Clinical Development Plan

A clinical development plan (CDP) is a description of clinical studies that will be carried out in order to assess the safety and effectiveness of the drug. A clinical development plan typically includes a development rationale, listing of trial characteristics, timeline, cost, and resource requirements. A good and flexible clinical development plan hence is extremely crucial and important to the success and unbiased assessment of a potential pharmaceutical entity. Although a typical CDP is based primarily on the validity of medical and scientific considerations, other factors that involve issues such as biostatistics, regulatory, marketing, and management are equally important. For a successful CDP, we first need to define a product profile for the promising pharmaceutical entity before any clinical development. Table 1.6.1 lists essential components of a product profile. These components set the goals and objectives for the clinical development program of a pharmaceutical entity. A clinical development program is referred to as the set of different clinical trial plans at different stages with milestones for assessment and decision making to evaluate the goals and objectives stated in the product profile. For example, if the drug product under development is for an indication intended for a particular population, the relative merits and disadvantages of the product as compared to other products either on the market or still under development should objectively be assessed. In order to evaluate the relative merits, minimum requirements and termination criteria on the effectiveness and safety of the product are usually set. These requirements and criteria are evaluated through statistical analysis of data collected from a series of clinical trials. The deadlines for milestones and decision making should also be scheduled in CDP according to the time when certain clinical trials to evaluate the requirements and criteria are completed and the data are adequately analyzed. Since a huge investment is usually necessarily committed to develop a new pharmaceutical entity, information based on efficacy and safety alone may not be enough to evaluate a potential product. It is therefore recommended that cost-effectiveness and quality of life be evaluated, especially for the me-too products in a saturated market. In this case requirements and criteria for cost-effectiveness and quality of life need to be included at milestones and/or decision-making points. As indicated earlier, although many factors such as statistics, marketing, regulatory, and management need to be considered in a CDP, the scientific validity of clinical investigations is the key to the success of a clinical development program.

In the pharmaceutical industry clinical development of a pharmaceutical entity starts with seeking alternatives or new drug therapies for an existing health problem (e.g., hypertension) or a newly identified health problem (e.g., AIDS). The health problem of interest may be related to virus, cardiovascular, cancer diseases, or other diseases. Once the health problem is selected or identified, whether it is worth developing an alternative or a new pharmaceutical entity for this particular disease is a critical development decision point. A clear decision point can increase the success of the project and consequently reduce the risk and cost. Suppose that it is decided to proceed with the development of a pharmaceutical

Table 1.6.1 Components of a Pharmaceutical Product Profile

Target population Innovation potentials Therapeutic concepts Innovative elements Technological advances Patent status Route of administrations Doses

Formulations Regimens Duration of dosing Status of market Current competitors On market Under development Advantages Disadvantages Minimum requirements Efficacy Safety Termination criteria Efficacy Safety Time frames Milestones entity (e.g., enzymes or receptors), a number of chemical modifications and ADME tests in animals may be necessary before it can be tested on humans. ADME studies are used to determine how a drug is taken up by the body, where it goes in the body, the chemical changes it undergoes in the body, and how it is eliminated from the body. ADME studies describe the pharmacokinetics and bioavailability of a drug. If the drug shows promising effectiveness and safety in animals, the sponsor normally will make a decision to go for an IND. As indicated in Section 1.4, an IND is a synthesis process that includes formulation, analytical method development and validation, stability, animal toxicity, pharmacokinetic/ pharmacology, previous human experience, and clinical development. The sponsor will then prepare a registration document that combines all the relevant data to allow the FDA to review and decide whether to approve marketing of the new drug. As discussed in Section 1.5, an NDA submission should include chemistry, pharmacology, toxicology, metabolism, manufacturing, quality controls, and clinical data along with the proposed labeling.

Good Clinical Practices

Good clinical practices (GCP) is usually referred to as a set of standards for clinical studies to achieve and maintain high-quality clinical research in a sensible and responsible manner. The FDA, the Committee for Proprietary Medicinal Products (CPMP) for the European Community, the Ministry of Health and Welfare of Japan, and other countries worldwide have each issued guidelines on good clinical practices. For example, the FDA promulgated a number of regulations and guidelines governing the conduct of clinical studies from which data will be used to support applications for marketing approval of drug products. The FDA regulations refer to those regulations specified in 21 CFR Parts 50, 56, 312, and 314, while the FDA guidelines are guidelines issued for different drug products such as Guidelines for the Clinical Evaluation of Anti-Anginal Drugs and Guidelines for the Clinical Evaluation of Bronchodilator Drugs. On the other hand, the European Community established the principles for their own GCP standard in all four phases of clinical investigation of medicinal products in July 1990. Basically these guidelines define the responsibilities of sponsors, monitors, and investigators in the initiation, conduct, documentation, and verification of clinical studies to establish the credibility of data and to protect the rights and integrity of study participants.

In essence GCP concerns patient protection and the quality of data used to prove the efficacy and safety of a drug product. GCP ensures that all data, information, and documents relating to a clinical study can be confirmed as being properly generated, recorded, and reported through the institution by independent audits. Therefore the basic GCP concerns are not only the protection of study subjects through informed consent and consultation by ethics committees such as IRB but also the responsibilities of the sponsors and monitors to establish written procedures for study monitoring and conduct and to ensure that such procedures are followed. In addition GCP emphasizes the responsibilities of investigator to conduct the study according to the protocol and joint responsibilities for data reporting, recording, analysis, and archiving as well as prompt reporting of serious adverse events. Moreover GCP calls for the most appropriate design for a valid statistical evaluation of the hypotheses of the clinical trials. The chosen design must suit the purpose with the best possible fit. Incorporating the concerns of GCP in the protocol will ensure a protocol of high standard, which in turn will help generate high-quality data.

Study conduct according to GCP standards requires regular visits to investigating center to monitor study progress. The activities of the sponsor's monitors that will affect the investigator and support staff should be stated in the protocol. Not only this is courteous, it prevents misunderstanding, facilities cooperation, and aids the speedy acquisition of completed case report form. The activities include frequency of monitoring visits, activities while on site (e.g., auditing CRFs), and departments to be visited (e.g., pharmacy). The practical effects of adopting GCP are that the investigator is audited by the sponsor's monitors (to confirm data on CRFs are a true transcript of original records), by a sponsor administratively separate from the clinical function and in some countries, by the national regulatory agency. The sponsor's monitors are audited by a compliance staff and by national regulatory agencies to confirm the accuracy of data recorded and the implementation of all written procedures such as standard operating procedure (SOP) and protocol.

Most of pharmaceutical companies and research institutions have a protocol review committee (PRC) to evaluate the quality and integrity of the protocol and hence to approve or disapprove the protocol. Some companies also ask the principal study medical monitor and statistician to submit a case report form (CRF) and a statistical analysis plan with mock tables and listing for presentation of the results to PRC at the same time when the protocol is submitted for review.

Lisook (1992) has assembled a GCP packet to assist the sponsors in the planning, execution, data analysis, and submission of results to the FDA. A summary of this GCP packet is given in Table 1.6.2. Most of these regulations have been discussed in the previous sections of this chapter. To improve the conduct and oversight of clinical research and to ensure the

Table 1.6.2 References to Keep at Hand for Good Clinical Practice

1. Information on FDA regulations

2. Center for Drug Evaluation and Research publications

3. Clinical Investigations (excerpt from the Federal Register, 9-27-1977)

4. Protection of Human Subjects, Informed Consent Forms

5. New Drug, Antibiotic, and Biologic Drug Product Regulations; Final Rule (excerpt from the Federal Register, 3-19-1987)

6. Investigational New Drug, Antibiotic, and Biologic Drug Product Regulations; Treatment Use and Sale; Final Rule (excerpt from the Federal Register, 5-22-1987)

7. Guideline for the Monitoring of Clinical Investigations

8. Investigational New Drug, Antibiotic, and Biologic Drug Product Regulations; Procedure Intended to Treat Life-Threatening and Severely Debilitating Illness; Interim Rule (excerpt from the Federal Register, 10-22-1988)

9. FDA IRB (Institution Review Board) Information Sheets

10. FDA Clinical Investigator Sheet

11. Reprint of Alan B. Lisook, M.D. FDA audits of clinical studies: Policy and procedure, Journal of Clinical Pharmacology, 30 (April 1990) 296-302.

12. Federal Policy for the Protection of Human Subjects; Notices and Rules (excerpt from the Federal Register, 6-18-1991)

13. FDA Compliance Program Guidance Manual-Clinical Investigators (10-1-1997)

14. FDA Compliance Program Guidance Manual-Sponsors, Contract Research Organization and Monitors (2-21-2001)

15. FDA Compliance Program Guidance Manuals-Institutional Review Board (10-1-1994)

protection of subjects participating in the FDA-regulated clinical research, the U.S. FDA established the Office of Good Clinical Practice (OGCP) within the Office of the Commissioned and its Office of Science Coordination and Communication in 2001. This new office has distinct roles from the Office of Human Research Protections (OHRP) of the Department of Health and Human Services (DHHS). These distinct roles include (1) coordination of the FDA's policies, (2) provision of leadership and direction through the administration of the FDA's Human Subject Protection/Good Clinical Practice Steering Committee, (3) coordination of the FDA's Bioresearch Monitoring program, (4) contribution to the international Good Clinical Practice harmonization activities, (5) planning and conducting training and outreach programs, and (6) serving as a liaison with OHRP and other federal agencies and other stakeholders committed to the protection of human research participants.

In the past, as demonstrated in Tables 1.5.2 and 1.5.3, Tables 1.5.5 and 1.5.6, health regulatory authorities in different countries have different requirements for approval of commercial use of the drug products. As a result, considerable resource had been spent by the pharmaceutical industry in the preparation of different documents for applications of the same pharmaceutical product to meet different regulatory requirements requested by different countries or regions. However, because of globalization of the pharmaceutical industry, arbitrary differences in regulations, increase of health care costs, need for reduction of time for patients to access new drugs, and of experimental use of humans and animals without compromising safety, the necessity to standardize these similar yet different regulatory requirements has been recognized by both regulatory authorities and pharmaceutical industry. Hence, The International Conference on Harmonization (ICH) of Technical Requirements for the Registration of Pharmaceuticals for Human Use was organized to provide an opportunity for important initiatives to be developed by regulatory authorities as well as industry association for the promotion of international harmonization of regulatory requirements.

Currently, ICH, however, is only concerned with tripartite harmonization of technical requirements for the registration of pharmaceutical products among three regions: The European Union, Japan, and the United States. Basically, the organization of the ICH consists of two representatives, one from a regulatory authority and one from the pharmaceutical industry, from each of the three regions. As a result, the organization of the ICH consists of six parties of these three regions which include the European Commission of the European Union, the European Federation of Pharmaceutical Industries' Associations (EFPIA), the Japanese Ministry of Health, Labor and Welfare (MHLW), the Japanese Pharmaceutical Manufacturers Association (JPMA), the Centers for Drug Evaluation and Research and Biologics Evaluation and Research of the US FDA, and the Pharmaceutical Research and Manufacturers of America (PhRMA). The ICH steering committee was established in April, 1990 to (1) determine policies and procedures, (2) to select topics, (3) to monitor progress, and (4) to oversee preparation of biannual conferences. Each of the six parties has two seats on the ICH steering committee. The ICH steering committee also includes observers from the World Health Organization, the Canadian Health Protection Branch, and the European Free Trade Area which have one seat each on the committee. In addition, two seats of the ICH Steering Committee are given to the International Federation of Pharmaceutical Manufacturers Association (IFPMA), which represents the research-based pharmaceutical industry from 56 countries outside ICH regions. IFPMA also runs the ICH Secretariat at Geneva, Switzerland which coordinates the preparation of documentation.

In order to harmonize technical procedures the ICH has issued a number of guidelines and draft guidelines. After the ICH steering committee selected the topics, the ICH guidelines initiated by a concept paper and went through a 5-step review process given in Table 1.6.3. The number of ICH guidelines and draft guidelines at various stages of review process is given in Table 1.6.4. Table 1.6.5 provides a list of currently available ICH guidelines or draft guidelines pertaining to clinical trials while Table 1.6.6 gives the table of contents for the ICH draft guideline on general considerations for clinical trials. In addition, the table of contents of the ICH guidelines for good clinical practices: consolidated guidelines, for structure and content of clinical study reports, and for statistical principles for clinical trials are given, respectively in Tables 1.6.7, 1.6.8, and 1.6.9. From these tables, it can be seen that these guidelines are not only for harmonization of design, conduct, analysis, and report for a single clinical trial but also for consensus in protecting and maintaining the scientific integrity of the entire clinical development plan of a pharmaceutical entity. Along this line, Chow (1997, 2003) introduced the concept of good statistics practice (GSP) in drug development and regulatory approval process as the foundation of ICH GCP. The concepts and principles stated in the ICH clinical guidelines will be introduced, addressed, and discussed in the subsequent chapters of this book.

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