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    be considered to be complied with unless such word, statement, or other information also appears on the outside container or wrapper, if any there be, of the retail package of such article, or is easily legible through the outside container or wrapper. Labeling Sec. 201(m): The term “labeling” means alll labels and other written, printed, or graphic matter (1) upon any article or any of its containers or wrappers or (2) accompanying such article. New Drug Sec. 201(p): The term “new drug” means (1) any drug (except a new animal drug or an animal feed bearing or containing a new animal drug) the composition of which is such among experts qualified by scientific training and experience to evaluate the safety and effectiveness of drugs, as safe and effective for use under the conditions prescribed, recom- mended, or suggested in the labeling thereof, except that such a drug notso recognized shall not be deemed to be a “new drug” if at any time prior to the enactment of this Act it was subject to the Food and Drugs Act of June 30, 1906, as amended, and if at such time its labeling contained the same representations concerning the conditions of its use or (2) any drug (except a new animal drug or an animal feed bearing or containing anew animal drug) the composition of which is such that such drug, asa result of investigations to determine its safety and effectiveness for use under such conditions, has become so recognized, but which has not, otherwise than in such investi- gations, been used to a material extent or for material time under such conditions, New Animal Drug Sec. 201(w): The term “new animal drug” ‘means any drug intended for use for animals other than man, including any drug intended for use in animal feed but not including such animal feed (1) the composition of which is such that such drug is not generally Fecognized, among experts qualified by ——s scientific training and e rience to evz the safety and effectivences of animal get as safe and effective for use under the conditions prescribed, recommended, or suggested in the labeling thereof; except thet such a drug not so recognized shall not be deemed to be a “new animal drug” if at any time prior to June 25, 1938, it was subject tp the Food and Drug Act of June 30, 1906, ag amended, and if at such time its labeling contained the same representations conces: ning the conditions of its use or (2) the composition of which is such that such as a result of investigations to determine itt safety and effectiveness for use under such conditions, has become so recognized but Which has not, otherwise than in such investi- gations, been used to a material extent ot for a material time under such conditions or (3) which drug is composed wholly or partly of any kind of penicillin, streptomycin, chlor tetracycline, chloramphenicol, orbacitracin, or any derivation thereof, except when there is in effect a published order of the Secretary declaring such drug not to be a new animal drug on the grounds that (A) the requirement of certification of batches of such drug, as provided for in section 512(n), is not necessary to insure that the objectives specified in Paragraph (3) thereof are achieved and (B) that neither subparagraph (1) nor (2) of this Paragraph (Ww) applies to such drug. Animal Feed Sec. 201(x): The term “animal feed,” as in paragraph (w) of this section, in: and in provisions of this Act referri Paragraph or section, means an art Js intended for use for food for anim ry (2 which affect a small Population. The small fairs 1139 jently viable market for dru 8 Sponsors Hecover the high costs of therapeutic addrac at to forch andl development, RUE Eee the hetthclated stety of bi profit, Food and Drug Administration prevent Bea Cone iba) amended the incentives estab ation proton agency in he Us federal gave orphan Drug Act (ODA) (1983) lished in ment, The USTDA ta scenic reglatory, Aste development of potentially ae Pee agency tha ovens Ratios pag, Sen ah et Say resistance from the FDA i by the cor ; tory DA in the form of Giririnartaaa sa vRstLED ar edn er than atten recommendations fornon-clinical and dinical investigations for marketing approval ‘meat and poultry), human and animal drugs, ‘ses, (ii) a tax credit covering 50% of the therapeutic agents of biological origin, Fiinical drug testing expenses, (iii) federal pete devices, radiation-emitting products funding of grants and contracts to help defray for consumer, medical, and occupational use, uch expenses and (iv) a seven-year eee eee feed. FDA monitors the Sarketing tights to the sponsor of the Bieepabenest tal ee por eae ees jnnovator drug after approval. To qualify for aS trillion worth of products these benefits, the sponsor would need to ei ee eae EAS an orphan drug designation from the r : original enacted, the FDA won grant Riecenee if the disease or a ae sae SESS aae iquestion occurred so infrequently (less than EDA is organized into a number of offices and 200,000 persons) in the United States that there centers headed by a commissioner who i was no reasonable expectation that the costs epee py A President with consent of wpa cveloping and making the drug available the senate. These offices and centers are Would be recovered from its sales in the assigned with different responsibsities "9 United States. As such, all sponsors were Seer eee of FDA. There are required to provide to the FDA detailed ey financial information to demonstrate the ° Center for Drug Evaluation and Research anticipated lack of profitability, regardless of (CDER) how rare a drug's target population would be. « Center for Biologics Evaluation and Research (CBER) ‘The Act initially allowed only designated 4 orphan drugs ior which a United States * Center for Devices and Radiological Health, ify (CDRH) «= Center forFood Safety and Applied Nutrition Letter of Patent may not be issued” to due for the seven-year marketing ‘exclusivity. In 1985, the Act was amended to make all 5 eligible for this incentive, regardless of their patentability. In addition, drified that antibiotics would for orphan drug incentives: all foods, drugs, cosmetics ma Inthe United States, th humans and medical devices for bo! Drug, and Cosmetic Act (Fl tum established the FDA. The “its regulations were created PY nt Ta Tre Treen restos incielie Sees imports, inspections, and enforcement policies. ORA supports the five FDA Product Centers by inspecting regulated products and manufacturers, conducting sample analysis on regulated products, and reviewing imported products offered for entry into the United States, ORA also develops FDA-wide policy ‘on compliance and enforcement, and executes FDA’s Import Strategy and Food Protection Plans. Office of Generic Drugs (OGD) OGD is a part of FDA’s Center for Drug Evaluation and Research. It is dedicated to approving safe, effective, high-quality and bioequivalent generic drug products for use by consumers. Office of Orphan Products (OOPD) OOPD is dedicated to promoting the develop- ment of products that demonstrate promise for the diagnosis and/or treatment of rare diseases or conditions since 1982. OOPD interacts with the medical and research communities, professional organizations, academia, and the pharmaceutical industry, as well as rare disease groups. The OOPD administers the major provisions of the ODA which provide incentives for sponsors to develop products for rare diseases. The ODA has been very successful—more than 200 drugs and biological products forrare diseases have been brought to the market since 1983. In contrast, the decade prior to 1983 saw fewer than ten such products coming into the market. Inaddition, the OOPD administers the Orphan Products Grants Program which provides funding for clinical research in rare diseases. Office of Combination Products (OCP) Combination Products Combination products are defined in 21 CFR 3.2(e). The term combination product includes: 1. A product comprising of two or more regulated components, i.e. drug/device, biologic/device, drug biologic, or drug/ device /biologic, that are physically, chemi- cally, or otherwise combined or mixed and produced as a single entity. 2. Two or more separate products pa togetherina singlepackageorae eee comprising of drug and device products device and biological products, ot biolo. gical and drug products. 3. A drug, device, or biological product packaged separately that according to its Investigational plan or proposed labeling is intended for use only with an approved individually specified drug, device, or biological product where both are required to achieve the intended use, indication, or effect and wherein upon approval of the proposed product, the labeling of the approved product would need to be changed, e.g. to reflect a change in the intended use, dosage form, strength, route of administration, or a significant change in the dose. 4, Any investigational drug, device, or biological product packaged separately that according to its proposed labeling is for use only with another individually specified investigational drug, device, o biological product and where both are required to achieve the intended use, indication, or effect. The FDA OCP was established on December 24, 2002. The specific roles of OCP are + To serve as a focal point for the issue of combination product for agency reviewers and industry, * To develop guidance and regulations to clarify the regulation of combination products. * To assign an FDA center to have primary jurisdiction for review of both combination and single entity (i.e. non-combination) products where the jurisdiction is or in dispute. f * To ensure timely and effé n review of combination oresolve disputes regarding the timeliness of pre-market review of combination ofucts. ite agreements, guidance documents, tices specific to the assignment of bination products. DA Office of Ombudsman is the agency's joint for addressing complaints and sting in resolving disputes between spanies or individuals and FDA offices ing fair and even-handed application FDA policy and procedures. It serves as a al and independent resource for ers of FDA-regulated industries when experience problems with the regulatory s that have not been resolved at the ter or district level. It works to resolve ally and internally generated problems there are no legal or established of redressing by finding approaches acceptable to both the affected party the agency. The organizational chart he FDA is presented in Fig. 30.1 with the FDA, other agencies which sponsibilities for regulating pharma- ical products are: Trade Commission (FTC) authority over business practices in ‘such as deceptive and anti-competitive . false advertising of drugs. In the advertising of ‘OTC t Commission zardous substances and ‘and other harmful jon Agency (EPA) s used in areal oducts. It basically m« a eate unnecessary and excessive murdens on the environment such and land. Occupational Safety and Health Admi ion (OSHA) It regulates the working environment of employees who may use FDA-regulated commodities, ie. syringes, chemotherapeutics, and chemical reagents. Drug Enforcement Administration (DEA) It enforces the federal Controlled Substances Act (CSA) and is charged with controlling and monitoring the flow of licit and illicit controlled substances, There are various state and local drug control agencies also which establish their ‘own regulations and procedures for manu- facturing, research, and development of pharmaceuticals. TYPES OF APPLICATIONS Following are the types of drug approval applications that are submitted to the FDA: * Investigational New Drug Application * New Drug Application ‘* Abbreviated New Drug Application © Biologic License Application * Over-the-counter (OTC) drug application. Investigational New Drug (IND) Current Federal law requires that a drug be the subject of an approved marketing appli- cation before it is transported or distributed across state lines. An IND, or investigational new drug application, is a submission to the US Food and Drug Administration (FDA) requesting permission to initiatea clinical study ofa new drug product in the United States. 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. During a new drug’s early pre development, the sponsor's pri determine if the products rea jnitial use in humans and if exhibits pharmacological activi commercial development. WE identified as a viable candi ke jment, the sponsor then focuses on the data and information necessary Bh that the product will not expose fo unreasonable risks when used in early-stage clinical studies. “g rale in the development of a new gins when a drug's sponsor (usually ‘ufacturer or potential marketer) ngscreened thenew molecule for pharma- Pal activity and acute toxicity potential tic potential in humans. At that point, changes in legal status under the Drug, and Cosmetic Act and new drug subject to specific of the drug regulatory system. IND types ion, and under whose immediate on the investigational drug is admi- ed or dispensed. A physician might nita research IND to propose studying unapproved drug, or an approved for a new indication or in a new cy use IND allows the FDA to e the use of an experimental drug ation must contain information in zi ‘and toxicology studies: Tt preclinical data to permit a Affairs 1143 assessment as to wh reasonably safe for it a ee Also included are any previous experiences i is experiences oe the drug in humans (often foreign use). etn information: Tt comprises of mn pertaining to the composition, manufacturer, stability, and controls used for manufacturing the drug substances and drug products. This information is assessed to ensure that the company can adequately produce and supply consistent batches of the drug. Clinical protocols and investigator informa- tion: Detailed protocols for the proposed clinical studies to assess whether the initial- phase trials will expose subjects to unnece- ssary risks. Also, information on the qualifi- cations of clinical investigators-professio- nals (generally physicians) who oversee the administration of the experimental com- pound to assess whether they are qualified to fulfill their clinical trial duties. Finally, it contains commitments to obtain informed consent from the research subjects, to obtain. review of the study by an institutional review board (IRB), and to adhere to the investigational new drug regulations. ‘Once the INDis submitted, the 5} yonsor must wait 30 calendar days before initiating any Clinical trials. During this time, FDA has an ‘opportunity to review the IND for safety to assure that research subjects will not be subjected to unreasonable risks. The act directs the FDA to place investigations on clinical hold if the drug involved presents risks to the safety of the subjects. Cli js an order issued by the FDA tot delay a proposed clinical investigatio suspend an ongoing investigation may not be given the investiga the hold may require that no enrolled into an ongoing study. hold can be issued before the er day IND review period to p from initiating a proposed p time during the life of an IND. 1144 jific evaluation of drugs is ae snevaluation of the drug's id safety. Therefore, although f Phase 1 ae eu ‘assessing the safety of Phase etna FDA's review of Phases 2 and 3 submissions will also include an assessment bf the scientific quality of the clinical investi- gations and the likelihood that the investi- gations will yield data capable of meeting Statutory standards for marketing approval. IND Application Process INDs can be withdrawn by the sponsor or terminated by the FDA. If no subjects are centered into clinical studies for a period of two ‘years or all investigations are on clinical hold for one year or more, the IND may be placed on inactive status, either at the sponsor's request or at the FDA’s initiative. If the IND remains on inactive status for five years or if FDA is unable to resolve deficiencies through a clinical hold or other alternative, it is terminated. of the scien! adequate to pe effectiveness an FDA’s review of Content and Format of IND Application A sponsor who intends to conduct a clinical investigation subject to this part shall submit an “Investigational New Drug Application” including, in the following order: (1) Cover sheet (Form FDA-1571) The Form 1571 is a required part of the initial IND and every subsequent submission related to the IND application. Each IND ‘Amendment, IND Safety Report, IND a, IND Annug, Must include hee 1571. It serves as a cover sheet 2o™ submissions and provides the FDA wah ND information about the submission se the sponsor, IND number, name of the ws! type of submission, serial number, and contents of the application. Each subavact® to the IND must be consecutively num starting with the initial IND applicatn” which is numbered 0000, The nextsubmnssey, (response to clinical hold, correspondence amendment, etc.) should be numbered 0001, with subsequent submissions numbered consecutively in the order of submission There are significant commitments involved with the signing of FDA Form 1571 and the sponsor should be aware that signing the Form 1571 is more than a formality, Making 3 willfully false statement on the Form 1571 or accompanying documentation is a criminal offence. Detailed information on completing the Form 1571 can be found on the FDA Website, in section 312.23(a)(1) and from the FDA review division responsible for reviewing the IND. ‘ IND Amendment A submission to the IND file that a or revised information. Every sub adds to, revises, or affects information within the IND considered an IND amend amendments and informati two examples of i Report, or general correspondence is submitted wh conduct a new s design or con study protocol, or Period after the adding new inves! r tion amendment: An infor _infrent is used to submit new ee eg col08y, clinical, or other informatie atpes not fall within the scope of a protocol eadment, armiual report, or IND safety in expedited report sent (within 15 calendar ays of sponsor's receipt) to the FDA and all articipating investigators of a serious and xxpected adverse experience associated use of the drug or findings from non- report to the FDA on the progress of cal investigations. It is submitted each thin 60 days of the anniversary date D went into effect. by section, volume, and page e table of contents should include red sections, appendices, attach- reports, and other reference material tory statement and general investi- nal plan; This part should include on about the indication(s) to be ied, name of the drug and all active the drug's pharmacological class iral formula (if known), the , dosage form(s) to be used, ‘and broad objectives of the proposed clinical ‘the drug has been previo- d to humans, the intro- Should include a brief yerience to date, of the drug in reasons, { reasons for withdrawal briefly discussed in the its 1145 Investigator’s brochure 1B): ‘The: a “ isa key document t! res a ope Seu esHeAler and the insti- sites. The oard at each of the clinical tes. The IB presents, in summary form, the ee ae (safety), clinical, and CMC juality) data that su . ee: c support the proposed Protocols: A clinical protocol describes how a particular clinical trial is to be conducted. It describes the objectives of the study, the trial design, the selection of subjects, and the manner in which the trial is to be carried out. The initial IND is required to have a clinical protocol for the initial planned study. Proto- cols for Phase 1 studies may be less detailed and more flexible than those for Phase 2 and 3 studies. In Phases 2 and 3 detailed protocols describing all the aspects of the study should be submitted. Content and format of the protocols are provided in detail in 21 CFR, Section 312.23 and ICH guidance E6: Good Clinical Practices guidance document. Chemistry, manufacturing, and control (CMC) information: This key section of an IND describes the quality information, comprising the composition, manufacturing process and control of the drug substance and drug product. The CMC ‘section must provide sufficient details and information to demons- trate the identity, quality, purity, and potency of the drug product. The amount of mation to be submitted depends upo scope of the proposed clinical inves For a phase 1 IND the CMC provided for the raw materi investigator's that is provided stance, and drug product ciently detailed to the safety of the st trial. A safety concern make it impossible f safety evaluation, are clinical hold based requires that any dru administration to in conformance products which manufactured i requirements. mation about the drug substance, inactives and final drug product, this section should also include a copy of all labels and labeling tobe provided to each investigator anda claim for categorical exclusion from environmental assessment, Pharmacology and toxicology information: The pharmacology and toxicology section of the IND includes the nonclinical safety data that the sponsor generated to conclude that the new drug is reasonably safe for clinical study. Such information is required to include the identification and qualifications of the individuals who evaluated the results of such. studies and concluded that it is Teasonably safe to begin the proposed investigations and a statement of where the investigations were conducted and where the records are available forinspection. As drug development proceeds, the sponsor is required to submit informa. tional amendments, as appropriate, with additional information pertinent to its safety. Requirements on content of this section can be found in 21 CFR, Section 312.23, Adeclara- tion that each nonclinical safety study reported in the IND was performed in full compliance with Good Laboratory Practices (GLP) or if a study was not conducted in compliance with GLP, a brief statement of why it was not, and a discussion on how this might affect the interpretations ofthe findings is required to be submitted, Previous human experience with the investi- Sational drug: A summary of previous human experience known to the applicant, if any, with the investigational dru as 8 ig should be information: In certain applicati as described below, information ea special {Opies may be needed. Such information shall experience, and studies i . Should be inch cuales in test animals it, Ratiactie drags Ifthe drug is radioactive, PUA sient data oom auimat ce gee s to allow a reasonable calculation, or aati vaneerte dose to the whole body and critical organs upon adminis- tration to a human subject should be included. Phase 1 studies of radioactive drugs must include studies which will obtain sufficient data for dosimetric calculations. é 5 Pediatric studies: Plans for assessing pediatric safety and effectiveness should be incorporated. iv. Other information: A brief statement of any other information that would aid the evaluation of the proposed clinical investi- gations with respect to their safety or their design and potential as controlled clinical trials to support marketing of the drug should be incorporated. Relevant information: Any information specifically requested by the FDA that is needed to review the IND application. It is common to place the meeting, minutes from. any pre-IND meeting or discussion in this section. This is especially useful if the information is referenced elsewhere in the IND. iq _tbeling investigational drugs: Labels of investigational drugs are required to carry the following statement: “Caution: New Dru 1 Limited by Federal (or United States) law to. investigational use”, Promotion and Charging of an IND A sponsor or investigator, or a1 acting on behalf of a sponsor or inv, shall not represent in a promotion: that an investigational new effective for the purposes for. investigation, or otherwise p Administra eo nee TV nsidered a part of the normal cost of s. The sponsor may not commer- investigational drug by charging a than that necessary to recover manufacture, research, development ing of the investigational drug” rug Application (NDA) the sponsor of a new drug believes that vidence on the drug’s safety and ess has been obtained to meet FDA's nents for marketing approval, the ‘submits to FDA a New Drug Appli- (NDA). The application must contain fom specific technical viewpoints for y, including chemistry, pharmacology, eutics, biopharmaceutics, and statistics, DA is approved, the product may be ‘in the United States. drug application is the single most ant filing necessary to obtain marketing, for a drug in the United States. The is organized into specific, technical s, which are evaluated by speciali: teams of highly qualified experts. her, the review teams will make 2 to rove or disapprove ter ey drug evaluation and research » group at the FDA charged with DAs for drugs and some biologic ‘s authority to require a jlicant marke- d States) is clearly food, drug and Bees cai such drug; (D) Fs of tien methods used inane and controls used fo and (G) any assessments requi 4 quired under Section 505B. The applicant shall file with the application the patent number and the Ren date ‘of any patent which claims the rug for which the applicant submitted the application or which claims a method of using such drug and with respect to which a claim of patent infringement could reasonably be asserted if a person not licensed by the owner engaged in the manufacture, use, or sale of the drug. Based on the requirements of the Act, FDA has published the detailed requirements on the content of NDA in 21 CFR, Part 314, which are as follow: Application form (FDA form 356H): This form is to be submitted with each original NDA and every supplement thereof. The form can be downloaded from the FDA website. FDA publishes and updates this form periodi- cally. The form contains information about the sponsor, the drug and the proposed indica- tion, as well as a checklist of the items contained in the NDA. If the applicant is not, located in the United States, the form must name an agent with a US address. Index (for paper copies only): Thearchival copy (copy that is retained by FDA as reference) of the application is required to contain a comprehensive index by volume number and page number to the summary under paragraph (c) of this section, the technical sections under paragraph (d) 0 section, and the supporting und paragraph (f) ofthis section. Summary: The applicatio (required for only original abbreviated version of the entire app) ‘Application summary should be ws enough detail that the reader may gain a general understanding of the information in the application, understanding of the quantit the data. The summary is the following information: ~The Treery ere renee oF indieie a nation under the following. Md subheadings inthe following specific inf headings an« o ighlightsofpresertbing information: This section should not be more than one page: It is incorporated to facilitate the inform: by prescribers. a tenn * Boxed warning * Recent major changes * Indications and usage * Dosage and administration * Dosage forms and strengths * Contraindications ‘+ Warnings and precautions * Adverse reactions + Drug interactions * Use in specific populations Full Prescribing Information: Contents a. Full prescribing information b. Boxed warning 1 Indications and usage 2. Dosage and administration 3. Dosage forms and strengths 4. Contraindications 5. Warnings and precautions 6. Adverse reactions 7. Drug interactions 8. Use in specific populations 8.1 Pregnancy 82 Labor and delivery 8.3 Nursing mothers 8.4 Pediatric use 85 Geriatric use 9. Drug abuse and dependence 9.41 Controlled substance 92 Abuse 93 Dependence 10. Overdosage 11. Description 2 Clinical pharmacology a. Carcinogenesis, mutagenesis, impaig. ment of fertility b. Animal toxicology and/or pharma. cology 14, Clinical studies 15. References 16. How supplied /storage and handling 17, Patient counseling information. Medication guide: A medication guide is required for prescription drug or biological products when FDA has determined that either the product poses a serious and significant public health concern or for that it isneeded to ensure patients’ safe and effective use of the product. The medication guide content outline is; * Brand name (established name). * Most important information to know about the drug Who should not take the drug How to take the drug What to avoid while taking the drug * Possible or reasonably likely side effects of the drug * General information. Manufacturer/distributor should ensure that a separate medication guide is made available to each patient to whom the drug Product is dispensed. Care should be taken to ensure that the content of the medication guide is not promotional in nature. : 1. Astatementidentifying the pha class, scientific rationale for the d intended use, and the potent benefits of the drug product, ~ Foreign marketing history. . A summary of the che: facturing, and controls sec application: This section s CMC information inactives and drug pi . A summary of the cology and toxicology application, . A summary of the hun cokinetics and bioay the application. a summary of the microbiology section Aine application (for anti-infective drugs only): As summary of the clinical data section the application, including the results 6 statistical analyses of the clinical trials. A concluding discussion that presents the benefit and risk considerations felated to the drug, including a discus- ion of any proposed additional studies or surveillance the applicant intends to conduct post-marketing Technical Sections The application is required to contain the technical sections described below. Each technical section is required to contain data and information in sufficient detail to permit the agency to make a knowledgeable judg- ment about whether to approve the applica- tion or whether grounds exist under Section 505(d) of the act to refuse to approve the application. The required technical sections areas follows: Chemistry, manufacturing and controls (CMC); A section describing the compo- “sition, manufacture, and specification of the drug substance and the drug I ; The applicant may, at its option, ‘a complete chemistry, manu- and controls section 90 to 120 efore the anticipated submission der of the application. FDA es permit, uclinical pharmacology and toxicology infective drug) Clinical data section. Statistical section: A section describing the Statistical evaluation of the clinical data. + Pediatric use section: A section describing __ the investigation of the drug for use in _ Pediatric populations. fairs 1149 Samples and Labeling Samples of the drug substance, drug product, reference standards, blanks and final ‘marketed package. Samples re tobe provided in sufficient quantity so as to enable FDA to perform the tests specified in the application up to three times. Copies of the label and alll labeling for the drug product (including, if applicable, any Medication Guide required) for the drug product (4 copies of draft labeling or 12 copies of final printed labeling). Case Report forms and Tabulations Patent Information ‘An applicant is required to disclose all patent information that is related to the drug for which the NDA is being filed and to verify that the sponsor has all rights necessary to legally manufacture, use, and sell the drug, if the NDA is approved. The patent inquiry is a broad one and covers drug substance (active ingredient) patents, drug product (formu- lation and composition) patents, and method- of-use patents Patent Certification and Claimed Exclusivity The NDA is required to contain information. regardingall financial interests or arrangements. between clinical investigators, their spouses and immediate family members, and the sponsor of the clinical trials that support the NDA. The applicant should submit an FDA Form 3454 to certify which investigators hi no financial interests or arrangemer FDA Form 3455 is submitted to dis financial interests or arrangement investigator that could affect the 0 the study and a description of the to minimize the potential bias of results. User Fee Cover Sheet (FORM | FDA charges the sponsors of reviewing and approving an N thus collected is utilized for employed with FDA and other 1150 le FDA. A User Fee Cover Sheet is to be comp! ted and submitted with each new drug or biologic product NDA. The form provides a cross-reference to the user fee paid by the applicant. Debarment Certification FDA uses its powers to debar persons from involving Peeve any activity related to the applications filed with FDA. This cae is taken against those individuals, who ED: thinks/finds have made false, misleading commitments to the FDA intentionally or unintentionally, which can render the approved drug unsafe for human consumption. All applications filed with FDA are required to contain a statement certifying that the applicant did not and will not use in any capacity the services of any person debarred by the FDA. Once an NDA is approved, any significant change in the manufacturing, control, packa- ging, or other physical properties of the drug, or any change in its labeling that may have an effect on safety and effectiveness relative tocither the drug itself or the mannerin which it is used must be covered by a supplemental new drug application. ‘The requirements of an NDA for prescrip- tion and over-the-counter drugs are similar. It is extremely rare, however, that any new chemical entity would be approved by the FDA for over-the-counter sale for reasons of lack of sufficient data to support the safety in Use of a totally “new” drug. Since the basic test is the ability to provide on the label adequate directions for use, most applications Specifically for over-the-counter drugs would is to be supplemental applications, mainly Particular showing that the drug might be safel it " Pe aately used without direct medical super- Once approved, iti several conditions must met in connection with an nee some prom, ia san submitted with clinical experience Reerepore of human basis. The first reports are due poe of three months, beginning with. a date of approval of the application, during the first three years, and annually thereafter. Records reflecting clinical experience with the drug must be retained, and must be available for inspection. The reports required at the aforementioned intervals must include unpublished reports of clinical experience, studies, investigations, and tests conducted by the applicant or reported to him, unpublished reports of animal experience, experience involving the chemical, or physical properties of the drug, and any information that might affect the safety or efficacy of the product, These may be submitted on forms FD-1639, FD-2253, or FD-2252. The FDA requires immediate reporti (called NDA Field Alert Report) of informa. tion concerning any mix-up in a drug or its labeling with another article; information concerning any bacteriologic or any significant chemical, physical, or other changes, or deterioration in the drug; or any failure of one or more distributed batches of the drug to meet the specifications established fort in the New drug application. This information could, of course, form the basis for a recall, Such information is to be submitted to the FDA within 3 working days from the day, when such information came into the notice of the applicant, Certain other information must mitted as soon as possible-in any eve 15 working days of receipt. This would pertain to serious and effects, injury, toxicity, incidents associated investigations, or t are determined to for the review and ultimate approval neric drug product. Generic drug sare called “abbreviated” because erally not required to include (animal) and clinical (human) data safety and effectiveness. Instead, icapplicant must scientifically demon. at its product is bioequivalent (ie. jin the same manner as the innovator nce approved, an applicant may e and market the generic drug provide a safe, effective and low tive to the American public. Harris Drug Amendment (1962) that facilitated the growth of the industry. Paper NDA (a provision efauver-Harris Drug Amendment, e the early equivalents to today's JA, wherein the submission used to in copies of published literature (on efficacy) and bioequivalence the generic drug to the idence of safety and “abbreviated” ly for drugs approved were labeled safe and balance the com- five aspects of the generic It created provisions for y, patent term-extension nd options of Suitability 505(b)2 and, 180-day jvity to the post-innovator licants were provided a protec~ ough Marketing exclusivity NCE exclusivity, 3 years for new tions). During this period no -was allowed to enter into the e provision was aimed at letting recover the investments mare the drugs. All the NDA were ist the relevant patents for the P . Besides this, NDA drugs 9 protected through patents. NDA were required to identify and patents with the NDA at the time of initial filing. New ital patents could b to this list over the life cycle of the eee Generic drug applications are required to prove that they are therapeutically: avait to innovator drugs. This is accomplished by demonstrating: * Bio-equivalence * Pharmaceutical equivalence * Compliance with cGMP requirements ‘* Sameness of labeling with the innovator approved labeling: Generic labels could not include the exclusivity or patent Protected information. Only differences allowed between the labeling of generic drugs and innovator drugs were those related to the manufacturers like descrip- tion of the finished products, ingredients of the formulations, NDC number of the formulations, etc. Generic drugs were also required to include certifications of the status of all patents to the reference innovator drug. Accordingly the generic submissions are categorized as: Paragraph I filings: No patent information has been previously submitted to the FDA. Paragraph If filings: All the submitted patents relevant to drug have expired. Paragraph III filing: If the applicant states that he intends to market the drug only after the expiry of the listed patents. Paragraph IV filings: If the applicant certifies that any product or used patent invalid or will not be infringed by the; drug approval. In such cases, the must give a notice to the innovate If the innovator thinks that g approval will infringe upon his pat he can sue the generic applican days of receiving the notice. ‘circumstances, an automatic stay p ‘to 30 months (pending resolution) on to the generic drug app! drug application is not revi during this period. FDA has icsied a of ANDA filings. to comply with this checklist CTD (common technical d soa — fr ET nse Application (BLA) Sea atone ee marke der the provisions of the Public vor {ing un PHS) Act. The Act requires a firm who ae res a biologic for sale in interstate aaa a fo holda license for the product. A commerce omission that contains specific information on the manufacturing recesses pharmacology, ¢

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