drug increases. No commitment or obligation for sponsor or FDA; ii. Intended to eliminate the need to revisit development issues that have already been discussed with FDA unless development goals change and to facilitate final labeling discussions related both to initial approvals and labeling supplements; iii. TTP links each specific labeling concept to a specific study or other source of data that is intended to support the labeling concept

What is a target product profile?

i. It is organized according to the key sections of the drug's intended labeling. Its prepared by the sponsor and submission is voluntary. It is a dynamic summary that will change as knowledge of the drug increases. No commitment or obligation for sponsor or FDA; ii. Intended to eliminate the need to revisit development issues that have already been discussed with FDA unless development goals change and to facilitate final labeling discussions related both to initial approvals and labeling supplements; iii. TTP links each specific labeling concept to a specific study or other source of data that is intended to support the labeling concept

An Investigational New Drug Application (IND) was submitted to FDA. New animal toxicology data is obtained and will be submitted to FDA as an:

information amendment submitted no more than every 30 days.

what is the process for proprietary name review?

initiated during the IND phase (*completion of phase 2), when submitted in IND phase FDA has 180 days to review, when submitted in NDA 90 days to review; FDA review: prosed name's safety and promotional aspects: safety: focuses primarily on prevention of medication errors and evaluating other products that may have similar appearance when written out by hand; Promotional review: determine whether the name implies being superior.

What are the same regulations that apply to both Rx and OTC?

manufacturing, testing, facility registration and inspection, clinical trials, importation, safety monitoring and risk management

After the preapproval inspection, there is an advisory committee meeting. Is this for all new drugs?

no, only for first in class and new molecular entities.

When would you have a type B meeting?

preIND, EOP1, EOP2, PreNDA, REMS/PMRs (FDA scheduling confirmation within 21 days, meeting within 60 days, briefing materials needed 1 month before);

What is required in order to extend the drug product shelft life?

present 3 years of real-time stability data on 3 consecuative batches following an approved stability protocol in the NDA annual report

What is the OTC monograph?

provides a framework by which "well-established ingredients" in specified therapeutic classes (e.g. analgesic, antacid) can go directly to market without FDA approval of a marketing application; no premarket approval required, no filing fees, public process, no marketing exclusivity, covers active ingredients/therapeutic classes, no mandated FDA review timelines, FDA approval of brand name no required, No FDA approval required for post-marketing changes that conform to monograph, clinical studies may be required for new claims, label must conform to monograph and drug fact label requirements

What type of submission would a change in, addition or deletion of a desiccant (solid that absorbs water)?

this would be considered a moderate change and would be a CBE-0

What type of submission would adding or strengthening a contraindiction, warning, precaution or adverse reaction?

this would be considered a moderate change and would be a CBE-0

What is the board of inquiry?

when specifically authorized by regulation, at the discretion of the FDA commissioner or as an alternative to a formal evidentiary public hearing and not comparable to legal trial

How do OTCs come to market?

with an NDA or the OTC monograph system