Question

Final report of GLP animal study

Study Groups

The groups in the study are as follows: Group 1 (Vehicle), Group 2 (Low Dose), Group 3 (Medium Dose), Group 4 (High Dose) Group 5 (High Dose with a 14 day Recovery Period) 10 male and 10 females per group Group 6 (Toxicokinetic Group - Vehicle (5 males & 5 females) & High Dose (5 males & 5 females).

Outcomes:

1) The test item was stated to be >98% pure by the Sponsor; however no Certificate of Analysis was received.

2) Following issuing of the study plan the Sponsor asked that the higher dose of the test item be administered at 600 mg/kg/day rather than 700mg/kg/day.

3) Due to an experimental error during the study, animals from Group 1 (vehicle) were administered vehicle twice rather than once on the 14th day of dosing.

4) During acclimatisation period some females and males were housed together for a single day. Fortunately assessment of the females during the course of the study indicated that they were not pregnant and therefore this error did not influence the study outcomes.

5) Three animals that received a low dose of the test item were without water for the 24 hours before necropsy. The Study Plan stated that they were to be fasted but have access to water.

6) The humidity of the room the animals were housed in reached 90% on day 14 of dosing. The Study Plan stated limits of 30-70%.

Biochemical Analysis

Group 1: Values for all parameter were within historical and literature range

Group 2: Values for all parameter were within historical and literature range

Group 3: Values for most parameters were within historical and literature range, with the exception of slightly elevated Alanine aminotransferase (ALT), Aspartate aminotransferase (AST) and Sorbitol dehydrogenase (SDH)

Group 4: Values for most parameters within historical and literature range, with the exception a significantly higher level of Alanine aminotransferase (ALT), Aspartate aminotransferase (AST) and Sorbitol dehydrogenase (SDH). ALT, AST and SDH were very high (ALT>AST) in the animals that were euthanised.

Group 5: For those animals that completed the study the values for all parameters, after a 14-day recovery period, were within historical and literature range.

Haematology

White blood differentials were normal in all animals.

The Haematocrit was elevated in 3 animals that received the low dose otherwise all other animals had Haematocrit levels within the normal range.

Histology

Light microscopy of tissue sections showed an increased recruitment of inflammatory cells in the liver. There were no changes in the spleen, kidney or any other organ examined.

General Observations

The vehicle and low dose groups exhibited no signs of toxicity.

The mid-level group showed mild to moderate signs of toxicity manifesting as an altered gait and lack of grooming in 3 of the 10 animals.

The high dose group showed moderate signs of toxicity manifesting as an altered gait and lack of grooming in 5 of the 10 animals. Three animals (2 male, 1 female) from group 4 and 4 animals from group 5 (2 male and 2 female) were found to exhibit severe signs of toxicity and were euthanised between the 19th and 24th day of dosing. These animals also exhibited a decrease in body weight of 5% per day for the 3 days prior. Blood was collected from these animals and all clinical biochemistry and haematology performed.

Toxicokinetics/Dose formulation

Toxicokinetic analysis indicated that mean Cmax, AUClast& T1/2 for the test item were comparable between males & females on Day 1.

Both Cmax & AUClast increased on Day 28, with mean values consistently higher for males compared to the corresponding females. T1/2 remained similar to Day 1 values for both males and females.

Analysis of the dose formulation indicated that the doses administered were as stated in the study plan.

Question

Assume the role of QA and, taking into account all the different aspects which may have been audited during the course of the study, prepare an appropriate QA Statement for inclusion in the Final Report.

Pls write in detail and follow the requirement below

A Quality Assurance Programme statement listing the types of inspections made and their dates, including the phase(s) inspected, and the dates any inspection results were reported to management and to the Study Director and Principal Investigator(s), if applicable. This statement would also serve to confirm that the final report reflects the raw data.

(Using OECD GLP # 1 & OECD Guideline 407 to assist you)

Answer 1

Please find the answers below:

The good-laboratory practices or GLP require the international guidelines to be followed for conducting the toxicological analysis of novel molecules. Acccording to the information, the toxicity analysis of the novel molecule was made over here and the following quality assurance flaws have been reported in the study:

1. The number of animals in each group is too low to consider the data statistically significant.
2. Under no circumstances, the males and females must be housed in the same cage.
3. All animals must have equal and liberal access to food and water, which was not possible in one of the experimental groups.
4. The dosage of the novel molecules for toxicological analysis must not be decreased under any circumstances. Since the acute toxicity (14 days) dose was decreased as compared to normal, it might affect the raw data findings.
5. The observations that medium and high-dose administration induced toxicity in animals suggests that the novel molecule is indeed toxic to these animals.
6. The finding that the plasma kinetics was different for males and females requires attention and reproductive toxicity to be conducted.

Thus, these are some of the quality-assurance points to be noted out and mentioned in the report for the prinicipal investigator.