MARKETING NEW OPHTHALMIC DRUG DELIVERY SYSTEMS FOR HUMAN USE

VI. MARKETING NEW OPHTHALMIC DRUG DELIVERY SYSTEMS FOR HUMAN USE

Once a manufacturer has obtained sufficient information from clinical trials in humans, safety testing in animals, and chemistry and manufacturing experience to establish that the new ophthalmic drug delivery system is safe and effective for its intended use, a New Drug Application is submitted to the FDA to obtain approval for distribution in interstate commerce.

Two types of NDAs for new drugs are recognized by the FD&C Act in Section 505(b):

1. A new drug requires full reports of investigations for safety and effectiveness among other requirements. For a new drug, first submitted for approval, the investigations providing the full reports will ordinarily have been conducted by the applicants or by others under contract with a full right of reference (21 CFR 314.3) to the results of the investigations for inclusion in the marketing application. This is the typical NDA for a new chemical entity (NCE) and is sometimes referred to as a ‘‘Full NDA.’’

2. The second type of NDA is one in which the applicant does not have a full right of reference for some or all of the investigations relied upon for demonstrating safety and effectiveness and is relying on data generated by others, for example, publicly avail- able information. This has been termed a ‘‘paper NDA’’ but is now referred to as a 505(b)(2) NDA for the section of the Act.

The 505(b)(2) NDA is applicable to the development of a new ophthalmic delivery system for an already approved drug because once the new drug is approved, and any applicable patent protection and market exclusivity per- iods have expired, the safety and efficacy data become public information and can be referenced by another applicant as part of a subsequent applica-

684 Roehrs and Krueger tion for a modification of the approved drug (21 CFR 314.430). For the new

ophthalmic delivery system of an approved drug, the basic human clinical and animal safety studies would not have to be repeated but only referenced to the approved drug’s NDA. Full reports would only be required for demonstration of safety and efficacy of the new delivery system, i.e., the changes made to the approved drug. A complete chemistry, manufacturing, and controls section would also be required as this is not public information (21 CFR 314.54). Additionally, for a Section 505(b)(2) NDA, a patent certi- fication is required in the application for any patent that claims the drug, drug product, or method of use for which prior investigations are relied upon without a right of reference from the original applicant. In addition to any patent protection, the new ophthalmic delivery system may be eligible for 3 years of Waxman-Hatch market exclusivity (21 CFR 314.108).

A. NDA Content and Requirements The format and content of an NDA is seen in Table 4. The FDA Form 356h

is the official signed application form. An index to the entire application is essential to direct the reviewer to the location of the contents by volume and page numbers.

A comprehensive summary of the entire application is written in the style of a review article. A copy of the index and summary is provided to each reviewer of the application. The summary begins with an annotated copy of the proposed labeling, i.e., the product’s proposed package insert. The applicant must be able to justify each statement in the labeling which is annotated to the supporting information in the Summary and Technical sections.

There are six major technical sections comprising the data generated to support the approval for the claimed indication(s). FDA guidelines for the technical sections are included on the FDA’s web site at www.fda.gov/cder/ guidance/index.htm.

Chemistry, Manufacturing and Control—drug substance and drug product Microbiology—applicable only if for an anti-infective drug Human Pharmacokinetics—ADME data from human studies Pharmacology—animal study data for pharmacology, toxicology, and

ADME Clinical—human data for safety and efficacy Statistics—mathematical analysis of the human clinical data

There are several sections ancillary to the technical sections. A section containing documentation for the analytical methods validation, drug sub-

Regulatory Considerations 685 Table 4 NDA—Format and Content Outline FDA Form 356h

Index to Entire Application Summary a. Labeling text annotated to both Summary & Technical Sections b. Pharmacological Class, Scientific Rationale, Intended Use(s), and

Potential Clinical Benefits c. Foreign Marketing History—Applicant and others if known i.

Countries in which marketed ii.

Countries where withdrawn from market for safety or efficacy iii. Countries where marketing applications pending d. Summary of Chemistry, Manufacturing and Controls Section e. Summary of Nonclinical Pharmacology & Toxicology Section f. Summary of Human P-Kinetics & Bioavailability Section g. Summary of Microbiology Section h. Summary of Clinical Section including Statistical Analysis i. Concluding Discussion—Benefit/Risk Consideration

Chemistry, Manufacturing, and Controls Section a. Drug Substance i.

Description of Chemical & Physical Characteristics ii.

Stability iii. Source & Location of Manufacturer(s) iv. Synthesis, Purification, and Controls v.

Specifications & Analytical Methods vi. Reference Standard b. Drug Product i.

Components ii.

Specs and Test Methods for Inactives iii. Composition iv. Name and Location of Each Manufacturer v.

Manufacturing & Packaging Procedures & In-Process Controls vi. Acceptance Specifications for Each Batch vii. Analytical and Microbiological Test Methods viii. Packaging Container/Closure Systems ix. Stability Data & Protocols x.

Proposed Expiring Dating & Storage Conditions c. Environmental Assessment of Manufacturing Process & Ultimate Use Samples, Methods Validation, Labeling a. Description & assay results of samples for FDA validation b. Methods Validation Package (Regulatory Specs & Methods) c. Container Labels & Package Insert Labeling

Nonclinical Pharmacology & Toxicology a. Pharmacology Studies b. Toxicology Studies c. Animal ADME Studies d. GLP Compliance Statements

686 Roehrs and Krueger Table 4 Continued

Human Pharmacokinetics & Bioavailability a. Waiver for topical or injectable product bioavailability studies b. For each human bio- or pharmacokinetic study:

i. Study report including analytical and statistical methods ii.

IRB/Informed Consent Compliance Statements c. For specs or methods to assure bioavailability of drug or product: i.

Rationale for establishing spec or method ii.

Data and information supporting rationale d. Summary Discussion & Analysis of: i.

Pharmacokinetics & metabolism or active ingredient ii.

Bioavailability and/or bioequivalence of drug product Microbiology (for Anti-Infectives Only) Clinical Data

a. Clinical Pharmacology Studies b. Controlled Clinical Studies c. Uncontrolled Clinical Studies d. All other data and information relevant to evaluation of the safety

and effectiveness of the drug product e. Integrated Summary of Effectiveness f. Integrated Summary of Safety g. Studies related to abuse potential or over dosages h. Integrated summary of Benefits and Risks i. Compliance Statements (IRB & IC) for each clinical study

j. Contract Research Organizations & Obligations Transferred k. List of studies where original subject records were audited or reviewed

to verify accuracy of case reports Reserved for Safety Update Reports a. Required After NDA Filed at: i.

4 months ii.

Approvable letter and whenever FDA requests update b. New Safety Information from any source that may reasonably affect

the labeling c. Case Report Forms for patients who died or were adverse event dropouts Statistical Section a. Copy of the following Clinical Data Sections i. Controlled Studies

ii. Integrated Summary of Effectiveness iii. Integrated Summary of Safety

b. Documentation and Supporting Statistical Analysis used to Evaluate

each of the above Clinical Data Sections Case Report Tabulations Data on each patient from

a. Each adequate and well-controlled study (Phase 2 & 3)

Regulatory Considerations 687 b. Each Phase 1 Clinical Pharmacology study

c Safety data from other clinical studies Case Report Forms a. For patients who: died during a clinical study or did not complete study due to adverse event whether or not thought to be drug related including patients on reference drug or placebo

b. Additional CRFs may be requested after submission and must be submitted within 30 days of FDA request Pediatric Studies—Information on use in Pediatric Population unless Waived or Deferred Patent Information—Listing of U.S. Patents that could be infringed which claim

a. Drug b. Drug product composition c. Intended use

Patent Certification—For 505(b)(2) Applications Claimed Market Exclusivity Financial Certification or Disclosure Statements

Source : Adapted from 21 CFR 314.50.

stance and drug product samples, and the container labels and package insert. The samples are submitted to one or more FDA district laboratories for validation of the regulatory analytical methods and to confirm the iden- tity, purity, and strength of the drug and drug product. The FDA uses the regulatory analytical methods to periodically test the drug product from regular production batches after approval. A section is reserved for periodic updates of new safety information that may be obtained after the NDA is submitted while under review and just prior to approval.

The case report tabulations contain the clinical data from each patient’s case report form (CRF). This is the raw data from the clinical studies and is tabulated by entry into sophisticated relational databases for evaluation and mathematical statistical analysis. A copy of the actual CRFs is only required in the initial submission and periodic safety updates for all deaths and patients discontinued due to adverse medical events. However, the FDA may request additional patient CRFs during the review.

Studies in pediatric patients (birth to 16 years) are required for all new drugs during development and for certain marketed drugs (21 CFR 314.55). The applicant may request a waiver or deferment of the studies. A waiver may be granted if the new drug may not provide a meaningful therapeutic benefit over existing pediatric treatments and is not likely to be used in a substantial number of pediatric patients. The scope of the regulation

688 Roehrs and Krueger includes new active ingredients, new indications, new dosage forms, new

dosage regimens, and new routes of administration. For marketed drugs, FDA can require pediatric studies for those that are used in a substantial number of pediatric patients for the claimed indications or would provide a meaningful therapeutic benefit over existing treatments and where the absence of adequate labeling could pose significant risks.

To provide adequate data to meet the requirements may not always require controlled clinical trials in pediatric patients and may not require separate studies. In some cases where the course of the disease and the product’s effects in adults and children are similar, the FDA may accept an extrapolation from adult studies with additional data such as dosing, pharmacokinetic, and safety data in pediatric patients. Also, adequate data may sometimes be obtained by including sufficient pediatric patients as well as adults in the original clinical studies where appropriate. The pediatric data is only required for the indications claimed by the applicant.

Since the Waxman–Hatch Act of 1984, NDAs must contain informa- tion of all unexpired U.S. patents for the drug substance, drug product, and methods of use (21 CFR 314.53). The applicant certifies the validity of the patent information and the FDA, without verification, upon NDA approval publishes the information in the Orange Book so that subsequent applicants are put on notice as to the patents that may be infringed and delay their entry into the marketplace.

For each patent that claims the drug, drug product, or method of use for which prior investigations are relied upon without a right of reference from the original applicant, a patent certification must be included (21 CFR 314.50(i)). The certification must show that there is no patent information filed with the FDA, that the patent has expired or the date the patent will expire, or that the patent is invalid or will not be infringed. If the certifica- tion that the patent is invalid or not infringed is made, notice must be given to the patent and NDA holder, who have 45 days to bring an infringement action in court, which enjoins the FDA from approving the application for

30 months or until the case is resolved by the court, whichever is shorter (21 CFR 314.52). The Act provides for periods of market exclusivity upon approval of most NDAs. The exclusivity period must be requested by the applicant and if granted by the FDA will be published in the Orange Book for notice to generic applicants (21 CFR 314.50(j)). A 5-year period of market exclusivity is provided for the first approval of a new chemical entity and a 3-year period for all others, such as new uses and new dosage forms. Certain criteria must be met for the grant of market exclusivity, primarily the requirement for the conduct of clinical studies essential to approval as well as criteria for their financial support. During the exclusivity period,

Regulatory Considerations 689 generic equivalent products cannot be marketed; however, during the 3-year

period a generic application may be submitted. For the 5-year period, a generic application cannot be submitted during the first 4 years and during the last year of exclusivity can be submitted only if there is a patent chal- lenge.

Congress included economic incentives for conducting pediatric stu- dies in the Modernization Act of 1997 for drugs that are eligible for market- ing exclusivity or patent protection under the Waxman-Hatch Act of 1984. The legislation makes available a 6-month extension of existing market exclusivity on drug products that the FDA has made a written request for pediatric studies and the manufacturer has conducted such studies meeting the requirements.

A long-standing requirement of clinical studies is that they are designed, conducted, analyzed, and reported in a manner that minimizes bias. One element that could introduce bias is the financial arrangements between the sponsor of the study and the clinical investigator. Since 1999, the FDA has required certain financial disclosure information for desig- nated clinical studies be included in NDAs for their use in assessing data reliability in making the final approval decision (21 CFR Part 54).

The FDA is interested in certain financial arrangements for clinical studies that are relied on for proof of efficacy, including comparisons to effective products, and those that make a significant contribution to the demonstration of safety. Specific financial arrangements that must be dis- closed for each such clinical investigator are those where the compensation of the clinical investigator is affected by the outcome of the study, or where there is significant equity interest in the sponsoring company, or compensa- tion is tied to product sales, or a proprietary interest in the product, or receives significant payments from the sponsor such as for grants to fund ongoing research, compensation in the form of equipment, retainer for ongoing consultation or honoraria, and any steps taken to minimize the potential for bias due to these financial arrangements. If none of the above financial arrangements were in effect for the clinical studies, then the company may submit a certification attesting to this fact for each such clinical investigator.

B. Electronic Submission The FDA has encouraged submission of parts or all of an NDA in electronic

form to expedite the review of large datasets such as clinical, animal safety, biopharmaceutics, and chemistry sections. These computer-assisted NDAs (CANDA) have been adopted by most pharmaceutical companies in the anticipation that they will expedite the review and approval of their submis-

690 Roehrs and Krueger sions. However, until recently, they could not be used to replace the official

paper copy version of the NDA, which can involve more than 100 volumes. In March 1997, a new Electronic Records regulation was promulgated, allowing acceptance of documents entirely in electronic format with a certi- fying electronic signature. The FDA has been active in providing guidance to industry so that regulatory submissions can increasingly be made in electronic format with the hope that entire regulatory submissions can be paperless. The FDA provides updated information and guidance for elec- tronic submissions on their website (www.fda.gov/cder/guidance/ index.htm).

C. Patent Term Extension The Waxman-Hatch Act makes available the possibility of extending the

term of one unexpired patent for the drug, drug product, or use but only upon the first NDA approval for a new chemical entity. This provision was enacted to partially restore the effective patent life that is lost during the time required to meet FDA approval requirements. The patent holder must apply within 60 days of NDA approval to the U.S. Patent and Trademark Office (PTO) for extension of the selected unexpired patent. The PTO and FDA cooperate to determine the eligibility of the patent and the period of time for the extension. The extension is determined by a formula based on the amount of time diligently pursuing development under the IND and the amount of time from NDA filing until approval. The term extension is subject to the limitations of a maximum of 5 years and a maximum of 14 years patent term remaining with the extension (21 CFR 60).

D. Accelerated Availability of Certain New Drugs The acquired immunodeficiency syndrome (AIDS) crisis focused attention

on the drug development and regulatory processes for making new therapies available for life-threatening and severely debilitating conditions, particu- larly where no approved therapy or suitable alternative therapies exist. FDA instituted new procedures to make promising new drug therapies available to treat patients as early in the drug development process as possible, whereas at the same time obtaining data on the drug’s safety and effective- ness in clinical trials.

The treatment IND regulations finalized in 1987 (21 CFR 312.34) make it possible for patients to receive promising new drugs for certain serious and life-threatening conditions as early as Phase 2 or 3 while con- trolled clinical trials are still underway to make a final determination on the new drug’s safety and effectiveness. In some cases the manufacturer may

Regulatory Considerations 691 charge for the investigational new drug product if necessary to undertake or

continue the clinical trials. The sponsor of the new drug must apply to FDA for treatment use and provide available data supporting the drug’s potential efficacy and safety. FDA may deny the request if the available scientific evidence, taken as a whole, is insufficient to support a reasonable conclusion that the drug may be effective for its intended use or would expose patients to unreasonable and significant additional risk of illness or injury. Also, clinical trials must be continuing to complete development and submission of an application to market the drug.

FDA also instituted accelerated drug development and review pro- grams for certain serious or life-threatening conditions so that approval can be obtained for marketing at the earliest possible point that safety and efficacy are reasonably established (21 CFR Part 312 Subpart E). The FDAMA of 1997 essentially codified these programs for certain new drugs designated as ‘‘fast track’’ products (FD&C Act Section 506). The fast track programs of FDA are designed to facilitate the development and expedite the review of new drugs that meet certain requirements as treatments for serious or life-threatening conditions and that demonstrate potential to address unmet medical needs. For these fast track products, FDA may approve an NDA using a clinical endpoint or a surrogate endpoint that is reasonably likely to predict clinical benefit. Also, FDA can accept for review portions of a marketing application prior to receipt of the complete applica- tion (21 CFR Part 314 Subpart H).

In addition to the fast track programs accelerating development and market availability of certain new drugs, the FDA, working with industry and Congress, has established NDA review time goals for all NDAs as part of the quid pro quo for payment of user fees. Priority applications are to be reviewed within 6 months of filing and all other applications (standard) are to be reviewed within 10 months. The review classification as a priority or standard NDA is established at the time the NDA is filed and is based on FDA’s estimate of the drug product’s medical value, compared to already available products, using the safety and effectiveness submitted in the ori- ginal application. To be designated for a priority review, the FDA must consider the drug product to be a significant improvement compared to marketed products as demonstrated by such elements as increased effective- ness, elimination or substantial reduction of an adverse drug reaction limit- ing use, documented enhancement of patient compliance, or evidence of safety and effectiveness in a new subpopulation.

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VII. INTERNATIONAL HARMONIZATION The technical requirements for registration of human pharmaceuticals vary

throughout the world, which makes global development more expensive and delays introduction of new products in many markets while studies are being repeated to meet local requirements. In 1990, a unique project was undertaken to bring together the regulatory authorities of the United States, the European Union, and Japan along with scientific and regula- tory experts from these three regions with the aim to produce a single set of technical requirements for the registration of new drug products and hence streamline the development process while maintaining the necessary safeguards to protect public health. The International Conference on Harmonization (ICH) is the driving force behind the project with repre- sentatives from the three major market regions and where most of the new drug development originates. The output of ICH are tripartite guidelines in the major areas of drug development: efficacy, safety, and quality. As of January 2000, 37 guidelines have been finalized and adopted as tripartite guidelines after rigorous scientific review and modification by the expert working groups. The efficacy topics cover clinical testing programs and safety monitoring, the safety topics cover preclinical toxicity and related tests, and the quality topics are concerned with chemistry and control specifications. Harmonized guidelines are also being developed for pro- ducts of biotechnology.

In addition to differing technical requirements in the three ICH regions, the requirements for the technical sections of registration applica- tions also differ, and a separate document must be prepared for each region. The concept of a Common Technical Document (CTD) for each of the three major topics has been adopted by ICH along with a standar- dized terminology for the reporting of adverse reactions in the Medical Dictionary for Regulatory Activities (MeDRA). Also being explored by ICH is harmonization of electronic information transfer standards (ESTRI) so that the CTD can be established eventually as an electronic document.

The ICH guidelines and additional information on the ICH process can be obtained from the ICH Secretariat website at www.ifpma.org/ ich1.html. The FDA publishes the ICH guidelines in the Federal Register at the draft stage for public comment and the finalized guidelines upon adoption. They can be obtained from the FDA web site at www.fda.gov/ cder/guidance/index.htm.

Regulatory Considerations 693 REFERENCES 1. Nielsen, J. R. (1986). Handbook of Federal Drug Law. Philadelphia, Lea &

Febiger. 2. J. L. Fink, et al., eds. (1991). Pharmacy Law Digest. Facts and Comparisons, Inc., p. DC-4. 3. Guidance for Industry, Environmental Assessment of Human Drugs and Biologics Applications (Rev. 1), July 1998. 4. Fed. Reg., 47 (200):46139, October 15, 1982. 5. Lerman, S., and Reininger, B. (1971). Can. J. Ophthalmol., 6:14. 6. Hackett, R. B. (1990). Non clinical study requirements for ophthalmic drugs and devices in the United States. Lens & Eye Toxic. Res., 7(3&4):181. 7. Guideline for Drug Master Files (Sept. 1989). Center for Drug Evaluation and Research, FDA. 8. Guidelines on Sterile Drug Products Produced by Aseptic Processing (1987). June, FDA. 9. Fed. Reg., 56 (198):51354, October 11, 1991. 10. Guideline on the Preparation of Investigational New Drug Products (Human & Animal) (1991). March, FDA.