The Drug Development
Process
Dr. Anum Gul
(BT-606)
2 Drug Development
Drug development is the process of bringing a
new pharmaceutical drug to the market once a lead
compound has been identified through the process of drug
discovery
General Steps/Strategies
3
Random screening of a wide range of biological materials OR
knowledge-based drug identification.
Safety and efficacy testing in non-human subjects (Invitro and
animal testing).
Formulation research.
Application to regulatory agencies for approval of clinical trials.
General Steps / Strategies (Continued..)
4
Clinical trials
Patenting
Dossier submission to the regulator for evaluation to ensure if
the drug is fit for general public use
Drug marketing
Manufacturing approval
Post marketing surveillance
The Drug Development Process
Pre-clinical studies
6
General Objectives/Rationale
New chemical entities (NCEs), or lead compounds are compounds that
emerge from the process of drug discovery.
These have promising activity against a particular biological target
that is important in disease.
Little is known about the safety, toxicity, pharmacokinetics,
and pharmacodynamics in humans.
Pre-clinical studies assess all of these parameters prior to human
clinical trials.
Pre-clinical studies
7
Miscellaneous Objectives
Recommendation of the dose and schedule for the first use in a human
clinical trial.
Establishing the physicochemical properties of the NCE: its chemical
makeup, stability, and solubility.
Examining the product for suitability to package as capsules, tablets,
aerosol, intramuscular injectable, subcutaneous injectable,
or intravenous formulations.
Pre-clinical studies
8
Miscellaneous Objectives
The information is gathered from preclinical testing, and
submitted to regulatory authorities, as an Investigational New
Drug (IND) application.
If the IND is approved, development moves to the clinical phase.
Pre-clinical studies
9
Pre-Clinical Toxicity Studies
The pre-clinical toxicity studies is done in following phases.
Reproductive Toxicity
Acute Toxicity Studies
Studies
Repeated Dose Studies Carcinogenicity Studies
Genetic Toxicity Studies Toxicokinetic Studies
Pre-clinical studies
10
Acute Studies
Acute toxicity studies look at the effects of single or multiple
doses administered over a period of up to 24 hours.
The animals are then monitored for 7–14 days, with all fatalities
undergoing extensive post-mortem analysis.
Usually, at least two mammalian species (one nonrodent) are tested.
Pre-clinical studies
11
Repeated Dose Studies
Depending on the duration of the studies, repeated dose studies may be
referred to as
Subacute
Subchronic
Chronic
Pre-clinical studies
12
Repeated Dose Studies
Sub-acute: Subacute systemic toxicity is defined as adverse effects
occurring after multiple or continuous exposure between 14 days and
28 days.
Sub-chronic: adverse effects occurring after the repeated or
continuous administration of a test sample for up to 90 days or not
exceeding 10% of the animal's lifespan.
Pre-clinical studies
Repeated Dose Studies
Chronic: Chronic toxicity is the development of adverse effects as
the result of long-term exposure (longer than 3 months and usually
up to 2 years) to a toxicant or other stressor.
Again, two species are typically required.
Pre-clinical studies
14
Genetic Toxicity Studies
These studies assess the likelihood that the drug compound is
mutagenic.
Procedures such as the Ames test (conducted in Salmonella
typhimurium) detect genetic changes.
DNA damage is assessed in tests using mammalian cells such as the
Mouse Micronucleus Test.
The Chromosomal Aberration Test and similar procedures detect
damage at the chromosomal level.
Ames test
Mouse Micronucleus Test
Chromosomal Aberration Test
Pre-clinical studies
18
Reproductive Toxicity Studies
Segment I reproductive toxicity studies look at the effects of
the drug on fertility.
Segment II and III studies detect effects on embryonic and
post-natal development respectively.
In general, reproductive toxicity studies must be completed
before a drug can be administered to women of child-bearing age.
Pre-clinical studies
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Carcinogenicity Studies
Carcinogenicity studies are usually needed only for drugs
intended for chronic or recurring conditions.
They are time consuming and expensive and must be planned
early in the preclinical testing process.
Pre-clinical studies
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Toxicokinetic Studies
These are typically similar in design to pharmacokinetic
studies except that they use much higher dose levels.
They examine the effects of toxic doses of the drug and help
estimate the clinical margin of safety.
Clinical Trials
21
Clinical trials are a type of research that studies new tests and treatments
and evaluates their effects on human health outcomes.
General Objectives / Rationale
There are two goals to testing medical treatments:
to assess whether they work well enough, called "efficacy" or
"effectiveness"
to assess whether they are safe enough, called "safety".
Both safety and efficacy are evaluated relative to how the treatment is
intended to be used.
The benefits must outweigh the risks.
Clinical Trials
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Miscellaneous Objectives
Therapeutic trial on a specific kind of patient, for example, a patient
who has been diagnosed with Alzheimer's disease.
Effectiveness of drug at varying dosages.
Evaluation of the study drug relative to two or more already
approved/common interventions for that condition, for example, therapy
A versus therapy B.
Phases of Clinical Trials
Phase – 0 Trials
Phase 0 trials are optional first-in-human trials.
Single subtherapeutic doses of the study drug or treatment are given
to a small number of subjects (typically 10 to 15).
Gather preliminary data on the agent's pharmacodynamics and
pharmacokinetics.
24 Phases of Clinical Trials
Phase – I Trials
Usually in healthy volunteers, determine safety and dosing
Phase – II Trials
Used to get an initial reading of efficacy and further explore
safety in small numbers of patients having the disease
targeted by the NCE.
25 Phases of Clinical Trials
Phase – III Trials
Large, pivotal trials to determine safety and efficacy in sufficiently
large numbers of patients with the targeted disease.
If safety and efficacy are adequately proved, clinical testing may
stop at this step and the NCE advances to the new drug
application (NDA) stage.
26 Phases of Clinical Trials
Phase – IV Trials
Practice of monitoring the safety of a pharmaceutical drug after it has
been released in the market.
Uses a number of approaches to monitor drug and device safety,
including spontaneous reporting databases, prescription event
monitoring, electronic health records, patient registries, and record
linkage between health databases.
Trial size design and study population
A clinical trial must obviously have a control group, against which the
test (intervention) group can be compared.
The control group may receive:
(a) no intervention at all
(b) a placebo
(c) the therapy to combat the target disease/condition.
Trial size design and study population
The size of the trial will be limited by a number of factors, including:
Economic considerations (level of supporting financial resources);
Size of population with target condition;
Size of population with target condition after additional trial
criteria have been imposed (e.g., specific age bracket, lack of
complicating medical conditions, etc.);
Size of eligible population willing to participate in the trial.
Trial size design and study population
Comprehensive phase III trial would normally require at least several
hundred patients, smaller trials would suffice if, for example:
The target disease is very serious/fatal;
There are no existing acceptable alternative treatments;
The target disease population is quite small;
The new drug is clearly effective and exhibits little toxicity.
Trial size design and study population
Study Designs
Observational Experimental
Non-Randomized Control
Randomized Control Trial
Trial
Informed Consent
31
Informed consent is a process for getting permission before conducting a
healthcare intervention on a person in which a health care provider
educates a patient about the risks, benefits, and alternatives of a given
procedure or intervention.
Informed Consent Process
32
The PI discusses the trial‟s risks, benefits and other aspects with the
potential participant and, if required, the participant‟s legal representative,
before the trial begins.
The PI gives the potential participant ample time and opportunity to ask
questions about the trial and discuss it with relatives and family members.
Informed Consent Process
If the potential participant decides to get involved in the trial, he or
she provides voluntary consent by signing and dating the written
informed consent document of which he or she also receives a copy.
The participant has the right to withdraw consent at any time without
penalty, repercussions or reason.
Informed Consent
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Elements of Informed Consent Document
They include the
Purpose, Additional expenses of the trial;
Duration, A description of the trial
Risks, procedures;
Benefits, Alternative care options; and
Costs Volunteers‟ rights.
Informed Consent
35
Elements of Informed Consent Document
The document also must have at least two signature and date lines:
One for the participant and another for the health care professional
Both the written document and the verbal consenting process must
be presented in language the participant understands.
Clinical Research Monitoring
Subject safety monitoring is the responsibility of several groups,
including
Research ethics committees (RECs) or institutional review boards
(IRBs)
Data monitoring committees (DMCs), also called data and safety
monitoring boards (DSMBs)
Sponsors
Investigators and their research staffs
Drug Regulatory Authorities
Food and Drug Administration (FDA)
European regulations
National regulatory authorities
The European Medicines Agency and the new EU drug approval
systems (EMEA)
The Food and Drug Administration
The FDA represents the American regulatory authority.
Its mission statement defines its goal simply as being to „protect
public health‟.
In fulfilling this role, it regulates many products/consumer items.
FDA responsibilities with regard to drugs
Assessing preclinical data to decide whether a potential drug is safe enough
to allow commencement of clinical trials.
Protecting the interests and rights of patients participating in clinical trials.
Assessing preclinical and clinical trial data generated by a drug and deciding
whether that drug should be made available for general medical use (i.e. if it
should be granted a marketing licence).
Overseeing the manufacture of safe effective drugs.
Ensuring the safety of the US blood supply.
Patenting
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A patent may be described as
“a monopoly granted by a government to an inventor, such that only
the inventor may exploit the invention/innovation for a fixed period
of time (up to 20 years).
In return, the inventor makes available a detailed technical
description of the invention/innovation so that, when the monopoly
period has expired, it may be exploited by others without the
inventor‟s permission”.
What is Patentable
41
In order to be considered patentable, an invention/innovation
must satisfy several criteria, the most important four of which
are:
novelty
non-obviousness
sufficiency of disclosure
utility
What cannot be patented
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Naturally obtained substance without any modification
The human body;
The cloning of humans;
The use of human embryos for commercial purposes;
Modifying the genetic complement of an animal if the
modifications cause suffering without resultant substantial
medical benefits to the animal/to humans.