PRESENTED BY: BHAVISHA JETHWA, M. PHARM. DEPARTMENT OF PHARMACEUTICS AND PHARMACEUTICAL TECHNOLOGY, L. M. COLLEGE OF PHARMACY HISTORY AND VARIOUS PHASES OF DRUG DEVELOPMENT AND DRUG APPROVAL PROCESS, NDA

Contents: History of drug development & drug approval process Various phases of drug development & drug approval process NDA References

History of drug development & drug approval process YearMilestone 1820 Eleven physicians met in Washington, D.C., to establish the U.S. Pharmacopeia, the first compendium of standard drugs for the U.S Drug Importation Act passed by Congress requires U.S. Customs Service inspection to stop entry of adulterated drugs from overseas.

1905 Samuel Hopkins Adams' ten-part exposé of the patent medicine industry, "The Great American Fraud," begins in Collier's. The American Medical Association, through its Council on Pharmacy and Chemistry, initiates a voluntary program of drug approval that would last until To earn the right to advertise in AMA and related journals, companies submitted evidence, for review by the Council and outside experts, to support their therapeutic claims for drugs.

1906 The original Food and Drugs Act is passed by Congress on June 30 and signed by President Theodore Roosevelt. It prohibits interstate commerce in misbranded and adulterated foods and drugs. The Meat Inspection Act is passed the same day. Shocking disclosures of insanitary conditions in meat-packing plants, the use of poisonous preservatives and dyes in foods, and cure-all claims for worthless and dangerous patent medicines were the major problems leading to the enactment of these laws.

1912 Congress enacts the Sherley Amendment to overcome the ruling in U.S. v. Johnson. It prohibits labeling medicines with false therapeutic claims intended to defraud the purchaser, a standard difficult to prove.

1914 The Harrison Narcotic Act imposes upper limits on the amount of opium, opium-derived products, and cocaine allowed in products available to the public; requires prescriptions for products exceeding the allowable limit of narcotics; and mandates increased record-keeping for physicians and pharmacists that dispense narcotics. A separate law dealing with marihuana would be enacted in 1937.

1933 FDA recommends a complete revision of the obsolete 1906 Food and Drugs Act. The first bill is introduced into the Senate, launching a five-year legislative battle. FDA assembles a graphic display of shortcomings in P'ceutical & other regulation under the 1906 Act, dubbed by one reporter as the Chamber of Horrors, exhibited nationwide to help draw support for a new law.

1937 Elixir Sulfanilamide, containing the poisonous solvent diethylene glycol, kills 107 persons, many of whom are children, dramatizing the need to establish drug safety before marketing and to enact the pending food and drug law.

1938 The Federal Food, Drug, and Cosmetic Act of 1938 is passed by Congress, containing new provisions: 1.Requiring new drugs to be shown safe before marketing -starting a new system of drug regulation. 2.Eliminating the Sherley Amendment requirement to prove intent to defraud in drug misbranding cases. 3.Extending control to cosmetics and therapeutic devices.

4. Providing that safe tolerances should be set for unavoidable poisonous substances. 5. Authorizing standards of identity, quality, and fill-of-container for foods. 6. Authorizing factory inspections. 7. Adding the remedy of court injunctions to the previous penalties of seizures and prosecutions.

1938 Under the Wheeler-Lea Act, the Federal Trade Commission is charged to oversee advertising associated with products, including pharmaceuticals, otherwise regulated by FDA. FDA promulgates the policy in August that sulfanilamide and selected other dangerous drugs must be administered under the direction of a qualified expert, thus launching the requirement for prescription only (non-narcotic) drugs.

1941 Insulin Amendment requires FDA to test & certify purity & potency of this life-saving drug for diabetes. Nearly 300 deaths and injuries result from distribution of sulfathiazole tablets tainted with the sedative, phenobarbital. The incident prompts FDA to revise manufacturing & quality controls drastically, the beginning of what would later be called good manufacturing practices (GMPs).

1945 Penicillin Amendment requires FDA testing and certification of safety and effectiveness of all penicillin products. Later amendments would extend this requirement to all antibiotics. In 1983 such control would be found no longer needed and abolished.

1948 Supreme Court rules in U. S. v. Sullivan that FDA's jurisdiction extends to the retail distribution, thereby permitting FDA to interdict in pharmacies illegal sales of drugs--the most problematical being barbiturates and amphetamines Durham-Humphrey Amendment defines the kinds of drugs that cannot be used safely without medical supervision and restricts their sale to prescription by a licensed practitioner.

1952 In U.S. v. Cardiff, the Supreme Court rules that the factory inspection provision of the 1938 FDC Act is too vague to be enforced as criminal law. A nationwide investigation by FDA reveals that chloramphenicol, a broad- spectrum antibiotic, has caused nearly 180 cases of often fatal blood diseases. Two years later FDA would engage the American Society of Hospital Pharmacists, the American Association of Medical Record Librarians, and later the American Medical Association in a voluntary program of drug reaction reporting.

1953 Factory Inspection Amendment clarifies previous law and requires FDA to give manufacturers written reports of conditions observed during inspections and analysis of factory samples HEW Secretary Olveta Culp Hobby appoints a committee of 14 citizens to study the adequacy of FDA's facilities and programs. The committee recommends a substantial expansion of FDA staff and facilities, a new headquarters building, and more use of educational and informational programs.

1962 Thalidomide, a new sleeping pill, is found to have caused birth defects in thousands of babies born in western Europe. News reports on the role of Dr. Frances Kelsey, FDA medical officer, in keeping the drug off the U.S. market, arouse public support for stronger drug regulation.

1962 Kefauver-Harris Drug Amendments are passed to ensure drug efficacy & greater drug safety. For the first time, drug manufacturers are required to prove to FDA the effectiveness of their products before marketing them. In addition, FDA is given closer control over investigational drug studies, FDA inspectors are granted access to additional company records, & manufacturers must demonstrate the efficacy of products approved prior to 1962.

1963 Advisory Committee on Investigational Drugs meet the first meeting of a committee to advise FDA on product approval and policy on an ongoing basis Drug Abuse Control Amendments are enacted to deal with problems caused by abuse of depressants, stimulants, and hallucinogens FDA made a contract with the National Academy of Sciences / National Research Council to evaluate the effectiveness of 4,000 drugs approved on the basis of safety alone between 1938 and 1962.

1968 FDA Bureau of Drug Abuse Control and the Treasury Department's Bureau of Narcotics are transferred to the Department of Justice to form the Bureau of Narcotics and Dangerous Drugs (BNDD), consolidating efforts to police traffic in abused drugs. A reorganization of BNDD in 1973 formed the Drug Enforcement Administration. FDA forms the Drug Efficacy Study Implementation (DESI) to incorporate the recommendations of National Academy of Sciences investigation of effectiveness of drugs marketed between 1938 and 1962.

1968 Animal Drug Amendments place all regulation of new animal drugs under one section of the Food, Drug, and Cosmetic Act-- Section 512--making approval of animal drugs and medicated feeds more efficient.

1971 FDA requires the first patient package insert: oral contraceptives must contain information for the patient about specific risks and benefits. The Comprehensive Drug Abuse Prevention and Control Act replaces previous laws and categorizes drugs based on abuse and addiction potential and also its therapeutic value 1972 Over-the-Counter Drug Review is initiated to enhance the safety, effectiveness and appropriate labeling of drugs sold without prescription.

1973 The U. S. Supreme Court upholds the 1962 drug effectiveness law & endorses FDA action to control entire classes of products by regulations rather than to rely only on time- consuming litigation Vitamins and Minerals Amendments ("Proxmire Amendments") stop FDA from establishing standards limiting potency of vitamins & minerals in food supplements or regulating them as drugs based solely on potency.

1982 Tamper-resistant packaging regulations issued by FDA to prevent poisonings such as deaths from cyanide placed in Tylenol capsules. The Federal Anti-Tampering Act passed in 1983 makes it a crime to tamper with packaged consumer products Orphan Drug Act passed, enabling FDA to promote research and marketing of drugs needed for treating rare diseases.

1984 Drug Price Competition and Patent Term Restoration expedites the availability of less costly generic drugs by permitting FDA to approve applications to market generic versions of brand-name drugs without repeating the research done to prove them safe and effective. At the same time, the brand-name companies can apply for up to five years additional patent protection for the new medicines they developed to make up for time lost while their products were going through FDA's approval process.

1987 FDA revises investigational drug regulations to expand access to experimental drugs for patients with serious diseases with no alternative therapies.

1988 The Prescription Drug Marketing Act bans the diversion of prescription drugs from other commercial channels. Congress finds that the resale of such drugs leads to the distribution of mislabeled, adulterated, sub- potent, and counterfeit drugs to the public. The new law requires drug wholesalers to be licensed by the states; restricts re- importation from other countries; and bans sale, trade or purchase of drug samples, and traffic or counterfeiting of redeemable drug coupons.

1991 FDA publishes regulations to accelerate reviews of drugs for life-threatening diseases Generic Drug Enforcement Act imposes debarment and other penalties for illegal acts involving abbreviated drug applications. Prescription Drug User Fee requires drug and biologics manufacturers to pay fees for product applications and supplements, and other services. The act also requires FDA to use these funds to hire more reviewers to assess applications.

1994 FDA announces that it could consider regulating nicotine in cigarettes as a drug, in response to a citizen's petition by the Coalition on Smoking OR Health. Uruguay Round Agreements Act extends the patent terms of U.S. drugs from 17 to 20 years FDA declares cigarettes to be "drug delivery devices." Restrictions are proposed on marketing and sales to reduce smoking by young people.

1997 Food and Drug Administration Modernization Act reauthorizes the Prescription Drug User Fee Act of 1992 and mandates the most wide- ranging reforms in agency practices since Provisions include measures to accelerate review of devices, advertising unapproved uses of approved drugs and devices, health claims for foods in agreement with published data by a reputable public health source, and development of good guidance practices for agency decision-making.

VARIOUS PHASES OF DRUG DEVELOPMENT AND DRUG APPROVAL PROCESS

NDA NEW DRUG APPLICATION

Introduction : For decades, the regulation and control of new drugs in the United States has been based on the New Drug Application (NDA). Since 1938, every new drug has been the subject of an approved NDA before U.S. commercialization. The data gathered during the animal studies and human clinical trials of an Investigational New Drug (IND) becomes part of the NDA.

When the Food, Drug, and Cosmetic Act (FD&C Act) was passed in 1938, NDAs were only required to contain information pertaining to the investigational drug's safety. In 1962, the Kefauver-Harris Amendments to the FD&C Act required NDAs to contain evidence that a new drug was effective for its intended use as well, and that the established benefits of the drug outweighed its known risks.

The NDA was again the subject of change in 1985, when the FDA completed a comprehensive revision of the regulations pertaining to NDAs. While this revision, commonly called the NDA Rewrite, modified content requirements, it was mainly intended to restructure the ways in which information and data are organized and presented in the NDA to easily access FDA reviews.

Fundamentals of NDA Submission As outlined in Form FDA-356h, Application to Market a New Drug for Human Use Or As An Antibiotic Drug For Human Use, NDAs can consist of as many as 15 different sections: 1.Index 2.Summary 3.Chemistry, Manufacturing, and Control; 4.Samples, Method Validation Package, and Labeling 5.Nonclinical Pharmacology and Toxicology 6.Human Pharmacokinetics and Bioavailability

7Microbiology (for anti-microbial drugs only); 8Clinical Data; 9Safety Update Report (typically submitted 120 days after the NDA's submission); 10Statistical; 11Case Report Tabulations; 12Case Report Forms; 13Patent Information; 14Patent Certification; and 15Other Information. (e.g. the marketing history of the drug (if any) outside the U.S., a concluding discussion of benefit/risk considerations and of proposed additional studies or postmarketing surveillance plans etc.)

NDA Content and Format Requirements NDA must provide all relevant data and information that a sponsor has collected during the product's research and development. The FDA has numerous guidelines that relate to NDA content and format issues. These guidelines can be obtained from CDER's Drug Information Branch (DIB).

NDA Classifications CDER classifies new drug applications with a code that reflects both the type of drug being submitted and its intended uses. The numbers 1 through 7 are used to describe the type of drug

1. New Molecular Entity 2. New Salt of Previously Approved Drug (not a new molecular entity) 3. New Formulation of Previously Approved Drug (not a new salt OR a new molecular entity) 4. New Combination of Two or More Drugs 5. Already Marketed Drug Product - Duplication (i.e., new manufacturer) 6. New Indication (claim) for Already Marketed Drug (includes switching marketing status from prescription to OTC) 7. Already Marketed Drug Product - No Previously Approved NDA

The following letter codes describe the review priority of the drug: S - Standard review: For drugs similar to currently available drugs. P - Priority review: For drugs that represent significant advances over existing treatments.

GENERAL REQUIREMENTS The new (present) NDA regulations require that an application be submitted in two copies : (a) an archival copy that serves as a permanent record of the submission, and (b) a review copy. The review copy is made up of a number of separate technical volumes, each tailored to the needs of the disciplines involved in the review. Both the archival and review copies are submitted in hard copy, the regulations permit an application to submit the archival copy as microfiche

The NDA application form (FORM NDA 356 h) consist of : Twelve items (including index) deals with the safety and efficacy features of drug product, two are concerned with patent information.

The application form is supplemented with detailed, technical guidelines to improve the quality of submissions: The format and content of an application summary Formatting, assembling and submitting new drug and antibiotic applications The submission in microfiche of the archival copy of an application The format and content of the human Pharmacokinetics and Bioavailability section of an application The format and content of the clinical and statistical sections of an application.

The format and content of the chemistry, manufacturing and control section of an application Post marketing reporting of adverse drug reactions

The chemistry section, because of its length, and highly detailed sections dealing with the manufacturing and control processes, is required to be submitted days prior to the submission of the application for facilitating the identification of deficiencies in the filed NDA. Submission of chemistry section earlier than 120 days and less than 90 days before the remainder of the application will not be accepted.

The archival copy of the application should include a comprehensive index by volume and page number. It is recommended that additional copies of the index be prepared and included with any material submitted to FDA for the NDA. This will easily access locating important parts of the submission that may be needed for meetings / view by individual technical reviewers.

SUMMARY It has been suggested that the summary consists of pages. The summary should discuss all aspects of the application and needs to be written at approximately level of detail required for publication and meet the editorial standards applied by referred scientific and medical journals. It is advantageous to provide data in the summary in tabular and graphic form with clear explanation of any terminology used in the tabulations or graphics.

THE SAFETY UPDATE REPORTS The required safety data (from view point of clinical studies, animal studies, other sources generated or reported to sponsor) must be submitted in same format as integrated summary of safety described under clinical data section of the NDA content and format (21 CFR ). Additionally the NDA format is required to include case report forms for each patient who died during a clinical study or who did not complete the study due to an adverse event.

Safety update reports must be submitted at (a) 4 months after the initial submission of an application, (b) following receipt of an approvable letter and (c) other times as requested by the FDA.

CHEMISTRY, MANUFACTURING AND CONTROLS Important point is the specific citation needed for the solid state forms of the drug substance and their relationship to bioavailability. Chemistry, manufacturing and controls summary must provide a general overview of the drug substance and drug product.

Drug substance: Description including physical and chemical characteristics and stability Drug product: Composition and type of dosage form, manufacture, specifications and analytical methods, container/closure system, stability, investigational formulations. Details are provided in 21CFR 25.1

NONCLINICAL PHARMACOLOGY AND TOXICOLOGY Nonclinical laboratory studies include any invivo/invitro experiment with the test drug to determine its safety, activity or disposition. This section includes Toxicological effects of drugs on reproduction and the developing fetus, ADME animal experiments of the drugs This section should provide a description, tabulation and graphics from Nonclinical laboratory studies of drug.

HUMAN PHARMACOKINETICS AND BIOAVAILIBILITY First section : There should be an overall tabulated summary of all invivo biopharmaceutic studies carried out on the drug grouped by type of study. Second section : The summary of bioavailability or pharmacokinetic data and overall conclusions (Cmax, Tmax, Kel, AUC etc.)

Third section : List of all formulations used in clinical trials and invivo bioavailability or pharmacokinetic studies together with each formulation used in studies. Fourth section : Analytical methods used to measure the levels of drug and major metabolite Fifth section : Dissolution data on each strength and dosage form for which approval is being sought. A comparative dissolution study with the lot(s) used. In vivo biopharmaceutics studies should also be included.

MICROBIOLOGY Applicable to anti-infective and antiviral drugs. It should include description of : Biochemical basis of the drug’s action / microbial physiology. Antimicrobial spectra of the drug, including results of invitro preclinical studies that demonstrate effectiveness. Any known mechanisms of resistance to the drug, including results of epidemiological studies to demonstrate privilege of resistance factors. Clinical microbiological laboratory methods needed for effective use of the drug.

CLINICAL DATA This section includes descriptions, summaries and analysis of : Clinical pharmacology studies including animal study and toxicology. Controlled clinical studies including the protocol and description of the statistical analyses used to evaluate the studies. Uncontrolled clinical studies, including all necessary details of the studies. Any other data/information relevant to an evaluation of safety and effectiveness obtained from any source, foreign or domestic (U.S.).

STATISTICS Statistics section should include: A statistical evaluation of the clinical data A copy of the data given in the description and analysis of each controlled clinical study, along with the statistical analysis. A copy of the data included in the integrated summary of all available information about the safety of the drug.

NDA REGULATIONS Review Time Frames (21 CFR ) This time frames includes: Within 180 days of receipt of an application, the FDA will review and issue an approval, approvable, or not approvable letter. This 180- day period is called the ‘review-clock” During the review period an applicant may withdraw an application (21 CFR ) and later resubmit it. The time period may be extended by mutual agreement between the FDA and the applicant or as the result of submission of a major amendment (21 CFR )

Filing Time Frames (21 CFR ): Within 60 days after the FDA receives an application, a determination will be made whether the application may be filed. This will determine whether sufficient information is provided to proceed with an in- depth review of application. If FDA files the application, the applicant will be notified in written. The date of filing will be the date 60 days after the FDA received the application. The date of filing begins the 180-days period of the review. If FDA refuses to file the application, the sponsor will be given the opportunity to meet with FDA to discuss the reasons why the application is not fileable.

APPROVAL OF NDAs BASED SOLELY ON FOREIGN DATA (21 CFR ) Clinical data will be considered on merit regardless of country of origin. Foreign Clinical data meeting U.S. criteria for approval may be approved if : The foreign data are applicable to the U.S. Population and U.S. Medical practice The studies have been performed by clinical investigators of recognized competence If an inspection is necessary, FDA is able to validate the data through an on-site inspection or other appropriate means or the data may be considered valid without the need for an on-site inspection by FDA.

FDA will apply this policy according to the nature of the drug and the data being considered. The FDA is willing to explore all areas to remove the need to conduct repetitive clinical testing in U.S. When adequate foreign data have been generated a pre-NDA submission meeting is encouraged when approval being solely on foreign data is sought.

FDA DIALOGUE ON SCIENTIFIC & MEDICAL ISSUES (21 CFR ) Approximately 90 days after the NDA is received, the FDA will provide applicants with an opportunity to meet with reviewers to discuss the general progress and status of the application Particularly for new chemical entities and major new indications of marketed drugs, this meeting will generally be held at the applicant’s option and may be held by telephone. With the issuance of an approvable/not approvable letter, an opportunity will be provided to applicants to meet with the FDA and discuss what further steps need to be taken before the applications can be approved. Priority for these meetings will be given to applications for new chemical entities and major new indications for marketed drugs.

NDA PRE-APPROVAL AND POST- APPROVAL SAFETY REPORTS In 21 CFR (d) (5) (vi) (b), the FDA details the necessity to periodically update a pending application with new safety information which affects the statements of contraindications, warnings, precautions and adverse reactions in the draft labeling. The safety update reports are required to include the same kinds of information from clinical or animal studies as well as other sources, and must be submitted in the same format as the previously described integrated summary of safety.

These safety reports must be submitted as follows: Four months after the initial submission Following receipt of an approvable letter At other times as requested by FDA

In case of any adverse drug experience, the surveillance system requires the reporting of such experience as soon as possible within 15 working days of initial receipt of the information. These ‘alert reports’ are required to be submitted on Form FDA 1639 (Drug Experience Report). All reactions subject to 15 day alert report require follow-up reports within 15 working days of receipt of new information Even if no such reports are reported, the follow up reports has to be submitted in separate cover and as a summary / tabular form to be presented in periodic report

NDA holders must review periodically (quarterly for the first three years and yearly thereafter) the frequency of adverse drug experience reports that are serious and unexpected and report any significant increase in frequency (e.g. a doubling) within 15 working days to determine whether a significant increase in frequency exists or not.

Applicants must adhere to a reporting schedule that calls for submission of each quarterly and each annual report within 60 days of the anniversary date of approval of the application.

A 15-day alert report based on information from the scientific literature must be accompanied by a copy of the published article. These literature reports should be either case reports or the reporting of a formal clinical trial Applicants should not include in post- marketing adverse experience reports of any adverse experiences that occurred in clinical trials if they were previously submitted as part of the approved application.

NDA REVIEW TIMES Following deficiencies are typically encountered in drug development: Sponsors do not pursue advice from the FDA regarding their drug development plan Sponsors routinely more ahead to the next clinical trial without completely analyzing results of the most recent trial Sponsors sometimes provide a minimal amount of data in an effort to get drug approvals

COMPUTER ASSISTED NEW DRUG APPLICATON (CANDA) Concept: it is designed to shorten FDA review time by submitting data to FDA in a form ready for manipulation by a computer. Importance is given on the clinical sections of the NDA, as they require the maximum time to review and often require manipulation of the data by FDA.

In a September 15, 1988 Federal Register Notice, FDA stated to increase the use of computers in field of improving efficiency of the drug review process. FDA had not provided exact blue print on how to best organize / submit a CANDA, but two basis computer systems have been developed so far: Involves keeping the data on a mainframe computer that is operated either by the sponsor / by the computer company assisting it with FDA able to access the information via a telephone connection. Putting the data on a floppy disk, laser disc, etc. for use by FDA via desktop computers that are provided by the sponsor.

One possible concern of CANDAs is the possibility of ‘data dredging’ by FDA reviewers, that is pursuing tangential rather than Central issues because the computer makes it easy to do so, but this has not been observed routinely.

HOW TO IMPROVE NDA HANDLING Be sure to supply additional (desk copy) submissions of the clinical data section and integrated summaries of safety and efficacy for the medical reviewer; the pharmacokinetic and bioavailability summary for the biopharmaceutics reviewer; the chemistry, manufacturing, and control process summary for the statistician reviewer; and extra copies of draft labeling for the medical reviewer. The submission should be placed in a proper jacket binders: use the proper numbering system

If requested, be prepared to submit for review draft copies for advertising and promotional material to be used in the initial or launch campaign to the Division of Drug Advertising and Labeling (HFN- 240). Place the IND, NDA, or petition number on every letter or submission: include supplement numbers where applicable.

Submit new information in reviewable bundles or marketed with references suitable to all the material FDA reviewers need to consider in making a decision – this will help avoid lengthy file searches. FDA files are chronological: submissions stating “this replaces, corrects, or up-dates section or page so- and-so,” do not fit well in the FDA document-tracking or review system.

APPLICABLE NDA REGULATIONS It is noteworthy to be familiar with the regulations applicable to the NDA. The general NDA requirements are coded in Title 21, Code of Federal Regulations, Part 314. Subpart A contains the general provisions, section to Subpart B details the sections for applications as follows:

a. Application b. Index c. Summary d. Technical Sections 1. Chemistry, manufacturing and controls 2. Nonclinical pharmacology and toxicology 3. Human pharmacokinetics and bioavailability 4. Microbiology 5. Clinical data 6. Statistical e. Samples and labeling f. Case report forms and tabulations g. Other h. Format of an original application

REFERENCES mlwww.fda.gov/cder/about/history/time1.ht m Remington: The Science And Practice Of Pharmacy, 20th edition, Lippincott,Williams & Wilkins, page no: New Drug Approval Process: second edition, revised and expanded, edited by Richard A. Guarino page no: 39-64,

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