Clinical research planning

The clinical drug development process required by the US FDA, arguably the most stringent in the world, starts with the investigational new drug (IND) application prior to human testing. It reveals information about all known compounds to be used and includes the description of the clinical research plan for the product as well as the protocol for phase I studies. Preclinical study results also need to be revealed. 

Regulatory Review Investigational New Drug (IND) Application—An application filed with the U.S. FDA prior to human testing. The IND application is a compilation of all known information about the compound. It also includes a description of the clinical research plan for the product and the specific protocol for phase I study. Unless the FDA says no, the IND is automatically approved after 30 days and clinical tests can begin. 

Every protocol must state a primary, quantifiable, study objective. Secondary objectives should be limited in scope and related to the primary question. Objectives must be specific and capable of answering a key clinical question required by the clinical research plan. 

Large CROs can be used for effective planning of large clinical research projects. They commonly have extensive experience in the disease areas to be studied, although they... 

In planning federally funded studies, attention must be paid to the current requirements for inclusion of sex/ gender and racial/ethnic minorities. According to the National Institutes of Health (NIH) policy, all clinical research must include female subjects and members of racial/ethnic minority groups, unless a clear and compelling rationale is provided indicating that inclusion is inappropriate with respect to the health of the subjects... 

Institutional Review Boards. In university clinics and other hospitals engaged in research, ethics committees (also called Institutional Review Boards, IRBs) have been formed over the last three decades to monitor clinical research activities from scientific, legal, ethical and social viewpoints. All protocols relating to clinical trials must be submitted to these committees, which are generally made up of one or several doctors, a lawyer, a representative of the nursing staff and also community representatives such as priests. This composition forces clinical researchers to set out their intentions in such a way as to be clear enough for a lay person to understand and to assess whether the inconvenience and risks involved for the patient are in a reasonable relationship to the possible benefit of the planned trial. 

Biostatistics has been recognized and extensively employed as an indispensable tool for planning, conduct, and interpretation of clinical trials. In clinical research and development the biostatistician plays an important role that contributes toward the success of clinical trials. Well-prepared and open communication among clinicians, biostatisticians, and other related clinical research scientists will result in a successful clinical trial. 

To avoid or limit problems in this area after submission of the NDA, the validation of analytical methods and the conduct of stability studies should be planned from the initial phases of clinical research. This will provide the type of data approvable by FDA. The reader is directed to the Guideline for Stability Studies for Human Drugs and Biologies and the final ICH Guideline for the Stability of Drug Substance and Drug Product for assistance in fulfilling this essential requirement. 

Bliss, A. R. (1984). Major disaster planning. British Medical Journal Clinical Research Education, 288(6428), 1433-1434. 

One aspect of clinical research that requires extensive contribution by the drug development team personnel is study monitoring. Study monitors oversee the planning. 

Official standards are absolutely necessary to ensure the quality, reliability, and homogeneity of herbal products for consumers. Standardized products are paramount to those in healthcare planning to conduct clinical research with these products. Independent laboratories and university-affiliated research reports have documented the considerable variation that exists in terms of quality and reliability in these products. Abroad, the ESCOP, composed of manufacturers of herbal medicines and herbal associations, is working with European research groups to develop quality-control standards for the production of natural products. This committee is developing monographs for incorporation into such references as the British Herbal Pharmacopoeia and the British Herbal Compendium. 

In addition, NCCAM plans to support a contract for the development and production of research grade cranberry (Vaccinium macrocarpon) products and placebos for use in clinical studies. There is evidence from small clinical trials suggesting that cranberry may relieve symptoms of urinary tract infection (UTI) and may reduce the need for antibiotics in treating such infections (23). The products developed under the contract will be evaluated in basic and clinical research studies on the role of cranberry in the prevention and treatment of UTIs and other conditions for which there is credible evidence of efficacy. 

Few people come to the pharmaceutical industry from academia and health-related positions with the requisite knowledge and skills necessary to plan, conduct and report clinical research to regulatory authority standards. This knowledge and skill usually need to be provided by sponsors to all levels of new staff by the way of in-house training. 

The following is a description of the typical knowledge and competencies needed to plan, conduct and report clinical research in a regulated environment. Each competency is described along with the knowledge and skills a sponsor s representative would need to be successful in completing the task. 

An effective QM system for clinical research helps assure that studies are planned, conducted, analyzed, reported and managed in compliance with GCP guidelines and ethical principles as noted in the Declaration of Helsinki, so that dependable trial results are achieved while ensuring that trial participants are protected. 

QA auditors core responsibility is to conduct audits in the various areas in clinical research. This requires the set up of an audit program which should be based on the clinical development plan for the substance(s), previous experience gained in audits and the importance of the trials in the light of a marketing submission. Ideally, the audit program should cover all clinical trials. 

For each individual audit, it is useful to prepare an audit plan to provide the auditee with an overview on the audit components and the conduct of the audit. An audit plan may also be useful as a basis for agreement between the sponsor, the (external) QA auditor and the audit team. It is common practice in clinical research to draw up an audit plan and distribute this information prior to the audit. 

Suppose one wishes to conduct a trial to test the efficacy of a new antihypertensive drug. The clinical research physician plans to enroll a certain number of subjects with mild to moderate hypertension and randomize them to receive either the experimental drug or placebo. The primary efficacy variable is the decrease in the diastolic blood pressure as compared to a pretreatment baseline. 

Phase IV studies can also take the form of retrospective pooled analyses which are designed to reflect the totality of clinical research experience with a new drug which is usually obtained via analysis of pooled clinical trial databases. Such data-mining efforts should not be considered inferior to data obtained from the conduct of an individual clinical trial. In fact, there are substantial benefits of such an approach, as the results of a given trial, especially if the end point is not prespecified to be primary because of power limitations, can be a function of chance. To assure that the results obtained from pooled analyses are not biased, a prespecified data analysis plan is often formulated as the first step, outlining the clear goals of the proposed analysis as well as its methodology. Key to this type of analysis is the definition of the outcome measure. Both efficacy and safety measures can be the focus of these types of analyses. 

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