Clinical studies/trials documentation

Clinical Trials. In Phase I studies, good documentation and additional investigations should be standard practice. Serious reactions are pretty unusual in these studies, which will detect only very common ADRs, in particular those that are pharmacologically mediated (e.g., bradycardia with beta adrenergic receptor antagonists). 

Regulations also exist to protect the confidentiality of the research participant. All information collected throughout the clinical trial remains with the study staff. For the purposes of data capture, each subject is identified by initials or study number only. In addition, the informed consent discusses who will have access to the trial documents. 

This term is generally used to denote the administration file kept for each trial and each investigation centre. Box 7.1 lists some of the documents that need to be present before a clinical trial starts. (See ICH GCP Chapter 8 for the full list.) Once the study has started, other documents will be added, including completed CREs, ICFs and subjects medical records and other documents directly involved in the study. Some documents have to be kept specifically at the sponsor s office or the controlling centre. Separate files will contain financial and budget-related documents. 

Japanese GCP requires that the head of the medical institute and the sponsor must execute a study contract, and does not allow the investigator to directly contract with the sponsor. Historically, a clinical trial is considered as an activity of the hospital as a whole, not of an individual investigator. The reason behind this is that the investigator cannot conduct any study without the full support of hospital staff and access to hospital facilities. The head of the medical institute is responsible for organising an IRB in-house or to make it available outside the hospital, if the hospital is not large enough to maintain an IRB. Once the sponsoring company submits the clinical study plan to the hospital, the head of the medical institute should submit the study document to the IRB for their opinion. The head cannot be a member of the IRB, is not allowed to discuss or vote on the clinical trial, but nevertheless attendance to the IRB is not prohibited. 

Clearly, some individuals with molluscan shellfish allergy are reactive to all species of molluscan shellfish. Cross-reactivity has been established by clinical history, challenge trials (in a few instances), skin prick testing, and IgE-binding studies. Most clinical studies of cross-reactivity have been limited to a few species often within one class of molluscan shellfish. However, the totality of the evidence indicates that individuals with documented reactivity to one molluscan species and evidence of IgE against that species should be counseled to avoid other molluscan shellfish species. This recommendation is especially prudent for the individual classes of molluscan shellfish gastropods, bivalves, and cephalopods. 

Many of the safety issues concerning naked pDNA are similar to those of conventional pharmaceutical agents, such as the inherent toxicity of the pDNA itself. However, the use of pDNA for the delivery of therapeutic proteins poses novel theoretical safety concerns. These concerns involve any toxicity associated with expression of the encoded protein, the potential for unexpected and untoward consequences as a result of the persistent expression of a therapeutic protein which could lead to autoimmune disease, the biodistribution of the pDNA, and the potential for a transformation event resulting from the integration of the pDNA into chromosomal DNA. The safety of naked pDNA has now been well documented in pre-clinical studies in animals, and more recently, in clinical trials in humans. 

This is not to say that cardiotoxicity is not seen with biopharmaceuticals. Cardiomyopathy is now a well-recognized complication of trastuzumab and and has been reported with bevacizumab treatment, in particular in combination with other cytotoxic cancer therapies [20]. Myocarditis and pericarditis are a well-documented complications of vaccinia immunization [21], and could also complicate use of a pox-virus vector for other therapeutics. In 1995 Genetics Institute suspended phase 2 cancer trials of Interleukin-12 for serious tox-icities including cardiac arrhythmia. However, such toxicities are best detected by incorporation of biomarkers for myocardial damage such as troponin-T into preclinical and early clinical studies, and continual ECG monitoring for arrhythmia in preclinical and early clinical studies, not by in vitro explorations of electrophysiology. 

A number of regulatory guidance documents touch on various aspects of the transition from preclinical to clinical study of a novel biopharmaceutical. The primary guidance documents describing the conduct and use of preclinical safety evaluation in supporting the initial clinical trials are as follows ... 

Phase III Clinical Trials Consist of controlled and uncontrolled trials that are performed after preliminary evidence of effectiveness of a drug has been established. They are conducted to document the safety and efficacy of the drug, as well as to determine adequate directions (labeling) for use by the physician. A specific patient population needs to be clearly identified from the results of these studies. Trials during Phase III are conducted using a large... 

The statement that the proof of effectiveness would be derived from "well-controlled investigations" has been the cornerstone of the FDA s position for the requirement of two positive adequate and well-controlled clinical trialS/ both of which must demonstrate effectiveness at the P < 0.05 level (16). However/ in practice/ most clinical development plans include more than just two studies to document efficacy and evaluate safety. In a pilot study reported by Peck (1) of a cohort of 12 of the 51 NDAs that were approved by the FDA in 1994-1995/ the total number of clinical trials in each submission ranged from 23 to 150. In those trials that were designed to establish efficacy and evaluate safety/ the number of study participants ranged from 1/000 to 13/000. Peck has pointed out that these NDAs probably reflect clinical plans that were designed in the mid-1980s. 

The cumulation of all the data from the clinical trials of a new drug product, assuming a fairly orthodox regulatory strategy for a typical dossier or NDA, will form the largest fraction of the application. However, these data are also needed for derivative documents within the application, one of which is a benefit-risk analysis, which forms the last part of an Integrated Safety Summary (Section 9 of the NDA), and is a central objective of the expert report in European applications. These benefit-risk assessments must be derived from the clinical study reports and summaries elsewhere in the applications. 

Complete, consistent and accurate trial documentation is the basis for any inspection by regulatory authorities or sponsor/client audit and is a proof that the study was conducted according to GCP regulations, the trial protocol and SOPs. The TMF plays a vital role in providing confidence to auditors and inspectors that the clinical data are valid and that the trial was conducted properly. 

At the termination of each clinical trial, the study-related documents should be archived so that they... 

Surfactant aerosol also has been tested in chronic bronchitis the modest improvement in FEV1 was small, and its expense would not justify use based on these data [175]. In tests of aerosol surfactant in adults with CF treated over 5 days, no improvement was found [176]. Although instilled surfactant has become common practice for the neonatal respiratory distress of premature infants, aerosol delivery is not yet adequately developed. A recent study showed no difference in outcome for spontaneously breathing newborns who inhaled either surfactant or placebo via a CPAP mask [177]. There continues to be great appeal for the use of surfactant in adults because of the apparent success in neonates, but its use should not become practice until well-controlled trials document clinically meaningful efficacy. 

The PI is responsible for maintaining records associated with the clinical study. These include case histories designed to record all observations or other pertinent data on each enrolled subject, independent of whether the subject received active treatment. Data for each trial subject is normally recorded on a case report form provided by the sponsor. The sponsor may also require study data to be recorded in a source document (patient chart). It is the responsibility of the PI to assure that the forms are filled out with the correct information and according to guidelines established by the sponsor. 

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