Regulatory Affairs Overview Regulatory Affairs (RA), also called Government Affairs, is a profession within regulated industries, such as pharmaceuticals, medical devices, energy, and banking Regulato.
Regulatory Affairs Overview Regulatory Affairs (RA), also called Government Affairs, is a profession within regulated industries, such as pharmaceuticals, medical devices, energy, and banking Regulatory Affairs also has a very specific meaning within the healthcare industries (pharmaceuticals, medical devices, Biologics and functional foods) Regulatory Affairs professionals usually have responsibility for the following general areas: Ensuring that their companies comply with all of the regulations and laws pertaining to their business Working with federal, state, and local regulatory agencies and personnel on specific issues affecting their business i.e working with such agencies as the Food and Drug Administration or European Medicines Agency (pharmaceuticals and medical devices); The Department of Energy; or the Securities and Exchange Commission (banking) Advising their companies on the regulatory aspects and climate that would affect proposed activities i.e describing the "regulatory climate" around issues such as the promotion of prescription drugs and Sarbanes-Oxley compliance Healthcare Regulatory Affairs: The Regulatory Affairs function in healthcare industries is vital in making safe and effective healthcare products available worldwide Individuals who ensure regulatory compliance and prepare submissions, as well as those whose main job function is clinical affairs or quality assurance are all considered regulatory professionals Regulatory professionals are employed in industry, are involved with a wide range of products, including: pharmaceuticals medical devices in vitro diagnostics biologics and biotechnology nutritional products cosmetics veterinary products The regulatory professional's roles and responsibilities often begin in the research and development phases, moving into clinical trials and extending through premarket approvals, manufacturing, labeling and advertising and post market surveillance Country Wise Regulations, regulatory systems and regulatory agencies a) Regulated countries: The regulated pharmaceutical markets are those markets where drug approval processes are very strict They follow intellectual property regulations which are harmonized with regulatory authorities (FDA, EU/EMEA) procedures, with strict patents, pricing and other regulatory rules E.g USA, Europe, Japan, Australia, Finland b) Semi regulated countries: Where regulatory requirements are relatively less stringent than regulated but more stringent than non regulated markets e.g GCC Countries, Maxico, Brazil, CIS countries (Russia, Ukraine etc.) Indonesia, Malaysia etc c) Non regulated countries: Where regulatory requirements are very simple e.g Pakistan, India, SriLanka, Kenya, Cambodia, Bangladesh etc Types of Drug Applications DMF & ASMF, EDMF: Drug Master File or DMF is a document prepared by a pharmaceutical manufacturer and submitted solely at its discretion to the appropriate regulatory authority in the intended drug market Drug Master File (DMF) is a document containing complete information on an Active Pharmaceutical Ingredient (API) The DMF contains factual and complete information on a drug product's chemistry, manufacture, stability, purity, impurity profile, packaging, and the cGMP status of any human drug product It is also known as European Drug Master File (EDMF) or Active Substance Master File (ASMF) in Europe and US-Drug Master file (US-DMF) in United States There are types of Drug Master File: Type I Manufacturing Site, Facilities, Operating Procedures, and Personnel Type II Drug Substance, Drug Substance Intermediate, and Material Used in Their Preparation, or Drug Product Type III Packaging Material Type IV Excipients, Colorant, Flavor, Essence, or Material Used in Their Preparation Type V FDA Accepted Reference Information IND, NDA & ANDA: Investigational New Drug Application (IND) After completing preclinical testing, a company files an IND with regulatory authority to begin to test the drug in people The IND enables a sponsor to ship an unapproved drug in interstate commerce Clinical trials may proceed 30 days after filing unless the regulatory authority places a hold on the proposal Investigational New Drug Application (IND) In many ways, the investigational new drug (IND) application is the result of a successful preclinical development program The IND is also the vehicle through which a sponsor advances to the next stage of drug development known as clinical trials (human trials) During a new drug's early preclinical development, the sponsor's primary goal is to determine if the product is reasonably safe for initial use in humans, and if the compound exhibits pharmacological activity that justifies commercial development When a product is identified as a viable candidate for further development, the sponsor then focuses on collecting the data and information necessary to establish that the product will not expose humans to unreasonable risks when used in limited, early-stage clinical studies Generally, this includes data and information in three broad areas: Animal Pharmacology and Toxicology Studies Preclinical data to permit an assessment as to whether the product is reasonably safe for initial testing in humans Manufacturing Information Information pertaining to the composition, manufacture, stability, and controls used for manufacturing the drug substance and the drug product This information is assessed as to ensure the company can adequately produce and supply consistent batches of the drug Clinical Protocols and Investigator Information Detailed protocols for proposed clinical studies to assess whether the initial-phase trials will expose subjects to unnecessary risks Also, information on the qualifications of clinical investigators-professionals (generally physicians) who oversee the administration of the experimental compound-to assess whether they are qualified to fulfill their clinical trial duties The IND is not an application for marketing approval Rather, it is a request for an exemption from the Federal statute that prohibits an unapproved drug from being shipped in interstate commerce Current Federal law requires that a drug be the subject of an approved marketing application before it is transported or distributed across state lines Because a sponsor will probably want to ship the investigational drug to clinical investigators in many states, it must seek an exemption from that legal requirement The IND is the means through which the sponsor technically obtains this exemption from the FDA; however, its main purpose is to detail the data that provide documentation that it is indeed reasonable to proceed with certain human trials with the drug Types of INDs "Commercial INDs" are applications that are submitted primarily by companies whose ultimate goal is to obtain marketing approval for a new product However, there is another class of filings broadly known as "noncommercial" INDs The vast majority of INDs are, in fact, filed for noncommercial research These types of INDs include "Investigator INDs," "Emergency Use INDs," and "Treatment INDs." Chemistry Review Each review division employs a team of chemists responsible for reviewing the chemistry and manufacturing control sections of drug applications In general terms, chemistry reviewers address issues related to drug identity, manufacturing control, and analysis The reviewing chemist evaluates the manufacturing and processing procedures for a drug to ensure that the compound is adequately reproducible and stable If the drug is either unstable or not reproducible, then the validity of any clinical testing would be undermined because one would not know what was really being used in the patients, and, more importantly, the studies may pose significant risks to participants At the beginning of the Chemistry and Manufacturing section, the drug sponsor should state whether it believes the chemistry of either the drug substance or the drug product, or the manufacturing of either the drug substance or the drug product, present any signals of potential human risk If so, these signals should be discussed, with steps proposed to monitor for such risks In addition, sponsors should describe any chemistry and manufacturing differences between the drug product proposed for clinical use and the drug product used in the animal toxicology trials that formed the basis for the sponsor's conclusion that it was safe to proceed with the proposed clinical study How these differences might affect the safety profile of the drug product should be discussed If there are no differences in the products, that should be stated Pharmacology/Toxicology Review The pharmacology/toxicology review team is staffed by pharmacologists and toxicologists who evaluate the results of animal testing and attempt to relate animal drug effects to potential effects in humans Pharmacology and Drug Distribution (21 CFR 312.23(a)(8)(I)): This section of the application should contain, if known: 1) a description of the pharmacologic effects and mechanism(s) of action of the drug in animals, and 2) information on the absorption, distribution, metabolism, and excretion of the drug The regulations not further describe the presentation of these data, in contrast to the more detailed description of how to submit toxicologic data A summary report, without individual animal records or individual study results, usually suffices To the extent that such studies may be important to address safety issues, or to assist in the evaluation of toxicology data, they may be necessary; however, lack of this potential effectiveness should not generally be a reason for a Phase IND to be placed on clinical hold Toxicology Data Present regulations (21 CFR 312.23(a)(8)(ii)(a)) require an integrated summary of the toxicologic effects of the drug in animals and in vitro The particular studies needed depend on the nature of the drug and the phase of human investigation When species specificity, immunogenicity, or other considerations appear to make many or all toxicological models irrelevant, sponsors are encouraged to contact the agency to discuss toxicological testing Medical Review Medical/clinical reviewers, often called medical officers, are almost exclusively physicians Medical reviewers are responsible for evaluating the clinical sections of submissions, such as the safety of the clinical protocols in an IND or the results of this testing as submitted in the NDA Within most divisions, clinical reviewers take the lead role in the IND or NDA review, and are responsible for synthesizing the results of the animal toxicology, human pharmacology and clinical reviews to formulate the overall basis for a recommended Agency action on the application During the IND review process, the medical reviewer evaluates the clinical trial protocol to determine: (1) if the participants will be protected from unnecessary risks; and (2) if the study design will provide data relevant to the safety and effectiveness of the drug Under Federal regulations, proposed Phase I studies are evaluated almost exclusively for safety reasons Since the late 1980's, FDA reviewers have been instructed to provide drug sponsors with greater freedom during Phase I, as long as the investigations not expose participants to undue risks In evaluating Phase II and III investigations, however, FDA reviewers also must ensure that these studies are of sufficient scientific quality to be capable of yielding data that can support marketing approval Safety Review Following review of an initial IND submission, CDER has 30 calendar days in which to decide if a clinical hold is necessary (i.e., if patients would be at an unacceptable risk or if CDER doesn't have the data to make such a determination) Generally, drug review divisions not contact the sponsor if no concerns arise with drug safety and the proposed clinical trials If the sponsor hears nothing from CDER, then on day 31 after submission of the IND, the study may proceed as submitted Statistical Review Statisticians evaluate the statistical relevance of the data in the NDA with the main tasks of evaluating the methods used to conduct studies and the various methods used to analyze the data The purpose of these evaluations is to give the medical officers a better idea of the power of the findings to be extrapolated to the larger patient population in the country Clinical Hold Decision A clinical hold is the mechanism that CDER uses when it does not believe, or cannot confirm, that the study can be conducted without unreasonable risk to the subjects/patients If this occurs, the Center will contact the sponsor within the 30-day initial review period to stop the clinical trial CDER may either delay the start of an early-phase trial on the basis of information submitted in the IND, or stop an ongoing study based on a review of newly submitted clinical protocols, safety reports, protocol amendments, or other information When a clinical hold is issued, a sponsor must address the issue that is the basis of the hold before the order is removed CDER's authority concerning clinical holds is outlined in Federal regulations The regulations specify the clinical hold criteria that CDER applies to various phases of clinical testing In addition, all clinical holds are reviewed by upper management of CDER to assure consistency and scientific quality in the Center's clinical hold decisions Notify Sponsor Once a clinical hold is placed on a commercial IND, the sponsor will be notified immediately by telephone by the division director For both individual and commercial INDs, the division is required to send a letter within five working days following the telephone call The letter should describe the reasons for the clinical hold, and must bear the signature of the division director (or acting division director) The sponsor may then respond to CDER by sending an "IND CLINICAL HOLD RESPONSE" letter to the division To expedite processing, the letter must be clearly identified as an "IND CLINICAL HOLD RESPONSE" letter The division then reviews the sponsor's response and decides within 30 days as to whether the hold should be lifted If the division does not reply to the clinical hold response within 30 calendar days, the division director will telephone the sponsor and discuss what is being done to facilitate completion of the review If it is decided that the hold will not be lifted, the hold decision is automatically sent to the office director for review The office director must decide within 14 calendar days whether or not to sustain the division's decision to maintain the clinical hold If the decision is made to lift the hold, the division telephones the sponsor, informs them of the decision, and sends a letter confirming that the hold has been lifted The letter will be sent within working days of the telephone call However, the trial may begin once the decision has been relayed to the sponsor by telephone Sponsor Notified of Deficiencies If other deficiencies are found in an IND that the review division determines are not serious enough to justify delaying clinical studies, the division may either telephone or forward a deficiency letter to the sponsor In either case, the division informs the sponsor that it may precede with the planned clinical trials, but that additional information is necessary to complete or correct the IND file, or that there are issues that need to be addressed prior to a marketing application (NDA) submission Study Ongoing Once CDER's 30-day initial review period expires; clinical studies can be initiated, unless a clinical hold has been placed Beyond the 30-day review period for an IND, subsequent clinical trials may begin immediately upon submission of the clinical protocol to the IND (i.e., there is no 30-day waiting period for subsequent clinical trials after the submission of the first clinical trial protocol) If the sponsor was notified of deficiencies that were not serious enough to warrant a clinical hold, the sponsor addresses these deficiencies while the study proceeds The New Drug Application (NDA) is the vehicle in the United States through which drug sponsors formally propose that the FDA approve a new pharmaceutical for sale and marketing The goals of the NDA are to provide enough information to permit FDA reviewers to establish the following: Is the drug safe and effective in its proposed use(s) when used as directed, and the benefits of the drug outweigh the risks? Is the drug’s proposed labeling (package insert) appropriate, and what should it contain? Are the methods used in manufacturing (Good Manufacturing Practice, GMP) the drug and the controls used to maintain the drug’s quality adequate to preserve the drug’s identity, strength, quality, and purity? Contents [hide] Before trials Clinical trials The actual application Requirements for similar products References See also [edit] Before trials To legally test the drug on human subjects in the U.S., the maker must first obtain an Investigational New Drug (IND) designation from FDA This application is based on preclinical data, typically from animal studies, that shows the drug is safe enough to be tested in humans Often the "new" drugs that are submitted are not new molecular entities, but old medications that have been modified [edit] Clinical trials The legal requirement for approval is "substantial" evidence of efficacy demonstrated through controlled clinical trials.[1] This standard lies at the heart of the regulatory program for drugs It means that the clinical experience of doctors, the opinion of experts, or testimonials from patients, even if they have experienced a miraculous recovery, have minimal weight in this process Data for the submission must come from rigorous clinical trials The trials are typically conducted in three phases: Phase 1: The drug is tested in a few healthy volunteers to determine if it is acutely toxic Phase 2: Various doses of the drug are tried to determine how much to give to patients Phase 3: The drug is typically tested in double-blind, placebo controlled trials to demonstrate that it works Sponsors typically confer with FDA prior to starting these trials to determine what data is needed, since these trials often involve hundreds of patients and are very expensive (Phase 4): These are post-approval trials that are sometimes a condition attached by the FDA to the approval The legal requirements for safety and efficacy have been interpreted as requiring scientific evidence that the benefits of a drug outweigh the risks and that adequate instructions exist for use, since many drugs are toxic and technically not "safe" in the usual sense Many approved medications for serious illnesses (e.g., cancer) have severe and even life-threatening side effects Even relatively safe and well understood OTC drugs such as aspirin can be dangerous if used incorrectly [edit] The actual application The results of the testing program are codified in an FDA-approved public document that is called the product label, package insert or Full Prescribing Information.[2] The prescribing information is widely available on the web, from the FDA, [3] drug manufacturers, and frequently inserted into drug packages The main purpose of a drug label is to provide healthcare providers with adequate information and directions for the safe use of the drug The documentation required in an NDA is supposed to tell the drug’s whole story, including what happened during the clinical tests, what the ingredients of the drug formulation are, the results of the animal studies, how the drug behaves in the body, and how it is manufactured, processed and packaged Once approval of an NDA is obtained, the new drug can be legally marketed starting that day in the U.S Once the application is submitted, the FDA has 60 days to conduct a preliminary review which will assess whether the NDA is "sufficiently complete to permit a substantive review" If the NDA is found to be insufficiently complete (and reasons for this can vary from a simple administrative mistake in the application to a requirement to reconduct much of the testing), then the FDA rejects the application with the issue of a Refuse to File letter which is sent to the applicant explaining where the application has failed to meet requirements.[4] Assuming that everything is found to be acceptable, the FDA will decide if the NDA will get a standard or accelerated review and communicate the acceptance of the application and their review choice in another communication known as the 74-day letter.[5] A standard review implies an FDA decision within about 10 months while a priority review should complete within months.[6] Of original NDAs submitted in 2009, 94 out of 131 (72%) were in eCTD format.[7] [edit] Requirements for similar products Biologics, such as vaccines and many recombinant proteins used in medical treatments are generally approved by FDA via a Biologic License Application (BLA), rather than an NDA Manufacture of biologics is considered to differ fundamentally from that of less complex chemicals, requiring a somewhat different approval process Generic drugs that have already been approved via an NDA submitted by another maker are approved via an Abbreviated New Drug Application (ANDA), which does not require all of the clinical trials normally required for a new drug in an NDA [8] Most biological drugs, including a majority of recombinant proteins are considered ineligible for an ANDA under current US law.[9] However, a handful of biologic medicines, including biosynthetic insulin, growth hormone, glucagon, calcitonin, and hyaluronidase are grandfathered under governance of the Federal Food Drug and Cosmetics Act, which appears to be because these products were already approved when legislation aimed at regulating biotechnology medicines was later passed as part of the Public Health Services Act Biologic medicines governed under the Federal Food Drugs and Cosmetics Act has been an area of considerable confusion and dispute for the FDA, because under section 505(b)(2) of the Federal Food, Drug, and Cosmetic Act, a "generic" need not be an exact duplicate of the brand-name original in order to be approved In July 2003, the Sandoz generics unit of Novartis filed, and the FDA accepted, an ANDA for a "follow-on" version of Pfizer's brand-name human growth hormone (Genotropin) that that Sandoz named Omnitrope using the 505(b)(2) pathway The application was submitted following lengthy discussions with the FDA and contained preclinical, clinical, and comparability data, as well as literature references to the FDA's original decision on Pfizer's Genotropin But on September 2, 2004, the FDA told Sandoz that the Agency was unable to reach a decision on whether to approve the company's application for Omnitrope Frustrated with the FDA's failure to give them a decision on Omnitrope, Sandoz then sued the FDA in U.S District Court in Washington, D.C., citing a statutory requirement that the FDA is required by law to act on drug applications within 180 days Medications intended for use in animals are submitted to a different center within FDA, the Center for Veterinary Medicine (CVM) in a New Animal Drug Application (NADA) These are also specifically evaluated for their use in food animals and their possible effect on the food from animals treated with the drug Medical devices are approved by a variety of methods depending on the class of the device A Pre-market Application (PMA) largely equivalent to an NDA is required for class III devices, and a 510(k) approval that shows the device is equal to or better than a predicate device already on the market is required for class II devices Class I medical devices (such as a toothbrush) not require any approval at all An Abbreviated New Drug Application (ANDA) is an application for a U.S generic drug approval for an existing licensed medication or approved drug The ANDA contains data which when submitted to FDA's Center for Drug Evaluation and Research, Office of Generic Drugs, provides for the review and ultimate approval of a generic drug product Once approved, an applicant may manufacture and market the generic drug product to provide a safe, effective, low cost alternative to the American public Electronic submissions of ANDAs have grown by 70% since November 2008 [1] The Section IV challenge has been credited with suppressing new drug innovation.[2] A generic drug product is one that is comparable to an innovator drug product in dosage form, strength, route of administration, quality, performance characteristics and intended use All approved products, both innovator and generic, are listed in FDA's Approved Drug Products with Therapeutic Equivalence Evaluations (Orange Book) Generic drug applications are termed "abbreviated" because they are generally not required to include preclinical (animal) and clinical (human) data to establish safety and effectiveness Instead, generic applicants must scientifically demonstrate that their product is bioequivalent (i.e., performs in the same manner as the innovator drug) One way scientists demonstrate bioequivalence is to measure the time it takes the generic drug to reach the bloodstream in 24 to 36 healthy volunteers This gives them the rate of absorption, or bioavailability, of the generic drug, which they can then compare to that of the innovator drug The generic version must deliver the same amount of active ingredients into a patient's bloodstream in the same amount of time as the innovator drug Using bioequivalence as the basis for approving generic copies of drug products was established by the Drug Price Competition and Patent Term Restoration Act of 1984, also known as the Hatch-Waxman Act This Act expedites the availability of less costly generic drugs by permitting FDA to approve applications to market generic versions of brand-name drugs without conducting costly and duplicative clinical trials At the same time, the brand-name companies can apply for up to five additional years longer patent protection for the new medicines they developed to make up for time lost while their products were going through FDA's approval process Brand-name drugs are subject to the same bioequivalence tests as generics upon reformulation Preparation of Drug Applications (Dossiers) in Different formats a) CTD Module Regional Administrative Information x 1.1 1.1.1 1.1.2 1.1.3 1.1.4 1.1.5 1.1.6 Forms FDA Form 1571 (not applicable) FDA Form 356h User Fee Cover Sheet (FDA Form 3397) Annual Report Transmittal Form (FDA Form 2252) (not applicable) Advertising and Promotional Labelling Form (FDA Form 2253) (not applicable) Transmittal of Labels and Circulars (FDA Form 2567) (not applicable) x 1 x x 1.2 - Cover Letter Comprehensive Table of Contents for Modules - 1 x x 1.3 1.3.1 1.3.2 1.3.3 1.3.4 1.3.5 1.3.5.1 1.3.5.2 1.3.5.3 Administrative Information Contact/Sponsor Information Field Copy Certification Debarment Certification Certification: Financial Interests and Arrangements of Clinical Investigators (FDA Form 3454) Patent & Exclusivity Patent Information (FDA Form 3542a) Patent Certification Statement of Claimed Exclusivity 1 1 1 1 x x x x x x x x x 1.4 1.4.1 1.4.2 1.4.3 1.4.4 References Letters of Authorization Statement of Right of Reference (not applicable) List of Authorized Persons to Incorporate by Reference .(not applicable) Cross Reference to Other Applications & Previously Submitted Information 1 x x x 1.5 Application Status x 1.5.1 1.5.2 1.5.3 1.5.4 1.5.5 1.5.6 1.5.7 1.5.8 IND Withdrawal Request Inactivation Request Reactivation Request Reinstatement Request Withdrawal of an Unapproved Application Withdrawal of a Listed Drug Request for Withdrawal of Application Approval Other Correspondence 1 1 1 1 x x x x x x x x Module Regional Administrative Information (continued) x 1.6 1.6.1 1.6.2 1.6.3 Meetings Meeting Request Meeting Background Materials Correspondence Regarding Meetings 1.7 Fast Track .(not applicable) 1.8 Special Protocol Assessment (SAP) Request (not applicable) 1.9 1.9.1 1.9.2 1.9.3 1.9.4 1.9.5 1.9.6 Pediatric Administrative Information Request for Waiver (not applicable) Request for Deferral (not applicable) Request for Pediatric Exclusivity Determination (not applicable) Proposed Pediatric Study Request & Amendments (not applicable) Proposal for Written Agreement .(not applicable) Other Correspondence Regarding Pediatric Exclusivity or Study Plans 1.10 1.10.1 1.10.2 Dispute Resolutions (not applicable) Request for Dispute Resolution Correspondence Relating to Dispute Resolution 1.11 1.11.1 1.11.2 1.11.3 Information Amendment (not covered under Modules – 5) (not applicable) Quality Safety Efficacy 1.12 1.12.1 1.12.2 1.12.3 1.12.4 1.12.5 1.12.6 1.12.7 1.12.8 1.12.9 1.12.10 1.12.11 1.12.12 1.12.13 1.12.14 1.12.15 1.12.16 Other Correspondence Pre-IND Correspondence Request to Charge .(not applicable) Notification of Charging Under Treatment IND (not applicable) Request for Comments and Advice on an IND Request for Waiver (not applicable) Exemption from Informed Consent for Emergency Research .(not applicable) Public Disclosure Statement for Emergency Care Research (not applicable) Correspondence Regarding Emergency Care Research .(not applicable) Notification of Discontinuation of Clinical Trial (not applicable) Generic Drug Enforcement Act (GDEA) Statement Basis for Submission Statement Comparison of Generic Drug and Reference Listed Drug (RLD) Request for Waiver of in vivo Studies Environmental Impact Analysis Statement Request for Waiver of in vivo Bioavailability Studies Field Alert Reports (not applicable) 1 1 x x x x x x 1 x x x 1 1 1 x x x x x x Module Regional Administrative Information (continued) x 1.13 1.13.1 1.13.2 1.13.3 1.13.4 1.13.5 1.13.6 1.13.7 1.13.8 1.13.9 1.13.10 1.13.11 1.13.12 1.13.13 1.13.14 Annual Reports (not applicable) Summary for Non-Clinical Studies Summary of Clinical Pharmacology Studies Summary of Safety Information Summary of Labelling Changes Summary of Manufacturing Changes Summary of Microbiological Changes Summary of Other Significant New Information Individual Study Information General Investigational Plan Foreign Marketing History Distribution Data Status of Post-Marketing Commitments Status of Other Post-Marketing Studies Log of Outstanding Regulatory Business 1.14 1.14.1 1.14.1.1 1.14.1.2 1.14.1.3 1.14.1.4 1.14.1.5 1.14.2 1.14.2.1 1.14.2.2 1.14.2.3 1.14.3 1.14.3.1 1.14.3.2 1.14.3.3 1.14.4 1.14.4.1 1.14.4.2 1.14.4.3 1.14.4.4 1.14.4.5 Labelling Draft Labelling Draft Carton & Container Labels Annotated Draft Labelling Text Draft Labelling Text Label Comprehension Studies (not applicable) Labelling History Final Labelling Final Carton & Container Labels Final Package Inserts Final Labelling Text Listed Drug Labelling Annotated Comparison with Listed Drug Approved Labelling Text for Listed Drug Labelling Text for Reference Listed Drug Investigational Drug Labelling Investigator’s Brochure Investigational Drug Labelling FILL IN FILL IN Foreign Labelling (not applicable) 1 1 x x x x x 1 1 1 1 1 1 x x x x x x x x x x x x x x 1.15 Promotional Material x 1.16 Risk Management Plans x Module Common Technical Document Summaries x x 2.1 Comprehensive Table of Contents for Module x 2.2 Introduction x 2.3 2.3.S 2.3.1 2.3.2 2.3.3 2.3.4 2.3.5 2.3.6 2.3.7 2.3.P 2.3.1 2.3.2 2.3.3 2.3.4 2.3.5 2.3.6 2.3.7 2.3.8 2.3.A 2.3.A.1 2.3.A.2 2.3.A.3 2.3.R Quality Summary Drug Substance General Information Manufacture Characterization Control of Drug Substance Reference Standards or Materials Container/Closure System Stability Drug Product Description and Composition of the Drug Product Pharmaceutical Development Manufacture Control of Excipients Control of Drug Product Reference Standards or Materials Container/Closure System Stability Appendices Facilities and Equipment Adventitious Agents Safety Evaluation Novel Excipients Regional Information 1 1 1 1 x 1 1 1 1 x 1 1 x x x x x x x x 2.4 2.4.1 2.4.2 2.4.3 2.4.4 2.4.5 2.4.6 Nonclinical Overview Overview of the Nonclinical Testing Strategy Pharmacology Pharmacokinetics Toxicology Integrated Overview and Conclusions List of Literature Citations 1 1 1 x x x x x x x 2.5 2.5.1 2.5.2 2.5.3 2.5.4 2.5.5 2.5.6 2.5.7 Clinical Overview Product Development Rationale Overview of Biopharmaceutics Overview of Clinical Pharmacology .Overview of Efficacy Overview of Safety .Benefits and Risks Conclusions .References x 1 1 1 x x x x x x x x x x x x x x x x x x x x Module Common Technical Document Summaries (continued) x x 2.6 Nonclinical Written and Tabulated Summaries 2.6.1 Introduction 2.6.2 Pharmacology Written Summary 2.6.2.1 Brief Summary 2.6.2.2 Primary Pharmacodynamics 2.6.2.3 Secondary Pharmacodynamics 2.6.2.4 Safety Pharmacology 2.6.2.5 Pharmacodynamic Drug Interactions 2.6.2.6 Discussion and Conclusions 2.6.2.7 Tables and Figures 2.6.3 Pharmacology Tabulated Summary 2.6.4 Pharmacokinetics Written Summary 2.6.4.1 Brief Summary 2.6.4.2 Methods of Analysis 2.6.4.3 Absorption 2.6.4.4 Distribution 2.6.4.5 Metabolism (interspecies comparison) 2.6.4.6 Excretion 2.6.4.7 Pharmacokinetic Drug Interactions 2.6.4.8 Other Pharmacokinetic Studies 2.6.4.9 Discussion and Conclusions 2.6.4.10 Tables and Figures 2.6.5 Pharmacokinetics Tabulated Summary 2.6.6 Toxicology Written Summary 2.6.6.1 Brief Summary 2.6.6.2 Single-Dose Toxicity 2.6.6.3 Repeat-Dose Toxicity 2.6.6.4 Genotoxicity 2.6.6.5 Carcinogenicity 2.6.6.6 Reproductive and Developmental Toxicity 2.6.6.7 Local Tolerance 2.6.6.8 Other Toxicity Studies (if available) 2.6.6.9 Discussion and Conclusions 2.6.6.10 References 2.6.7 Toxicology Tabulated Summary 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 x x x x x x x x x x x x x x x x x x x x x x x x x x x x x x x x x x x Module Common Technical Document Summaries (continued) x x 2.7 Clinical Summary 2.7.1 Summary of Biopharmaceutic and Associated Analytical Methods 2.7.1.1 Background and Overview 2.7.1.2 Summary of Results of Individual Studies 2.7.1.3 Comparison and Analyses of Results Across Studies 2.7.1.4 Appendix 2.7.2 Summary of Clinical Pharmacology Studies 2.7.2.1 Background and Overview 2.7.2.2 Summary of Results of Individual Studies 2.7.2.3 Comparison and Analyses of Results Across Studies 2.7.2.4 Special Studies 2.7.2.5 Appendix 2.7.3 Summary of Clinical Efficacy 2.7.3.1 Background and Overview of Clinical Efficacy 2.7.3.2 Summary of Results of Individual Studies 2.7.3.3 Comparison and Analyses of Results Across Studies 2.7.3.3.1 Study Populations 2.7.3.3.2 Comparison of Efficacy Results Across All Studies 2.7.3.3.3 Comparison of Results in Sub-Populations 2.7.3.4 Analysis of Clinical Information Relevant to Dosing Recommendations 2.7.3.5 Persistence of Efficacy and/or Tolerance Effects 2.7.3.6 Appendix 2.7.4 Summary of Clinical Safety 2.7.4.1 Exposure to the Drug 2.7.4.1.1 Overall Safety Evaluation Plan and Narratives of Safety Studies 2.7.4.1.2 Overall Extent of Exposure 2.7.4.1.3 Demographic and Other Characteristics of Study Population 2.7.4.2 Adverse Events 2.7.4.2.1 Analysis of Adverse Events by Organ System or Syndrome 2.7.4.2.2 Narratives 2.7.4.2.3 Deaths 2.7.4.2.4 Other Serious Adverse Events 2.7.4.3 Clinical Laboratory Evaluations 2.7.4.4 Vital Signs, Physical Findings, Observations Related to Safety 2.7.4.5 Safety in Special Groups and Situations 2.7.4.5.1 Intrinsic Factors 2.7.4.5.2 Extrinsic Factors 2.7.4.5.3 Drug Interactions 2.7.4.5.4 Use in Pregnancy and Lactation 2.7.4.5.5 Overdose 2.7.4.5.6 Drug Abuse 2.7.4.5.7 Withdrawal and Rebound 2.7.4.5.8 Effects on Ability to Drive or Operate Machinery or Impairment of Mental Ability 2.7.4.6 Post-Marketing Data 2.7.4.7 Appendix 2.7.5 References 2.7.6 Synopses of Individual Studies Module Quality x 1 1 1 1 1 1 1 1 1 1 1 1 1 1 x x 1 1 1 1 x x 1 1 1 x x x x x x x x x x x x x x x x x x x x x x x x x x x x x 3.1 Comprehensive Table of Contents for Module 3.2 Drug Substance 3.2.S.1 General Information 3.2.S.1.1 Nomenclature 3.2.S.1.2 Structure 3.2.S.1.3 General Properties 2 2 2 x x x x x x x x x x x x x x x x x x x x 3.2.S.2 3.2.S.2.1 3.2.S.2.2 3.2.S.2.3 3.2.S.2.4 3.2.S.2.5 3.2.S.3 3.2.S.3.1 3.2.S.3.2 3.2.S.4 3.2.S.4.1 3.2.S.4.2 3.2.S.4.3 3.2.S.4.4 3.2.S.4.5 3.2.S.5 3.2.S.6 3.2.S.7 3.2.S.7.1 3.2.S.7.2 3.2.S.7.3 3.2.P 3.2.1 3.2.2 3.2.2.1 3.2.2.2 3.2.2.3 3.2.2.4 3.2.2.5 3.2.2.6 3.2.3 3.2.3.1 3.2.3.2 3.2.3.3 3.2.3.4 3.2.3.5 3.2.4 3.2.4.1 3.2.4.2 3.2.4.3 3.2.4.4 3.2.4.5 3.2.4.6 3.2.5 3.2.5.1 3.2.5.2 3.2.5.3 3.2.5.4 3.2.5.5 3.2.5.6 3.2.6 3.2.7 3.2.8 3.2.8.1 3.2.8.2 3.2.8.3 Manufacture Manufacturer(s) Description of Process and Process Controls Control of Materials Control of Critical Steps and Intermediates Process Validation and/or Evaluation Characterization Elucidation of Structure and Other Characteristics Impurities Control of Drug Substance Specifications Analytical Procedures Validation of Analytical Procedures Batch Analyses Justification of Specification Reference Standards or Materials Container/Closure Systems Stability Stability Summary and Conclusions Post-approval Stability Protocol and Commitment Stability Data 2 2 2 2 2 2 2 2 2 2 x x x x x x x x x x x x x x x x x x x x x Drug Product Description and Composition of the Drug Product Pharmaceutical Development Composition of Drug Product Formulation, Overages, Properties Manufacturing Process Development Container/Closure System Microbiological Attributes Compatibility Manufacture Manufacturer(s) Batch Formula Description of Manufacturing Process and Process Controls Controls of Critical Steps and Intermediates Process Validation and/or Evaluation Control of Excipients Specifications Analytical Procedures Validation of Analytical Procedures Justification of Specifications Excipients of Human or Animal Origin Novel Excipients Control of Drug Product Specifications Analytical Procedures Validation of Analytical Procedures Batch Analyses Characterization of Impurities Justification of Specifications Reference Standards or Materials Container/Closure System Stability Stability Summary and Conclusions Post-Approval Stability Protocol and Stability Commitments Stability Data 3 3 3 3 3 3 3 3 3 3 3 3 3 3 3 3 3 x x x x x x x x x x x x x x x x x x x x x x x x x x x x x x x x x x x 3.2.A 3.2.A.1 3.2.A.2 3.2.A.3 Appendices Facilities and Equipment Adventitious Agents Safety Evaluation Novel Excipients 4 4 x x x x 3.2.R 3.2.R.1 Regional Information Batch Records Lot #### (STRENGTH) Lot #### (STRENGTH) Methods Validation Packet x 5 x x x 3.3 Key Literature References x 3.2.R.2 Module Non-Clinical Study Reports x 4.1 Comprehensive Table of Contents for Module 4.2 Study Reports 4.2.1 Pharmacology 4.2.1.1 Primary Pharmacodynamics 4.2.1.2 Secondary Pharmacodynamics 4.2.1.3 Safety Pharmacology 4.2.1.4 Pharmacodynamic Drug Interactions 4.2.2 Pharmacokinetics 4.2.2.1 Analytical Methods and Validation Reports 4.2.2.2 Absorption 4.2.2.3 Distribution 4.2.2.4 Metabolism 4.2.2.5 Excretion 4.2.2.6 Pharmacokinetic Drug Interactions 4.2.2.7 Other Pharmacokinetic Studies 4.2.3 Toxicology 4.2.3.1 Single-Dose Toxicity 4.2.3.2 Repeat-Dose Toxicity 4.2.3.3 Genotoxicity 4.2.3.3.1 In vitro Studies 4.2.3.3.2 In vivo Studies 4.2.3.4 Carcinogenicity 4.2.3.5 Reproductive and Development Toxicity 4.2.3.5.1 Fertility and Embryonic Development 4.2.3.5.2 Embryo-Fetal Development 4.2.3.5.3 Pre- and Post-natal Development & Maternal Function 4.2.3.5.4 Offspring, Juvenile, Second & Third-Generation Studies 4.2.3.6 Local Tolerance 4.2.3.7 Other Toxicity Studies 4.2.3.7.1 Antigenicity 4.2.3.7.2 Immunogenicity 4.2.3.7.3 Mechanistic Studies (not included elsewhere) 4.2.3.7.4 Dependence 4.2.3.7.5 Metabolites 4.2.3.7.6 Impurities 4.2.3.7.7 Other 4.3 Literature References 6 6 6 6 6 6 6 6 6 6 6 6 6 6 x 6 x x x x x x x x x x x x x x x x x x x x x x x x x x x x x x x x x x x x Module Clinical Study Reports x 5.1 Comprehensive Table of Contents for Module x 5.2 Tabular Listing of All Clinical Studies x 5.2.1 CLIENT Studies x 5.2.2 Tabular Listing of Clinical Investigators x 5.3 Clinical Study Reports x 5.3.1 Reports of Biopharmaceutic Studies x 5.3.1.1 Bioavailability (BA) Study Reports x 5.3.1.1.1 CLIENT Studies x Protocol #### (Food-Effect) x Protocol #### (Food-Effect) (continued) x Protocol #### (Food-Effect) (continued) x Protocol #### (Food-Effect) (continued) 10 x 5.3.1.1.2 REFERENCE LISTED DRUG SPONSOR STUDIES 10 x 10 x Fill in data from NDA Summary Basis of Approval Review 5.3.1.1.3 Published Studies 10 x 5.3.1.1.4 Summary x 5.3.1.2 10 Comparative BA & BE Study Reports 5.3.1.2.1 CLIENT Studies 11 11 x Protocol #### 11 Appendices 16.0 11 40 Appendices 16.1 – Study Information 11 40 Appendices 16.1.1 – Protocol & IRB Approval 11 40 Appendices 16.1.2 – Sample Case Report Form (CRF) 11 58 Appendices 16.1.3 – IRB Membership Roster 11 69 Appendices 16.1.4 – List of Investigators 11 78 Appendices 16.1.5 – Signature Page 11 113 Appendices 16.1.6 – Table of Dosing Dates and Times 11 114 Appendices 16.1.7 – Randomization Scheme and Codes 11 123 Appendices 16.1.8 – Audit Certificate 11 124 Appendices 16.1.9 – Statistical Report 11 125 Protocol #### (continued) 12 Appendices 16.1.9 – Statistical Report (continued) 12 Appendices 16.1.10 – Analytical Report 12 132 Addendum to Method Validation Report 12 200 Protocol #### (continued) 13 Appendices 16.1.10 – Analytical Report (continued) 13 Appendix 16.1.11 – Publications Based on this Study (NA) 13 - Appendix 16.1.12 – Publications Referenced in Report (NA) 13 - Appendix 16.2 – Subject Data Listings 13 419 Appendix 16.2.1 – Discontinued Subjects 13 419 Appendix 16.2.2 – Protocol Deviations (none) 13 - Appendix 16.2.3 – Concomitant Medications 13 421 Appendix 16.2.4 – Subject Demographics 13 422 Appendix 16.2.5 – Table of Deviations from Scheduled Collections 13 425 Appendix 16.2.6 – Individual Efficacy Response (NA) 13 - Appendix 16.2.7 – Adverse Event Listings 13 426 Appendix 16.2.8 – Listing of Individual Lab Measurements ((NA) 13 - Appendix 16.3 – Case Report Forms (CRF) (Subjects – 44) 13 - Appendix 16.3.1 – CRFs for Deaths, Serious AE, & Discontinuations 17 XX Appendix 16.3.2 – Other CRFs Submitted (NA) 13 - Appendix 16.4 – Individual Patient Listings 17 XX Protocol #### 14 Protocol #### 14 Appendices 16.0 14 80 Appendices 16.1 – Study Information 14 80 Appendices 16.1.1 – Protocol & Protocol Amendments 14 81 Appendices 16.1.2 – Sample Case Report Form (CRF) 14 187 Appendices 16.1.3 – IRB Membership & Sample Informed Consent 14 219 Appendices 16.1.4 – List of Investigators 14 270 Appendices 16.1.5 – Signature Page 14 278 Multiple Batches (NA) 14 - Appendices 16.1.7 – Randomization Scheme and Codes 14 281 Appendices 16.1.8 – Audit Certificate (NA) 14 - 14 285 Standardization Methods and QA Procedures 14 304 Appendix 16.1.11 – Publications Based on this Study (NA) 14 320 Appendix 16.1.12 – Publications Referenced in Report (NA) 14 321 Protocol #### (continued) 15 Appendix 16.2 – Subject Data Listings 15 Appendix 16.2.1 – Discontinued Subjects (none) 15 Appendix 16.2.2 – Protocol Deviations – Blood Samples 15 Appendix 16.2.3 – Subjects Excluded from Analysis (none) 15 Appendix 16.2.4 – Demographic Data & Baseline Characteristics 15 Appendix 16.2.5 – Drug Concentration Data 15 12 Appendix 16.2.6 – Individual Data 15 48 Appendix 16.2.7 – Adverse Event Listings 15 93 Appendix 16.2.8 – Listing of Individual Lab Measurements 15 103 Appendix 16.2.9 – Statistical Analysis 15 177 Appendices 16.1.6 – List of Subjects Receiving Test Drugs from Appendices 16.1.9 – Documentation of Pharmacokinetic and Statistical Methods Appendices 16.1.10 – Documentation of Inter-Laboratory Appendix 16.3 – Case Report Forms (CRF) 15 196 Withdrawals for AE (none) 15 196 Appendix 16.3.2 – Other CRFs Submitted (NA) 15 198 Appendix 16.4 – Individual Subject Data Listings 15 199 Appendix 16.5 – Analytical Report 15 200 Appendix 16.6 – Validation Report 15 365 5.3.1.2.2 REFERENCE LISTED DRUG SPONSOR STUDIES 16 x FILL IN AS NEEDED: Summary Basis of Approval Review 16 x FILL IN AS NEEDED: Summary Basis of Approval Review 16 x FILL IN AS NEEDED: Summary Basis of Approval Review 16 x Appendix 16.3.1 – CRFs for Deaths, Other Serious Adverse Events, & 5.3.1.2.3 Published Studies 16 x 5.3.1.2.4 Summary x 16 5.3.1.3 In vitro/In vivo Correlation (IV/IVC) 16 x 5.3.1.4 Bioanalytical and Analytical Methods 16 x 5.3.2 Reports of Studies Pertinent to Human PK 16 x 5.3.2.1 Plasma Protein Binding Study Reports 16 x 5.3.2.2 Hepatic Metabolism/Drug Interactions 16 x 5.3.2.3 Studies Using other Human Materials 16 x 5.3.3 Reports of Human PK Studies 16 x 5.3.3.1 Healthy Subject PK and Tolerability 16 x 5.3.3.2 Patient PK and Initial Tolerability 16 x 5.3.3.3 Intrinsic Factor PK 16 x 5.3.3.4 Extrinsic Factor PK 16 x 5.3.3.5 Population PK 16 x Reports of Human PD Studies 16 x 5.3.4.1 Healthy Subject PD and PK/PD Studies 16 x 5.3.4.2 Patient PD and PK/PD 16 x 5.3.5 Reports of Efficacy and Safety Studies 16 x 5.3.5.1 Controlled Clinical Studies on Indication 16 x INDICATION # 16 x 5.3.5.1.A.1 CLIENT Studies 16 x 5.3.5.1.A.2 NDA ##,### Sponsor Studies 16 x 5.3.5.1.A.3 Published Studies 16 x 5.3.5.1.A.4 Summary 16 x 5.3.5.3.1.B INDICATION # 16 x 5.3.5.1.B.1 CLIENT Studies 16 x 5.3.5.1.B.2 NDA ##,### Sponsor Studies 16 x 5.3.5.1.B.3 Published Studies 16 x 5.3.5.1.B.4 Summary 16 x Uncontrolled Clinical Studies 16 x 5.3.4 5.3.5.1.A 5.3.5.2 5.3.5.2.1 CLIENT Studies 16 x 5.3.5.2.2 NDA ##,### Sponsor Studies 16 x Summary Basis of Approval: Clinical Review 16 x 5.3.5.2.3 Published Studies 16 x 5.3.5.2.4 Summary x 16 5.3.5.3 Reports of Analyses of Data from More than One Study 16 x 5.3.5.3.1 Integrated Summary of Safety 16 x 5.3.5.3.1.A INDICATION # 16 x 5.3.5.3.1.B INDICATION # 16 x 5.3.5.3.2 Integrated Summary of Efficacy 16 x INDICATION # 16 x INDICATION # 16 x 5.3.5.4 Other Clinical Study Reports 17 x 5.3.6 Reports of Post-Marketing Experience 17 x 5.3.6.1 Regulatory History of NDA ##,### 17 x 5.3.6.2 Generic Approvals 17 x 5.3.6.3 Safety Data from Post-Marketing Surveillance 17 x 5.3.6.3.1 Foreign Marketing Data in Support of the Original NDA 17 x 5.3.6.3.2 US Post-Marketing Surveillance Data 17 x 5.3.7 Case Report Forms (CRF)/Individual Patient Listings 17 x 5.3.7.1 Protocol ##### – BE Study 17 x 5.3.7.2 Protocol ##### – Food-Effect Study 17 x 5.4 Literature References 18 x Literature References (continued) 19 x b) ACTD c) eCTD Importance of stability studies while submitting dossiers Importance of Impurity profile (Related Substances) while submitting dossiers Bioavailability and Bioequivalence studies (BA & BE) ... 2.5.7 Clinical Overview Product Development Rationale Overview of Biopharmaceutics Overview of Clinical Pharmacology .Overview of... Nonclinical Overview Overview of the Nonclinical Testing Strategy Pharmacology Pharmacokinetics Toxicology Integrated Overview. .. prepared by a pharmaceutical manufacturer and submitted solely at its discretion to the appropriate regulatory authority in the intended drug market Drug Master File (DMF) is a document containing