clinical trial usa europe india various phases

Clinical trials are fundamental to the development and approval of new drugs, ensuring their safety, efficacy, and quality before public use. The Indian drug regulatory framework, governed by the Central Drugs Standard Control Organization (CDSCO) and Drug Controller General of India (DCGI), plays a crucial role in the approval, monitoring, and import/export of drugs. Clinical research encompasses various methodologies, including randomized controlled trials and observational studies, to generate reliable medical data. The drug development process progresses through pre-clinical testing and multiple human trial phases (Phase 0–IV), each designed to evaluate safety, dosage, efficacy, and long-term effects. Despite scientific rigor, many trials fail due to bias, inadequate design, or attrition. The European Union (EU) and United States (USA) have established robust regulatory systems—EU Regulation No. 536/2014 and FDA’s Good Clinical Practice (GCP)—to safeguard participants and ensure data integrity. Understanding these international frameworks enhances global collaboration and ethical standards in clinical research.

1. SMT. R. D. GARDI B. PHARMACY COLLEGE (263)
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1.Abstract:
Clinical trials are fundamental to the development and approval of new drugs, ensuring their
safety, efficacy, and quality before public use. The Indian drug regulatory framework,
governed by the Central Drugs Standard Control Organization (CDSCO) and Drug Controller
General of India (DCGI), plays a crucial role in the approval, monitoring, and import/export
of drugs. Clinical research encompasses various methodologies, including randomized
controlled trials and observational studies, to generate reliable medical data. The drug
development process progresses through pre-clinical testing and multiple human trial phases
(Phase 0–IV), each designed to evaluate safety, dosage, efficacy, and long-term effects.
Despite scientific rigor, many trials fail due to bias, inadequate design, or attrition. The
European Union (EU) and United States (USA) have established robust regulatory systems—
EU Regulation No. 536/2014 and FDA’s Good Clinical Practice (GCP)—to safeguard
participants and ensure data integrity. Understanding these international frameworks enhances
global collaboration and ethical standards in clinical research.
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2. Introduction:
Indian drug regulatory system is CDSCO regulatory authority responsible for the clinical
research trial (CTs) for the approval process and inspections. To regulating sale and
importation the drugs in CTs were responsible for the India drug controller general of India
(DCGI) heads CDSCO. The CDSCO is also responsible for the granting clinical trial protocol
permission regulating the export, importation of drugs, sale and for use in human trials.
CDSCO is responsible for conducting CT studies, established in standard drugs, approving
new medicines, assessing the quality of import and exported drugs, manufacturing,
distribution of medicines and coordinating the state licensing authorities were regulates the
sale
.[1]
In India, each state’s drugs control authority has given rights to DCGI apart from CDSCO
approval. So, in India has been centre of conducting various multicentre trials and is also
essential for CTs conducted in India should as per the ICH-GCP (international conference of
harmonization-good clinical practices guidelines) follow the recently amended new CTs rules
and regulations of the drug, cosmetic act. In today’s turbulent scenario in the pharmaceutical
industry have good knowledge
.[2]
National Academies of Sciences, Engineering, and Medicine, Health and Medicine Division,
Board on Health Sciences Policy, Board on Global Health, Committee on Clinical Trials During
the 2014-2015 Ebola Outbreak. In: Busta ER, Mancher M, Cuff PA, McAdam K, Keusch G, eds.
Integrating clinical research into epidemic response: the ebola experience. Washington (DC):
National Academies Press; 2017.
Clinical trials explorehowtreatment reacts in the human body and are designed to ensure drug
is tolerated and effective before it is licensed by regulatory authorities and made
available for use by doctors. Studies varying their primary goal or endpoint (i.e. the most
important outcome of the trial), the number of patients involved, and the specifics of the study
design. However, all clinical studies conform to strict setoff criteria to protect the patients
involved and to ensure rigorous evaluation of the drug.
[1]
For safety purposes, clinical trials start with small groups of patients to find out whether a
new approach causes any harm. In later phases of clinical trials, researchers learn more about
the new approach's risks and benefits. A clinical trial may find that a new strategy, treatment,
or device
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Improves patient outcomes;
Offers no benefit or causes unexpected harm.
2.1 What Are Clinical Trials and Studies?
By participating in clinical research, you can help scientists develop new medications and other
strategies to treat and prevent disease. Many effective treatments that are used today, such as
chemotherapy, cholesterol-lowering drugs, vaccines, and cognitive-behavioural therapy, would
not exist without research participants. Whether you’re healthy or have a medical condition,
people of all ages and backgrounds can participate in clinical trials. This article can help you
learn more about clinical research, why people choose to participate, and how to get involved
in a study.
(https://www.nia.nih.gov/health/clinical-trials-and-studies/what-are-clinical-trials-and-
studies)
Clinical trials are research studies that test a medical, surgical, or behavioural intervention in
people. These trials are the primary way that researchers determine if a new form of treatment
or prevention, such as a new drug, diet, or medical device (for example, a pacemaker), is safe
and effective in people.
3. Drug Development Process
New medicines originate in the laboratory where researchers identify isolate and study
thousands of molecules for their potential as future therapies.
Once a candidate molecule (compound)has been identified in the laboratory, it is subjected to
rigorous pre-clinical testing (in the laboratory and/or in animals) to assess its chemical,
biological and toxicological properties (how harmful it is).
These pre-clinical tests allow researchers snapshot of whether a compound may have
pharmacological activity.
If results of pre-clinical studies are positive, the compound may be entered into a clinical trial
program: this involves several ‘phases’ of study, starting with small studies usually in healthy
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volunteers and progressing insteps through to evaluation of the drug in people with the disease.
At each phase, only those compounds that meet strict criteria for safety and effectiveness
(Efficacy) advance to the next phase.
When results of clinical trials indicate the compound being studied is safe and
The clinical trial phases are same in all the three countries. They are: effective the company
applies to regulatory authorities for marketing
authorization (permission to sell.
[3]
Figure 1: Drug Development Process
Figure 2: Clinical trial phases
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4. Introduce Clinical Research Method
Clinical research involves all research in humans with different study designs (Clinical means
humans and Trials means Experiment] 1,2Clinical research is synonymously used for clinical
trials. A clinical trial is any research study that prospectively assigns human participants or
groups of humans to one or more health-related interventions to evaluate the effects on
predefined health outcomes
.[3]
As per regulatory requirements, clinical trials are mandatory
before drugs are approved and marketed
.[4]
4.1 First Controlled Clinical Research
There are many records in history for the conduct of studies in humans. In the 18th century
(early modern era), one of the first controlled studies was performed by a Scottish physician
named James Lind, who is regarded as the “Father of Naval Medicine.” Scurvy was considered
a dreadful disease among sailors. Sailors with scurvy (gum disease, dry mouth, dry eyes, loss of
teeth) were provided with citrus fruits such as oranges and lemons, cider, sulphuric acid,
vinegar, salt water and garlic paste, mustard seed, horseradish, balsam of Peru, and gum myrrh.
The sailors supplemented with citrus fruits recovered. This was the first controlled study
performed across sailors for the treatment of scurvy
.[5],[6].
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Clinical Trials Observational Studies
Experimental Observational
Data from controlled settings, which is difficult to
achieve in real practice
Real-world data are natural confounders
Expensive Relatively less expensive, retrospective studies
are even cheaper than cohort studies
Long duration Relatively shorter duration when compared to
clinical trials
Could be multicentre Possible in any facility
Mostly sponsored by pharmaceutical companiesMostly performed by independent agencies,
professionals
Populations are covered, but limited in many aspects
like pregnant, paediatric, geriatric, etc.
Flexible to perform in different populations
Unethical to study mutagen city studiesLess ethical concerns as interventions are not
required
Table 1: Differences Between Clinical Trials and Observational Studies
Differences Between Clinical Trials and Observational Studies
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4.2 Clinical Research Methods
One of the key objectives of clinical research is to generate health-related information.
Randomized clinical trials are considered as the gold standard in generating high-quality
medical information, but epidemiologist’s challenge that clinical trials do not generate real-
world data. Studies at real-practice settings with natural bias mimic the results that are normally
achieved once a drug is marketed (more realistic outcomes). Pragmatic trials solve this issue by
being conducting in real practice settings.8The differences of clinical trials and observational
studies are compared in Table (3) and types of research methods are shown in….
Figure 3: Types of research based on quality of evidence generated with higher
quality research methods at the top
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Figure 4: Choice of different clinical research methods
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5. The Phases of Clinical trial
5.1 Phase 0 clinical trial (or) pre-clinical trial
Even though phase 0 studies are done inhuman, this type of study is not like the other phases
clinical trials. The purpose of this phase is to help speed up and streamline the drug approval
process.
Phase 0 studies are exploratory studies that often use only a few small doses of a new drug in
the biggest difference between phase 0 and the later phases of clinical trials is that there is no
chance the volunteer will benefit by taking Partin a phase 0 trial – the benefit will be for other
people in the future. Because drug doses are low, there is also less risk to the patient in phase0
studies compared to Phase I studies.
Phase 0 studies help researchers find out whether the drugs do what they’re expected to do. If
there are problems with the way the drug is absorbed or acts in the body, this should become
clear very quickly in a phase 0 clinical trial. This process may help avoid the delay and
expense of finding out years later in phase II or even phase III clinical trials that the drug
doesn’t act as expected to base on lab studies.
Phase 0 studies aren’t used widely, and there are some drugs for which they wouldn’t be
helpful. Phase 0 studies are very small, often with fewer than 15 people, and the drug is given
only for a short time. They are not a required part of testing a new drug.
5.2 Phase 1
Usually carried out in a smaller number of people (12e30 numbers) and performed after animal
toxicity studies or phase 0 studies are completed. This phase has been carried out with healthy
volunteers with exceptions being patients who are being treated for a disease such as cancer
and HIV/AIDS. As it is with fewer people, the researchers can monitor the maximum dose
required with fewer side effects. These are also called dose escalation studies. Single and
multiple doses will be escalated gradually to determine the maximum tolerated dose (MTD).
Safety and tolerability of the drug are determined at this level.
Phase 1 studies are executed in two methodologies:
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Single ascending dose study – SAD
Multiple ascending dose study – MAD
Single Ascending Dose Study
In a given period of time (e.g., up to 3 months), pharmacokinetic parameters are determined.
Three to four volunteers (a small group) receive the lowest single dose (e.g., 1 mg) and are
observed for any toxicity/adverse events. If no adverse events and toxicity are established at this
dose level of 1 mg, this type of study can be escalated sequentially to a new small group of
volunteers with the next higher dose (2 mg). If toxicity is observed at a 1 mg dose, however, the
same tested dose (1 mg) is administered to a new set of three subjects and observed for adverse
events. This is done until the volunteers experience an adverse event at a defined dose, and the
dose before this is considered as the MTD.[7]
Maximum Tolerated Dose
MTD refers to the highest dose of a pharmacological drug, which would produce the desired
effect without unacceptable toxicity.[8]
Example of Single Ascending Dose
Considering an X axis as time in hours (h) and a Y axis as the average of volunteer’s plasma
drug concentration in monogram/millilitre (ng/mL)
The graph depicts that 1 mg (group I) of drug X has been initiated in a small group of people
(in 3e5 numbers). The pharmacokinetic data are predicted. With no toxicity is established at
this level, the dose of drug X is further escalated to 2 mg (group II) and 3 mg (group III) with a
different group of people. The dose escalation continues as long as the maximum concentration
is reached as stated in the protocol. The dose of 4 mg (group IV) is discontinued before the
concentration maximum could be reached due to the possible occurrence of unacceptable
toxicity. Hence MTD is decided as 3 mg for drug X. Further dose escalation is terminated
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Figure 5: Phase 1- single ascending dose study.
Figure 6: Phase 1 - multiple ascending dose study
Multiple Ascending Dose Study
A group of people receives multiple doses of a drug to determine pharmacokinetic and
pharmacodynamic properties. A second group receives an escalated amount of multiple doses,
and the same would be determined at various groups until tolerability is established.[9]
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From the figure, dose escalation happens within the group to study the pharmacokinetic
parameters. The fate of the drug is determined with multiple dose levels. The escalation of the
dose levels among different groups is certainly decided from SAD studies to evaluate the
therapeutic drug concentration in the human body.
Example of Multiple Ascending Doses
According to the graphs (X axis: time in hours and Y axis: concentration in ng/mL), the
concentration maximum (Cmax) lies around 55 ng/mL (Fig. 23.11AeG) to 180 ng/mL (Fig.
23.11AeG) and the time taken to reach the maximum concentration is 0e4 h. Assessment of the
pharmacokinetics parameter using multiple groups assists in determining the toxicity profile.
5.3 Phase 2 - Therapeutic Exploratory Phase
This phase handles a considerably greater number of patients compared to phase I. The
numbers may gradually increase to 100 or more depending on the number of sites. Unlike
phase I trials, these trials are intended to treat the patients with an expected indication to find
out safety issues as the primary objective. Therefore, this is also termed a therapeutic
exploratory phase. Safety of the drug is assessed with priority followed by its efficacy.[19] This
may be categorized as phase 2a and phase 2
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Figure 6: (A-G) Examples of
multiple ascending dose (Plasma
drug concentration on Y-axis and
time on X-axis).
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Figure 7 : Responses for different doses.
Phase 2a - Proof of Clinical Concept Studies
These studies are pilot studies, single centric, and a continuation of phase I studies where the
tolerated dose level appropriate for desired therapeutic action has been decided. This phase
plays a vital role for prolongation of drug development into later phases. Depending on the
tolerability, the new intervention can be determined to be included in other phases or not.
These are dose-ranging studies. The study end points and the nature of the population (severity
of the disease) should be prefixed. Because the MTD is analysed in the early phase, dose
ranging is fixed among groups as placebo controlled, low, medium, and high. Certainly, the
response to a defined dose can be studied.
The dose-dependent pharmacological activity of the drug (mechanism of action) can be
established. Therefore, the dosing intervals and frequency of the drug administration can also
be predicted for later phases. The therapeutic dose and its toxicity, if any, can be ascertained.
The toxicity profile among the diseased population and their concomitant drugs provide a
pathway for the continuation of phase 2b pivotal studies.
Phase 2b Pivotal Studies/Randomized Controlled Trials - RCTs
These are pivotal studies, and new intervention may be compared with a dummy drug (placebo)
or with an intervention already in existence. Thus, these can be termed randomized controlled
trials (RCTs)
.[20]
These are crossover studies and can be performed at multiple sites. As the dose requirements
are determined in phase 2a, the efficacy of the dose is established (how well the suggested dose
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works on receptor mechanisms). The efficacy that has been proved should be determined from
the target condition (a drug intended for a specific condition) as these are patient populations.
5.4 Phase 3 - Therapeutic Confirmatory Phase
In a phase 3 trial, efficacy and safety of the molecule can be determined. These are therapeutic
confirmatory phase trials. They are generally carried out in a relatively high number
(100e3000) of patients, depending on therapeutic areas, at various centres; hence they are
called multicentre trials. These trials are generally carried out for a longer duration (few years)
to analyse the exact dosage levels that would prove beneficial to a lesser degree/extent of
adverse events. With phase 3 study efficacy, post marketing studies (phase 4) could study
effectiveness. The difference between efficacy and effectiveness is compared.
Figure 8: Randomized controlled trials - phase 2b.
Table 2: Difference Between Efficacy and Effectiveness
Table: Difference Between Efficacy and Effectiveness
Efficacy Effectiveness
Results from normal clinical trials
(randomized)
Results from normal clinical practice
Efficacy is established in inclusion of
population as specified in protocol
Effectiveness is established in inclusion of
population as specified in protocol as well as
with co morbidity conditions
A new intervention and a standard intervention are randomized among the patients. Sometimes
a placebo-controlled trial may also be carried out. The researchers prefer to have a comparison,
which could be more than two treatment groups. There are possibilities to study drug
interactions due to heterogeneous population selections
.[21]
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Example Phase 3 Type 1 Diabetic Studies
The possible occurrence of withdrawal cases due to adverse drug reactions could be more than
expected. Assuming the clinical end point for a diabetic study would be lowering of:
HbA1C (glycosylated haemoglobin),
fasting blood sugar (FBS),
postprandial blood sugar,
Triglycerides and cholesterol.
The outcome of this study can be determined from the efficacy of the drug (mechanism of
action of the drug on the receptor site, dose response relationship) and its safety. The data
should be statistically significant for expansion of the drug into the marketing phase.
Phase 3a and Phase 3b Studies
These are further categorized as phase 3a and phase 3b studies. Phase 3a: These studies are
conducted after demonstrating the efficacy but before the submission of a new drug
application (NDA). Phase 3b: These trials are carried out after NDA but before approval of
the drug.
5.5 Phase 4 Post marketing Surveillance
Phase 4 trials are conducted after a drug is approved and comes into a market. These trials
will evaluate the effectiveness and safety of the drug in different population groups, not only
in patients with intended diseases, but the drug will also be administered to patients with
other concurrent diseases in real-world medical practice. Drugs during this phase, which
show adverse toxicities, may not further be continued for marketing and could be banned in a
given market. These trials are carried out in a patient undergoing clinical care. The statistical
effectiveness of a drug on larger patient groups is known to a greater extent, and drug
interactions can also be estimated as patients with a secondary illness may participate in the
trials
.[12]
Sometimes regulatory agencies may also request to conduct long-term post marketing
surveillance (PMS) studies to rule out the long-term adverse events, carcinogenicity, and
mutagenic effects of the marketed drug. Data collected after such long-term PMS studies may
describe potential long-term adverse reactions in which the drug may be withdrawn from the
market.
[12]
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Group-1New
Intervention
Group-2 Standard

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Figure 8: Example of participant withdrawal from clinical trial.
6.Choosing the appropriate phase design:
Although the phase design framework helps the investigator to choose the appropriate phase
and thus design the study based on its main objectives, the choice of phase is not always easy
to determine. For example, the amount of phase II data needed in order to move to a phase III
trial is not always clear. Below, we created a framework based on the risk that the trial will
fail vs. the chance that results will be beneficial to help the investigator choose the
appropriate phase design.
[13]
6.1 Understanding clinical trial failure
A successful clinical trial answers its primary research question in a valid way to advance the
science. It is important to underscore that failure to reject the null hypothesis (or failure to
show positive results, i.e. a negative trial) does not mean trial failure (or that the trial did not
advance science). Indeed, failing to reject the null hypothesis also teaches us something
important. Well-designed negative trials can generate useful data, and have been published in
high-impact journals
[14]
Trial failure means that results are not valid and so we are unable to
either reject or not reject the null hypothesis.
Although a positive outcome is frequently seen as the only indicator of a trial’s success and
publish-worthiness, a positive trial could be invalid if associated with significant biases.
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Therefore, significance does not necessarily mean validity of results. Accordingly, the
investigator must assess two important components when designing a trial:
1.Factors that would lead to invalid results (e.g., biases)
2.Whether the trial (assuming it is valid) would advance science regardless of whether it is
positive or negative. If a valid trial with negative results would not advance science, then the
investigator needs to assess the likelihood his/her hypothesis will be confirmed given the
current evidence.
6.2 Failed (invalid) clinical trials vs. negative (but valid) clinical trials:
One way to see the importance of this problem is by analysing the attrition rate from early to
late phases. Attrition means the drop in the number of drugs that make it to market compared
to those studied in preclinical and clinical trials. Most drugs studied (about 90%)never make
it to market, as human trials do not show efficacy
(15-17).
This attrition may happen at all phases
and may result from differences between animal models and humans, disparities in designing
basic science studies vs. clinical trials, lack of mechanistic data and also by building on
invalid early positive clinical data that are not confirmed in later phases
[15,16,18-21].
Attrition is
highly costly and frustrating, yet such studies help by showing us what does not work –
“validation using known failures
”[20].
assuming they are published.
The problem of failed trials may also be seen indirectly by the large rate of unpublished trials.
Chen et al. demonstrated that only 29% of the trials were published in journals and13%
reported on ClinicalTrials.gov (upon examining over 4300 ClinicalTrials.gov registered trials
conducted in 2007-2010 across 51 US institutions). By 2014, only two thirds of the trials
were either reported or published
[22].
This was consistent with previous studies showing that
25-50% of trials went unpublished for years
[22-26].
Trials may not be published due to lack of
time (or interest) for the researcher to write up results
[27]
however, it is likely that many go
unpublished due to methodological shortcomings such as unexpected unbinding, large
attrition rates, inability to recruit, etc.
6.3 How to increase the impact of a clinical trial:
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Clinical trials consume tremendous human and financial resources. Thus, it is important that
to maximize the chances that the trial will be Feasible, Interesting, Novel, Ethical and
especially Relevant (FINER criteria).
It is critical to assess how the results of a trial will better the field if its aims are achieved -
before selecting these aims. An investigator must carefully consider the problem the study is
trying to solve. The more prevalent and devastating the problem is, and the greater the
potential benefits, the easier it is to justify performing the trial. Conversely, if the study is on,
for example, a very rare genetic disorder or a common but minor cosmetic issue, then the
benefits of the trial may not justify the costs (especially for trials funded by taxpayers).
The impact of improving medical knowledge is conditional on this knowledge changing
clinical practice. Thus, surrogate outcomes should not stand alone but be clinically validated,
and clinical outcomes should reach the minimum clinically important difference. Eventually,
study outcomes should lead to cures and treatments for previously untreatable conditions,
improved therapeutic options for different patient subgroups, more efficient or less costly
healthcare delivery, or similarly meaningful improvements to healthcare.
7. EUROPEAN (EU) Clinical Trials
REGULATION (EU) No 536/2014 OF THE EUROPEAN PARLIAMENT AND OF THE
COUNCIL of 16 April 2014 on clinical trials on medicinal products for human use, and
repealing Directive 2001/20/EC
General principle
A clinical trial may be conducted only if:
a)the rights, safety, dignity and well-being of subjects are protected and prevail over all
other interests; and
b)it is designed to generate reliable and robust data.
7.1 AUTHORISATION PROCEDURE FOR A CLINICAL TRIAL
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7.1.1 Prior authorisation:
A clinical trial shall be subject to scientific and ethical review and shall be authorised in
accordance with this Regulation.
The ethical review shall be performed by an ethics committee in accordance with the law of
the Member State concerned. The review by the ethics committee may encompass aspects
addressed in Part I of the assessment report for the authorisation of a clinical trial as referred
to in Article 6 and in Part II of that assessment report as referred to in Article 7 as appropriate
for each Member State concerned.
Member States shall ensure that the timelines and procedures for the review by the ethics
committees are compatible with the timelines and procedures set out in this Regulation for the
assessment of the application for authorisation of a clinical trial.
7.1.2 Submission of an application
In order to obtain an authorisation, the sponsor shall submit an application dossier to the
intended Member States concerned through the portal referred to in Article 80 (the ‘EU
portal’)
The sponsor shall propose one of the Member States concerned as reporting Member State.
If a Member State concerned other than the proposed reporting Member State is willing to be
the reporting Member State or where the proposed reporting Member State does not wish to
be the reporting Member State, this shall be notified through the EU portal to all Member
States concerned not later than three days after the application dossier is submitted.
If only one Member State concerned is willing to be the reporting Member State or if the
clinical trial involves only one Member State, that Member State shall be the reporting
Member State.
If there is no Member State concerned willing to be the reporting Member State or if there is
more than one Member State concerned willing to be the reporting Member State, the
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reporting Member State shall be selected by agreement among the Member States concerned
taking into account the recommendations referred to in point.
If there is no agreement among the Member States concerned, the proposed reporting
Member State shall be the reporting Member State.
The reporting Member State shall notify the sponsor and the other Member States concerned
that it is the reporting Member State, through the EU portal, within six days from the
submission of the application dossier.
2. The sponsor shall, when applying for a low-intervention clinical trial, where the
investigational medicinal product is not used in accordance with the terms of the marketing
authorisation but the use of that product is evidence-based and supported by published
scientific evidence on the safety and efficacy of that product, propose one of the Member
States concerned where the use is evidence-based, as reporting Member State.
3. Within 10 days from the submission of the application dossier, the reporting Member State
shall validate the application taking into account considerations expressed by the other
Member States concerned and notify the sponsor, through the EU portal, of the following:
a) Whether the clinical trial applied for falls within the scope of this Regulation
b) Whether the application dossier is complete in accordance with Annex I.
Member States concerned may communicate to the reporting Member State any
considerations relevant to the validation of the application within seven days from the
submission of the application dossier.
4. Where the reporting Member State has not notified the sponsor within the period referred
to in the first subparagraph of paragraph 3, the clinical trial applied for shall be deemed to fall
within the scope of this Regulation and the application dossier shall be considered complete.
5. Where the reporting Member State, taking into account considerations expressed by the
other Member States concerned, finds that the application dossier is not complete, or that the
clinical trial applied for does not fall within the scope of this Regulation, it shall inform the
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sponsor thereof through the EU portal and shall set a maximum of 10 days for the sponsor to
comment on the application or to complete the application dossier through the EU portal.
Within five days from receipt of the comments or the completed application dossier, the
reporting Member State shall notify the sponsor as to whether or not the application complies
with the requirements set out in points (a) and (b) of the first subparagraph of paragraph 3.
Where the reporting Member State has not notified the sponsor within the period referred to
in the second subparagraph, the clinical trial applied for shall be deemed to fall within the
scope of this Regulation and the application dossier shall be considered complete.
Where the sponsor has not provided comments or completed the application dossier within
the period referred to in the first subparagraph, the application shall be deemed to have lapsed
in all Member States concerned.
6. For the purposes of this Chapter, the date on which the sponsor is notified in accordance
with paragraph 3 or 5 shall be the validation date of the application. Where the sponsor is not
notified, the validation date shall be the last day of the respective periods referred to in
paragraphs 3 and 5.
7.1.3 Assessment report — Aspects covered by Part I
1.The reporting Member State shall assess the application with regard to the following
aspects:
(a) Whether the clinical trial is a low-intervention clinical trial, where claimed by the sponsor:
(b)Compliance with Chapter V with respect to the following:
(I) The anticipated therapeutic and public health benefits taking account of all of the
following:
The characteristics of and knowledge about the investigational medicinal products.
The relevance of the clinical trial, including whether the groups of subjects participating in
the clinical trial represent the population to be treated, or if not, the explanation and
justification provided in accordance with point (y) of paragraph 17 of Annex I to this
Regulation; the current state of scientific knowledge; whether the clinical trial has been
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recommended or imposed by regulatory authorities in charge of the assessment and
authorisation of the placing on the market of medicinal products; and, where applicable, any
opinion formulated by the Paediatric Committee on a paediatric investigation plan in
accordance with Regulation (EC) No 1901/2006 of the European Parliament and of the
Council
.(28)
the reliability and robustness of the data generated in the clinical trial, taking account of
statistical approaches, design of the clinical trial and methodology, including sample size and
randomisation, comparator and endpoints.
(ii) The risks and inconveniences for the subject, taking account of all of the following:
— the characteristics of and knowledge about the investigational medicinal products and the
auxiliary medicinal products.
— The characteristics of the intervention compared to normal clinical practice.
— The safety measures, including provisions for risk minimisation measures, monitoring,
safety reporting, and the safety plan.
— The risk to subject health posed by the medical condition for which the investigational
medicinal product is being investigated.
(c) Compliance with the requirements concerning the manufacturing and import of
investigational medicinal products and auxiliary medicinal products set out in Chapter IX.
(d) Compliance with the labelling requirements set out in Chapter X.
(e) The completeness and adequateness of the investigator's brochure.
2. The reporting Member State shall draw up an assessment report. The assessment of the
aspects referred to in paragraph 1 shall constitute Part I of the assessment report.
3. The assessment report shall contain one of the following conclusions concerning the
aspects addressed in Part I of the assessment report.
(a) The conduct of the clinical trial is acceptable in view of the requirements set out in this
Regulation.
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(b) the conduct of the clinical trial is acceptable in view of the requirements set out in this
Regulation, but subject to compliance with specific conditions which shall be specifically
listed in that conclusion or
(c) The conduct of the clinical trial is not acceptable in view of the requirements set out in this
Regulation.
4. The reporting Member State shall submit, through the EU portal, the final Part I of the
assessment report, including its conclusion, to the sponsor and to the other Member States
concerned within 45 days from the validation date.
5.For clinical trials involving more than one Member State, the assessment process shall
include three phases.
(a) an initial assessment phase performed by the reporting Member State within 26 days from
the validation date.
(b) a coordinated review phase performed within 12 days from the end of the initial
assessment phase involving all Member States concerned.
(c) a consolidation phase performed by the reporting Member State within seven days from
the end of coordinated review phase.
During the initial assessment phase, the reporting Member State shall develop a draft Part I of
the assessment report and circulate it to all other Member States concerned.
During the coordinated review phase, all Member States concerned shall jointly review the
application based on the draft Part I of the assessment report and shall share any
considerations relevant to the application.
During the consolidation phase, the reporting Member State shall take due account of the
considerations of the other Member States concerned when finalising Part I of the assessment
report and shall record how all such considerations have been dealt with. The reporting
Member State shall submit the final Part I of the assessment report to the sponsor and all
other Member States concerned within the period referred to in paragraph 4.
6. For the purposes of this Chapter, the date on which the final Part I of the assessment report
is submitted by the reporting Member State to the sponsor and to the other Member States
concerned shall be the reporting date.1
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26. SMT. R. D. GARDI B. PHARMACY COLLEGE (263)
7. The reporting Member State may also extend the period referred to in paragraph 4 by a
further 50 days for clinical trials involving an advanced therapy investigational medicinal
products or a medicinal product as defined in point 1 of the Annex to Regulation (EC) No
726/2004, for the purpose of consulting with experts. In such case, the periods referred to in
paragraphs 5 and 8 of this Article shall apply mutatis mutandis.
8. Between the validation date and the reporting date, only the reporting Member State may
request additional information from the sponsor, taking into account the considerations
referred to in paragraph 5.
For the purpose of obtaining and reviewing this additional information from the sponsor in
accordance with the third and fourth subparagraph, the reporting Member State may extend
the period referred to in paragraph 4 by a maximum of 31 days.
The sponsor shall submit the requested additional information within the period set by the
reporting Member State which shall not exceed 12 days from the receipt of the request.
Upon receipt of the additional information, the Member States concerned shall jointly review
any additional information provided by the sponsor together with the original application and
shall share any considerations relevant to the application. The coordinated review shall be
performed within a maximum of 12 days of the receipt of the additional information and the
further consolidation shall be performed within a maximum of seven days of the end of
coordinated review. When finalising Part I of the assessment report, the reporting Member
State shall take due account of the considerations of the Member States concerned and shall
record how all such considerations have been dealt with.
Where the sponsor does not provide additional information within the period set by the
reporting Member State in accordance with the third subparagraph, the application shall be
deemed to have lapsed in all Member States concerned.
The request for additional information and the additional information shall be submitted
through the EU portal.
7.1.4 Assessment report — Aspects covered by Part II
(1) Each Member State concerned shall complete its assessment within 45 days from the
validation date and submit, through the EU portal, Part II of the assessment report, including
its conclusion, to the sponsor. Each Member State concerned may request, with justified
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27. SMT. R. D. GARDI B. PHARMACY COLLEGE (263)
reasons, additional information from the sponsor regarding the aspects referred to in
paragraph 1 only within the period referred to in the first subparagraph.
(2) For the purpose of obtaining and reviewing the additional information referred to in the
second subparagraph of paragraph 2 from the sponsor in accordance with the second and third
subparagraph, the Member State concerned may extend the period referred to in the first
subparagraph of paragraph 2 by a maximum of 31 days.
The sponsor shall submit the requested additional information within the period set by the
Member State concerned which shall not exceed 12 days from the receipt of the request.
Upon receipt of the additional information, the Member State concerned shall complete its
assessment within a maximum of 19 days.
Where the sponsor does not provide additional information within the period set by the
Member State concerned in accordance with the second subparagraph, the application shall be
deemed to have lapsed in that Member State concerned.
The request for additional information and the additional information shall be submitted
through the EU portal.
7.2 Decision on the clinical trial
1. Each Member State concerned shall notify the sponsor through the EU portal as to whether
the clinical trial is authorised, whether it is authorised subject to conditions, or whether
authorisation is refused.
An authorisation of a clinical trial subject to conditions is restricted to conditions which by
their nature cannot be fulfilled at the time of that authorisation.
2. Where the conclusion of the reporting Member State as regards Part I of the assessment
report is that the conduct of the clinical trial is acceptable or acceptable subject to compliance
with specific conditions, that conclusion shall be deemed to be the conclusion of the Member
State concerned.
3. Where, regarding the aspects covered by Part I of the assessment report, the clinical trial is
acceptable or acceptable subject to compliance with specific conditions, the Member State
concerned shall include in its decision its conclusion on Part II of the assessment report.
4. A Member State concerned shall refuse to authorise a clinical trial if it disagrees with the
conclusion of the reporting Member State as regards Part I of the assessment report on any of
the grounds referred to in the second subparagraph of paragraph 2, or if it finds, on duly
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28. SMT. R. D. GARDI B. PHARMACY COLLEGE (263)
justified grounds, that the aspects addressed in Part II of the assessment report are not
complied with, or where an ethics committee has issued a negative opinion which in
accordance with the law of the Member State concerned is valid for that entire Member State.
That Member State shall provide for an appeal procedure in respect of such refusal.
5. Where the conclusion of the reporting Member State as regards Part I of the assessment
report is that the clinical trial is not acceptable, that conclusion shall be deemed to be the
conclusion of all Member States concerned.
6. Where the Member State concerned has not notified the sponsor of its decision within the
relevant periods referred to in paragraph 1, the conclusion on Part I of the assessment report
shall be deemed to be the decision of the Member State concerned on the application for
authorisation of the clinical trial.
7. The Member States concerned shall not request additional information regarding the
aspects addressed in Part I of the assessment report from the sponsor after the reporting date.
7.2 Authorisation procedure for a substantial modification of a clinical trial
The authorisation procedure for a Substantial Modification (SM) of a clinical trial in Europe
is governed by the Clinical Trials Regulation (EU) No 536/2014 (CTR) and managed entirely
through the Clinical Trials Information System (CTIS).
A modification is considered Substantial if it is likely to have a significant impact on the
safety or rights of the trial subjects or on the reliability and robustness of the data
generated in the clinical trial.
Here is an overview of the procedure and key timelines:
(1)Submission and Validation
Platform: The sponsor must submit the application for the Substantial Modification via the
CTIS portal.
Scope: The sponsor must clearly indicate whether the modification affects Part I
(scientific/medicinal product-related), Part II (national/ethics-related), or Both Parts (I &
II).
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Documentation: The submission must include a cover letter, a detailed description and
justification of the modification(s), and the updated versions of the relevant documents (e.g.,
protocol, Investigator's Brochure, Informed Consent Form) with tracked changes.
Validation: The Reference Member State (RMS) for the initial application is also the RMS
for the Part I aspect of the substantial modification. The RMS validates the application within
6 days. If the application is incomplete, the sponsor has 10 days to supplement it.
2. Assessment Phase
The assessment timeline depends on whether the modification affects Part I, Part II, or both.
Table 2: Assessment Phase
Modification PartLead Assessor Total Assessment
Timeline
Key Steps
Part I (Scientific)Reference Member
State (RMS), in
coordination with all
Member States
Concerned (MSCs).
Max. 38 days
(extendable by 31
days for Request for
Information (RFI)).
The RMS
coordinates the joint
assessment and
drafts the Part I
Assessment Report.
Part II
(National/Ethics)
Each Member
State Concerned
(MSC) individually.
Max. 45 days
(extendable by 31
days for RFI).
Each MSC assesses
the Part II aspects
(e.g., suitability of
facilities, patient
recruitment,
informed consent).
Part I & II
(Combined)
Both RMS (Part I)
and MSCs (Part II)
follow their
respective timelines,
synchronized by the
RMS validation.
The Part I timeline
(up to 69 days)
generally dictates
the overall
maximum timeline.
The process is
integrated, with all
parts running in
parallel after
validation.
Request for Information (RFI): During the assessment, the RMS (for Part I) or the MSCs
(for Part II) may issue an RFI. The sponsor has a maximum of 12 days to submit the
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30. SMT. R. D. GARDI B. PHARMACY COLLEGE (263)
response. Failure to respond within the deadline results in the application automatically
lapsing in the Member States concerned.
3. Decision
Final Report: Once the assessment is complete, the RMS issues the final Part I
Assessment Report, and the MSCs finalize their Part II reports.
Notification: Each Member State Concerned must notify the sponsor of its decision via
CTIS within 5 days of the date of the final report. The decision will state whether the
substantial modification is authorised, authorised subject to conditions, or refused.
Implied Authorisation: If an MSC does not notify the sponsor of its final decision within
the regulatory timeline, the substantial modification is deemed to be approved in that
Member State based on the conclusion of the Assessment Report.
Key Constraints
No Parallel SMs: Generally, a sponsor cannot submit a new Part I substantial
modification if another Part I substantial modification or an application for adding a new
Member State is already under assessment. This requires careful strategic planning to bundle
all necessary changes.
Immediate Implementation: Once a substantial modification is authorised, the changes
can be implemented, but the sponsor must also ensure compliance with any national
requirements regarding the implementation date.
https://www.ema.europa.eu/en/news/new-targets-clinical-trials-europe
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8. USA Clinical Trial
"USA clinical trials" is a broad topic encompassing the processes, regulations, and platforms
related to medical research involving human volunteers in the United States.
8.1. Primary Registry and Database: ClinicalTrials.gov
The official and most comprehensive database for clinical trials in the U.S. and around the
world is ClinicalTrials.gov.
What it is: A protocol registry and results database maintained by the National Library of
Medicine (NLM) at the National Institutes of Health (NIH).
Purpose: Sponsors or investigators of certain clinical trials are required by U.S. law
(FDAAA 801) to register their trials and submit results to this platform to ensure
transparency.
How to find a trial: You can search the website by condition, drug, location, or other
keywords to find information about a trial's purpose, which may participate, and contact
details.
8.2 Regulations and Oversight
Clinical trials in the U.S. are heavily regulated to protect participant safety and ensure
scientific integrity.
FDA Oversight: The U.S. Food and Drug Administration (FDA) oversees clinical trials for
drugs, biologics, and medical devices. Before a clinical trial can begin, the sponsor must
generally submit an Investigational New Drug (IND) or Investigational Device Exemption
(IDE) application to the FDA.
IRB Approval: Every study must be approved and monitored by an Institutional Review
Board (IRB) or Ethics Committee. The IRB is an independent committee of doctors,
statisticians, and community members that ensures the trial is ethical and that participants'
rights and welfare are protected.
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Informed Consent: All participants must go through the Informed Consent process, where
a researcher explains the study's purpose, procedures, risks, and potential benefits before the
person decides to enroll. Participants can withdraw at any time.
8.3 Clinical Research Phases (Human Testing)
Table 3: Clinical Research Phase
Phase Purpose Participants Key Question
Answered
Phase I Safety, Dosage, and
Pharmacokinetics
Safety, Dosage, and
Pharmacokinetics
Is it safe in
humans? What is
the maximum
tolerated dose, and
how does the body
process it?
Phase II Effectiveness and
Side Effects
Larger group (up to
several hundred) of
people with the
condition.
Does the drug work
for the disease?
What are the
common short-term
side effects?
Phase III Confirmation,
Comparison, and
Monitoring
Large group (300 to
3,000+) in multiple
locations, reflecting a
diverse patient
population.
FDA Review Approval
Application
N/A Review of all pre-
clinical and clinical
data by the FDA
(New Drug
Application or
Biologics License
Application).
Phase IV Post-Marketing
Surveillance
Thousands of people in
the general population
What are the long-
term effects and
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after the drug is
approved.
optimal usage in a
broad, diverse
population?
Clinical trials for new drugs, biologics, and devices are conducted in a series of sequential
phases, each designed to answer specific questions about the investigational product.
Progressing to the next phase depends on successful safety and efficacy results from the
preceding one.
8.4 USA Clinical Trial Methodology Chart (Drug/Biologic Development)
8.4.1 Core Methodological Principles:
The Core Methodological Principles for conducting a clinical trial in the USA are the
foundational scientific and ethical requirements that ensure the safety of participants and the
reliability of the results. These principles are mandated by the FDA (Food and Drug
Administration) and international guidelines like Good Clinical Practice (GCP).
To ensure scientific integrity and participant safety, all phases typically adhere to these
principles:
8.4.2 Scientific Integrity and Bias Reduction
Protocol: A detailed study plan approved by the IRB and FDA, governing every action in
the trial.
Informed Consent: Mandatory process where participants voluntarily agree to join after
understanding all risks and benefits.
Randomization: Assigning participants to treatment or control groups by chance to
prevent selection bias.
Blinding (Masking): Hiding which treatment (active drug or placebo/standard care) a
participant receives to prevent psychological bias (e.g., Double-Blind where neither the
patient nor the doctor knows).
Control Group: A comparison group that receives either a placebo (inactive substance) or
the standard of care treatment.
Table 4: Core Methodological Principles
Principle Description Purpose
Protocol Adherence Following a detailed, writtenEnsures consistency and
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plan that outlines the study's
objectives, design, and
procedures without
deviation.
reproducibility of data
across all trial sites and
personnel.
Control Group Including a comparison
group that receives either an
inactive substance (Placebo)
or the existing standard
treatment.
Provides a baseline to prove
that any observed effect is
due to the investigational
intervention, not external
factors or the placebo effect.
Randomization Using a chance-based
method (like a computer
program) to assign
participants to either the
intervention group or the
control group.
Minimizes selection bias
and ensures the treatment
and control groups are
comparable in terms of
known and unknown
factors.
Blinding (Masking) Hiding the identity of the
intervention (active or
control) from key parties.
Double-blind is the gold
standard.
Prevents expectations and
prejudices of participants,
researchers, or data analysts
from influencing the results.
Inclusion/Exclusion CriteriaClear rules defining who can
and cannot enrol in the
study (based on age, disease
stage, etc.).
Ensures the trial is
conducted on the
appropriate patient
population for safety and
scientific relevance.
https://clinicaltrials.gov/
8.5 Core guidelines for clinical trials
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The core guidelines for clinical trials in the USA are set by the Food and Drug Administration
(FDA) and are primarily based on the principles of Good Clinical Practice (GCP) and the
regulations outlined in the Code of Federal Regulations (CFR), specifically Titles 21 and 45.
The guidelines are designed to ensure:
1. Protection of Human Subjects
2. Integrity and Reliability of Data
8.5.1 Key Regulatory Frameworks
Table: 5 Key Regulatory Frameworks
Regulation Scope Primary Purpose
Good Clinical Practice
(GCP) (ICH E6)
International ethical and
scientific quality standard.
Assures that clinical trial
data is credible and that
the rights, safety, and
well-being of trial
subjects are protected.
21 CFR Parts 50 & 56FDA regulations for
drugs, biologics, and
devices.
Mandates Informed
Consent (Part 50) and
Institutional Review
Board (IRB) review (Part
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56).
21 CFR Part 312 / 812Investigational
Applications.
Regulates the submission
and conduct of trials for
Investigational New
Drugs (IND) (Part 312)
and Investigational
Device Exemptions (IDE)
(Part 812).
45 CFR Part 46
(Common Rule)
U.S. federal policy for the
protection of human
subjects.
Applies to most federally
funded or supported
research, reinforcing the
need for IRB oversight
and consent.
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https://www.ecfr.gov/current/title-21/part-50#p-50.1(b)
8.5.2 Essential Pre-Trial Requirements
Before a clinical trial can begin in the US, the sponsor must meet the following three main
requirements:
A. FDA Authorization (IND or IDE)
The sponsor must submit an application to the FDA and receive authorization to proceed.
Investigational New Drug (IND) Application (21 CFR Part 312): Required for a drug or
biologic to be shipped across state lines for human testing. The FDA has 30 days to review
the initial submission; if no concerns are raised (Clinical Hold), the trial may proceed.
Investigational Device Exemption (IDE) Application (21 CFR Part 812): Required for a
significant risk medical device to be legally tested on human subjects.
B. Institutional Review Board (IRB) Approval
A trial cannot begin until it has been reviewed and approved by an IRB (also known as an
independent ethics committee).
The IRB, which consists of scientists, non-scientists, and community members, must
approve the protocol, the informed consent form, and any participant recruitment
materials.
They continuously monitor the study to ensure the risks to participants are reasonable in
relation to the potential benefits.
C. Informed Consent.
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This is a continuous process, not just a document signature.
Investigators must provide potential participants with all key information about the trial—
including its purpose, procedures, risks, and benefits—in an understandable language.
The consent must be voluntary, and participants must be clearly informed of their right to
withdraw at any time without penalty
8.5.3 Ongoing Trial Conduct and Reporting
A. Safety Reporting
All parties (Investigators, Sponsors, and IRBs) have strict requirements for reporting safety
issues.
 The Sponsor must report to the FDA, all participating investigators, and the IRB any
serious and unexpected adverse events (SAEs) that may be related to the study
drug/device, often within 7 or 15 days, depending on severity.
Investigators must track all adverse events (AEs) and report them to the sponsor.
B. Good Clinical Practice (GCP)
Compliance with GCP is the operational standard for conducting the trial. It covers:
Protocol Adherence: The study must be conducted exactly as described in the approved
protocol.
Source Data Verification: All data recorded on Case Report Forms (CRFs) must be
verifiable against source documents (e.g., medical records).
Investigator Responsibilities: The Principal Investigator (PI) must be qualified, oversee
the trial, and delegate tasks properly.
C. Public Disclosure
The law requires registration of most clinical trials and public reporting of results.
Trials that meet the definition of an "applicable clinical trial" must be registered on the
ClinicalTrials.gov database no later than 21 days after the first participant is enrolled.
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Summary results, including adverse event information, must also be submitted to
ClinicalTrials.gov after the trial is complete.
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