CLINICAL TESTING OF NEW OPHTHALMIC DRUG DELIVERY SYSTEMS

V. CLINICAL TESTING OF NEW OPHTHALMIC DRUG DELIVERY SYSTEMS

A. Human Versus Animal Testing Human drug products are often tested during development in animals for

potential acute and chronic signs of toxicity as well as for their primary and secondary pharmacological effects. If the new drug is shipped inter- state for the purpose of clinical investigation in animals, an exemption similar to a human IND is required, and the label must bear the following statement (21 CFR 511.1b): ‘‘Caution. Contains a new animal drug for use in investigational animals in clinical trials. Not for use in humans. Edible products of investigational animals are not to be used for food unless authorization has been granted by the U.S. Food and Drug Administration or by the U.S. Department of Agriculture.’’ However, if the interstate shipment is intended solely for use in animals used only for laboratory research purposes, then it is exempted from the IND require- ments if it is labeled as follows (21 CFR 312.160): ‘‘Caution. Contains a new drug for investigational use only in laboratory research animals or for tests in vitro. Not for use in humans.’’ The exemption also requires that due diligence be used to assure that the consignee is regularly engaged in conducting such tests and shipment will actually be used as stated in the Caution. Records of the shipments must be kept for a period of 2 years after shipment and delivery and made available to an FDA inspector if requested.

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B. Federal Versus State Regulation Clinical investigations conducted solely intrastate do not escape federal

regulation if the drug or dosage form or any components of these articles are obtained through interstate shipments.

C. IND Exemption for Clinical Investigations in Humans The FD&C Act provides for an exemption from prior approval for inter-

state shipment of new drugs if the shipment is for the purpose of clinical testing in humans. The investigational new drug application (IND) is the notice of exemption that must be submitted prior to the shipment (21 CFR 312). The applicant agrees not to begin clinical use for 30 days or longer if so notified by the FDA. During the 30-day period, the FDA makes an initial assessment of the clinical testing plans and the data supporting safe use in human subjects. If the FDA has serious questions about the application, the investigations may be put on a clinical hold until the applicant removes the deficiencies. Beyond the initial 30-day review period, the FDA will conduct

a more in-depth review of the data submitted and may from time to time notify the sponsor of the application regarding deficiencies that must be corrected prior to additional clinical investigations being undertaken. The sponsor is required to update the application with certain amendments to ongoing investigation protocols and all new testing protocols. Also, the sponsor is required to submit an annual progress report of the investigations and immediate reports of serious and unexpected adverse reactions in humans and certain serious findings in animal safety tests.

D. IND Application FDA regulations specify the format and content requirements of an IND.

This is shown in Table 1.

1. Clinical Testing The first section of the IND informs the FDA as to what drug is to be tested,

the objectives of the clinical experiments, and the scientific rationale and existing knowledge. The FDA uses this information to determine the ade- quacy of the technical data to support the proposed human experiments.

Clinical testing usually occurs in several phases, and an IND can be filed for one or more of these phases (Table 2). Typically, an IND would be filed with specific protocol(s) for Phase 1 and a general outline of the plan for Phase 2. The IND can be amended as necessary to add additional pro- tocols and a revised clinical plan included in the annual report. The clinical

Regulatory Considerations 675 Table 1 IND—Format and Content Outline Part 1

Form FDA 1571 Part 2

Table of Contents Part 3

Introductory Statement—brief introductory statement to include:

a. Name(s) of the drug Drug’s pharmacological class Drug’s structural formula Dosage form and formulation Route of administration Broad objectives and planned duration of the proposed clinical

investigations b. Brief summary of previous human experience with the drug: Reference of other IND/NDAs, if pertinent Investigational or marketing experience in other countries that may

be relevant to the safety of the proposed clinical investigation(s) c. Identification of countries where drug has been withdrawn from investigation or marketing for any reasons related to safety or effectiveness and reasons for withdrawal

Part 4 General Investigational Plan—brief description of the overall plan for investigating the drug product for the following year to include:

a. Rationale for drug study b. Indication(s) to be studied c. General approach to be followed in evaluating the drug d. Kinds of clinical trials to be conducted in the first year (indicate if

plans not developed for full year) e. Estimate number of patients to be given the drug f. Safety risks anticipated—any risks of particular severity or

seriousness anticipated based on toxicology data or prior human experience with the drug or related drugs

Part 5

Investigator’s Brochure—to contain the following information:

a. Brief description of the drug (include structural formula) and the formulation b. Summary of the pharmacological and toxicological effects of the

drug in animals and, to the extent known, in man c. Summary of pharmacokinetics and biological disposition of the drug in animals and, if known, in man d. Summary of information relating to safety and effectiveness in humans from prior clinical studies (can append reprints when pertinent and useful) e. Description of possible risks and side effects to be anticipated based on experience with the drug or with related drugs. Precautions or special monitoring to be done as part of the investigations

Part 6 Clinical Investigation a. Protocol for each planned study

676 Roehrs and Krueger Table 1 Continued

b. Investigators Name, address and CV of each investigator Name of each subinvestigator Name and address of research facilities Name and address of IRB

c. Monitor—name, title, and CV (The person responsible for monitoring the conduct and progress of the clinical investigations) Safety Monitor(s)—name, title and CV (The person or persons responsible for review and evaluation of

information relevant to safety of the drug) d. Contract Research Organizations (CRO) i. Name and address of CRO used for any part of the clinical studies ii. Identify the studies and CRO monitor iii. List sponsor obligations transferred to CRO, if any e. Labeling for clinical supplies Part 7

Chemistry, Manufacturing, and Controls Information a. Drug Substance

1. Description of physical and chemical characteristics 2. Name and address of manufacturer 3. Method of preparation 4. Reference standard 5. Specifications 6. Methods of analysis 7. Stability

b. Drug Product 1. Components (reasonable alternatives)

i. Inactive components—tests and specifications 2. Composition (reasonable variations) 3. Name and address of manufacturer 4. Manufacturing and packaging procedure 5. Specifications 6. Methods of analysis 7. Packaging 8. Stability 9. Labeling for clinical supplies

10. Placebo—composition, manufacture, and control 11. Environmental analysis—Claim for categorical exclusion

Part 8 Pharmacology and Toxicology a. Pharmacology and drug disposition 1. Section describing the pharmacological effects and mechanism(s) of action of the drug in animals 2. Section describing the ADME of the drug, if known

Regulatory Considerations 677 b. Toxicology

1. ID and qualifications of persons conducting and evaluating results of studies concluding reasonably safe to begin purposed investigations

2. Statement where studies conducted and where records available for inspection 3. Integrated summary of the toxicological effects of the drug in animals and in vitro 4. Detailed tox study reports with full tabulations of data for each study primarily intended to support the safety of the proposed clinical investigation

5. GLP Compliance Statement(s) Part 9

Previous Human Experience Summary of known prior human experience with the investigational drug to include:

a. If previously investigated or marketed (anywhere): i. Detailed information about such experience relevant to safety of proposed investigation or rationale ii. If drug has been subject of controlled clinical trials, detailed information on such trials relevant to an assessment of the drug’s effectiveness for the proposed investigational use

iii. Published material directly relevant to safety or effectiveness for the proposed investigational use—provide full copies

Published material less directly relevant—bibliography b. For combination of drugs—Part 9a information for each drug c. Foreign marketing

i. List of countries where marketed ii. List of countries where drug has been withdrawn from marketing for reasons potentially related to safety or effectiveness Part 10

Pediatric Studies—plans for assessing pediatric safety and effectiveness Source : Adapted from 21 CFR 312.23

protocol is a critical element of the investigational phase for a new drug. FDA regulations establish requirements for the protocol (Table 3). The FDA medical officer reviewing the protocol will provide a critique as to its scientific and regulatory acceptability as well as the acceptability of the risk to human subjects. If the study is intended to be used as part of the NDA to establish safety and effectiveness, it would be important to know if the FDA has any serious questions about the protocol before proceeding.

Ophthalmic drug clinical development generally follows three phases, particularly if the drug is a new molecule and this is its first introduction into humans. Phase 1 for ophthalmic drugs usually is focused on the potential for

678 Roehrs and Krueger Table 2 Clinical Testing Phases Phase 1 : Initial introduction into man—closely monitored patients or normal

volunteers. Primarily for side effects with increasing doses, ADME and clinical pharmacology and early readout on effectiveness. Used to design well-controlled, scientifically valid Phase 2 studies. Also used for structure-activity and mechanism of action studies as well as using drugs as research tool to explore biology and disease processes. Usually involve fewer than 100 subjects. Phase 2 : Controlled studies for effectiveness in patients and determination of common short-term side effects and risks. Well-controlled and closely monitored studies in usually no more than several hundred patients. Used to screen out drugs with limited potential for safety and/or effectiveness. Data critical to design Phase 3, particularly for dosage regimens and patient populations. Phase 3 : Expanded studies in patients both controlled and uncontrolled to gather data on safety and effectiveness needed to evaluate overall benefit-risk and provide basis for labeling. Usually involve several hundred to several thousand subjects. Phase 4 : Studies usually conducted after initial marketing. May be requested by FDA as condition of approval. May be used to examine specific patient subpopulations such as geriatric or pediatric or to increase exposure to further define benefit-to-risk ratio.

ocular toxicity in healthy subjects. Because of the potential for systemic absorption for ocular dosing, attention is also given to the possibility of systemic effects, and concurrently, or in separate studies, the extent of sys- temic absorption is determined.

In Phase 2 of clinical testing, the drug is usually first introduced into patients with the disease and a dose-response relationship is investigated.

Table 3 Clinical Protocol Requirements Objectives and purpose of study

Identification of each investigator and subinvestigator, research facilities, and each IRB Criteria for patient selection and exclusion and estimated number of patients Study design including group (if any) and methods to minimize bias on part of subjects, investigators, and analysts Method for determining doses to be used, the maximum dose and duration of patient exposure Description of the observations and measurements to fulfill objectives of study Description of clinical procedures, lab tests, or other measures to monitor drug effects in subjects and to minimize risk

Regulatory Considerations 679 For oral drugs, the dose-response testing is a crucial parameter; however, it

has not been a rigorous part of most topical ophthalmic drug-development programs. The drug delivery researcher may find that these data are missing for his or her drug and needs to establish this relationship for optimization. An example of this occurred during the development of the Ocusert contain- ing pilocarpine in which patients were given multiple micro doses of pilo- carpine topically to establish the required release rate to provide the desired IOP-lowering response (5).

The final Phase 3 testing is essential for providing the substantial evidence from adequate and well-controlled studies required for proof of safety and effectiveness. It is particularly important that the endpoints used to measure the response of the delivery system be clinically relevant and that enough patients are included to detect a significant difference if one exists.

The FDA has established standards for the conduct of clinical studies in order to ensure the quality and integrity of the data on which the safety and effectiveness decisions will be based and also, importantly, the protec- tion of the rights and health of the participating subjects. These are com- monly referred to as Good Clinical Practices (GCPs) but are not embodied in one regulation. They are a combination of the Informed Consent regula- tion for clinical subjects (21 CFR 50), the Institutional Review Board (IRB) regulations (21 CFR 56), and the obligations of sponsors and investigators defined in the 1987 IND Rewrite regulations (21 CFR 312).

2. Preclincal Testing The nonclinical or preclinical section addresses the biological data that

support the pharmacological rationale for the intended use of the drug, the animal toxicology data to assess the safety risks for human exposure, and, if available, systemic and ocular pharmacokinetic data. These data may necessarily be limited at this point, particularly if the drug is a new molecule. If the delivery system is being developed with a known drug, then compara- tive tests will be useful to assess the risk. If the delivery system contains a new component, such as a polymer or surfactant to prolong ocular residence and/or enhance bioavailability, then additional safety testing may be required for the new component if the supplier has not already provided this information. In some cases this component may have already been used in other drug applications or sometimes for food or cosmetic uses and have established a generally recognized as safe (GRAS) status. The toxicologist will have to assess the relevance of these data to the intended topical appli- cation.

FDA does not have specific requirements or guidelines to answer the often asked question: How much animal safety data do I need for an

680 Roehrs and Krueger ophthalmic IND? In general, to begin clinical testing, FDA will require at

least the same duration of testing in animals as proposed for human expo- sure. The requirements will vary with the particular drug and the novelty of the particular delivery system. The approach of one company in establishing the safety/toxicity profile of ophthalmic drugs and devices has recently been published (6).

FDA implemented Good Laboratory Practice (GLP) regulations in 1976, which established standards for the conduct and reporting of all ani- mal safety-related studies to be used in support of an IND or NDA. This was a reaction to the discovery that some industrial and contract toxicology testing labs were conducting studies in a sloppy manner and in instances had falsified data that were submitted to FDA. FDA now routinely audits on a periodic basis all labs conducting such studies. Therefore, if animal safety data are generated in an academic institution and the results are to be used in support of an IND, the studies must meet GLP regulations and any deviations from these requirements must be explained. A certification of GLP compliance is required in the IND for each safety study (21 CFR 58).

3. Chemistry, Manufacturing, and Controls The next major section of the IND describes the chemistry of the drug

substance and the composition, manufacturing, packaging, quality control, and stability of the dosage forms to be used in the clinical trials. Inadequacies in this section can cause FDA to withhold the approval to conduct the proposed clinical trials, particularly if the deficiencies cause a concern related to safety.

a. Drug Substance. The drug substance must be characterized as to its structure and adequate analytical procedures must be specified to ana- lyze routinely the identity and purity of the drug. If the drug is in an offi- cial pharmacopeia, the monograph for the drug may be referenced; however, the FDA is not bound by these requirements and may require additional tests and specifications. For example, the assay method for the drug should be stability indicating, and some monographs may not meet this standard. Also, FDA will be interested in the major impurities and re- quire specific tests and specifications for them, which may not be part of

a monograph. The supplier of the drug substance is required to be identified as well as the methods of synthesis and controls used by the manufacturer. This will also be required for compendial drugs. Since the information on synthesis is usually considered proprietary, FDA has established a mechanism by which this confidential information can be supplied for their review directly from the manufacturer through a Drug Master File (DMF) (7). The manufac-

Regulatory Considerations 681 turer will send the FDA a letter authorizing the IND sponsor to access this

information in a specific DMF, and the sponsor is required to include a copy of this letter of authorization in this section of the IND.

An authentic reference standard is required for each drug substance. If not available from USP, it will have to be established independently, must

be of the highest purity available, and the method of synthesis and purifica- tion must be included.

b. Drug Product. The dosage form containing the active drug sub- stance and its vehicle or delivery system must be described in detail:

Components—Listing of all active and inactive ingredients that are used in preparation of the finished product. Inactive Components—The quality standard which is used and, if other than compendial items, the actual tests and specifications. Composition—The quantitative composition for the entire formula expressed in terms of percent, milligrams per milliliter, and a typical batch quantity.

Manufacture—The name and address of each firm involved in the manufacture, packaging, labeling, and testing of the drug product. Method of Manufacturing—The method of manufacturing, packa- ging, and labeling the product and the controls used in these pro- cesses.

Packaging Components—The packaging is identified and the compo- nents are described and specified. The USP specifies tests required for suitability of plastics in ophthalmic containers, which are both physicochemical and biological. The tests should be conducted on the containers after they are cleaned and sterilized.

Stability—Sufficient stability data using stability-indicating methods should be submitted to assure a stable product for the duration of the clinical trials.

Labeling—Copy of the labels to be applied to the containers of the clinical supplies. These are usually multipart labels so as to provide complete labeling information during shipment, which can be removed before given to the patient to mask the identity of the product from the patient and the physician. The label must bear the statement: ‘‘Caution: New Drug Limited by Federal Law to Investigational Use.’’

Placebo—Many studies require the drug to be compared to a placebo, which is usually the vehicle or delivery system itself. The same information described above for the active drug product is provided for the placebo dosage form.

682 Roehrs and Krueger Environmental Assessment—The environmental regulations provide

for a categorical exclusion from preparing an environmental assess- ment for clinical trials.

c. Sterilization. FDA regulation requires that all ophthalmic drug products be manufactured and packaged in a sterile manner. This can be accomplished in two ways: by terminal sterilization or by aseptic combi- nation of sterile components. Terminal sterilization is preferred, since it provides the greatest assurance of final product sterility. Often this is not feasible because of the heat lability of the ingredients or the packaging system. Terminal sterilization is usually done by radiation or steam under pressure. Many drug products are made sterile by sterilizing the individual components, including the packaging materials, and then aseptically com- bining them in a sterile environment. The FDA has provided guidelines for the proper validation of the aseptic process for sterile products (8).

Because of the much greater sterility assurance offered by a terminal sterilization process, the FDA will require the applicant to justify the use of an aseptic process for sterilization (9). Data, therefore, should be generated during the development of the delivery system to determine the impact of a terminal sterilization process on the final packaged dosage form. This would usually involve chemical and physical analyses of the product for degrada- tion products and any change in the toxicology profile.

d. Preservation. If the delivery system is a liquid in a multiple dose package, the requirement for addition of substance(s) to inhibit the growth of microorganisms during use needs to be considered. The regula- tion states that these substances must be added or the product packaged in such a manner that harmful contamination cannot reasonably occur during use (21 CFR 200.50). Therefore, the regulation does not absolutely require a preservative be used in all multidose packages. However, FDA has not given any published guidance as to their interpretation of what type of unpreserved multidose product would meet the requirements of this regulation.

The regulation specifically states a requirement for liquid products and provides no guidance for multidose semisolids such as aqueous gels. The drug delivery scientists should work closely with the microbiologist and packaging scientist to determine the best means to accomplish the safe administration of a sterile product.

New ophthalmic delivery systems in unit dose form offer the oppor- tunity to improve the ability of the patient to comply with the prescribed dosage regimen and also obviate the need for the addition of a preservative agent.

Regulatory Considerations 683

e. Good Manufacturing Practices. Clinical supplies of the new ophthalmic drug delivery system should be manufactured in conformance with the GMP regulations. The pharmaceutical industry has recognized that the official GMP regulations are not always practical or suitable for clinical supplies. The quantities are usually small, and since this is a re- search and development process, changes will necessarily occur as experi- ence is gained and the scale of manufacture increases. FDA has also recognized these facts and has issued guidelines that address the allowable differences in GMP compliance for clinical trial manufacture (10).