Exploring the Drug Development Process

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Laura Elizabeth Lansdowne

Drug development is the process of bringing a novel drug from “bench to bedside”. It can take
10 to 15 years for a drug to be designed, developed and approved for use in patients (Fig 1). In
some circumstances, the drug development and approval process can be expedited – for
example, if the drug is the first available treatment for a condition, or it shows a significant
benefit over existing drugs.

Before a drug can reach a patient, it must go through rigorous testing to determine whether it is
safe, effective at treating the condition it was developed for, and to ascertain the correct dosage
and appropriate administration route.

Pharmaceutical regulatory authorities are responsible for overseeing and regulating

therapeutics; including prescription and over-the-counter drugs, vaccines, cell therapies and
medical devices. They play a key role throughout the drug development process and are
designed to ensure the safety, efficacy, accessibility and security of approved drugs.
Throughout the development of the drug, the responsible pharmaceutical company will
conduct pharmacovigilance activities.

Numerous different regulatory authorities exist worldwide. The USA’s regulatory agency is
the US Food and Drug Administration (FDA) and the UK equivalent is known as

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the Medicines and Healthcare products Regulatory Agency (MHRA) – every country has its
own regulatory authority.

The Stages of Developing a Drug

1. Early Drug Discovery

2. Preclinical Research
3. Investigational New Drug Application
4. Clinical Research
5. Regulatory Review, Approval and Post-Marketing Safety Surveillance

Figure 1: An overview of the drug discovery, development and approval process.

1. Early Drug Discovery

There are several core “steps” that are carried out during drug discovery. Academic and
industry scientists collaborate to identify potential druggable targets for a specific disease and
work to discover and optimize drug compounds that can elicit an effect on a specific biological
target implicated in a disease – in the hopes of treating it. Work at this stage is performed in the
laboratory using in vitro and animal models.

 Target Identification and Validation

Having a clear understanding of the clinical spectrum of a disease and the exact role a
target plays in that disease are key factors when designing a “good” drug. A biological
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 target is deemed “druggable” if its activity can be altered by a therapeutic agent –
whether it be a small molecule or biopharmaceutical. “Good” drug targets typically have
“universal” advantageous properties and can be discovered in a variety of ways:
scouring published scientific literature, searching available databases, or via “practical”
methods such as target deconvolution and target discovery. Once a target is identified it
is validated to verify its suitability for pharmaceutical development, prior to
commencing a screening campaign designed to identify “hits”.

 Hit Identification and Validation

Numerous screening approaches can be used to identify a “hit” compound. A “hit” can
be defined as a compound that interacts with the target of interest. There are
several strategies that can be used to discover “hits” including high-
throughput screening, phenotypic screening, virtual screening, fragment-based screening
and structure-based design.

In phenotypic screens, the specific drug target may not be immediately evident as the
approach is based on determining if a compound exerts a desired effect by observing a
change in phenotype. The target underlying the observed phenotypic change may be
identified later – although there isn’t a regulatory requirement to know the target of a
drug provided it demonstrates good safety and efficacy properties.

 Hit-to-Lead and Lead Optimization

The primary aim at this stage is to refine several of the most promising “hits” to create
more potent and selective candidates with “optimized” pharmacokinetic properties.
Typically the “original hits” have very low affinity to the biological target; medicinal
chemists work to increase the affinity by several orders of magnitude. With advances in
artificial intelligence (AI), an increasing number of pharma companies are realizing the
value of adopting AI approaches – encouraging their medicinal chemists to work hand-
in-hand with AI systems to quickly accumulate vast amounts of valuable biological,
structural and chemical data. Off-target interactions are another key consideration at this
stage as these can lead to adverse effects, so improving selectivity of the molecule
against other biological targets should be investigated and addressed.

 Candidate Selection

At this stage you will need to determine, from several promising “high-quality” leads,
which one you want to take forward as a clinical candidate. For a drug candidate to be
deemed suitable for preclinical and clinical testing it should: bind selectively to the
target, elicit the desired functional response when interacting with the target molecule,
and must have adequate bioavailability and biodistribution to elicit the desired response.
It must also have a toxicity profile. In addition to the above properties, you should also
consider the following factors: future manufacturing suitability and scale-up,
commercial viability and cost-effectiveness, as these will heavily impact the long-term
success of the drug.
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2. Preclinical Research
Preclinical testing is designed to deliver important information about a drug candidate’s
efficacy and safety before it is tested in human subjects. Both in vitro and in vivo models are
typically used to provide evidence of a candidate’s biological effect. Preclinical studies are
required by regulatory authorities such as the FDA and MHRA before submitting an
investigational new drug application (IND) which is required to progress to clinical
development. Numerous questions are addressed at this stage:

  What does the drug do to the body?

  What does the body do to the drug?
  It is potent, but is it safe?

It is extremely important that the most appropriate animal model is used at this stage, as well as
considering the gender of animals to be used to prevent sex-specific bias. A drug could elicit a
different response in a male animal compared to a female. You will also need to consider
species-specific physiology and similarities in terms of metabolic pathways and genetics (for
example 99% of all mouse genes overlap with human ones).

3. Investigational New Drug Application

The FDA groups INDs into three different types:

  Investigator

This is submitted by the physician responsible for initiating and investigating. The same
physician will manage the administration and/or dispensing of the investigational drug.
This type of application is typically requested for the study of an unapproved drug, or an
approved drug for use of the drug in an unlicensed indication, or a different patient
population.

 Emergency use

An emergency use IND enables the regulator (FDA) to authorize the use of an
investigational drug in an urgent situation, without the obligation to submit and IND in
accordance with 21 CFR, Sec. 312.23 or Sec. 312.20. This type of application is used for
patients who do not meet existing clinical study criteria, or in situations where an
approved clinical protocol doesn’t actually exist.

 Treatment

This type of IND application is submitted to gain access to an experimental drug that has
shown promise in clinical trials for treating a serious or life-threatening condition, whilst

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 the final clinical work is completed, and the new drug application is reviewed by the
FDA.

An IND can be categorized as either “commercial” or “research”. For an IND application there
are key areas that must be covered; animal model pharmacology and toxicology studies,
manufacturing information, clinical study protocols and investigator information.

The IND sponsor is required to wait 30 days before starting clinical trials – this delayed period
gives regulators the opportunity to review the information contained within the IND
application.

4. Clinical Research
Clinical trials are designed to answer specific research questions related to an investigational
drug. The trials must follow a study protocol – a document that describes exactly how the
clinical trial will be conducted. It details key study objectives, study design, and statistical
considerations, to ensure the safety of participants and the integrity of the data collected
during the study.

Figure 2: The attrition of compounds as they move through the drug development process.

The clinical stage of drug development follows a series of “Phases”.

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Phase I

Number of participants: 20–100. These can either be “healthy” people or people diagnosed

with the specific condition/disease you are developing the drug to treat.

Study length: Typically, several months.

Primary purpose: To determine safety in humans, and to gather information on dosage. Phase I
studies also guide how best to administer the drug to limit toxicity and enhance therapeutic
effect.

Phase II

Number of participants: Several hundred. The participants will be diagnosed with the
condition/ disease you are developing the drug to treat. 

Study length: Spans from several months to two years.

Primary purpose: To acquire additional safety data – to determine efficacy and adverse effects.
This information is used to optimize the design of the larger Phase III study.

Phase III

Number of participants: 300–3000. The participants will be diagnosed with the

condition/disease you are developing the drug to treat.

Study length: Spans from one to four years in length.

Primary purpose:  To determine the drug’s efficacy and to monitor adverse reactions. Due to
the increased number of participants during Phase III, long-term or rarer side effects that may
have gone undetected in Phase I and Phase II are usually detected. The greatest proportion of
safety information is collected during Phase III.

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5. Regulatory Review, Approval and Post-Marketing Safety Surveillance

New Drug Application

The application process for marketing authorization in the USA is known as a New Drug
Application (NDA). In the European Union and other countries worldwide, this same process
is referred to as a Marketing Authorisation Application (MAA).

The regulatory authority is responsible for the scientific evaluation of the NDA or MAA. The
goal of the application is to provide the regulator with enough information – gathered during
preclinical and clinical studies – for them to be able to determine if:

 The drug is safe and effective as a treatment for the condition it has been developed for
 The drug’s therapeutic benefits outweigh the risks
 The drug’s labeling is fit-for-purpose and whether all required details are included
 The methods used to manufacture the drug and measures to ensure the drug's quality are
satisfactory

Biologics License Application

The approval of biological products in the USA falls under the provisions of the Public Health
Service (PHS) Act. The Act requires the manufacturer of the biologic to hold a license for that
product. A Biologics License Application (BLA) must be submitted for therapeutic biological
products including (but not limited to); monoclonal antibodies (for in vivo use), cytokines,
growth factors, enzymes, immunomodulators, proteins, and non-vaccine
therapeutic immunotherapies.

Product Launch
Once the drug receives approval from the relevant regulatory authority, numerous activities
will need to be initiated to prepare for the launch of the product. These include:

 Manufacturing scale-up and serialization

 Printing of final product label information, packaging and artwork
 Product storage, shipping and distribution arrangements
 Production staff and quality team availability

Post-marketing Safety Surveillance 

Post-marketing safety surveillance is the term used for the monitoring of a drug after it has
received approval and has reached the market. It is designed to evaluate the long-term safety
and efficacy of a drug, potential “real-world” problems with formulation, and use for
unapproved conditions or “off-label” (e.g. use in an age group or at a dosage outside of that
advised in the product label).

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Phase IV

Phase IV studies are conducted after approval of the drug has been granted.

Number of participants: Several thousand. The volunteers will be diagnosed with the
condition/disease that the drug is approved to treat.

The purpose of a Phase IV study is to obtain additional information about the long-term risks
and benefits of taking a drug now that it is being more widely used. The “real-world” data can
also help determine if there is scope to develop the drug further, for example:

 To explore the use of the drug for additional indications/ additional age groups
 To develop an alternative route of administration

Acronyms and Key Terms

FDA US Food and Drug Administration

EFPIA European Federation of Pharmaceutical Industries and Associations

EMA European Medicines Agency

IFPMA International Federation of Pharmaceutical Manufacturers & Associations

MHRA Medicines and Healthcare Regulatory Agency

PIPA Pharmaceutical Information and Pharmacovigilance Association

ADR Adverse Drug Reaction

AE Adverse Event

AR Adverse Reaction

BLA Biologics License Application

BTD Breakthrough Therapy Designation

ERB Ethical Review Board

IEC Independent Ethics Committee

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IND Investigational New Drug

IRB Institutional Review Board

MAA Marketing Authorisation Application

MAH Marketing Authorisation Holder

NDA New Drug Application

ODD Orphan Drug Designation

PV Pharmacovigilance

SAE Serious Adverse Event

SUSAR Suspected Unexpected Serious Adverse Reaction