licensing a new drug Flashcards

Question

what are the Hazard integration and risk assessment

Answer 1

``` • Regarding patient safety – Co-morbidities – Co-medications – Age • Risk-benefit – Effect of drug on symptoms, disabilities and prognosis balanced against unwanted effects ```

Answer 2

• Seeks to establish facts – Things known to have occurred or be true (OED) • Contributes to knowledge • Confirms, adds to or establishes theory – a conceptual framework that explains existing observations and predicts new ones * Should be controlled so as to be free of bias * Should be designed on a scale that the results can be statistically evaluated

Answer 3

``` • Are expensive to conduct • Require specialised skilled operators to – Design – Analyse – Interpret the data ```

Answer 4

- Animal studies | - In- vitro studies

Answer 5

* Study of how often diseases occur in different groups of people and why * Used to plan and evaluate strategies to prevent illness and as a guide to the management of patients * Relate primarily to groups of people * Epidemiology is the method used to find the causes of health outcomes and diseases in populations. In epidemiology, the patient is the community and individuals are viewed collectively. By definition, epidemiology is the study (scientific, systematic, and data-driven) of the distribution (frequency, pattern) and determinants (causes, risk factors) of health-related states and events (not just diseases) in specified populations (neighborhood, school, city, state, country, global). It is also the application of this study to the control of health problems

Answer 6

* Qualitative research * Focus groups * Individual interviews * Observational studies * Case studies * Cohort studies * Cross-sectional studies * Experimental studies * Clinical trials

Answer 7

``` • Collecting and analysing non-numerical data • Understanding – Concepts – Opinions – Experiences • Gather in-depth insights into problems • Generate new ideas for research ```

Answer 8

• Researchers observe the effect of something on a population – Disease – Risk factor – Diagnostic test – Treatment or intervention • Is not experimental – Do not try to change who is or isn’t affected

Answer 9

* Measure the frequency of a disease or condition in a defined population at a given time * A census of occurrence of characteristic(s)

Answer 10

• Medical history of one (or small group of) patient • No control group – Anecdotal evidence

Answer 11

• Compares patients who have a condition with a group who do not have that condition • Looks retrospectively at risk factors that may impact on the condition – Also known as retrospective studies

Answer 12

* Good for studying rare conditions * Relatively quick to set up * Can look at multiple risk factors * Clinical records may be inconsistent * May rely on memory (recall bias)

Answer 13

* Observational studies of subjects with a specific disease or characteristic * May be compared to a control group * Usually over a long time period

Answer 14

n a retrospective cohort study, the group of interest already has the disease/outcome. In a prospective cohort study, the group does not have the disease/outcome, although some participants usually have high risk factors.

Answer 15

* Introduce an intervention | * Study the effects on the treated population

Answer 16

* Specified condition * Specified treatment * Test and control group * Measure the outcomes

Answer 17

* Population of patients chosen * Divided into 2 groups * Trial group compared with control group

Answer 18

* A type of systematic review that focuses on the numerical results * Aim is to combine the results to produce an estimate of the overall effect size * Data from several trials are pooled and averaged to estimate the overall effect * No new raw data collected

Answer 19

* Systematic review / meta analysis * Randomised control trials * Cohort studies * Case control studies * Case series /reports

Answer 20

``` • Administration of new substances with therapeutic potential to people under controlled conditions for the purpose of determining – Efficacy – Bioavailability – Safety – Tolerability – Acceptability ```

Answer 21

* Good Clinical Practice * Good Manufacturing Practice * Regulatory inspection and enforcement * Protection of incapacitated adults * Protection of minors * Pharmacovigilance arrangements

Answer 22

* Risks and potential benefits must be assessed before trials are started * Interests of the individual study subject must take precedence over those of science or society * All trial subjects must give consent * Trials must be scientifically sound * Trials must have a clear protocol * Trials must be approved by a properly constituted ethics committee * Only properly qualified staff may be involved (including physicians to provide care if needed) * Should be adequate preclinical testing of the product * Product should be of adequate quality (as defined in ICH guidelines for medicines) * Trial subjects privacy and confidentiality must be respected and assured * Data must be recorded, handled and stored in a way that allows accurate reporting, interpretation and verification

Answer 23

phase 1: First administration and safety evaluation in man – usually healthy volunteers phase 2: Early exploratory and dose-finding studies in patients phase 3: Large scale studies in patients phase 4: Post-marketing safety monitoring

Answer 24

``` • Most Phase I volunteers are men – Women of reproductive age? – In EU, only post-menopausal or surgically sterilised women can participate • Genetic polymorphisms – Fast or slow metabolisers – Accumulation of drug in slow metabolisers – Consider the target population – Where is the drug to be marketed? ```

Answer 25

• 4-8 cohorts of 6-8 participants • Escalating dose from one cohort to the next • Maximum tolerated dose determined – Before safety / tolerability issues arise – For low toxicity drugs, the highest practicable dose • Establishes pharmacokinetic parameters – Cmax:Peak drug / metabolite concentration – Tmax: Time to peak drug / metabolite concentration – AUC: to infinity and to specified time • Establishes bioavailability and total exposure – T1/2: rate of elimination – VD: Volume of distribution – MRT: Mean residence time • – average time the drug remains in the body after administration

Answer 26

* Similar participants to Phase Ia * Escalating repeat-dose * Establishes ‘steady state’ dosing requirements

Answer 27

``` • Insufficient biological activity • Unacceptable toxicity • Problems in the design of the trial – Measurement criteria (endpoint) – Patient selection – Sample size – duration • Problems in the execution of the trial – Randomisation of patients – Analysis of data ```

Answer 28

* Reports made by patients and health professionals * Assessed at the MHRA – medics, pharmacists and other scientists * If a new side effect is identified, information is considered in the context of the overall side effect profile for the medicine, and how the side effect profile compares with other medicines used to treat the same condition. * The MHRA takes action to ensure that medicines are used in a way that minimizes risk, while maximizing patient benefit

Answer 29

• Black Triangle symbol (▼) indicated in – British National Formulary (BNF) – British National Formulary for Children (BNFC) – Monthly Index of Medical Specialities (MIMS) – Association of the British Pharmaceutical Industry (ABPI) Medicines Compendium – on advertising material in Drug Safety Update

Answer 30

* Monitored for 2 years (usually) after marketing * Healthcare professionals are asked to report all suspected adverse drug reactions to these products through the Yellow Card Scheme

Answer 31

* Relatively limited information about safety of new drugs from clinical trials in the UK * Trials generally involve only small numbers of eligible patients who take the medicine for a relatively short period of time * Patients in clinical trials may not be fully representative of those who will use the medicine when it is marketed

Answer 32

* Contains a new combination of active substances * New route of administration or drug delivery system * Significant new indication which may alter the established risk/benefit profile of that drug * Established medicine which is to be used in a new patient population

Answer 33

* Information supplied by manufacturers, including Phase IV clinical trials * Side effects revealed through Yellow Card Scheme * Alerts on newly marketed drugs through the Black Triangle Scheme * Research stored in the General Practice Research Database * Quality checks on products, including labelling and packaging carried out by MHRA inspectors * Tip-offs about criminal activity, such as the sale of fake (counterfeit) medicines * Monitored by Commission on Human Medicines (CHM)

Answer 34

``` • Issues alerts – Healthcare professionals – Hospitals – GP surgeries – wholesalers • Tells them when a medicine is being recalled or when there are concerns about the quality that will affect its safety or effectiveness ```

Answer 35

Class 1: Life threatening: immediate recall required e.g. Nurofen Plus Tablets containing rogue Seroquel XL 50mg tablets capsules ``` class 2: Harmful: recall is required within 48 hours e.g. Tramadol 50mg capsules - risk of fungal contamination ``` ``` class 3:Unlikely to harm patients: action required within 5 days e.g. certain batches of a cream/pessary, used to treat fungal infections, such as thrush (Gyno-Pevaryl), because of errors in the patient information leaflet ``` ``` class 4: No threat to patient safety: caution advised e.g. Xenidate XL 36mg prolonged-release tablets (methylphenidate hydrochloride) - incorrect number of tablets in packs from a specific batch ```

Answer 36

* Inspection revealed data manipulations of electrocardiograms (ECGs) during the conduct of some studies of generic medicines * Manipulations appeared to have taken place over a period of at least five years * Their systematic nature, the extended period of time during which they took place and the number of members of staff involved cast doubt on the integrity of the way trials were performed at the site generally and on the reliability of data generated at that site

Answer 37

* Why are they so expensive? * Is big pharma just there for the money? * How many new medicines disasters have there been since 1960’s? * http://bmjopen.bmj.com/content/3/2/e002088.full.pdf * Is society better or worse off for it?

Answer 38

• To place a medicinal product on the market requires authorisation from an appropriate regulatory authority – Medicines and Healthcare Products Regulatory Agency (MHRA) • Demonstrate evidence – Quality – Safety – Efficacy

Answer 39

* Have taken a lead activity molecule * Made structural modifications to achieve best possible pharmacodynamic and pharmacokinetic properties * Formulated it into an elegant and acceptable medicine

Answer 40

• Have to demonstrate convincingly that the new product is efficacious – Produces the desired effect • It provides the means for a therapeutic intervention that will be of benefit to the patient – Including tolerability and acceptability

Answer 41

• The risk of an event occurring in a specified population – E.g. a myocardial infarction in hypertensive patients • Event rate = number of people experiencing an event (e.g. myocardial infarction) as a proportion of the population (e.g. people with hypertension) – Commonly expressed as a %

Answer 42

* In the high risk group there is an absolute risk reduction of 10% * The relative risk reduction is 25% * In the low risk group there is an absolute risk reduction of 2.5% * The relative risk reduction is still 25% * Which indicator would you choose?

Answer 43

E.g. A RCT is designed to determine the reduction in the risk of stroke of a new anti-hypertensive drug (loTens) Patients on active treatment (Drug loTens) 1800 stokes occurred in 15000 patients over an average follow up period of 5 years Patients on placebo treatment 3000 stokes occurred in 15000 patients over an average follow up period of 5 years

Answer 44

Absolute risk for the treatment group (proportion of events in treatment group - ART) i.e. strokes who received drug loTens ART = 1800/1500 = 0.12 Absolute risk for the control group (proportion of events in control group -ARC) i.e. strokes who received placebo ARC = 3000/1500 = 0.2 Absolute Risk Reduction (ARR) ARR = ARC - ART ARR = 0.2 - 0.12 = 0.08 (or 8%) i.e. Patient who receives loTens is 8% less likely to have a stroke over a 5 year period than the patient on placebo Relative Risk Reduction (RRR) RRR = ARC - ART ARC RRR = 0.2 - 0.12 = 0.4 (OR 40%) 0.2 i.e. if patient took drug loTens for 5 years they are 40% less likely to have a stroke than a patient on placebo Are measuring the reduction of risk of the treatment group relative to the control group

Answer 45

* Average mark for an assessment for students who attended lectures on a census day = 40.3% * Average mark for an assessment for students who did not attended lectures on a census day = 31.4% * Absolute difference: 8.9% * Relative difference: attending students achieved 28.3% higher on average than non-attending * Which message is correct?

Answer 46

• The number of patients who would have to receive treatment for 1 of them to benefit • Calculated as 100/absolute risk reduction – High risk group example: need to treat 10 people for 1 person to benefit from it – Low risk group example: need to treat 40 people for 1 person to benefit

Answer 47

• Provide robust evidence that the product will do what it purports to do • Evidence has to be capable of being verified – Needs to be scientific – Capable of statistical analysis

Answer 48

• A placebo is an inert substance or dosage form which is identical in appearance, flavor and odour to the active substance or dosage form. It is used as a negative control in a bioassay or in a clinical study

Answer 49

* Requires a comparison between two groups | * Use mathematical calculations to establish whether the behaviour of the two groups is the same or different

Answer 50

* An essential tool in hypothesis testing * Hypothesis: Patients receiving drug X will show an improved clinical outcome compared to those receiving placebo * Null hypothesis: The clinical outcome for patients receiving drug X will be not be better than those receiving placebo

Answer 51

* The outcome of the trial disproves the null hypothesis | * i.e. the outcomes for the test group are different from those of the control group

Answer 52

• Recruit a number of patients with a condition • Divide them into two – Test group – Control group • At the end of the trial, compare outcomes • Simple!????

Answer 53

``` • Statistical errors – The hypothesis – The statistical set up – power of the study – Analysis of data • Bias – Setting up the groups (selection bias) – Observation bias – Confounding factors ```

Answer 54

• The outcomes from a trial will be applicable to the treatment population as a whole

Answer 55

* MUST mirror the treatment population | * Need to have criteria in place to match the trial population to the treatment population

Answer 56

``` • Nature of the condition – Inclusion and exclusion criteria • Demographics – Age – Gender – Ethnicity – Social background (if it may affect the disease) ```

Answer 57

• Identify the condition to be treated precisely • Use clinical diagnosis and standardised measurement scales – ADAS-cog (Alzheimer's Disease Assessment Scale-cognitive subscale) designed to measure the severity of the most important symptoms of Alzheimer's disease – American College of Rheumatology (ACR) Core Data Set2–4 includes seven measures of activity or activity and damage

Answer 58

• Exclude those for whom the treatment would not apply – E.g. - Exclude type-1 diabetics from a trial for a drug for type-2 diabetes • Identify factors that might interfere with the results – Co-morbidities – Other medications – Factors affecting adherence to protocol

Answer 59

• A population, when measured against a criterion, will usually show some level of variance • This variance is likely to show a distribution around an average value • Trial population MUST mirror the treatment population in all criteria • Trial population is divided into two – Test or intervention group – Control group

Answer 60

• For the outcome to be true, the test group must be the same as the control group in all respects • Best way to allocate to test and control is random – Can involve use of a random number generator – Should be done by an independent person not involved in the trial

Answer 61

* Test and control groups are the same at the start of the trial * Outcomes at the end of the trial for test and control are different if this can be demonstrated statistically

Answer 62

• The operators should not know what treatment an individual has had – Easier to do with medicines than with physical procedures – Highlights importance of the placebo • Double-blind: neither the operators nor the patients know the treatment

Answer 63

• Half-way through the trial the test and control groups are swapped over – Requires measurements all the way through – Trial usually runs for some time – Trial can be stopped if it becomes clear that one treatment is significantly better than the other • Applicable to certain conditions – Pain relief – Insomnia – Some chronic conditions

Answer 64

* The trial must be designed to be capable of disproving the null hypothesis * Needs to be of a size large enough to show that the outcomes for the two comparison groups are statistically different from each other * Large enough to eliminate the play of chance

Answer 65

• What kind of statistical test is being performed • Sample size – the larger the sample size, the larger the power – increasing sample size = increased costs • The size of experimental effects – If the null hypothesis is wrong by a substantial amount, power will be higher than if it is wrong by a small amount. • The level of error in experimental measurements – Error = ‘noise’

Answer 66

• ITT analysis includes all randomised patients in the groups to which they were assigned – Regardless of treatment received or whether they completed the trial – Participants could drop out due to adverse effects / unacceptability of treatment etc • A high drop-out rate compromises the power of the trial and could hide a confounding factor • ITT reduces the risk of bias in the analysis of data

Answer 67

• Seen in older clinical trials • Analyse data from patients who complete the trial – Drop-outs not accounted for

Answer 68

• All participants must be treated in the same way – Data collected according to the same protocol and at the same times – Deviation can lead to bias

Answer 69

• How precise are the results? • Data analysis should give statistically meaningful indications of the precision obtained – Confidence intervals – Coefficient of variance

Answer 70

• Outcome of the trial should relate to the overall health benefit of the therapy – Relative risk reduction – Absolute risk reduction – Numbers needed to treat

Answer 71

• Can also be measured • Number needed to harm – Number of patients who would have to receive the treatment for 1 of them to experience an adverse event

Answer 72

1. Systematic review of randomized trials 2. Randomized trial or observational study with dramatic effect 3. Non-randomized controlled cohort/follow-up study 4. Case-series, case-control studies, or historically controlled studies 5. Mechanism-based reasoning

Answer 73

``` • Primary and secondary literature – Requires subscriptions – Can be time consuming – Gives minutiae of detail • NHS website http://www.nhs.uk/pages/home.aspx – Good at an overview level • Cochrane database – Source of detailed information on meta-analysis of clinical trials • NICE guidelines ```

Answer 74

* How do we know which treatments or interventions really work? * How can you tell whether a piece of research has been done properly and that the information it reports is reliable and trustworthy? * How can health care commissioners know which treatments or services are truly worth funding? * How can patients decide whether the benefits of a particular intervention are likely to outweigh the harms and costs? * How can you decide what to believe when making a health care decision, when research on the same topic comes to different conclusions?

Answer 75

``` • Is the study valid? – What type of study is it? – Is there evidence of bias? – Are the methods used OK? • What are the results? – Are the results significant? • Are the results useful? – Do they apply to your population of patients? ```

Answer 76

``` • A scientific study – Animals, in vitro • Observational studies – Case study – Cohort study – Cross sectional study • Clinical trial • Meta-analysis or systematic review ```

Answer 77

``` • Section A – Is the study design valid? • Section B – Is the study methodologically sound? • Section C – What are the results? • Section D – Will the results help locally? ```

Answer 78

• Was the study designed to assess the outcomes of an intervention? • Is the research question ‘focused’ in terms of: – Population studied – Intervention given – Comparator chosen – Outcomes measured

Answer 79

* How was randomisation carried out? Was the method appropriate? * Was randomisation sufficient to eliminate systematic bias? * Was the allocation sequence concealed from investigators and participants?

Answer 80

* Were losses to follow-up and exclusions after randomisation accounted for? * Were participants analysed in the study groups to which they were randomised (intention-to-treat analysis)? * Was the study stopped early? If so, what was the reason?

Answer 81

* Were the participants ‘blind’ to intervention they were given? * Were the investigators ‘blind’ to the intervention they were giving to participants? * Were the people assessing/analysing outcome/s ‘blinded’?

Answer 82

• Were the baseline characteristics of each study group clearly set out? – Age – Sex – Socio-economic group • Were there any differences between the study groups that could affect the outcome/s?

Answer 83

• Were they treated equally? • Was there a clearly defined study protocol? • If any additional interventions were given (e.g. tests or treatments), were they similar between the study groups? – Tests – Treatments • Were the follow-up intervals the same for each study group?

Answer 84

* Was a power calculation undertaken? * What outcomes were measured, and were they clearly specified? * How were the results expressed? * For binary outcomes, were relative and absolute effects reported? * Were the results reported for each outcome in each study group at each follow-up interval? * Was there any missing or incomplete data? * Was there differential drop-out between the study groups that could affect the results? * Were potential sources of bias identified? * Which statistical tests were used? * Were p values reported?

Answer 85

* What statistically rigorous measures of precision were used? * Were confidence intervals (CIs) reported?

Answer 86

• What was the size of the intervention or treatment effect? • Were harms or unintended effects reported for each study group? • Was a cost-effectiveness analysis undertaken? – Comparison between different interventions used in the care of the same condition or problem

Answer 87

* Are the study participants similar to the people in your care? * Would any differences between your population and the study participants alter the outcomes reported in the study? * Are the outcomes important to your population? * Are there any outcomes you would have wanted information on that have not been studied or reported? * Are there any limitations of the study that would affect your decision?

Answer 88

* What resources are needed to introduce this intervention taking into account time, finances, and skills development or training needs? * Are you able to disinvest resources in one or more existing interventions in order to be able to re-invest in the new intervention?

Answer 89

1. Did the review address a clearly focused question? 2. Did the authors look for the right type of papers? 3. Do you think all the important, relevant studies were included? 4. Did the review’s authors do enough to assess quality of the included studies? 5. If the results of the review have been combined, was it reasonable to do so? 6. What are the overall results of the review? 7. How precise are the results? 8. Can the results be applied to the local population? 9. Were all important outcomes considered? 10. Are the benefits worth the harms and costs?

Answer 90

``` • Choice of intervention and control • Choice of treatment population – Inclusion and exclusion criteria • Stratification and randomisation of participants • Outcome measures • Trial protocol – Intention to treat • Statistical analysis – Confidence intervals • Summary outcome data – Absolute and relative risk reduction, NNT ```

Answer 91

``` • Abstract Summary of the paper • Methods What they did • Results What they found • Discussion ```

Answer 92

Methods • Why they did the trial – Evaluate the effects of potential treatments in patients hospitalized with Covid-19 • Inclusion and exclusion criteria – Hospitalized patients with clinically suspected or laboratory confirmed SARS-CoV-2 infection – Excluding those with medical history that might put them at substantial risk

Answer 93

• Consent • Principles for conducting the trial, ethics approval • Randomization – 2 groups: standard care alone, or with addition of dexamethasone • Procedures – Recording of the outcomes – Plus any other relevant information

Answer 94

``` • Primary outcome – all-cause mortality within 28 days • Secondary outcomes – Time until discharge – Additional treatments needed • Dialysis, haemofiltration, ventilation, cardiac arrythmias – Cessation of additional treatments • Ventilation ```

Answer 95

• Power calculation difficult to do from start • Once trial was underway could estimate number of patients needed in order to achieve power of 90% and P value = 0.1 – If 28 day mortality was 20%, would need 2000 pts in intervention group and 4000 in the normal care group • Specified statistical methods to be used

Answer 96

• Was the intervention successful? • Does the data provide compelling evidence for treatment? • Would you recommend it? • Can you work out some summary statistics? – Risk reduction (absolute and relative) – NNT

Answer 97

MHRA - FDA - European medicines agency

Answer 98

– the Clinical Practice Research Datalink (CPRD), a data research service that aims to improve public health by using anonymised NHS clinical data – the National Institute for Biological Standards and Control (NIBSC), a global leader in the standardisation and control of biological medicines – the Medicines and Healthcare products Regulatory Agency (MHRA), the UK’s regulator of medicines, medical devices and blood components for transfusion, responsible for ensuring their safety, quality and effectiveness

Answer 99

* Ensuring that medicines, medical devices and blood components for transfusion meet applicable standards of safety, quality and efficacy * Ensuring that the supply chain for medicines, medical devices and blood components is safe and secure * Promoting international standardisation and harmonisation to assure the effectiveness and safety of biological medicines * Helping to educate the public and healthcare professionals about the risks and benefits of medicines, medical devices and blood components, leading to safer and more effective use * Supporting innovation and research and development that’s beneficial to public health * Influencing UK, EU and international regulatory frameworks so that they’re risk-proportionate and effective at protecting public health

Answer 100

* Development of regulatory policy * Establishment of regulations and guidance document in support of the FDA act * Review and approval of pre-marketing submissions for drugs and devices * Inspection of facilitates and products with follow-up enforcement actions, where necessary * Ensuring that labeling, packaging and promotional material is truthful, informative and not misleading * Participation in international initiatives on global harmonisation

Answer 101

• The centre is responsible for – Reviewing application for new and generic pharmaceuticals – Manages US GMP regulations for pharmaceutical manufacturing – Determines which medications require a medical prescription – Monitors advertising of approved medications – Collects and analyses safety data about pharmaceuticals already in the market

Answer 102

- facilitates developments and access to medicines - evaluate applications for marketing authorisation - provide reliable information on human and veterinary medicines in any language

Answer 103

• An IND application is required if: – A sponsor intends to conduct a human clinical investigation with an investigational new drug • A pre-IND meeting can be arranged with the regulator to discuss: – The design of animal research, which is required to lend support to clinical studies – Intended protocol for conducting the clinical trial – Chemistry, manufacturing and control of investigational drug

Answer 104

• IND application contains – Cover sheet (Form FDA-1571) – Table of contents – Part A – Introductory statement and general investigational plan – Part B – Protocols – Part C – Chemistry, manufacturing and control information – Part D – Pharmacology and toxicology information – Part E – Previous human experience with the investigational drug – Part F – Additional information

Answer 105

• “Do the data supplied support the use of this product, administered in this way, in the proposed dose for the proposed duration, to this ‘type’ of participant?”

Answer 106

Common technical document (CTD) New drug application (NDA)

Answer 107

``` • Identity – Recommended International Non-proprietary Name (INN) • Characterisation – Structural information – Chemical and physical properties – Spectral/chromatographic properties • Manufacturing process • Control • Stability ```

Answer 108

``` • Pharmacology – Primary, secondary pharmacology – Safety pharmacology – Pharmacological drug interactions • Pharmacokinetics (PK) – Analytical methods and validation – ADME – Pharmacokinetic drug interactions ```

Answer 109

``` – Single and double dose – Genotoxicity: in vitro and in vivo – Carcinogenicity: medium to long-term studies – Reproductive and Development Toxicity – Local tolerance – Other toxicity studies • Antigenicity • Immunotoxicity • Metabolites and impurities ```

Answer 110

• Biopharmaceutical studies – Bioavailability – Bioequivalence – In vitro to in vivo correlations – Bioanalytical methods for human studies • Pharmacokinetics studies using human biomaterials – Plasma protein binding studies – Hepatic metabolism and drug interactions – Using other human biomaterials

Answer 111

``` – Subject PK and tolerability study reports – Intrinsic and extrinsic factor • Human pharmacodynamic (PD) studies – Healthy subject PD – Patient PD • Efficacy and Safety reports – Controlled clinical studies to claimed indication – Uncontrolled clinical studies – Meta-analysis ```

Answer 112

* Non-clinical and clinical Overviews should present critical discussions and assessments of results with conclusions * Non-clinical and clinical Summaries should provide abbreviated factual data present as written summaries and support by summary tables