The content of an IND is prescribed in the Code of Federal Regulations and is submitted under a cover sheet (Form FDA-1571) (1).
Among the items required
Name, address, and telephone number of the •
sponsor of the drug
Name and title of the person responsible for •
monitoring the conduct and progress of the investigation
Names and titles of the persons responsible •
for the review and evaluation of the informa- tion relevant to the safety of the drug
Name and address of any contract research •
organization involved in the study
Identifi cation of the phase or phases of the •
clinical investigation to be conducted Introductory statement and general investiga- •
tional plan: the name of the drug and all active ingredients, the drug’s structural formula and pharmacologic class, the formulation of the dosage form and route of administration, and the broad objectives and planned duration of the study
Description of the investigational plan: •
the rationale for the drug or research study, the indication or indications to be studied, the approach to evaluating the drug, the types of studies to be conducted, the estimated num- ber of subjects to be given the drug, and any serious risks anticipated based on animal stud- ies or other human experiences with the drug Brief summary of previous human experience •
with the drug (domestic or foreign), including the reasons if the drug has been withdrawn from any other investigation and/or marketing CMC information: a complete description of •
the drug substance, including its physical, chemical, and biologic characteristics; its method of preparation and analytical meth- ods to ensure its identity, strength, quality, purity, and stability; a quantitative list of the active and inactive components of the dosage form to be administered; the methods, facili- ties, and controls employed in the manufac- ture, processing, packaging, and labeling of the new drug to ensure appropriate qualita- tive and quantitative standards; and product stability during the clinical investigation Pharmacology and toxicology information: the •
drug’s mechanism of action if known; informa- tion on the drug’s absorption, distribution,
Chap02.indd 45
reproductive or developmental toxicity from use of the investigational drug (40). There are other instances in which drug studies or drug use dur- ing pregnancy is justifi ed, for example, agents intended to prevent Rh immunization and hemo- lytic disease of the newborn (41).
When a proposed drug is likely to have signifi - cant use in the elderly, elderly patients are required to be included in clinical studies to yield age- related data of a drug’s effectiveness and any adverse effects. Older people handle a drug differently because of altered body functions such as dimin- ished liver and kidney function, reduced circula- tion, and changes in drug ADME. Furthermore, the elderly have a greater incidence of chronic ill- ness and multiple disease states than younger adults, and as a result, take multiple medications daily, increasing the potential for drug–drug inter- actions. This potential is studied and defi ned.
Recognition of the need to examine in children new drugs intended for the pediatric patient has a similar requirement to ensure a drug’s safe and effective use in this population. Also, differentia- tion in a drug’s activity in minority groups and their subpopulations is important in the full assess- ment of a drug’s potential. It is well known that there are interethnic variations both in disease incidence and in biologic response to some medi- cations, and these factors must be considered in the clinical evaluation of drug substances (42).
Each IND submission must have the prior approval of the IRB with jurisdiction over the site of the proposed clinical investigation. An IRB is a body of professional and public mem- bers that has the responsibility for reviewing and approving any study involving human subjects in the institution they serve. The purpose of the IRB is to protect the safety of human subjects by assessing a proposed clinical protocol, evaluating the benefi ts against risks, and ensuring that the plan includes all needed measures for subject protection. By law, the IRB shall be constituted to include persons competent to review clinical research proposals and be diverse in member- ship, with consideration of race, gender, cultural background, and sensitivity to issues affecting the subjects and the community (43). Any sub- stantive change or amendment to an originally approved clinical protocol must be submitted, reviewed, and approved by the IRB and the FDA before implementation.
Each clinical investigator must receive from the sponsor an investigator’s brochure, which changes. This may involve changes of dosing levels,
testing procedures, the addition of new investiga- tors, additional sites for the study, and so on.
For many years, women and the elderly were included only rarely in clinical drug investiga- tions. Women of childbearing age were excluded from early drug tests out of fear that the subject would become pregnant during the investigation with possible harm to the fetus. Exceptions were made only in cases of potentially lifesaving drugs. However, in recognition that the general exclu- sion of women from drug investigations results in inadequate data on any gender-based differ- ences in a drug’s effects, the FDA now calls for the inclusion of women in numbers adequate to allow detection of clinically signifi cant differ- ences in drug response.
The FDA Guideline for the Study and Evalu- ation of Gender Differences in the Clinical Eval- uation of Drugs issued in 1993 states the agency’s gender inclusion policy (37). Although the guide- line does not require participation of women in any particular trial, it sets forth FDA’s general expectations regarding the inclusion of both women and men in drug development, analysis of clinical data by gender, and assessment of potential pharmacokinetic differences between genders. In 1994, the National Institutes of Health (NIH) similarly issued its policy that women and minorities be included in all NIH- supported biomedical and behavioral research projects involving human subjects “unless there is a clear and compelling rationale and justifi ca- tion that their inclusion is inappropriate with respect to the health of the subjects or the pur- pose of the research” (38).
Pregnancy is a concern in drug investigations because drugs are readily transported from the maternal to the fetal circulation (39). Because of undeveloped drug detoxication and excretion mechanisms in the fetus, concentrations of drugs may actually reach a higher level in the fetus than in the maternal circulation, with toxic levels resulting. To reduce the risk of fetal exposure to investigational drugs in women of childbearing age, the FDA guideline calls for pregnancy test- ing, use of contraception, and full information disclosure of potential fetal risks to prospective study subjects. The FDA has made a special effort to ensure that women who have a life-threatening disease (e.g., AIDS-related) are not automatically excluded from investigational trials of drug prod- ucts for that disease because of a perceived risk of
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comply with and to be responsible for ensuring that the study is conducted according to the IND’s investigational plan and clinical protocol; protecting the rights, safety, and welfare of the human subjects; control of the investigational drug; written records of case histories and clini- cal observations; and the timely submission of progress reports, safety reports, and a fi nal report. It is the responsibility of the sponsor to monitor the progress of all clinical investigations under its IND. If a sponsor discovers that an investigator is not in compliance with the inves- tigational plan, it is the sponsor’s responsibility to gain compliance or to terminate the investigator’s participation in the study.
Any serious, unexpected, life-threatening, or fatal adverse experience that may be associated with the use of the drug during a clinical investi- gation must be reported promptly to the sponsor and subsequently to the FDA for investigation. Depending on the severity and assessment of the adverse experience, an alert notice may be sent to other investigators, a clinical hold may be placed on the study for further evaluation and assessment, or the IND may be withdrawn by the sponsor, placed on inactive status, or termi- nated by the FDA.