Screening of lead molecules from phases I- IV to a final drug molecule.

Phase I: Phase 1: Discovery and Identification

1. Phase I begins with the first tests in humans, healthy volunteers without cytotoxic
problems (such as cancer patients), to assess safety, tolerance,
pharmacodynamics, pharmacokinetics, and toxic effects that do not depend on
population effects.
2. Other studies like drug-drug interaction, the effect of food on absorption, age, and
genetic influences are also conducted.
3. Phase I studies require approval from a research ethics committee and regulatory
agencies.
4. During Phase 1, Regulatory Affairs Professionals (RAP) submit an Investigational
New Drug (IND) Application, answering the safety questions, to the respective
regulatory agency of that country.
5. ( Example: The United States Food and Drug Administration). With no adverse
comments coming from the regulatory authorities, usually in a 30-day period, the
clinical study is started with usually 10–20 normal human subjects, receiving single
doses of the drug and 24-h medical monitoring.
6. If the drug is found to be safe and well tolerated as a single dose, multiple escalating
doses will be administered to normal subjects to better assess the safety and
tolerability with a more prolonged exposure.
7. The data obtained during this Phase 1 trial may include information on the drugs:
Metabolism, Pharmacology, Safe dosing range, Side effects, and Possibly some
evidence of effectiveness.

Phase II: Preclinical Testing

“About 70% of the drugs tested in Phase 1 make it to Phase 2”

1. The main objective of Phase II is to determine the drug’s efficacy (effectiveness) and
safety in a target population.
2. Groups with common and controlled pathologies (such as hypertension) are chosen to
try the drug, and the results are compared with control groups, which were given a
placebo.
3. Phase II is usually divided into Phase IIa and Phase IIb.
4. In Phase IIa (called the “proof of concept”), the drug is tested in a subgroup of
patients (namely 12–100 individuals).
5. The dosing requirements need to be met for the minimum through maximum doses,
over longer time periods, based on the drug’s side effect profile, and
6. Phase IIb is performed with several dose level tests in the target population (dose-
ranging studies).
7. This task aims to define the minimally effective or ineffective dose and to find the
optimal dose, where efficacy is first assessed, with an eye to using the dose(s) that
demonstrate low, medium, and high efficacy with the fewest possible side effects.
8. The doses selected here will likely proceed into the Phase 3 efficacy studies.

Human study and Pharmacokinetics: Drug screening on healthy volunteers to determine

dose toxicity and unexpected side effects.
Proof of principle and dose fixation: Drug screening on small group of patients to
determine the beneficial effects and dose fixation.

1. At about this time, the long-term (2 year) animal carcinogenicity studies (two animal
species, usually rats and mice) and human pharmacokinetic (body’s effect on the
drug) and pharmacodynamics (drug’s effect on the body) studies are initiated; these
reports will need to be available to support the drug’s development path, in Phase 3.
2. Both the animal safety and drug stability studies are important scientific pillars that
support the human testing done in Phase 2

Phase III: Clinical Trails

About 25%–30% of the Phase 1 drugs make it to Phase 3, and the filing of a New Drug
Application.

1. The last phase of the development of a new drug before its commercialization aims to
determine its clinical dosage, prescription, and frequency of use.
This study could involve thousands of patients and sheds new light on the drug’s
efficacy and safety in large populations.
2. This phase can take several years, with monitoring of mortality and comorbidity rates,
and its details vary from country to country.
In populations, genetic issues are very relevant and account for differences in
effectiveness between different communities.
3. It is estimated that the overall success rate of Phase III is around 70% and can cost up
to USD 100 million.
4. The regulatory authorities (example: FDA), after review of the final Phase 3 study
reports, may choose to agree or disagree with the sponsors’ designated pivotal studies.
5. These studies may last another 1–4 years depending on the disease state and outcomes
measured.
6. These pivotal studies form the basis for a finding of substantial evidence, which is a
critical step in regulatory authorities (FDA) approval of the drug. With these multi-
year, Phase 3, study reports having been completely reviewed by the regulatory
authorities ( FDA )and a finding of substantial evidence, it will move on to creating an
action package for the drug’s formal approval.

Late Phase III

FDA PRE-APPROVAL Inspection – THE PAI
Later in the new drug application (NDA) review period, depending on the available resources
of the drug developer, the factory making the drug must be ready for the inspection
The factory must be in full-scale operation and have produced multiple lots of drug with
subsequent stability testing to qualify for an regulatory authority (FDA) Pre-approval
Inspection . Usually, the regulatory authority (FDA) district office nearest to the factory
conducts the inspection. The results of the inspection are fed into the main FDA review
division at headquarters.

CLINICAL STUDY SITE AUDITS

The regulatory authority’s ( FDA) Bioresearch Monitoring Program (BIMO) will be
Conducting audits of some of the clinical sites that produced the clinical study data that FDA
has claimed as pivotal.
The FDA review division will want assurances that the clinical study data in the NDA,
declared as pivotal, are authentic.

Large efficacy and safety studies: Drug screening on larger group of patients and it also
includes placebo studies.

ADVISORY COMMITTEE MEETINGS :

The FDA holds an Advisory Committee meeting on all new drug products using the NDA
path for approval or provides an explanation about why it will not hold such a meeting. The
notice of an Advisory Committee meeting is usually given within the last few months of the
drug’s final NDA review cycle.

Registration of the clinical studies at ClinicalTrials.gov

In either Phase 2 or 3, depending on the scope of the clinical trials and the indication or
intended use of the drug, reporting of clinical trial information will also need to be made to
the National Library of Medicine’s, (NLM’s), ClinicalTrials.gov database.

Phase IV:

DRUG APPROVAL and post-approval phases Post-Marketing Surveillance:

1. The legal issues related to public health in each region of the world will guide this
additional phase of the birth of a new drug, and it involves government agencies that
work in areas as diverse as: economy, sanitation, hospital administration, health
surveillance, and manufacturing rights. Patent issues are raised and managed by
regular intra- and international agencies.
2. Depending on the performance of the new drug, its use may be reconsidered, limited
or regulated. From this point onwards, repositioning studies, which aim to find new
applications for it, can be undertaken.
3. At the close of this strenuous path of label negotiations, factory inspections, clinical
site audits, and an Advisory Committee meeting, the drug developer is hoping that the
drug receives FDA approval. About 20% of the drugs entering Phase 1 make it
successfully to final FDA approval. Assuming a positive finding by FDA on the
drug’s safety and efficacy, the drug enters the marketing phase of its lifecycle. During
this time, FDA may have imposed some Phase 4 requirements.
4. These Phase 4 requirements often involve large population studies (10,000+) centered
on the drug’s safety profile.
5. Phase 3 efficacy studies, while often employing large numbers (5,000+) of patients,
may not totally be representative of the drug’s routine use in real patient treatment
situations involving multiple millions of prescriptions annually and may not reflect
the drug’s complete safety profile.

(Post market surveillance): This phase monitors any side effects and toxicity associated
with the approved drug candidate and medical device.