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Drug Development Life Cycle
Transcript of Drug Development Life Cycle
Drug Development Life Cycle
the study of the distribution and determinants of health-related states or events (inc. disease)
the application of this study to the control of diseases and other health problems.
surveillance and descriptive studies can be used to study distribution
analytical studies are used to study determinants.
efficiency, effectiveness, value and behavior in the production and consumption of health and health care
US increase in antidepressant sales
carried out trials while at sea, 1747
scurvy patients were given the same general diet but this was supplemented with cider, elixir vitriol, vinegar, seawater, nutmeg and (crucially) oranges and lemons
six days later patients taking citrus fruits were fit for duty.
nearly 50 years before the Navy eventually made lemon juice a compulsory part of the seafarer's diet (this was soon replaced by lime juice because it was cheaper)
Selection of Lead Compound
Methodology follows GLP
Drug Delivery Systems
Clinical Trials in Humans:
protocols following GCP
procedures following GMP
Compliance with regulatory requirements necessary
1. The Pharmaceutical Industry
2. Key Job Roles
3. Product Development Process
Lots of time and money!
can take 12–15 years
costs can be upwards of £1/2bn
ideas for a target can come from a variety of sources
takes years to build up a body of supporting evidence before selecting a target for a costly drug discovery programme.
pharmaceutical companies and academic centres have identify molecules which possess suitable characteristics to make acceptable drugs.
US President Clinton applauds Tony Blair during a joint teleconference to announce that the Human Genome Project had been completed. "This discovery is one of history's great scientific milestones, the biological equivalent of the moon landing."
- January 27, 2000 -
People who are forced by legislation to wear a bicycle helmet, meanwhile, may be different again. Firstly, they may not wear the helmet correctly, seeking only to comply with the law and avoid a fine. Secondly, their behaviour may change as a consequence of wearing a helmet through “risk compensation,” a phenomenon that has been documented in many fields.4 5 One study—albeit with a single author and subject—suggests that drivers give larger clearance to cyclists without a helmet.6
Even if helmets do have an effect on head injury rates, it would not necessarily follow that legislation would have public health benefits overall. This is because of “second round” effects, such as changes in cycling rates, which may affect individual and population health. Modelling studies have generally concluded that regular cyclists live longer because the health effects of cycling far outweigh the risk of crashes.7 This trade-off depends crucially, however, on the absolute risk of an accident: any true reduction in the relative risk of head injury will have a greater impact where crashes are more common, such as for children.8
The impact on all cause mortality, and on head injuries, may be even further complicated if such legislation has varying effects on different groups. For example, a recent study identified two broad subpopulations of cyclist: “one speed-happy group that cycle fast and have lots of cycle equipment including helmets, and one traditional kind of cyclist without much equipment, cycling slowly.” The study concluded that compulsory cycle helmet legislation may selectively reduce cycling in the second group.9 There are even more complex second round effects if each individual cyclist’s safety is improved by increased cyclist density through “safety in numbers,” a phenomenon known as Smeed’s law.10 Statistical models for the overall impact of helmet habits are therefore inevitably complex and based on speculative assumptions.11 This complexity seems at odds with the current official BMA policy, which confidently calls for compulsory helmet legislation.
Lead compound(s) has been optimized and tested and pharmacological studies have been conducted to show it has the potential to become a drug.
Any investigation in human subjects intended to discover or verify the clinical, pharmacological and/or other pharmacodynamic effects of an investigational product, and/or to identify any adverse reactions to an investigational product, and/or to study absorption, distribution, metabolism, and excretion of an
with the object of ascertaining its safety and/or efficacy.
exploratory, first-in-human trials
human microdosing studies
administration of single subtherapeutic dose
n ≈ 10 - 15
gather preliminary data on pharmacodynamics
no data on safety or efficacy
not required - effort to streamline trials
Phase 1 - clinical / human pharmacology
assess the safety of the new drug
pharmacokinetics (ADME) / pharmacodynamics
normally healthy volunteers (may be paid)
critically ill patients can have option to be included (after due consideration of the risk-benefit ratio)
usually conducted with open label
n ≈ 10 - 100
starting doses based on preclinical; dosage increased
monitored closely to check their tolerance / side effects
samples of blood, urine or stool and other physiological information
£6M - several months to a year
examine the safety and effectiveness of the drug in the targeted disease group
doses of varying strengths
control group may be used: risk-benefit profile
phase 2b efficacy trials - extension to the safety and efficacy
information needed to determine the
effective dose and the dosing regimen of frequency and duration
clinical endpoints or markers used to assess interaction of drug and disease
definitive and surrogate
statistical analysis used to determine optimum conditions
n ≈ 50 - 500
£12M - 1 to 2 years
Phase 3 (pivotal)
confirm efficacy of the drug in large patient group
methodology of trial carefully prepared so that meaningful results can be gathered at conclusion
extensive statistical analyses
drug does not show significant advantage over current treatment
result may be refined and certain
subgroups analyzed to determine if effects are greater in one group than another
comprehensive data for understanding critical parameters of safety and effectiveness
results enable pharmaceutical company to set:
target patient groups
Info. / analysis / CMC - sent for marketing authorization.
n ≈ 100s - 1000s
£30-60M - 3-5 years
Phase 4 (post-market surveillance trial)
post-marketing approval trials
monitor the efficacy & side effects in uncontrolled real-life situation
effectiveness compared with established treatment
side effects, patient’s quality of life, and cost-effectiveness collated.
adverse events reported and acted on to ensure patients’ welfare
serious events are reported to regulatory authorities within a specified time
if necessary: drug is recalled; doctors and patients notified.
Phase 5 (post marketing studies)
licensed drugs can only be prescribed for a specific condition
it may become apparent that the drug will be useful for similar conditions
license can be extended to cover other conditions
trials large (1000s) but inexpensive
may not be possible to test 1,000 patients
enhanced patent protection and marketing rights
clinical research financial subsidization
Cell Media announced that the EMA Committee for Orphan Medicinal Products has issued a positive opinion on an application for orphan designation of a T cell immunotherapy under development by the company.
nstitute for Health and
Quality Standards drive and measure
internationally recognised method to compare different drugs and measure their clinical effectiveness
turned down 40% of new medicines ('12)
decision points between trials
sad / mad
study the physical or chemical properties of drug substances and formulations, with a view to determining the quality and stability of drug products
Abid - Covance
massive human capital
day-to-day care of laboratory animals
also assist scientists with their experiments involving the animals in my care
daily running of the animal facility and mentoring and training junior technicians
GCSE - BSc in 8 years
3.5 million animals (over three-quarters of which are rodents) used in UK each year.
different requirements of each species / each set of experiments: working environment varies considerably
Paul - NovImmune - Switzerland
scientific and legal responsibilities for the co-ordination, conduct and reporting of in-life studies
maintain contact with sponsors
prepare study protocols
schedule resources (staff and equipment)
collate and interpret data - write reports
Italian Medicines Agency
national authority responsible for drugs regulation
Home Office License - in vivo
Kelli - Touchlight Genetics - synthetic
(biometry or biometrics) application of statistics to biology
production of clinical trial reports and the provision of statistical services
Biostatistician - Team Leader - Principal Biostatistician - Manager
Ivelina - Europe wide - Amgen UK
"Consistent Quality and Reliable Supply"
develop the business strategy
lead and manage business change
measure business performance against business strategy
Harriet - Barc "esoteric testing" - Ghent
R&D to Marketing
Toby - Janssen - Germany
Chemical Biologists deal with novel chemical compounds applied to biology
uses chemistry to understand the
biological processes that cause disease
ensure a portfolio of projects that deliver most value to drug discovery efforts
ensure work fits the overarching strategy of the chemistry discipline within company
supports undergraduate / postgraduate activities & scientific initiatives
opportunities for collaboration
uthorisation and Restriction of
European Regulation concerning chemicals and their safe use
aims to improve the protection of human health and the environments directly in all 28 Member States of the European Union
also applies to Iceland, Liechtenstein and Norway as member countries of the European Economic Area.
people who have to deal with the REACH regulation may also be responsible for company's compliance with the CLP (Classification, Labelling and Packaging) regulation
involved in the design, development, construction and operation of industrial processes for the production of a diverse range of products and specialty chemicals
Charles - Akzo - Sweden
Esomeprazole - gastrointestinal
Rosuvastatin - cholesterol
lead project teams
negotiate with CROs so that company can manage its work load
liaise between company and those organisations
Marketa - CRA
develops measurements and analyzes performance for more than 600,000 physicians
applies Natural History of Disease analytics to identify early disease markers for life- and cost-saving intervention
identifies patients with chronic conditions and health risks, alerting physicians to gaps in care
Clinical Quality Assurance
conduct assessments of:
Clinical Research Organisations (CROs)
company's Medical Departments
ensure compliance to:
local regulatory requirements
GSK - Andy or Liam - QA
2.1.14 - GSK added its anonymised patient-level data from the online request system it launched in May 2013 to a new multi-sponsor request system that includes studies from multiple organisations.(clinicalstudydatarequest.com)
coordinate lab activities
write sampling instructions
ensure samples are been sent to different CROs
works with physicians / scientists who oversee the clinical research
interacts directly with patients:
screen as potential candidates
collect data needed for the study
CRA not to be confused with CRA(ssociate)
Lambda '10 / Ivelina '13
runs clinical trials to test drugs
risks and benefits
are they safe to market?
work on new as well as existing drugs
employed by either PC or CRO
involved in all stages of clinical trials including:
identifying / setting up investigational site
initiating / monitoring / closing down trial
Alex - live - CR specialist
bought Tryx - often precedes layoffs
proactively monitor & evaluate all aspects of safety profile in human patients
ensure the benefit of taking a medicine is greater than the risk of taking it
provide the safety documentation (patient information leaflet) found within the package of medicine
who should and who shouldn’t take it
how much they should take
potential interactions with other medicines
possible side effects
keep regulators up to date with the safety profile of medicines by sending regular reports of adverse events
tests for illegal drugs
provides scientific input into all steps involved in the preparation of a study:
planning and set up
production of Clinical Study Report
develop medical protocols and instruments for clinical applications
analyse / create drug dose and immunization standards / procedures
placed variety of roles at Hoffmann-La Roche in Basel
avoid overproduction, oversupply, and inventory expiration
supply chain logistics
returns and destruction
coordination with third-party vendors and technical systems
to verify that study drugs are available in sufficient quantity / quality
full traceability of drug supply from manufacturing to dispensation and destruction
support outsourcing for clinical trials
finding, contracting and managing relationships with suitable suppliers
develop IT system to better manage contracts
reports to account management and business development
reviewing and comparing contracts to contracting strategy approaches
to discuss data quality, liaise with:
ensure that by the end of my trial the data collected accurately reflects all events and tests
address any anomalies (particularly those anomalies that meant the patient did not adhere to the study protocol)
important that anomalies are addressed in a timely manner therefore placing subject safety and well-being first.
receive, follow-up and report adverse events
review and process adverse events reported by investigators
research and provide medical and scientific information to health care professionals and to various functional areas within the company
conduct and analyze, medical and scientific literature searches using critical judgment and professional / scientific expertise to support projects or queries
review clinical trial protocols, bioequivalence study protocols and provide inputs, support the clinical trial team
Bernado - clinical trial - Spain
monitor the safety of post-marketed products and products that are currently in development
write periodic safety update report (PSUR) or quality check those written by another safety officer
distribute case reports to other relevant parties
entry of adverse event reports onto safety database.
look at disease trends
identifying individuals who are at risk
analyse the impact of interventions such as drug and vaccination programmes.
covers most stages of R&D from the beginning – genetic epidemiology identifies potential new targets for drugs – to phase IV clinical trials
looking at safety in medicines that have already been launched.
promote company's products to healthcare professionals and deliver presentations to:
lunch meetings at surgeries
geneticists examine samples of patients' DNA to identify genetic abnormalities which may be part of inherited diseases
help to predict whether any abnormal genes that are detected can be passed on to the next generation
screen individuals both before and after the appearance of symptoms.
three main categories:
confirmation of diagnosis
use testing techniques to examine non-inherited conditions
analysing changes in cancer tumours
devise or develop new tests and procedures
very few roles in a ballooning sector
prepare health economic submissions considering line extensions, new pack sizes, new formulations & price increases
design health economics models that incorporate epidemiological
use modeling to relate clinical trial endpoints to subsequent events and to determine the efficacy necessary to justify the product’s price.
form collaborative relationships with other health economic professionals
monitor changes in the external environment (regulatory/reimbursement changes, managed care arrangements) and advise senior management on threats and opportunities with suggested action plans.
work with sales & marketing to develop health economics and cost effectiveness arguments into interactive computer programmes and other promotional tools for sales representative use.
on database and very happy at NovoNordisk!
carry out sampling, testing, measuring, recording and analysing of results as part of a scientific team
provide all required technical support to enable lab. to function effectively
adhere to correct procedures & health and safety guidelines
carry out work that assists in the advancement and development of modern medicine and science
few on database
responsible for operating the machinery that makes pharmaceuticals
we don't place, but sometimes place managers who:
are responsible for product production
obtaining the raw materials
manufacture and packaging of tablets and capsules
managing a team including
ensure continuous supply of products to tight deadlines
creates documents that effectively & clearly describe:
ensures that documents comply with regulatory, journal, or other guidelines in terms of content, format, and structure
became established in the pharmaceutical world because the industry recognized it requires special skill to produce well-structured documents that present information clearly and concisely
discovering or improving drugs
mathematical equation modeling
Abid - few
securing legal rights (patents) for ideas generated within the company
advise / educate colleagues on issues relating to intellectual property (trade marks)
work is with:
also with commercial, clinical and regulatory teams
protocol design/input for Pharmacokinetics/Toxicokinetics studies
evaluating data and authoring company reports
design, conduct and interpretation of mechanistic in vivo and in vitro pharmacokinetic studies
early identification of development risks/opportunities
Charles / Alex - GSK / Quotient
preparation of Clinical Pharmacology sections of clinical trial materials
collaboration with the pre-clinical team on toxicology and translational activities
contributies to regulatory activities
preparation of regulatory documentation relative to Clinical Pharmacology
collecting, monitoring, researching, assessing and evaluating information from healthcare providers and patients on the adverse effects of medications to ensure that drugs on the market are safe for patients and to identify new hazards associated with the medication.
assessment and processing of adverse events received from healthcare professional and consumers and the submission of these reports to boards of health, which in turn helps to identify any potential hazards for the patient.
maintain access to company products by building and maintaining significant relations with relevant parties in:
health care environment
representatives of government
politics and media
capabilities in market access
pricing and reimbursement
real world data
inform internal stakeholders about important environmental changes & developments that may influence the performance of the organisation
manage and coach co-workers
ensure an optimal process of recruitment and selection and career planning
Global Quality and Compliance Director - Baxter Healthcare
Baxter - Liam - Quality - Switzerland
ensure that the product or service is fit for purpose:
consistent and meets both external and internal requirements
monitor and advise on the performance of quality management system
report on performance
measuring against set standards
liaise with other managers and staff throughout the organisation to ensure that the quality system is functioning properly
advise on changes and their implementation
provides training, tools and techniques to enable others to achieve quality
make sure that manufacturing or production processes meet international and national standards
monitor performance by gathering relevant data and producing statistical reports
prepare clear explanatory documents such as customers' charters (customer service)
ensure company's products comply with the regulations of the Medicines and Healthcare products Regulatory Agency (MHRA)
keeping abreast of international legislation, guidelines and customer practices in all countries company is exporting to
collect, collate & evaluate scientific data that has been researched by colleagues
develop and write clear arguments and explanations for new product licences / licence renewals
write clear, accessible product labels and patient information leaflets
plan & develop product trials and interpret trial data
advise scientists & manufacturers on regulatory requirements
providing strategic advice to senior management throughout the development of a new drug
undertake and manage regulatory inspections
negotiate with regulatory authorities for marketing authorisation
International Conference on Harmonisation
computer modeling can predict toxicity based on: knowledge of intended target and chemical structure / existing knowledge of properties of chemical
in vitro screening tests can quickly indicate if the new drug is likely to cause skin or eye irritation / damage DNA.
computer models / in vivo tests - whether metabolism within the body is likely to affect the toxicity of the drug
comprehensively test candidate drug for toxicity - use of animals
determine whether drug may cause cancer or is likely to cause developmental / reproductive toxicity - such as effects on fertility or birth defects.
design specialised studies
biochemical, immunological, molecular or microscopical techniques
toxicologists working in regulatory authorities demonstrate safety of drug before given to patients
occasionally a rare unexpected side effect is discovered once a drug is approved and in use in wider population
toxicologists find out why the side effect occurs, and if and how the drug can be used safely.
clinical trial application
• Sponsors must apply to and receive approval
from the Medicines and Healthcare products
Regulatory Agency (MHRA) for a Clinical
Trial Authorisation (CTA), and for substantial
• Investigators must apply to and receive
approval from a REC for the protocol and
substantial amendments; the type of REC
depends on whether the trial is in healthy
subjects (Type 1) or patients (Type 2 or 3).
Previously, any REC could review a
phase 1 trial.
• The MHRA and REC must respond to
applicants within 30 and 60 days
respectively. Both must respond to protocol
amendments within 35 days.
Key Opinion Leaders
physicians who influence their peers' medical practice, including but not limited to prescribing behavior
pharmaceutical companies generally engage key opinion leaders early in the drug development process to provide advocacy activity and key marketing feedback.
often KOLs are chosen more for their high prescribing habits than for their knowledge or other attribute that would enable them to influence their peers
physicians are more interested in true thought leaders who have credentials such as
and/or have performed clinical trials.
write protocols, clinical trials reports, and patient information for the pharmaceutical industry regulatory authorities
write, design and develop
for medical sales representatives, posters and presentations for conferences
involved in the design of training and learning resources and articles for journals
inclusion of product information documents in
all available EU languages (EMA)
1. Submission of eligibility request.
(18 to 7 months in advance of submission.)
2. Notification of intention to submit an application.
(~7 months in advance of submission.)
3. Appointment of rapporteurs. (~7 months in advance of submission.)
4. Pre-submission meeting. (~7 months in advance of submission.)
5. Submission of the application.
6. Scientific evaluation. (210 days of assessment.)
7. CHMP scientific opinion.
8. European Commission decision on the
Humans and animals share hundreds of illnesses, and consequently animals can act as models for the study of human illness.
How will the immune system respond?
rabbits - atherosclerosis, emphysema, and birth defects such as spina bifida
dogs - cancer, diabetes, cataracts, ulcers and bleeding disorders such as haemophilia
cats - visual impairments
rats - spinal chord
mice - transgenic
ensuring that Good Manufacturing Practice (GMP) has been adhered to
the requirements of the product registration and of the manufacturer’s licence have been met
manufacturing and testing processes have been validated
all necessary quality control checks and tests have been conducted
the legal requirements for imported products have been met. For products imported from outside the European Union (EU) or European Economic Area (EEA) the QP should ensure testing within the EU/EEA to requirements of the product registration and any other tests to assure quality of the products, unless a Mutual Recognition Agreement exists between the EU and the third country concerned
certifying in a register or other appropriate record before the batch is released for sale that each batch of medicinal product satisfies the conditions set out in the certificate of registration.
ensuring that the register or record is regularly maintained and that entries are made as soon as practicable after each such batch has been manufactured and before the batch is released for sale.
QPs are responsible for:
is responsible for safeguarding products against potential hazards arising from poor distribution practice
ensures that the conditions of the wholesale dealer’s licence are met, and the guidelines of Good Distribution Practice are complied with
must be resident within the UK
▼ This medicinal product is subject to additional monitoring.
it contains a new active substance; new medicines or vaccines authorised on or after January 2011 are assigned a Black Triangle
it is a biological medicine, such as a vaccine or a medicine derived from plasma (blood);
it has been given a conditional approval (where the company that markets the medicine must provide more data about it) or approved under exceptional circumstances (where there are specific reasons why the company cannot provide a comprehensive set of data);
the company that markets the medicine is required to carry out additional studies: for instance, to provide more data on long-term use of the medicine, or on a rare side effect seen during clinical trials.
has been in place in the UK for many years to signify medicines that are subject to intensive monitoring
now used in all EU Member States and the list has been agreed Europe-wide
the Black Triangle will start appearing in the package leaflets of the medicines concerned from the autumn of 2013
The MHRA and the Commission on Human Medicines (CHM) run the UK's spontaneous adverse drug reaction (ADR) reporting scheme - called the
Yellow Card Scheme
. This receives reports of suspected adverse drug reactions (ADRs) or side effects from healthcare professionals and patients for medicines and vaccines.
The Yellow Card Scheme is the main ADR reporting scheme in the UK and was introduced in 1964 after the thalidomide tragedy highlighted the urgent need for routine monitoring of medicines. It receives about 25,000 reports of possible side effects each year.
detailing and Selling of Product Portfolio to Specialists, supportive care staff, medical aid case managers, Private and State Hospitals
individual customer potential analysis and developmental plans
customer relationship management
key opinion leader identification and development
presentations to academic groups
Association of the British Pharmaceutical Industry
exam within 2 years
In the European Union (EU), a company may submit a single application to the European Medicines Agency (EMA) for a marketing authorisation (licence) that is valid simultaneously in all EU Member States, plus Iceland, Liechtenstein and Norway. This is called the centralised (or community) authorisation procedure, and is mandatory for certain types of medicines and optional for others.
Each EU Member State has its own procedures for the authorisation of medicines that fall outside the scope of the centralised procedure. Applicants must submit an application to the competent authority of the Member State. In the UK, this is the
Mutual recognition procedure
In the mutual recognition procedure, a medicine is first authorised in one EU Member State.
Countries concerned agree to recognise the validity of the original, national marketing authorisation.
Using the decentralised procedure, companies may apply for simultaneous authorisation in more than one EU country of products that have not yet been authorised in any EU country and that do not fall within the mandatory scope of the centralised procedure.
Companies spending increasing amounts of money to bring roughly the same amount of compounds to stage! -
R o I
NHS target of £20bn savings by 2015 - 4% a year
key priority for 2013 was generic prescribing
GPs with expensive prescribing habits required to explain their decisions to their Clinical Commissioning Group
conflicts between CCGs
brings together the
of Europe, Japan and the US
discusses scientific and technical aspects of drug registration
responds to the increasingly global face of drug development
benefits of international harmonisation for better global health can be realised worldwide
greater harmonisation ensures that safe, effective, and high quality medicines are
developed and registered in the most resource-efficient manner
conduct of stability studies, defining relevant thresholds for impurities
flexible approach to pharmaceutical quality based on GMP
to uncover potential risks like carcinogenicity
assess QT interval prolongation liability: single most important cause of drug withdrawals in recent years.
design, conduct, safety and reporting of clinical trials
novel types of medicines derived from biotechnological processes
use of pharmacogenetics/genomics techniques to produce better targeted medicines
Patent protection 20 years
+5 years supplementary protection certificate introduced to encourage innovation by compensating for lengthy regulatory approval procedure
1 in 5,000-10,000 compounds tested eventually reach consumers
2 out of every 10 compounds that enter clinical testing reach the market
Basic Patent Criteria
Period of monopoly to inventor/author in exchange for enriching the public domain
support departmental compliance to Corporate Compliance, Human Resources and training requirements
assist in the establishment and maintenance of procedures, tools and methodologies to cover all computer systems lifecycle phases
consult within suppliers to facilitate timely and complete resolution to computer systems validation issues
partner on departmental or company-wide projects for computer systems validation
manage or assist with audits of current and prospective suppliers of software applications and services
The Prescription Medicines Code of Practice Authority (
) administers The Association of the British Pharmaceutical Industry's (ABPI) Code of Practice at arm's length from the ABPI itself.
ocument is divided into five modules:
1.Administrative and prescribing information
2.Overview and summary of modules 3 to 5
3.Quality (pharmaceutical documentation)
5.Clinical – efficacy (Clinical Trials)