Drug Development

This educational cluster focuses on aspects of drug development in the pharma industry. Drug
development is the process of discovering, testing, and bringing new medications to market. It is a
complex and time-consuming process that involves a variety of different steps, from basic research to
clinical trials and regulatory approval.

Drug development in commercial biopharma may be divided into three sequential domains: Pre-Clinical,
Clinical, Postmarketing.

Two R&D experimental-driven domains requiring long-term evidence data collection:

• Pre-clinical – using in vitro and in vivo data: The process of drug development begins with basic
research, which involves identifying a potential new drug and determining how it might work in
the body. This can involve studying the biological mechanisms of diseases and identifying
potential targets for new drugs. Once a potential drug has been identified, it undergoes
preclinical testing, which involves testing the drug in the laboratory and in animal models. This
helps to determine the safety and effectiveness of the drug and to identify any potential side
effects.
 • Clinical drug development (CLINICAL) – using in-human data: If the drug shows promise in
preclinical testing, it can move on to clinical trials, which involve testing the drug in humans.
Clinical trials are conducted in three phases, with each phase involving a larger number of
participants. Phase 1 trials involve a small number of healthy volunteers and are designed to
assess the safety of the drug. Phase 2 trials involve a larger number of people with the target
disease and are designed to assess the effectiveness of the drug and to identify any side effects.
Phase 3 trials involve an even larger number of people and are designed to confirm the
effectiveness of the drug and to monitor its side effects in a larger population. If the drug is
successful in clinical trials and meets regulatory requirements, it can be approved for use by
regulatory agencies, such as the US Food and Drug Administration (FDA). Once a drug is
approved, it can be produced and distributed for use in the general population.

And one covering “rapid” analysis of real-time data

• Postmarketing surveillance using Real-World Data (RWD) and Real-World Evidence (RWE) data.
After a new drug has been approved by the U.S. Food and Drug Administration (FDA), it
becomes available for prescription and use by the general public. However, the process of
developing and approving a new drug is ongoing and does not end with FDA approval. The
manufacturer of the drug is required to continue monitoring the safety and effectiveness of the
drug through postmarketing surveillance. This involves collecting and analyzing data on the
potential risks and benefits of the drug, as well as identifying and evaluating any adverse events
that may occur in people who use the drug. The manufacturer is required to report any
significant findings from this surveillance to the FDA.

The following table introduces all the different topics this educational cluster will cover in its various
sub-clusters.

These domains are the result of a long evolutionary process in drug development.

The statistical era of medicine is one of the most recent conquests to have firmly shaped the three
domains above over the last 100 years.

One of the key reasons for the separation into these domains, particularly for a New Drug Application
(NDA[i]), is the intrinsic nature and complexity of the data, depending on the therapeutic area, at intra-
and inter-domain levels, the specificity of their regulatory, safety, medical and ethical frameworks and
the high diversity of educational background of departmental teams working in each domain.

The context of data acquisition in biopharma R&D is primarily:

 • pre-clinical and clinical data for a New Drug Application (NDA): patient data, with the aim to
generate scientific evidence of the safety and efficacy of new biopharma compounds

or

• Real-World Data and Real-World Evidence (RWD & RWE): extend the indication and/or label
update for already approved and commercially marketed medicines.

There are fundamental differences in data collection, management, usability and generalisability
between those two categories. For the remainder of this overview, we will focus on the clinical drug
development programme domain.

[i] [Link]

Pre-Clinical Drug Development

In drug development, pre-clinical development, also named pre-clinical studies and nonclinical studies,
is a stage of research that begins before clinical trials (testing in humans) can begin, and during which
important feasibility, iterative testing and drug safety data are collected, typically in laboratory animals.

The main goals of pre-clinical studies are to determine a starting, safe dose for first-in-human study and
to assess potential toxicity of the product, which typically includes new medical devices, prescription
drugs, and diagnostics.

Clinical Drug Program Development (CLINICAL)

A very long and rather slow, step-wise, set of experiments with humans organised in phases. Each phase
is composed of several clinical trials.

Phases I and II are primary safety studies and secondary “exploratory” or “proof of concept”.

Finally, the Phase III are rather confirmatory clinical trials that focus on efficacy.

• Phase I – First-in-Humans: Highly selected healthy volunteers are enrolled, and the drug is
tested for safety and pharmacokinetics. The focus in Phase I is looking at what the drug does to
the human body and what the body does with the drug while subjects are within a very
controlled environment. Phase I trials usually include a small number of subjects (typically up to
a few dozen).

• Phase II – First-in-Patients: If a new compound is found to have an acceptable benefit-risk

balance at the conclusion of Phase I clinical trials, it can then be tested in patients to further
explore its safety profile, to optimise dose finding and, depending on the study design, to
explore some hints about its efficacy (“proof of concept”).

There is an important cue here, particularly for statisticians and data scientists new to biopharma R&D.
For NDAs, first-in-patient clinical trials are exploratory in nature and most often can only recruit, for
safety and ethical reasons, patients who did not respond to local standard of care treatments (that often
vary significantly between regions[i]). This has important implications for any kind of statistical & data
science inferences made with this kind of data, particularly when the clinical trial datasets are used as
“historical data”.

On average, each Phase II clinical trial involves a total of 150 patients. But that varies heavily per
therapeutic area, labelling indication target (as designed in clinical drug programme development) and
study design.

• Phase III – They are usually called confirmatory studies as the study design and its primary
study objectives and endpoints focus on “therapeutic efficacy assessment” for the intended
therapeutic purpose. These Phase III clinical trials, as in the previous Phases, include control
groups, who receive a placebo or approved standard of care treatment. Usually, the statistical
design for efficacy Phase III trials requires hundreds, sometimes thousands, of patients per study
arm. Once again, that may vary significantly according to the therapeutic & labelling indication
or regulatory strategy chosen to be followed by the company clinical drug programme
development.

It is important to understand that pre-clinical and clinical drug programme development are often
tailored and customised according to the regions (NA, EU, Asia) in which the company intends to market
the drug. It is often the case that regulatory authorities from key markets in each region (the FDA, EMEA,
PPDA and now China and India) have their own specific requirements for pre-clinical and/or clinical data
study designs (inclusion and exclusion criteria, primary endpoints, study procedures based on local
standard of care, etc.).

What may be relevant for one may not be for another, so increasingly the number of clinical trials
performed[ii].

Therefore, such factors must be taken into account about the Generalizability[iii][iii] of the clinical trial
datasets when used as historical data.

1 - Safety Analytics

Post-Marketing Surveillance of Drug Development

Postmarketing surveillance (PMS) (also postmarket surveillance) is the practice of monitoring the
safety of a pharmaceutical drug or medical device after it has been released on the market and is an
important part of the science of pharmacovigilance. Since drugs and medical devices are approved on
the basis of clinical trials, which involve relatively small numbers of people who have been selected for
this purpose – meaning that they normally do not have other medical conditions which may exist in the
general population – postmarketing surveillance can further refine, or confirm or deny, the safety of a
drug or device after it is used in the general population by large numbers of people who have a wide
variety of medical conditions.[1]

Postmarketing surveillance 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.[1] These data are reviewed to highlight
potential safety concerns, in a process known as data mining.

This sub-cluster will cover examples on registration, pharmacovigilance, Phase IV clinical trials, real-
world data, real-world evidence, and other important topics pharmaceutical companies need to cover
after bringing a new drug to patients.

Reference Materials

• “The progress of Experiment – Science and Therapeutic Reform in the United States, 1900-1990”
Harry M. Marks (1995).

• “Raise Standards for preclinical cancer research” – Nature 2013.

[Link]

• “Different worlds – Confirmatory versus exploratory research” Simon Schwab and Leonhard
Held – “Significance” – April 2020.

• From Molecules to Medicine by Bayer

Recommended Videos

• From idea to Medicine – Drug Development at Roche

• Novartis. (2011, Jan 14). Drug discovery and development process [Video].
[Link]

• Pod of Asclepius. (2020, Mar 22). Risks and Opportunities of AI in Clinical Drug Development |
David Madigan and Demissie Alemayehu [Video]. YouTube.
[Link]