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Similar to Evaluation of Preclinical Data to get to First in Man - Gabriel Assagba
Similar to Evaluation of Preclinical Data to get to First in Man - Gabriel Assagba (20)
Evaluation of Preclinical Data to get to First in Man - Gabriel Assagba
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- 7. TGN1412 study problem Detail Learning Point Interpretation of preclinical (primate) studies Low-level cytokine release in primate studies should have promoted more caution Minor but potentially important effects in preclinical studies should raise caution in crossing the species barrier Use of human in vitro studies Insufficient in-vitro human studies were performed In vitro studies on human material as close as possible to the target tissue can be important. Choice of starting dose Subtle difference between primate and human target ligand may explain marked difference in potency – the calculation of an initial dose based on a fraction of predicted ‘no adverse effect level’ proved dangerously wrong Prediction of risk and dose range from animal studies may prove unreliable: extra caution with wider margins of safety are required with ‘potentially risky modes of action’ Dosing interval between subjects No ‘proper interval’ allowing for the observation of possible side effects was left between the dosing of one subject and the next In fisrt-in-man studies, investigators should expect the unexpected Preparation for adverse events Preparation for possible adverse events (cytokine storm) was inadequate – investigators did not expect it, recognize it or treat early. Where there is a known theoretical risk, investigators should plan for its potential occurrence 7 Summary of learning points from the TGN1412 phase I study
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- 16. 16 Maximum Duration of Clinical Trial Recommended Minimum Duration of Repeated-Dose Toxicity Studies to Support Clinical Trials Rodents Non-rodents Up to 2 weeks 2 weeksa 2 weeksa Between 2 weeks and 6 months Same as clinical trialb Same as clinical trialb > 6 months 6 monthsb, c 9 months b, c, d Recommended Duration of Repeated-Dose Toxicity Studies to Support the Conduct of Clinical Trials:
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Editor's Notes
- Since sequencing of the human genome which allowed rapid cloning and synthesis of large quantities of purified proteins, it has become common practice to use high throughput screening of large compounds libraries against isolated biological targets which are hypothesized to be disease modifying in a process known as reverse pharmacology. Hits from these screens are then tested in cells and then in animals for efficacy. Modern drug discovery involves the identification of screening hits, medicinal chemistry and optimization of those hits to increase the affinity, selectivity (to reduce the potential of side effects), efficacy/potency, metabolic stability (to increase the half-life), and oral bioavailability. Once a compound that fulfills all of these requirements has been identified, it will begin the process of drug development prior to clinical trial
- Even the investigation brochure had in its text mentioned caution about possibility of cytokine release syndrome. Despite of knowing these facts infusion of TGN1412 given to all six volunteers within a short span of time was a serious concern in conduct of the trial. Moreover, when the last volunteer was to be infused, the first volunteer had already started showing adverse effects. Despite of this observation, sixth volunteer was still infused with the drug.
- Before conducting human trials, Fialuridine was tested on different animals including mice, rat, dog, monkeys, and woodchucks. These studies demonstrated that doses hundred times higher than that administered to humans did not induce any toxic reactions. Moreover, animal models showed bone marrow and heart toxicity with no signs of mitochondrial injury. one of the preclinical toxicity studies on laboratory animals could predict the toxic outcomes observed in phase II studies. Even a pilot study on 43 patients treated for 2 and 4 weeks duration with Fialuridine did not reveal any signs of hepatic toxicity on initial examination. Even after discontinuation of Fialuridine administration, seven other patients showed signs of severe hepatic toxicity five of which could not survive and other two could survive only after liver transplantation.
- The Medicines and Healthcare Products Regulatory Agency initiated an investigation, but the BMJ and other journals called for a more far reaching inquiry independent of the regulatory agency that had approved the trial. On 5 April the agency released its interim report,2 and the government announced that an independent Expert Scientific Group, chaired by Professor Gordon Duff, would be appointed “to learn from the Parexel clinical trials incident.” On 25 July this group released their interim report and recommendations.
- The purpose of this document is to recommend international standards for and to promote harmonization of the nonclinical safety studies needed to support human clinical trials of a given scope and duration. Harmonization of the guidance for nonclinical safety studies will help to define the current recommendations and reduce the likelihood that substantial differences will exist between regions. The recommendations for the extent of nonclinical safety studies to support the various stages of clinical development differ among the regions of Europe, the United States, and Japan. This raises the important question of whether there is scientific justification for these differences and whether it would be possible to develop a mutually acceptable guidance.
- This information is important for the estimation of an initial safe starting dose for the human trials and the identification of parameters for clinical monitoring for potential adverse effects. The nonclinical safety studies, although limited at the beginning of clinical development, should be adequate to characterize potential toxic effects under the conditions of the supported clinical trial. Safety Pharmacology: These evaluations may be conducted as additions to toxicity studies or as separate studies. Toxicokinetic Studies: Appropriate information should usually be available by the time the Phase I completed
- This information is important for the estimation of an initial safe starting dose for the human trials and the identification of parameters for clinical monitoring for potential adverse effects. The nonclinical safety studies, although limited at the beginning of clinical development, should be adequate to characterize potential toxic effects under the conditions of the supported clinical trial. Safety Pharmacology: These evaluations may be conducted as additions to toxicity studies or as separate studies. Repeated Dose Toxicity Studies: In principle, the duration of the animal toxicity studies conducted in two mammalian species (one nonrodent) should be equal to or exceed the duration of the human clinical trials up to the maximum recommended duration of the repeated dose toxicity studies
- It should be noted that within two weeks of the TeGenero incident, the CHMP issued a concept paper on the ‘‘Development of a CHMP Guideline on the Non-Clinical Requirements to Support Early Phase I Clinical Trials with Pharmaceutical Compounds’’ (EMEA 2006). (Purely Coincidental) The subtle change in title highlights a change in the intent of the guideline from ‘‘potential high-risk medicinal’’ products to all investigational medicinal products (IMPs). The scope of the draft guidance was expanded from a focus on biologics to include both biologics and new chemical entities (NCEs).
- Repeated-dose toxicity studies in two species (one non-rodent) for a minimum duration of 2 weeks (Table 1) would generally support any clinical development trial up to 2 weeks in duration. Clinical trials of longer duration should be supported by repeated-dose toxicity studies of at least equivalent duration. Six month rodent and 9 month non-rodent studies generally support dosing for longer than 6 months in clinical trials
- The estimation of the first dose in humans is an important element to safeguard subjects participating in first-in-human studies. All of the relevant nonclinical data, including the pharmacological dose response, the pharmacological/toxicological profile, and pharmacokinetics, should be considered when determining the recommended starting dose in humans. In general, the No Observed Adverse Effect Level (NOAEL) determined in nonclinical safety studies performed in the most appropriate animal species gives the most important information. The proposed clinical starting dose will also depend on various factors, including PD, particular aspects of the molecule, and the design of the clinical trials.
- Local tolerance studies: To support limited human administration by non-therapeutic routes (e.g., a single i.v. dose to assist in the determination of absolute bioavailability of an oral drug), a single dose local tolerance study in a single species is considered appropriate. Genotoxicity studies: To support multiple dose clinical development trials, an additional assessment capable of detecting chromosomal damage in a mammalian system(s) should be completed. A complete battery of tests for genotoxicity should be completed before initiation of Phase II trials Carcinogenicity studies: Carcinogenicity studies are recommended for the clinical indication, they should be conducted to support the marketing application. Reproduction toxicity studies should be conducted as is appropriate for the population that is to be exposed, example being Men, Women (Child Bearing Potentials and Non Child Bearing Potentials), and Pregnant Women Paediatric populations: When paediatric patients are included in clinical trials, safety data from previous adult human experience would usually represent the most relevant information and should generally be available before initiation of paediatric clinical trials. The appropriateness and extent of adult human data should be determined on a case-by-case basis Immunotoxicity: All new human pharmaceuticals should be evaluated for the potential to produce immunotoxicity using standard toxicity studies and additional immunotoxicity studies conducted as appropriate based on a weight-of-evidence review, including immune-related signals from standard toxicity studies. Photosafety: Initial assessment of phototoxic potential based on a drug’s photochemical properties and pharmacological/chemical class should be performed Nonclinical abuse liability: These early indicators would typically be available before first human dose and include the PK/PD profile to identify the duration of action, similarity of chemical structure to known drugs of abuse, receptor binding profile, and behavioural/clinical signs from in vivo nonclinical studies. Other toxicity studies: Additional nonclinical studies (e.g., to identify potential biomarkers, to provide mechanistic understanding) can be useful if previous nonclinical or clinical findings with the product or related products have indicated special safety concerns. Combination drug toxicity testing: The principles outlined can also apply when developing products that will have product information recommendations for co-use with a specific drug, even if not in a fixed combination, and for which there is minimal clinical information regarding the combination. Combinations covered might involve: (1) two or more late stage entities (defined as compounds with significant clinical experience (i.e. from Phase III studies and/ or post marketing)); (2) one or more late stage entity(ies) and one or more early stage entities (defined as compounds with limited clinical experience (i.e. Phase II studies or less)); or (3) more than one early stage entity.
- Animal Pharmacology and Toxicology Studies- Preclinical data to permit an assessment as to whether the product is reasonably safe for initial testing in humans. Manufacturing Information- Information pertaining to the composition, manufacture, stability, and controls used for manufacturing the drug substance and the drug product. This information is assessed as to ensure the company can adequately produce and supply consistent batches of the drug Clinical Protocols and Investigator Information- Detailed protocols for proposed clinical studies to assess whether the initial-phase trials will expose subjects to unnecessary risks. Also, information on the qualifications of clinical investigators--professionals (generally physicians) who oversee the administration of the experimental compound--to assess whether they are qualified to fulfil their clinical trial duties.
- Clinical Hold: If this occurs, the Center will contact the sponsor within the 30-day initial review period to stop the clinical trial. CDER may either delay the start of an early-phase trial on the basis of information submitted in the IND, or stop an ongoing study based on a review of newly submitted clinical protocols, safety reports, protocol amendments, or other information. Notify Sponsor: The letter should describe the reasons for the clinical hold, and must bear the signature of the division director (or acting division director). The sponsor may then respond to CDER by sending an "IND CLINICAL HOLD RESPONSE“ letter to the division. To expedite processing, the letter must be clearly identified as an "IND CLINICAL HOLD RESPONSE" letter.
- Preclinical research can fall short in three ways. First, it may fail to predict human risks, leading to adverse effects in human trials. Second, it may predict clinical benefits that fail to materialize in humans. Third, it may predict nonexistent risks in humans. Although the challenge of extrapolating from laboratory data to humans makes each type of mistake unavoidable, commentators think the error rate could be reduced. One source of inaccurate prediction is the use of an inadequate animal model. For example, human subjects in the TGN1412 trial had serious adverse reactions to 1/500 of a dose that was safe in monkeys. Experts said that the reliance on monkeys may have been misplaced, given differences in the relevant monoclonal antibody receptors in human and non-human primates.