Licensing a New Drug PY367

Thalidomide issues

• Phocomelia

• Correlated with increased exposure to

  • Television

  • radioactive fallout from atomic bomb testing

• Birth defects became apparent within a year of launch of the drug and ceased within 9 months of withdrawal

Expectations for medicines?

• Safety - safe for consumption

• Quality - equal quality for each dose

• Efficacy - is it working?

What is the MHRA?

Medicines and healthcare products regulatory agency

What do the MHRA do?

• Maintaining safety, quality and efficacy for all products like insulin pumps and blood components

• Educate public and HCP about benefits and risks of medicine for safer practise

• Promote international standardisation and harmonisation to assure the effectiveness and safety of biological medicines

What are the key questions for the MHRA?

• Do advantages outweigh disadvantages?

• Does medicine do most good than least harm for most people taking it?

• Are side effects acceptable?

The MHRA handles the safety profile, but who handles the commercial side and how?

• NICE handle commercial side

  • Funding of the drug

  • Whether its routinely used in NHS

  • Is the drug better than its opposition already on market

Why is an increase in HIV diagnosis not bad?

• Increases are because of more testing and screening than prior

• No correlation with deaths as it did not change after this

What was the Government’s 20 point plan of action?

1. Fund testing

2. Government

3. Tackle stigma

4. Mandatory training for staff

5. Prioritise partner notification

6. Treat all late diagnosis as serious incidents

7. Fund HIV prevention

   • PrEP = pre-exposure prophylaxis

8. Publicly available granular data

9. Funding

What is Combination Prevention?

• Use condoms when possible

1. PEP - Treat with high dose Efavirenz ASAP

   • Prevents acquisition following potential exposure

2. Treatment as prevention - Prevents transmission between partners

3. PrEP - Prevents acquisition

   • EMTRICIBINE + TENOFOVIR

4. Expand HIV testing - Very sensitive and easy to use

Structure of HIV

• Single stranded RNA

• Reverse transcriptase

• Inside capsid

• Inside matrix

• Inside cell

• gp120 spike protein which helps virus infiltrate CD4+

• Host cell proteins come from person you caught virus from

HIV Lifecycle

1. Binding - HIV Gp120 binds to receptors on CD4 surface

2. Fusion - HIV envelope and CD4 cell membrane fuse which allows HIV to enter CD4 cell

3. Reverse transcription - HIV releases this to convert RNA to DNA, allows HIV to enter CD4 nucleus and combine with cell DNA

4. Integration - Inside nucleus, HIV uses integrase to insert viral DNA into CD4 DNA

5. Replication - Begin to make long HIV proteins

6. Assembly - Move to cell surface and assemble to immature HIV

7. Budding - Immature HIV pushes out cell and releases protease to break up long chains to form mature HIV

What two things does HIVRT do?

• Two enzymes in one

1. Builds DNA strand using viral RNA template

2. Degrades original RNA strand to build complimentary DNA strand because body has TLR3 (toll-like receptors) which protects cell against foreign RNA

   • Can continue replication process

What should a scientific study do?

• 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 to be free of bias

• Should be designed on a scale that the results can be statistically evaluated

What is the 4 step basis for clinical trials?

1. Hypothesis

2. Experiments

3. Data

4. Conclusions

What are two issues with detailed scientific studies?

1. Expensive to conduct

2. Require specialised skilled operators

   • Design

   • Analyse

   • Interpret data

What is Epidemiology?

• 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 specific groups of people

What are 3 types of clinical studies?

• Qualitative research

  • Focus groups and individual interviews

• Observational studies

  • Case studies

  • Cohort studies

  • Cross-sectional studies

• Experimental studies

  • Clinical trials

What is qualitative research?

• Collect and analyse non-numerical data

• Understand concepts, opinions and experiences

• Gather in-depth insights into problems

• Generate new ideas for research

What are observational studies?

• Researchers observe effect of something on a population

  • Disease

  • Risk factor

  • Diagnostic test

  • Treatment or intervention

• Not experimental

What are cross-sectional studies?

Measure frequency of a disease or condition in a defined population at a given time

What are case studies?

• Medical history of one (or small group of) patient

• No control group

What are case control studies?

• Compares patients who have condition with a group who do not have that condition

• Look at risk factors that may have impact on condition

• Advantages:

  • Good for studying rare conditions

  • Quick to set up

• Limitations:

  • Clinical records may be inconsistent

  • May rely on memory

What are cohort studies?

• Observational studies of subjects with a specific disease or characteristic

• May be compared to a control group

• Usually over a long time period

What time period do these 3 focus on?

• Case control - past

• Cross sectional - present

• Cohort - future

What are experimental studies?

Introduce intervention and study effects on treated population

What are 4 requirements for clinical trials?

1. Specified condition

2. Specified treatment

3. Test and control group

4. Measure outcomes

What are randomised controlled trials?

• Population of patients

• Divided into 2 groups

• Trial group compared with control group

What is meta-analysis?

• Systematic review that focuses on numerical results

• Combine results to produce estimate of overall effect size

• Data from several trials are pooled and averaged to estimate overall effect

• No new raw data collected

Hierarchy of evidence

• Systematic review / meta analysis↓

• Randomised control trials↓

• Cohort studies↓

• Case control studies↓

• Case series /reports

What 5 things does admin of new substances with therapeutic potential determine? EBSTA

1. Efficacy

2. Bioavailability

3. Safety

4. Tolerability

5. Acceptability

The medicines for human use regulations 2004

• GCP

• GMP

• Regulatory inspection and enforcement

• Protections of incapacitated adults

• Protection of minors

• Pharmacovigilance arrangements

What is good clinical practice under IHC guidelines?

• Risks and potential benefits assessed before trials starts

• 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 and have clear protocol

• Trials must be approved by ethics committee

• Only qualified staff

• Preclinical testing complete

• Product of adequate quality

What are the 4 phases of clinical trials?

1. First admin and safety evaluation in man - usually healthy volunteers (don’t have to do this for older drugs being used for new disease trials)

2. Early exploratory and dose-finding studies in patients

3. Large scale studies

4. Post-marketing safety monitoring

Some complications to consider with population

• Most phase 1 volunteers are men

  • In EU, Only post-menopausal woman can participate

• Genetic polymorphisms

  • Fast or slow metabolisers

What are phase 1a trials and what do they test?

• Single dose trials

• Escalating dose from one cohort to the next

• Max tolerated dose determined

• Establishes pharmacokinetic parameters

  • Peak

  • Time to peak

  • Vol. of distribution

  • Rate of elimination

  • Bioavailability

What are phase 1b trials?

• Similar participants to phase 1a

• Escalating repeated-dose

• Establishes steady state dosing requirements

What is the difference between phase 2a and 2b trials?

• a is exploratory, b is confirmatory

• a aims for preliminary safety and efficacy to support go/no-go decision

  • Dose and regimen based on p1 data

  • Randomised or double blind trials

• b aims for dose selection to support registration

• b uses selected dose levels whereas a works off p1a

What does phase 3 trials do?

• Patients in target indications

• Provides efficacy and safety data to support registration

• May include pharmacoeconomics

• Includes different ages and ethnic groups rather than singular cohort groups

• Data is statistically rigorous

What are phase 4 trials?

• Post-marketing surveillance

• Reveals unexpected adverse events and/or toxicity

• Done on treated patients

Why do trials fail?

• Insufficient biological activity (Lack of therapeutic efficacy)

• Unacceptable toxicity

• Problems in design of trial

  • Patient selection

  • Sample size and duration

• Problems in execution of trial

  • Patient randomisation

What is the yellow card scheme?

• Reporting system for side effects in medication

• Used by HP and made by pts.

• MHRA takes action to ensure medicines are used in way that minimises risk, maximising benefit

What are black triangle drugs and products?

• Monitored for 2 years after marketing

• HP recommended to report all suspected adverse reactions to these products through yellow card scheme

• There is relatively limited info about safety of new drugs from clinical trials in UK

• They contain new combo of active substances

• New routes of admin or drug delivery systems

• Significant new indications which may alter established risk/benefit profile of that drug

What do the DMRC do?

• Issues alerts to HP, hospitals, GP surgeries and wholesalers

• Tells them when a medicine is being recalled or when there is concern about quality

What are 4 classes of recalls?

1. Life threatening: immediate e.g. complete wrong drug inside packaging

2. Harmful: within 48 hours e.g. fungal contamination

3. Unlikely to harm: action required within 5 days e.g. PIL errors

4. No threat to patient safety: caution advised e.g. Wrong number of tablets in packs

What is marketing authorisation?

• Given by MHRA to freely place products on the market

• Demonstrates evidence of quality safety and efficacy before MA approved

What is the process of making the product work?

1. Take lead activity molecule

2. Make structural modifications to achieve best possible pharmacodynamic and kinetic properties

3. Formulate into acceptable medicine

How is efficacy shown?

• Animal models at start then to human models (in-vitro to in-vivo)

• If it has effect you wanted but does not benefit pt. it won’t get approved

• Provides benefit to patient with minimal SE

  • Improves symptoms as well as having desired effect

Does showing efficacy reduce the risk of something happening?

Event rate = number of people experiencing an event (e.g. myocardial infarction) as a proportion of the population (e.g. HTN pt.)

How is the benefit quantified?

• loTens technique

• ARR = ARC - ART

• RRR = (ARC - ART) ÷ ARC

Number needed to treat (NNT) Equation

How do you demonstrate efficacy?

• Provide robust evidence that product will do as label describes

• Evidence needs to be scientific and capable of statistical analysis

What is a placebo?

• Inert substance or dosage form which is identical in appearance, flavour and odour to active form

• Used as negative control in bioassay

Are placebos always acceptable?

No because of ethics as not treating conditions like HIV would be unethical

What does statistical analysis require?

Requires comparison between two groups by use of maths

What is the null hypothesis?

Clinical outcome for patients receiving drug X will not be better than those receiving placebo

How to set up clinical trials?

• Recruit a number of patients with a condition which depends on frequency of condition e.g. diabetes easier than Lupus (poor market)

• Divide them into two groups, test and control

• At end of trial compare results

How to remove the play of chance in clinical trials?

Use a bigger sample to remove play of chance

What are confounding factors?

Difference in groups that may affect results e.g. City A is industrial, City B is seaside town

What is central assumptions made on results?

• Outcomes of trial applicable to treatment population as whole

• DOES NOT always follow this so we have POST TRIAL MA

• Also try to mirror treatment population as much as possible

Possible flaws in trials

• Are there enough people to see a statistically significant event?

• Unethical to run underpowered study

• There could be observation bias hence double blind trials

• Confounding factors like lifestyle and diet

• Type I and II errors

How to identify treatment population?

• Must mirror treatment population

• Nature of condition

• Demographics

  • Age

  • Gender

  • Ethnicity

  • Social background (probably not married people for HIV)

Inclusion criteria

• Identify the condition to be treated precisely

• Use clinical diagnosis and standardised measurement scales

Exclusion criteria

• 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 e.g. Alzheimer’s

Normal distribution

• Population shows variance when measured against criteria

• Trial population MUST mirror the treatment population in all criteria

• Trial population is divided into two

  • Test or intervention group

  • Control group

How to make outcome of trial true?

• Randomisation of allocation of test and control

• Test and control groups same at start of trial

• Outcomes at end of trial for test and control are different if demonstrated statistically

What is double-blind trial?

Neither operators nor patients know treatment

What is crossover trial?

• Switch control and test groups halfway through which should show in results

• Applicable to conditions like pain relief, insomnia and some chronic conditions

What is the power of trial determined by?

• Sample size

  • Larger sample size, larger power

  • Increasing sample size = Increased costs

• Size of experimental effects

  • If null hypothesis is wrong by a substantial amount, power will be higher than if is wrong by a small amount

• Level of errors in experimental measurements

Intention to treat (ITT)

• ITT analysis includes all randomised patients in the groups to which they were assigned

  • Regardless of treatment received and drop-outs

    • They leave cuz of AE and do not want continue

• High drop-out rate compromises power of the trial and could hide confounding factor

• ITT reduces risk of bias

On-treatment analysis (OT)

Analyse data from the completionists (drop-outs not accounted for)

How to maintain consistency in data collection?

• All participants treated equally

• Data collected by same protocol for each person

• Deviation = bias

Impact of the outcome of a trial relates to……

• Overall health benefit of therapy

  • Relative risk reduction

  • Absolute risk reduction

  • Numbers needed to treat

How to measure Adverse Effects?

• Number needed to harm

  • SAME AS NNT

What 3 centres form MHRA?

• Clinical practise research datalink

• National institute for biological standards and control

• Medicines and healthcare products regulatory agency

What is an IND?

• Investigation into a new drug

Requirement for IND application

• Extensive evidence of pre-clinical studies on animal cells

• Therapeutic evidence

• Pharmaco and kinetic evidence

• Design of trial

• How was it manufactured

Parts of IND application

• Part A: Introductory statement and general investigational plan

• Part B: Protocols

• Part C: Chemistry, manufacturing and control info

• Part D: Pharmacology and toxicology info

• Part E: Previous human experience with investigational drug

• Part F: Additional info

Assessment process

• Medicinal group look at your plan

• Chemical group look at standard of manufacturing

• Pharmaco and toxic group look at pre-clinical studies

• Statistical group in depth evaluation on number of sampling done

What is the CTA?

Clinical trial authorisation

What does the toxicologist, medical assessor and pharmacist look at?

• Toxicologist: Safety of product from non-clinical testing and design side

• Medical assessor: Look at safety of trial from human data and pre-clinical perspective

• Pharmacist: Look at safety of quality of drug

What happens with a MA application?

• Common technical document or new drug application

• Module 2: Detailed appendix of whole application - most critical area

• Module 3: Quality

• Module 4: Non-clinical study reports

• Module 5: Clinical study reports

Explain Module 3: Quality

• Variety of info on compound and its manufacturing

• Recommended international non-proprietary name

• Characterisation of compound

• Manufacturing process

• Control and stability

Explain Module 4: Non-clinical study reports

• Pharmacology and pharmacokinetics

• Toxicology data

  • Genotoxicity

  • Carcinogenicity

  • Productive and developmental toxicity

Explain Module 5: Clinical study reports

• Biopharmaceutical studies

• Pharmacokinetic studies using human biomaterials

• Human pharmaco and kinetic studies

• Efficacy and safety reports

How is new drug application assessed?

• Reviewed by Medical, pharmacology, chemistry, biopharm, statistical, microbio groups

• Module 3 would be chemistry or biopharm

• Module 4 would be pharmacology

• Module 5 would be medical

• All modules looked at by stats

• Module 3 looked at by microbio

• Final things are label review and site inspections acceptable

Generic drug review process

• Plant inspection

• Chem and micro review

• Labelling review

• Bioequivalence review

What is mutual recognition?

When two countries are happy with a single process used for supply of a drug

What does antiviral chemotherapy try to do? And 3 targets?

• Try to exploit differences that exist between viral and host cells

1. Targets unique to virus

2. Targets in virus similar but not identical to those in host cells

3. Target in virus shared by host cell, but vary in importance between viral and host cell

What are the 4 aims of HIV treatment? as well as why it is incurable?

• Eradication of HIV infection cannot be achieved with current antiretroviral regimens

  • In earliest stage of HIV infection, large pool of infected CD4s

• Primary goals for initiating antiretroviral therapy:

  • Reduce mortality and morbidity

  • Restore and preserve immunological function - recoup CD4s

  • Maximally and durably suppress plasma HIV viral load

  • Reduce transmission of disease - condoms + treatment

What is latent infection?

• Retroviral genome is present but is not transcribing viral genome or mRNA for structural proteins

• Only DNA present, RNA indicates active infection

3 more aims of HIV treatment?

• Balance of prevention of latent → active and risks of toxicity

• Need commitment to treatment and adherence

• Drug resistance generally overcome by using drug combo

When to start treatment?

Start treatment ASAP after diagnosis

Advantages of HIV treatment

• Once viral load undetectable, HIV cannot be passed on

• Less illness due to restoring CD4 function

• Treatment stops HIV reproducing in body

• Immune System gets stronger

What are key target sites for treatment and drug classes?

• Fusion inhibition

  • Chemokine receptor antagonists

• Inhibition of reverse transcriptase

  • NRTIs and NNRTIs

• Inhibition of DNA integration

  • INIs

• Interference with protein manipulation

  • Protease inhibitors

• Interference with capsid maturation

  • Maturation inhibitors

What are 4 examples of fusion/entry inhibitors?

1. Fusion inhibitor - Enfuvirtide

   • Unclear MOA

2. CCR5 antagonists - Maraviroc

   • Most commonly used

   • - Virus requires CCR5 to enter cell

3. Post-attachment inhibitors - Ibalizumab

   • After HIV binding, prevents entry

4. Attachment inhibitor - Fostemsavir

   • Prevent initial binding

How do NRTIs work?

• They are nucleoside analogs that when phosphorylated, mimic deoxyribonucleoside triphosphates (DNA bases)

• Become incorporated into growing DNA chain and terminate elongation because they’re recognised as foreign so not full length of DNA

• This is competitive inhibition

• Examples

  • Zidovudine (side)

  • Abacavir (side)

  • Emtricitabine (side)

  • Lamivudine (side)

  • Tenofovir (tide)

What can cause resistance to NRTIs?

• Mutations in HIV RT’ase can cause resistance via two mechanisms

1. Discrimination: RT becomes smarter and detects difference between drug and DNA base so drug isn’t incorporated into chain

2. Excision: Removes drug from chain to continue chain addition

How to prevent resistance to NRTIs?

• Combo of different drugs like Emtricitabine and Tenofovir = nucleoside and tide

• RT struggles to mutate to differentiate between nucleoside and nucleotide

How do NNRTIs work?

• Non-competitive inhibition of HIV-1 RT

1. Binds hydrophobic pockets adjacent to enzyme-active site

2. Changes structure of active site so you lose enzyme activity

• Not chain breaker

• Resistance possible as RT can change shape of pocket where NNRTI binds so they can’t bind and work

• Examples

  • Nevirapine

  • Efavirenz

    • Increased incidence of TDM, CNS events and cardiac events

Name a 2nd gen NNRTI and any changes from 1st gen

• Etravirine

  • Continued development due to high toxicities with earlier drugs

  • Still one of first line drugs

  • Taken every single day so toxicity reduction is necessary

• Rilpivirine

• Improved tolerability esp. CNS and less susceptible than other NNRTIs to resistance mutations