19.2  Drug Product Approval Process

Every drug must be approved by the country’s health authority before it can be marketed in that country. In the United States, that health authority is the US Food and Drug Administration (FDA). The commissioner of the FDA reports to the Secretary of the Department of Health and Human Services. The FDA has publicized federal regulations based on the Federal Food Drug and Cosmetic Act that was passed in 1938 and its amendments that provide the basic requirements for obtaining approval of a New Drug Application (NDA). Chapter 1, Title 21 of the Code of Federal Regulations (21 CFR) covers the US federal regulations that govern the testing, manufacture and sale of pharmaceutical agents, and medical devices. In addition, the FDA regularly disseminates guidelines and guidances that provide greater detail on a given topic and reflects the FDA’s current thinking on that topic. These documents are drafted by the FDA and are open for review before finalization. The corresponding subject matter experts from the industry and academia provide their scientific input for consideration by the FDA. The acceptance of their comments and suggestions is completely at the discretion of the FDA.

Since most drugs are developed with the intention of marketing them worldwide, not just in the United States, the International Conference on Harmonization (ICH) of Technical Requirements for Registration of Pharmaceuticals for Human Use was established in 1990. The conference members are regulatory and pharmaceutical industry representatives from the European Union, United States, and Japan, the major pharmaceutical powers at that time. The main purpose of ICH was to harmonize the requirements that a sponsor will need to fulfill in order to get product approval in major markets around the world. The harmonization is achieved by issuing guidelines which have been accepted as law in several countries but are only used as guidances in the United States. A secondary purpose of this harmonization is to help reduce the cost and time of research and development by avoiding the need for sponsors to repeat many time-consuming and expensive studies to meet country specific requirements and also significantly reduce the use of animals by avoiding study repetition without compromising the quality, safety, and efficacy of the final product.

Even though United States, the European Union, and Japan are the major pharmaceutical markets in the world, emerging markets are becoming significantly important in today’s world. These include Brazil, Russia, India, and China (BRIC) and other countries such as Mexico, Taiwan, South Africa, Poland, etc. The BRIC countries contribute more than 40% of the current world population and occupy more than 25% of the world’s land area. The regulatory systems for pharmaceutical product approval in some of these countries are not yet well developed. However, these countries provide a large customer base as well as a significant subject population for clinical trial enrollment with the following key advantages:

1. Faster enrollment of subjects into clinical trials which results in significant time and cost savings for the sponsor.

2. Lower cost of operations.

3. Enrollment of local subjects in clinical trials making it easier for future marketing of the drug in that region.

For these reasons, many sponsors prefer to include Ex-US sites in their clinical trials. However, including these Ex-US sites in the clinical trials requires knowledge about the regulatory environment in those countries and a good understanding of the regulatory requirements, obligations, and process of interacting with the local health agency. Additionally, the sponsor also needs to take into account the operational challenges that it may encounter in some of these countries. Some of these challenges include:

1. Lack of access to experienced and well-trained physicians. 2. Longer regulatory review timelines in certain countries.

3. Requirement that the regulatory filing be done in local language – giving rise to the need for translation.

4. Lack of harmonized clinical trial requirements, processes, and reporting rules.

In most cases, the advantages far outweigh the challenges making inclusion of these Ex-US sites in the clinical trials a very appealing proposition. A description of the regulatory environment of individual countries is beyond the scope of this chapter and the reader is encouraged to visit the individual countries health agency website to obtain the appropriate information. We will use the United States as a template for further discussion. It is important to note, however, that in most countries, the quality and nonclinical study requirements will be quite similar to those in the United States. The process of obtaining approval to start the clinical trials, the review timelines, clinical study conduct and documentation, and interactions with the health agency will differ from country to country.

In the United States, an Investigational New Drug Application (IND) needs to be filed with the FDA in order to begin Phase I clinical trials to evaluate the safety and tolerance of the drug in healthy volunteers. The IND contains all the quality and nonclinical information required to support Phase I clinical testing. Additionally, it also contains all the details of the clinical study protocol and information on the qualification of clinical investigators. The nonclinical information is typically obtained in two species (rodent and nonrodent) using the intended route of administration and should justify the dose selection in Phase I trials. Following the acceptance of the IND by the FDA, there is a 30-day review period after which the sponsor can proceed with the Phase I study provided the FDA does not raise any potential issues or respond to the IND with a “clinical hold.” Subsequent to the successful completion of Phase I clinical trials, the sponsor will start Phase II clinical trials, with the approval of the FDA. Unlike, Phase I clinical trials, Phase II clinical trials are conducted in the intended patient population and will evaluate the therapeutic efficacy, dose–efficacy relationships, Pharmacokinetics and Drug Metabolism (PKDM), and safety in the patient population. Phase II clinical trials typically involve a moderately high number of patients and run for durations that are longer than Phase I clinical trials. Additional quality and nonclinical data to support the longer duration are submitted to the agency as IND amendments prior to start of

these trials as needed. After the successful completion of Phase II clinical trials, a thorough evaluation of all the available data should be done to obtain crucial understanding of the drug’s formulation feasibility and characteristics, safety profile and safety margins, dose–response relationships, and pharmacokinetics and metabolism. This evaluation also helps in choosing the correct doses that have the highest probability of success for potential future Phase III clinical trials. The decision to proceed with Phase III clinical trials that are generally long, expensive and involve a significantly higher number of patients should be made following this evaluation. The FDA requires at least two successful Phase III studies powered adequately to demonstrate statistically significant proof of the claimed therapeutic efficacy. Additional data from reproductive and developmental toxicity studies are needed before initiating Phase III clinical trials. Once Phase III clinical trials are complete and the sponsor has enough confidence in the statistical significance of the results, a NDA can be filed with the FDA for marketing authorization of the drug.

During the course of this regulatory process to obtain product approval, the FDA offers several mechanisms for the sponsor to consult with the agency before proceeding with the clinical trials. These come in the form of Type A, Type B, or Type C meetings between the sponsor and the FDA. These meetings can be officially requested by the sponsor and are granted by the FDA based on urgency of the matter and resources available to the agency. A comprehensive description of the types of meetings, procedures for requesting these meetings, content and timing of submission of information packages, and the procedures for the conduct of these meetings are detailed in the Guidance document prepared by the Review Management Working Group comprising individuals in the Centers for Drug Evaluation and Research (CDER) and Biologics Evaluation and Research (CBER) at the FDA in February 2000.

19.3  Considerations for Back of the Eye Treatments

None of the health agencies around the world have established a specific set of guidelines to assist in development of drug products for treatment of diseases of the back of the eye. However, assessing the quality of formulation development (chemistry, manufacturing, and control – CMC), ensuring the safety and efficacy of the drug product via nonclinical testing, and obtaining clinical evidence of the safety and efficacy using a rigorous clinical development program are the cornerstones of any drug development program and apply to the development of drug products for treatment of back of the eye diseases as well. The overall drug product approval process is similar to that mentioned in the previous section. The CMC section is geared towards assuring the quality of the drug substance and the drug product and comprises, at a minimum, documents supporting the following:

1. Description of the synthetic process for manufacturing the drug substance. 2. Physicochemical properties of the drug substance.

3. Development and validation of analytical methods for the drug and potential impurities.

4. Details on the composition and characterization of the formulation (composition, sterility testing, endotoxin testing, pH, etc.).

5. Proof of stability of the drug substance and the drug product. 6. In vitro release rates from the formulation.

All drug products designed for intraocular injection should be completely sterile and free of endotoxin to prevent any potential complications due to infections and/ or endophthalmitis. It is the responsibility of the sponsor to demonstrate that the sterilization procedures do not change the nature and composition of the drug product. The best way to avoid any complications from this is to treat the drug product used in nonclinical studies in the same way as the potential commercial product. This accounts for any chemical changes or residual by-products of sterilization and evaluates the corresponding safety risk in nonclinical species before progressing into clinical trials. Furthermore, since longer duration of action is preferred for drugs delivered to the posterior segment of the eye (to reduce the frequency of intraocular injection), most of the drug delivery systems need to demonstrate consistent release rates to ensure steady delivery of the drug to the target tissue over the intended duration. The FDA has stated that the release rates should be within ± 10% of nominal. If the release rates fall out of specification at a later stage in the development program, the initial preclinical and clinical study data could be rendered invalid (Gryziewicz and Whitcup 2005). The use of Good Manufacturing Practices (GMP) is critical during this phase.

The IND-enabling nonclinical studies are part of a standardized pharmacology, pharmacokinetics, and toxicology package required by the FDA (as well as other health agencies around the world). The aim of these studies is to demonstrate the safety and efficacy characteristics of the drug product in acceptable in vitro and in vivo models. The scope and nature of the studies should be based on sound scientific principles and astute scientific judgments based on all the available data.

The standard pharmacology, pharmacokinetics, and toxicology package required for any drug typically includes but is not limited to the following:

1. Pharmacology

(a)Primary pharmacodynamics

(b)Secondary pharmacodynamics

(c)Safety pharmacology

(d)Pharmacodynamic drug interactions

2. PKDM

(a)Analytical methods and validation

(b)Absorption (via the intended route of administration)

(c)Distribution

(d)Metabolism

(e)Excretion

(f)Pharmacokinetic Drug Interactions

3. Toxicology

(a)Local tolerance

(b)Single dose toxicity

(c)Repeat dose toxicity

(d)Genotoxicity

(e)Carcinogenicity

(f)Reproductive and developmental toxicity

In addition to the nonclinical toxicology studies, the nonclinical pharmacokinetic studies are crucial during the development of drug products for back of the eye diseases since it is very difficult to obtain clinical ocular samples. Therefore a good understanding of the target tissue(s) and development of a good pharmacokinetic– pharmacodynamic (PKPD) model based on drug concentration in the target tissue(s) goes a long way in scaling up the findings from nonclinical species (most likely rabbit, dog, or monkey) to humans. For retinal diseases like macular degeneration, the drug concentration at the retinal pigment epithelium, or choroid is important while for retinal diseases like proliferative vitreoretinopathy, vitreous levels may be the target (Gryziewicz. 2005).

A detailed description of these nonclinical studies is provided in Section C (Preclinical Development) of this book and most of these studies are conducted under the auspices of Good Laboratory Practices (GLP). Depending on the nature and marketing status of the drug, a formal request to waive some of these studies can be made by the sponsor to the agency based on scientific justification. For example, if the drug has been previously marketed for nonocular indications (systemic use), a fair amount of systemic pharmacokinetics, metabolism, and toxicity data can possibly be obtained from the literature, providing the option of utilizing the 505(b)(2) approval route (FDA Draft Guidance). This data combined with the potential lack of significant systemic exposure following intraocular administration (high safety margins) could be used to justify a waiver for some of the nonclinical studies such as systemic distribution and metabolism studies, chronic systemic toxicity studies, reproductive and developmental toxicity studies, and carcinogenicity studies. However, if the drug is a new chemical entity (NCE) with unknown safety characteristics, the full complement of studies may be needed for registration filing. These concerns can be discussed at Pre-IND or end of Phase II (EOP2) meetings between the sponsor and the agency. The approval of such requests is completely at the discretion of the agency. During the meeting, the sponsor may request a waiver of some studies. If granted, these waivers can save the sponsor a significant amount of time, money, and resources during the drug development process without jeopardizing the integrity of the overall submission package.

The clinical development of drug products is carried out in accordance with Good Clinical Practice (GCP) that set the standard for ethical and scientific quality for all aspects of clinical trial conduct and reporting. Typically, the sponsor progresses through Phase I, Phase II, and then Phase III clinical trials in a logical sequential manner with the data from each trial guiding the design of the next larger and more definitive trial. But with increasing cost and time of clinical trials, some

476 A.A. Kulkarni

STAGE 1: Open Label Staggering Dose Escalation

STOP

ESCALATION*

*Dose escalation may be stopped following review of the safety data from each cohort

STAGE 2: Masked Randomized Dose-Response

Fig. 19.1  Example of a two-stage Phase I/II clinical trial design

sponsors prefer conducting Phase I/II trials in a multistage fashion. One example of such multistage trial is shown in Fig. 19.1. In addition, the initial multistage clinical trials can be designed as proof-of-concept trials to exhibit efficacy over a shorter period of time even though the ultimate goal is for a longer duration (ideally ³ 6 months to 1 year). If these shorter trials demonstrate the activity of the drug when administered via its intended route of administration, it provides the sponsor with confidence to proceed with larger, expensive, and longer trials (Phase III) aimed at demonstrating the efficacy for a longer duration.

Phase III clinical trials are designed to demonstrate one of the following outcomes:

1. The drug product is superior to a placebo.

2. The drug product is equivalent or noninferior to an approved marketed product for similar indication.

3. The drug product has superior efficacy and/or safety compared to an approved marketed product for similar indication.