Questions for Assessment of Medical Writers

PART 1:
Q1:What are modules 2.4 and 2.6 and briefly describe what data is incorporated in these
modules?
“Module 2.4 - Nonclinical Overview - should provide an integrated overall analysis of the
information in the Common Technical Document (CTD).
The non clinical overview should present an integrated and critical assessment of the pharma-
cologic, pharmacokinetic, and toxicologic evaluation of the pharmaceutical.
The Nonclinical Overview should be presented in the following sequence:
Overview of the nonclinical testing strategy
Pharmacology
Pharmacokinetics
Toxicology
Integrated overview and conclusions
List of literature references“ - ICH topic M4S - Common technical document for the
Registration of Pharmaceuticals for Human Use - Safety
In this case the briefly data that are incorporated are about:
- “the studies conducted to establish the pharmacodynamic effects, the mode of action, and the
potential side effects should be evaluated
- the assessment of the pharmacokinetic, toxicokinetic and metabolism data should address the
relevance of the analytical method used, the pharmacokinetics models, and the derived param-
eters. “ - ICH topic M4S - Common technical document for the Registration of Pharmaceuticals
for Human Use - Safety
“Module 2.6 - Non Clinical Written and Tabulated summaries
Is about the content of the nonclinical pharmacology pharmacokinetics, and toxicology written
summaries format and also tabulated summaries.
The following sequence is recommended for Module 2.6:
Introduction
Written Summary of Pharmacology
Tabulated Summary of Pharmacology
Written Summary of Pharmacokinetics
Tabulated Summary of Pharmacokinetics
Written Summary of Toxicology
Tabulated Summary of Toxicology"-ICH topic M4S - Common technical document for
the Registration of Pharmaceuticals for Human Use - Safety
Basically the data from the non clinical studies will be arranged and tabulated “to provide the
best possible presentation of the informations, in order to facilitate the understating and evalu-
ation of the results.”-ICH topic M4S - Common technical document for the Registration of
Pharmaceuticals for Human Use - Safety

Q2: What is the difference between primary and secondary pharmacodynamic studies?

Confidential Page 1 of 9
“Studies on the mode of action and/or effects of a substance in relation to its desired therapeutic
target are primary pharmacodynamic studies. Studies on the mode of action and/or effects of a
substance not related to its desired therapeutic target are secondary pharmacodynamic studies”
- Guidance for Industry S7A Safety Pharmacology Studies for Human Pharmaceuticals
Q3: What are safety pharmacology studies? What are different types of safety pharma-
cology studies? Please provide few examples?
“Safety pharmacology studies are defined as those studies that investigate the potential unde-
sirable pharmacodynamic effects of a substance on physiological functions in relation to expo-
sure in the therapeutic range and above"-Guidance for Industry S7A Safety Pharmacology
Studies for Human Pharmaceuticals
Some different types of safety pharmacology studies:
"-Safety pharmacology Core Battery: the purpose is to investigate the effects of the test
substance on vital functions. In this case, the cardiovascular, respiratory and central nervous
system are usually considerate the vital organ system that should be studied in the core battery.
- Follow up Studies for Safety Pharmacology Core Battery: are meant to provide a greater
depth of understanding that provided by the core battery on vital functions.
- Central Nervous System - behavioural pharmacology, learning and memory, ligand-
specific binding, neurochemistry, visual, auditory and/or electrophysiology examinations
- Cardiovascular System-cardiac output, ventricular contractility, vascular resistance,
the effects of endogenous and/or exogenous substances on the cardiovascular responses
- Respiratory System-Airway resistance, compliance, pulmonary arterial pressure,
blood gases, blood pH
- Supplemental Safety pharmacology studies: are meant to evaluate potential adverse phar-
macodynamic effects on organ system functions not addressed by the core battery or repeated
dose toxicity studies when there is a cause for concern.
-Renal/Urinary System
-Autonomic Nervous System
-Gastrointestinal System
-Other Organ Systems"-Guidance for Industry S7A Safety Pharmacology Studies for
Human Pharmaceuticals

Q4: What is Reproductive and Developmental Toxicity? Please give different stages of
studies?
“Developmental toxicity: Any adverse effect induced prior to attainment of adult life. It in-
cludes effects induced or manifested in the embryonic or fetal period and those induced or
manifested postnatally
The aim of reproduction toxicity studies is to reveal any effect of one or more active sub-
stance(s) on mammalian reproduction.

For this purpose both the investigations and the interpretation of the results should be related
to all other pharmacological and toxicological data available to determine whether potential
reproductive risks to humans are greater, lesser or equal to those posed by other toxicological
manifestations. Further, repeated dose toxicity studies can provide important information re-
garding potential effects on reproduction, particularly male fertility. To extrapolate the results

Confidential Page 2 of 9
to humans (assess the relevance), data on likely human exposures, comparative kinetics, and
mechanisms of reproductive toxicity may be helpful.
Other test systems are considered to be any developing mammalian and non-mammalian cell
systems, tissues, organs, or organism cultures developing independently in vitro or in vivo”-
ICH Topic S 5 (R2)
Detection of Toxicity to Reproduction for Medicinal Products & Toxicity to Male Fertility

Q5: Enlist few pre-clinical studies which are to be included in a module 2.4 prepared for
a generic drug application and for a new drug application?
- screening test
- Tests on isolated organs, bacterial cultures
- Tests on animal models for human disease
- General observational test
- Confirmatory test and analogous activities
- Mechanism of action
- Systemic pharmacology
- Quantitative test
- Pharmacokinetics
- Toxicity test

Q6:What are modules 2.5 and 2.7 and briefly describe what data is incorporated in these
modules?
“Module 2.5 - Clinical Overview: is intended to provide a critical analysis of the clinical data
in the Common Technical Document and should be presented in the following sequence:
Product Development Rationale
Overview of Biopharmaceutics
Overview of Clinical Pharmacology
Overview of Efficacy
Overview of Safety
Benefits and Risks Conclusions
The Clinical Overview will necessarily refer to application data provided in the comprehensive
Clinical Summary, the individual clinical study reports (ICH E3), and other relevant reports;
but it should primarily present the conclusions and implications of those data, and should not
recapitulate them.
Module 2.7 - Clinical Summary - is intended to provide a detailed, factual summarisation of
all of the clinical information in the Common Technical DocumentThis includes information
provided in ICH E3 clinical study reports; information obtained from any meta-analyses or
other cross-study analyses for which full reports have been included in Module 5; and post-
marketing data for products that have been marketed in other regions. The comparisons and
analyses of results across studies provided in this document should focus on factual observa-
tions” - ICH Topic M4E Common Technical Document for the Registration of Pharmaceuticals
for Human Use – Efficacy
Q7:What information should be discussed in section 2.5.1 Product Development Ra-
tionale
"-Identify the pharmacological class of the medicinal product.
- Describe the particular clinical/pathophysiological condition that the medicinal product
- Intended to treat, prevent, or diagnose (the targeted indication).

Confidential Page 3 of 9
- Briefly summarise the scientific background that supported the investigation of the medicinal
product for the indication(s) that was (were) studied
- Briefly describe the clinical development programme of the medicinal product, including
ongoing and planned clinical studies and the basis for the decision to submit the application
at this point in the programme. Briefly describe plans for the use of foreign clinical data (ICH
E5).
- Note and explain concordance or lack of concordance with current standard research ap-
proaches regarding the design, conduct and analysis of the studies. Pertinent published liter-
ature should be referenced. Regulatory guidance and advice (at least from the region(s) where
the Clinical Overview is being submitted) should be identified, with discussion of how that
advice was implemented. Formal advice documents (e.g., official meeting minutes, official
guidance, letters from regulatory authorities) should be referenced, with copies included in
the references section of Module 5.”-ICH Topic M4E Common Technical Document for the
Registration of Pharmaceuticals for Human Use – Efficacy
Q8:What information should be discussed in section 2.5.4 Overview of Efficacy?
The following issues should generally be considered:
"-Relevant features of the patient populations, including demographic features, disease stage,
any other potentially important covariates, any important patient populations excluded from
critical studies, and participation of children and elderly (ICH E11 and E7). Differences be-
tween the studied population(s) and the population that would be expected to receive the me-
dicinal product after marketing should be discussed.
- Implications of the study design(s), including selection of patients, duration of studies and
choice of endpoints and control group(s). Particular attention should be given to endpoints for
which there is limited experience. Use of surrogate endpoints should be justified. Validation of
any scales used should be discussed.
- For non-inferiority trials used to demonstrate efficacy, the evidence supporting a determina-
tion that the trial had assay sensitivity and justifying the choice of non- inferiority margin (ICH
E10).
- Statistical methods and any issues that could affect the interpretation of the study results (e.g.,
important modifications to the study design, including endpoint assessments and planned anal-
yses, as they were specified in the original protocol; support for any unplanned analyses; pro-
cedures for handling missing data; and corrections for multiple endpoints).
- Similarities and differences in results among studies, or in different patient sub-groups within
studies, and their effect upon the interpretation of the efficacy data.
- Observed relationships between efficacy, dose, and dosage regimen for each indication, in
both the overall population and in the different patient subgroups (ICH E4).
- Support for the applicability to the new region of data generated in another region, where
appropriate (ICH E5).
- For products intended for long-term use, efficacy findings pertinent to the maintenance of
long-term efficacy and the establishment of long-term dosage. Development of tolerance
should be considered.
- Data suggesting that treatment results can be improved through plasma concentration moni-
toring, if any, and documentation for an optimal plasma concentration range.
- The clinical relevance of the magnitude of the observed effects.
- If surrogate endpoints are relied upon, the nature and magnitude of expected clinical benefit
and the basis for these expectations.
- Efficacy in special populations. If efficacy is claimed with inadequate clinical data in the
population, support should be provided for extrapolating efficacy from effects in the general

Confidential Page 4 of 9
population.” - ICH Topic M4E Common Technical Document for the Registration of Pharma-
ceuticals for Human Use – Efficacy

Q9: What is the purpose of section 2.5.6 Benefits and Risks Conclusions? Please list the
subsections of section of 2.5.6?
The purpose is: “to integrate all of the conclusions reached in the previous sections about the
biopharmaceutics, clinical pharmacology, efficacy and safety of the medicinal product and to
provide an overall appraisal of the benefits and risks of its use in clinical practice
Subsection of 2.5.6:
- The efficacy of the medicinal product for each proposed indication.
- Significant safety findings and any measures that may enhance safety.
- Dose-response and dose-toxicity relationships; optimal dose ranges and dosage regimens.
- Efficacy and safety in sub-populations, e.g., those defined by age, sex, ethnicity, organ
function, disease severity, and genetic polymorphisms.
- Data in children in different age groups, if applicable, and any plans for a development
programme in children.
- Any risks to the patient of known and potential interactions, including food-drug and
drug-drug interactions, and recommendations for product use.
- Any potential effect of the medicinal product that might affect ability to drive or operate
heavy machinery.” - ICH Topic M4E Common Technical Document for the Registration of
Pharmaceuticals for Human Use – Efficacy

Q10: What kind of clinical efficacy and safety data is to be specifically included in a mod-
ule 2.5 planned to be submitted via legal basis 10(a) / bibliographic route of application?
According to ICH Topic M4E Common Technical Document for the Registration of Pharma-
ceuticals for Human use - Efficacy the data for module 2.5 regarding Safety are: “
- Adverse effects characteristic of the pharmacological class.
- Special approaches to monitoring for particular adverse events
- Relevant animal toxicology and product quality information
- The nature of the patient population and the extent of exposure, both for test drug and control
treatments.
- Common and non serious adverse events, with reference to the tabular presentation of events
with the test drug and with the control agents
- Serious adverse events
- Similarities and differences in results among the studies, and their effect upon the interpre-
tation of the safety data
- Relation of adverse events to dose, dose regimen, and Treatement duration
- Long term safety
- Reaction due to overdose
- World wide marketing experience: the extent of the worldwide experience, any new or dif-
ferent safety issues identified, any regulatory actions related to safety
- Support for the applicability to the new region of data generated in another region. “

PART 2:

Confidential Page 5 of 9
Please do a published literature search for Module 2.4 and 2.5 for Simvastatin, putting
together safety & efficacy data. Prepare a list of such references. Please note, you do not
need to purchase any articles, just list them
Module 2.4 : Non clinical overview
1.“Simvastatin is in a group of drugs called HMG CoA reductase inhibitors, or "statins." It
reduces levels of "bad" cholesterol (low-density lipoprotein, or LDL) and triglycerides in the
blood, while increasing levels of "good" cholesterol (high-density lipoprotein, or HDL).
Simvastatin is used to lower cholesterol and triglycerides (types of fat) in the blood.
Simvastatin is also used to lower the risk of stroke, heart attack, and other heart complica-
tions in people with diabetes, coronary heart disease, or other risk factors.
Simvastatin is used in adults and children who are at least 10 years old.
Optic nerve degeneration was seen in clinically normal dogs treated with Simvastatin for 14
weeks at 180 mg/kg/day, a dose that produced mean plasma drug levels about 12 times
higher than the mean plasma drug level in humans taking 80 mg/day.
A chemically similar drug in this class also produced optic nerve degeneration (Wallerian de-
generation of retinogeniculate fibres) in clinically normal dogs in a dose-dependent fashion
starting at 60 mg/kg/day, a dose that produced mean plasma drug levels about 30 times
higher than the mean plasma drug level in humans taking the highest recommended dose (as
measured by total enzyme inhibitory activity). This same drug also produced vestibulococh-
lear Wallerian-like degeneration and retinal ganglion cell chromatolysis in dogs treated for 14
weeks at 180 mg/kg/day, a dose that resulted in a mean plasma drug level similar to that seen
with the 60 mg/kg/day dose.
CNS vascular lesions, characterised by perivascular haemorrhage and edema, mononuclear
cell infiltration of perivascular spaces, perivascular fibrin deposits and necrosis of small ves-
sels were seen in dogs treated with Simvastatin at a dose of 360 mg/kg/day, a dose that pro-
duced mean plasma drug levels that were about 14 times higher than the mean plasma drug
levels in humans taking 80 mg/day. Similar CNS vascular lesions have been observed with
several other drugs of this class.
There were cataracts in female rats after two years of treatment with 50 and 100 mg/kg/day
(22 and 25 times the human AUC at 80 mg/day, respectively) and in dogs after three months
at 90 mg/kg/day (19 times) and at two years at 50 mg/kg/day (5 times)”
2.”An extensive battery of in vitro and in vivo genetic toxicity tests have been conducted on
both simvastatin and its corresponding open acid L-654,969. These include assays for micro-
bial mutagenesis, mammalian cell mutagenesis, single stranded DNA breakage and tests for
chromosome aberrations. The results of these studies provided no evidence of an interaction
between simvastatin or L-654,969 with genetic material at the highest soluble noncytotoxic
concentrations tested in vitro assay systems or at maximally tolerated doses tested in vivo”
3. “In a 72-week carcinogenicity study, mice were administered daily doses of simvastatin of
25, 100, and 400 mg/kg body weight, which resulted in mean plasma drug levels approxi-
mately 1, 4, and 8 times higher than the mean human plasma drug level, respectively (as total
inhibitory activity based on AUC) after an 80-mg oral dose. Liver carcinomas were signifi-
cantly increased in high-dose females and mid- and high-dose males with a maximum inci-
dence of 90% in males. The incidence of adenomas of the liver was significantly increased in
mid- and high-dose females. Drug treatment also significantly increased the incidence of lung
adenomas in mid- and high-dose males and females. Adenomas of the Harderian gland (a
gland of the eye of rodents) were significantly higher in high-dose mice than in controls. No
evidence of a tumorigenic effect was observed at 25 mg/kg/day.

Confidential Page 6 of 9
In a separate 92-week carcinogenicity study in mice at doses up to 25 mg/kg/day, no evidence
of a tumorigenic effect was observed (mean plasma drug levels were 1 times higher than
humans given 80 mg simvastatin as measured by AUC).
In a two-year study in rats at 25 mg/kg/day, there was a statistically significant increase in the
incidence of thyroid follicular adenomas in female rats exposed to approximately 11 times
higher levels of simvastatin than in humans given 80 mg simvastatin (as measured by AUC).
A second two-year rat carcinogenicity study with doses of 50 and 100 mg/kg/day produced
hepatocellular adenomas and carcinomas (in female rats at both doses and in males at
100 mg/kg/day). Thyroid follicular cell adenomas were increased in males and females at both
doses; thyroid follicular cell carcinomas were increased in females at 100 mg/kg/day. The
increased incidence of thyroid neoplasms appears to be consistent with findings from other
statins. These treatment levels represented plasma drug levels (AUC) of approximately 7 and
15 times (males) and 22 and 25 times (females) the mean human plasma drug exposure after
an 80 milligram daily dose.
No evidence of mutagenicity was observed in a microbial mutagenicity (Ames) test with or
without rat or mouse liver metabolic activation. In addition, no evidence of damage to genetic
material was noted in an in vitro alkaline elution assay using rat hepatocytes, a V-79
mammalian cell forward mutation study, an in vitro chromosome aberration study in CHO
cells, or an in vivo chromosomal aberration assay in mouse bone marrow.
There was decreased fertility in male rats treated with simvastatin for 34 weeks at 25 mg/kg
body weight (4 times the maximum human exposure level, based on AUC, in patients receiving
80 mg/day); however, this effect was not observed during a subsequent fertility study in which
Simvastatin was administered at this same dose level to male rats for 11 weeks (the entire cycle
of spermatogenesis including epididymal maturation). No microscopic changes were observed
in the testes of rats from either study. At 180 mg/kg/day, (which produces exposure levels 22
times higher than those in humans taking 80 mg/day based on surface area, mg/m2),
seminiferous tubule degeneration (necrosis and loss of spermatogenic epithelium) was
observed. In dogs, there was drug-related testicular atrophy, decreased spermatogenesis,
spermatohytic degeneration and giant cell formation at 10 mg/kg/day, (approximately 2 times
the human exposure, based on AUC, at 80 mg/day). The clinical significance of these findings
is unclear”
List of references:
1. https://www.drugs.com/pro/simvastatin.html
2. http://www.medsafe.govt.nz/profs/Datasheet/s/SimStatintab.pdf
3. http://www.druglib.com/druginfo/zocor/description_pharmacology/
2.5 : Clinical overview
1. Simvastatin can be safely and effectively used to treat dyslipidemia in HIV-infected patients
receiving efavirenz-based HAART without compromising viral or immunologic control. How-
ever, our results are suggestive of slight lessening of the LDL-lowering effects, which might
be explained by the known reduction in simvastatin levels with efavirenz -
2. Data indicated that the Simvastatin in Children Study randomised a group of boys and girls
who were representative of patients with heFH of a similar age group. Lipid levels were above
the 95th percentile for age and gender. The study outcomes will provide important data on
lipid-altering efficacy, safety and tolerability to support the use of simvastatin in this group of
patients at relatively high risk of CHD. In addition to the effects on the lipid, lipoprotein and
apolipoprotein profile, important data will be available regarding the effects of simvastatin on
markers of muscle effects, and on growth and pubertal development

Confidential Page 7 of 9
3. Simvastatin appears to be a well tolerated and highly efficacious drug for the management
of severe primary hypercholesterolemia.
4. The long term clinical experience with simvastatin confirms its efficacy and tolerability pro-
file for the treatment of hypercholesterolaemia
5. Statin treatment is safe and can improve liver tests and reduce cardiovascular morbidity in
patients with mild-to-moderately abnormal liver tests that are potentially attributable to non-
alcoholic fatty liver disease.
6. Simvastatin appears to be a safe and effective treatment for the reduction of serum non-HDL
cholesterol levels in both HD and, particularly, CAPD patients.
7. Long-term clinical experience with simvastatin continues to indicate that it is an efficacious
and well-tolerated lipid-lowering agent.
8. Based on the primary intention-to-treatanalysis,the results of this study demonstrate that
simvastatin and atorvastatin provide similar low-density lipoprotein cholesterol and trigly-
ceride reductions at commonly used doses in patients with primary hypercholesterolemia. Over
short-term use, both drugs had similar safety and tolerabilityprofiles
9. Simvastatin was generally well tolerated by all patients across the dosage range of 20 mg–
80 mg. No cases of rhabdomyolysis or myopathy were reported in either study.

List of references:
1. Safety and efficacy of Simvastatin for the treatment of dyslipidemia in human immunodefi-
ciency virus-infected patients receiving efavirenz-based highly active antiretroviral therapy. -
https://www.ncbi.nlm.nih.gov/pubmed/18576906
2.Efficacy, Safety and Tolerability of Simvastatin in Children With Familial Hypercholes-
trolaemia - - https://www.medscape.com/viewarticle/441302_6
3. Simvastatin in Severe Primary Hypercholesterolemia: Efficacy, Safety, and Tolerability in
595 Patients over 18 Weeks-
http://onlinelibrary.wiley.com/store/10.1002/clc.4960160406/as-
set/4960160406_ftp.pdf?v=1&t=jcq3jet6&s=921ebed02b8d550d27e6d4addfb3c1ac4098501f
4. Long Term Experience with Simvastatin - https://link.springer.com/arti-
cle/10.1007/BF03259587
5. The efficacy and safety of statins for the treatment of non-alcoholic fatty liver disease-
https://www.sciencedirect.com/science/article/pii/S1590865814005970
6. Safety and efficacy of simvastatin in hypercholesterolemic patients undergoing chronic renal
dialysis-https://www.ncbi.nlm.nih.gov/pubmed/11840368
7.Long-term safety and efficacy profile of simvastatin-https://www.sciencedirect.com/sci-
ence/article/pii/000291499190182K
8. Comparison of the Efficacy and Tolerability of Sirnvastatin and Atorvastatin in the Treat-
ment of Hypercholesterolemia-
http://onlinelibrary.wiley.com/store/10.1002/clc.4960230910/as-
set/4960230910_ftp.pdf?v=1&t=jcq3a7ho&s=da97307075f04dd9b9c2ae21c9eac6bc51312e6
5
9. Efficacy and safety of simvastatin in Asian and non-Asian coronary heart disease patients:
a comparison of the GOALLS and STATT studies-
http://www.tandfonline.com/doi/abs/10.1185/030079904125004367

Confidential Page 8 of 9
Confidential Page 9 of 9