R-2-M

ROUTE-TO -MARKET GUIDE FOR INVENTO R S

A UCT ED I T I O N

Pharmaceutical
Products
AN INNOVATION
GUIDE FROM LAB TO
COMMERCIALISATION
2018
PHARMACEUT i ca l PR O D U CTS 1

About the Route-to-Market Series

The Route to Market (R2M) series is being other institutions to customise them for their
developed by the Department of Research own use.
Contracts & Innovation (RC&I) at the University of
Cape Town using funding from the Department Technology Transfer professionals generally
of Science and Technology’s National Intellectual have to deal with a multitude of inventions that
Property Office (NIPMO). Each booklet focuses span a broad range of categories. This can be
on a specific sector/product type and highlights challenging for new entrants to the field as well
the key steps and considerations in bringing as to those whose invention falls into a ‘new’
such a product to market in that sector – with an sector that the TTO has not previously worked
emphasis on the local South African context. in. Researchers are often unsure of the steps
The hope is that this and other booklets will that lie ahead in the areas of development
be useful to both Researchers and Innovators, and innovation that follow once their research
as well as Technology Transfer professionals has been completed. As the support for
working at institutional Technology Transfer creating impact from research outputs grows,
Offices (TTOs). The books have been released Researchers are increasingly finding good
under a Creative Commons license to enable sources of innovation funding.

Hardcopies of this and other publications may be obtained at cost by contacting innovation@uct.ac.za
A number of sector experts have provided RC&I with material and we are grateful to them for their
valuable contribution.

Authors who have contributed to this guide are:

Dr Richard Gordon, Private Consultant
Dr Delva Shamley, Director: UCT Clinical Research Centre
Dr Robert McLaughlin, former Head Office of Research Integrity, UCT

RC&I
Dr Andrew Bailey, Senior Manager: Innovation
Dr Revel Iyer, formerly Technology Commercialisation Manager
Alyx Casarin, formerly NIPMO Marketing Intern

Bridgette Hunt, design and layout

Nadia Krige, writer

This work is licensed under a Creative Commons Attribution 4.0 International License
(http://creativecommons.org/licenses/by/4.0/)

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TABLE OF CONTENTS

1 Introduction 3

2 Stages of Drug Discovery and Development 4

3 Technology Readiness Levels 10

4 UCT’s Involvement in the Drug discovery process 11

5 Combining Effective IP Protection and Publication: the UCT Strategy 14

6 Role of the Technology Transfer Office 18

7 Seed & Innovation Funding 21

8 Commercialisation from a UCT Perspective 22

9 Patenting and Data Exclusivity as Protection Strategies 24

10 Key Considerations in Setting up Clinical Trials 25

11 Ethics 29

12 Regulatory Issues 30

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1 INTRODUCTION
This guide provides information on the steps and curtailed research and development (R&D).
involved in taking a new pharmaceutical drug
to market. During a National Intellectual Drugs are costing ever increasing amounts
Property Management Office (NIPMO)-funded to take through the regulatory hurdles and
project in which Dr Richard Gordon reviewed into the market. To improve their profitability,
the pharmaceutical portfolio at the University companies have looked to more of the high-
of Cape Town (UCT), it was evident that UCT risk early stages of new drug discovery,
was patenting too early when compared to opening up opportunities for universities.
industry.
This high-risk space is ideal from an academic
This, coupled with a slower progression to research perspective and it is generally grant-
market entry, shortens the patent life that funded by government and philanthropic
remains when the new drug eventually reaches individuals/organisations. Pharmaceutical
the market, which significantly reduces companies can then cherry-pick promising
the value of the intellectual property (IP). A drugs to augment their pipelines,
strategy has been developed to overcome this, cofounding further research and establishing
which is described in this guide. collaborations with leading research groups.

It was also found that in many instances Another trend has seen pharma companies
different research groups were building buying small biotech companies who have
expertise related to screening the potential sufficiently derisked new drugs. The biotech
drugs for their efficacy / properties, which itself companies raise funding to develop promising
took time and slowed progress. To avoid this, it compounds outside a university environment
is preferable to outsource these key tests and and look to focus on test work and research
make use of platforms such as the H3-D Drug that will sufficiently derisk them, making them
Discovery and Development platform hosted attractive to next-stage investors or pharma
at UCT. companies.

“Biopharmaceutical Research & Development: “Derisking” primarily involves proving the

The Process Behind New Medicines” is drug’s efficacy and safety.
an excellent external guide that has been
produced by the Pharmaceutical Research and Biotechs can create significant value by
Manufacturers of America (PhRMA) and is a merely moving a drug closer to the market but
valuable reference that has been drawn on in without ever getting physical products onto a
preparing this guide. 1 truck.

Over just more than the last decade, there has Strategic patenting and the granting of
been a significant trend in the pharmaceuticals patents when associated with leading
sector, where companies have consolidated compounds also significantly increases value.

1
http://www.phrma.org/sites/default/files/pdf/rd_brochure_022307.pdf
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2 Stages of Drug
Discovery and Development

2.1 Overview throughput screen is used to find the

The Pharmaceutical R&D process is “needle in the haystack”.
a well-validated process (Figure 1)
during which new drug candidates Bringing a new drug to market is a
are discovered as active compounds in lengthy process which requires the skills
biochemical assays and are developed of a number of scientific teams working
into life-saving medicines. Most together to deliver a desired outcome.
compounds are synthesised, and The mechanism of the drug’s action
companies often have extensive libraries needs to be understood. Globally, this is a
of compounds that are screened for highly regulated industry that is carefully
efficacy. Often a robot-assisted, high- controlled in the interest of public safety.

DRUG DISCOVERY PRECLINICAL CLINICAL TRIALS FDA REVIEW LG-SCALE MFG

PHASE 4: POST-MARKETING SURVEILLANCE

PRE-DISCOVERY

5 000 - 10 000 250 5

COMPOUNDS ONE FDA
APPROVED
PHASE PHASE PHASE DRUG
1 2 3
NDA SUBMITTED
IND SUBMITTED

NUMBER OF VOLUNTEERS

20 - 80 100 - 300 1000 - 3000

3 - 6 YEARS 6 - 7 YEARS 0.5 - 2

YEARS

Figure 1: Drug Discovery and Development: A long, risky road (based on PhRMA drawing1)

A key part of this is the use of understood, the process of getting

biochemical assays to identify active a drug from the ideation phase to
compounds. At the end of the process commercialisation is a difficult one. A
the final product is highly purified, number of studies have shown that on
standardised and tested. average around 14 years is required to
complete the process. This is assuming
A consequence of the high-level that certain efficiencies are involved.
legislative regulations and the fact Unfortunately, university systems operate
that the mode of action is often poorly at a sub-optimal efficiency with the net

1
http://www.phrma.org/sites/default/files/pdf/rd_brochure_022307.pdf

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result being that the process typically characterised by extensive product

takes longer there. evaluation and testing, external
market approval in a highly regulated
The high cost of development is environment, a complex stakeholder
another reason very few drugs reach setup in an iterative network model, a
commercialisation. The cost of getting high relevance of the speed to market,
a single drug to the market is around and extremely high R&D expenditure.
US$150 million. If one includes the cost of
failures along the way, this amount can There are three key value inflection points
be as large as US$800 million. along this process. The first is at the end
of preclinical trials where initial proof of
The ability to patent a drug is, concept needs to have been established.
therefore, paramount for successful The second follows first phase data,
commercialisation. Any disclosure prior to which establishes or proves the concept.
patenting destroys the patentability. The Finally, receiving regulatory approval
knock-on effect is that a pharmaceutical is the last inflection point. Typically, at
firm cannot recoup its investment in this point the drug enters large scale
the drug and hence would not invest manufacture before entering the market.
in its development. Often philanthropic
researchers have thought that by
strategically publishing to prevent 2.2 Drug Discovery
patenting woud ensure accessibility to the This is a generic term summarising the
drug. But without the patent protection to activities of Hit-to-Lead (H2L) and Lead
give a pharmaceutical firm even a modest Optimisation (LO). H2L is the process
opportunity to recover costs, the drugs where compounds display some activity
just do not make it to market. against a chosen organism (or molecular
target) and a series of compounds are
Manufacturers of generic drugs hover synthesised to explore whether this is a
in the wings, waiting to launch their general phenomenon associated with
alternative products the moment a each chemotype. This process typically
patent expires. But these manufacturers requires a team of 3-4 experienced
are often reliant on the data that the chemists, working on several chemical
original manufactuer submitted to the series, in parallel. At the end of H2L,
regulator, e.g. the FDA. preferred series are chosen to progress
into Lead Optimisation (LO).
The FDA have, depending on the length
of the regulatory process, restricted It is very unlikely that projects entering
access beyond the patent life which also the LO would be a perfect drugs, as
gives the primary manufacturer more fewer than 1 in 20 programs progress
time to enjoy market exclusivity. to any degree. LO is a process whereby
In contrast, the clinical trial is more about each chemical series of interest would
efficient operations and ‘translation.’ be optimised by medicinal chemists
Clinical trials distinguish themselves who would attempt to improve certain
from other industries with regard to features of the lead compound. These
late development stages as they are optimisations would typically include:
6 R-2-M ROUTE-TO - M A R K E T G U I D E FO R I NVE N TO R S

• Increased potency of the chemical series • Active Pharmaceutical Ingredient (API)

(and preferably a back-up series as well). production
• Enhanced physicochemical properties of • Product Registration (Medicines Control
the molecule including (for example): Council (MCC) for clinical trials).
o Solubility
o Metabolic stability Phase I /First in Man (FIM) studies:
o Toxicity: cellular, genetic, cardiac and These studies are carried out to ensure
cytotoxity compounds are safe in humans and that
o Permeability blood levels are achieved for them to
o Plasma Protein binding have a therapeutic effect. Patients will be
monitored to evaluate if any side effects are
This LO process would require a large present and that doses are tolerated.
number of iterative compounds to
make test cycles involving integrated
teams of medicinal chemists, biologists, The Budgets for these activities are typically:
pharmacologists and computational Pre-Clinical studies: R15m-R20m per
compound
chemists. LO projects typically take 12-
18 months to complete with a team of
First in Man Studies: R5-R10m per study
8-10 scientists. Typically, 1 in 5 LOs are
successful where a lead compound Phase 2 study: R50-100m*
series is established with sufficient target
potency, selectivity and a favourable Phase 3 study: R300-500m*
pharmacological profile. * conservative estimates.

One or two compounds would then be

proposed for drug development. The ADME and toxicity
best of these is generally called the “lead” During pre-clinical testing ADME testing is a
compound while a “backup” compound, key requirement. In vitro ADME (Absorption,
commonly from a different chemical class, Distribution, Metabolism and Excretion)
would be developed in parallel. Patents are studies have long played a critical role in
usually filed at the END of LO. optimizing both pharmacokinetic (PK) and
pharmacodynamic (PD) properties of drugs,
thereby decreasing attrition rates in drug
2.3 Pre-clinical activities development.
For the compound to enter the market, it
needs to undergo pre-clinical development Because transporters regulate the cellular
and human clinical trials – a process entry and exit of most small molecules,
which typically takes between 6 and 8 they are critical determinants of every
years. The product, if successful in Phase aspect of drug ADME properties. In
I development, will then undergo Phase particular, many new molecular entities
II and III studies. Pre-clinical activities are (NCEs) synthesised today are hydrophilic
routinely carried out to address: compounds with low cell membrane
• Toxicology permeability, which are more dependent
• Drug Metabolism and Pharmacokinetics on transporters to achieve acceptable
(DMPK) bioavailability, desirable tissue distribution,
• Formulation studies and optimized PK profiles.

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Where will it go? DRUG

CNS Efflux
Distribution
CNS
Influx

Will it remain intact? Renal

Filtration/
Secretion
Transporters
Metabolism
Renal
Hepatic Efflux Biliary Reabsorption
Secretion
Hepatic Uptake

Absorption Excretion

Will it get in? Will it stay in?

Figure 2: Transporters are key determinants of drug ADME properties.

Animal trials Often specific animal models are developed

By law, all new medicines must first be tested to study the drug’s action in terms of
on animals1 to ensure patient safety and are controlling a particular disease.
referred to as “pre-clinical” trials. When these
tests have been shown to be successful, 2.4 Clinical trials
clinical trials will be conducted on humans. Clinical trials are typically a highly dynamic
and competitive environment that requires
It is important to note that animals are only a complex network of stakeholders and
used in medical research when absolutely alliances. There are four main ‘actors’ to be
necessary and unavoidable - after ethical considered:
review and in situations where appropriate • Trial sponsors – most often
alternatives are not available. pharmaceutical companies
• Sites – mostly hospitals or clinics
UCT has an Animal Research Ethics • Subcontractors – often research
committee that operates separately from organisations
the Human Research Ethics Committee. • Patients

1
http://www.abpi.org.uk/our-work/mandi/Pages/animals-research.aspx
8 R-2-M ROUTE-TO - M A R K E T G U I D E FO R I NVE N TO R S

These trials can take between 6 and 7 years. It is during this time that formal go/no-go
Throughout this period, all these actors decisions are made with respect to drug
depend on each other to conduct ethical testing. Most clinical trials happen in three
and efficient work. phases. We take a more detailed look below:

PHASE PHASE 1 PHASE II PHASE III

Duration 6 months to 1 year 1-2 years 2-5 years

Patients <100 100-500 500-5000
Healthy subjects or Patients with the target Patients with the target
patients with the target disease disease in multiple
disease centres
Scope Determine the safety and Assess the effectiveness of the Demonstrate the
tolerability over a wide drug (pharmacodynamics) therapeutic efficacy,
range of doses tolerability, and safety
Assess the dose(s) for phase
Define a pharmacokinetic III and the frequency of
profile of the drug administration
Obtain preliminary Determine the common
pharmacodynamics short-term side effects and
evidence risks

Table 1: Summary of Clinical Trial Phases (Buonansegna et al. (2014)1

Phase 1: Perform initial testing in a small help researchers determine whether a drug
group of healthy human volunteers should move on to further development and
During this phase, the candidate drug what a safe dosing range would be.
is tested in people for the first time. This
normally involves a cohort of about 20 to Phase 2: Test in a small group of patients
100 healthy volunteers. During Phase 2, the candidate drug’s
effectiveness is evaluated in a cohort of
The main goal here is to establish whether about 100 to 500 patients with the disease
the drug is safe for humans. In order to or condition under study.
do this, researchers have to look at the
pharmacokinetics: Researchers also have the opportunity
- How is it absorbed? to examine any possible short-term side
- How is metabolised and eliminated from effects and risks that could be associated
the body? with the drug.

They also have to study the drug’s The aim is also to answer the following
pharmacodynamics: questions:
- Does it cause side effects? - Is the drug working by the expected
- Does it produce the desired effects? mechanism?
- Does it improve the condition in
Phase 1 trials are closely monitored and aim to question?

1
https://onlinelibrary.wiley.com/doi/epdf/10.1111/radm.12053

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The optimal dose strength is established proteins) from a range of expression

and so are schedules for using the drug. platforms, such as mammalian cell
If the drug continues to show promise, culture, yeast or E. coli fermentation or
preparations are put in place for the through transient expression in plants,
much larger Phase 3 trials. such as tobacco.

Phase 3: Test in a large group of patients Whilst one is working through the pre-
This phase is all about generating clinical stage the chemical or biological
statistically significant data about safety process needs to be scaled-up to ensure
and efficacy. Research is conducted in that sufficient quantities of the active
a large cohort of patients, numbering pharmaceutical ingredient (AI) can be
between 1,000 and 5,000. produced to support commercialisation.
This is where techno-economics will play
Phase 3 is key in establishing whether a role in selecting synthesis routes from
the drug is truly safe and effective and a number of different options, in terms
also provides the basis for labelling of the number of steps involved (the
instructions. fewer the better) and the yields at each
stage and the complexity of operation.
Unsurprisingly, these trials are the Disasters have happened where one of
longest and costliest, as they typically the enantiomers or isomers of a molecule
include hundreds of different sites across can be beneficial to health and the other
the country and even internationally. deleterious.
Coordination of sites and data is key and
makes for a rather monumental task. As part of the process development, the
Simultaneously, researchers will also be impact of variations in raw materials
conducting many other studies required will be understood, different sources
for FDA approval. These may include evaluated and specifications for them
plans for full-scale production and drawn up. It is likely that the AI will need
preparation of the complex application. to be formulated with other ingredients
to produce the final product – often
Chemical Process Scale-Up dependent on the mode of delivery
Another important aspect that will not (inhaled, tablet, capsule, injectable, drip,
be covered in this booklet, but may be etc.) and to improve shelf life. Both cold-
in another R2M booklet in the series, chain requirements and shelf life studies
is the scale-up of the manufacture of would also be required and form part of
the actual pharmaceutical product. the dossier that is ultimately submitted
Pharmaceuticals are generally made to the regulator.
through extraction from, or purification
of a natural resource (e.g. a medicinal AIs need to be produced under Good
plant) or chemically synthesised, or Manufacturing Practice and often for
biologically synthesised, e.g. as a natural clinical trials, the manufacture of batches
product of a microorganism, or expressed of test product will be outsourced to a
by genetically modified microorganisms suitably certified facility to manufacture
that will produce products (often on a “toll” basis.
10 R-2-M ROUTE-TO - M A R K E T G U I D E FO R I NVE N TO R S

3 Technology Readiness Levels

Technology readiness levels (TRL) are a method also to understand the level of maturity that
of classifying technology maturity as one will be reached once a funded project has been
moves from TRL 1, where the research had completed.
been initiated to TRL 9, where the technology
has been commercialised and has been in the TRLs are useful, as one can classify a project
market for some time. within UCT and understand the steps that
need to be taken to bring a product or service
RC&I developed the table below, which to market.
provides definitions of technology maturity at
each TRL in a number of different sectors. TRLs were conceived by NASA1 and their
Funders are increasingly using TRLs to describe current nine-level scale has gained wide
the target of the funding that they provide and acceptance.

Level TRL 1 TRL 2 TRL 3 TRL 4 TRL 5 TRL 6 TRL 7 TRL 8 TRL 9
Basic Idea Concept Experimental Proof Lab Demonstration Lab scale validation Prototype Capability validated on Capability validated Capability validated
Developed of Concept (early prototype) demonstration economic runs over range of parts on full range of
parts over long
periods
Science & Engineering

Pilot system System incorporated in Proven system

demonstrated commercial design ready for full
deployment
Component and/or Laboratory scale, Engineering/pilot‐ Full‐scale, similar Actual system Actual system
system validation in similar system scale, similar (prototypical) system completed and operated over the
laboratory validation in relevant (prototypical) system demonstrated in qualified through test full range of
environment environment validation in relevant relevant environment and demonstration expected mission
environment conditions

Software to test and Escalate model to Model contains all No specialist Install, run and evaluate Evaluation done by Product proven
evaluate basic more realistic major elements of intervention required software in actual goal target representative ready through
concepts on simple representation of need. Solve industrial from environment (e.g. clients on successful
model problems industrial system. strength problems by programmers/develo prospective client’s representative operations in
Software

representative of Confirm basic code developers OR pers. This includes computers). hardware platforms. operating
final need. formulation. achieve functionality basic GUI interface. If Demonstrate use by Complete GUIs, users environment.
by expert users. required, clients manuals, training,
Document programming to be software support etc.
performance. GUI. according to ISO Typical user driven
standards. “bug hunting”
Medical Basic Research Preclinical Research Late Preclinical Phase I Trials Phase II Trials Phase III Trials Phase IV Trials
Science Research
Phase
Research Translation/Development Commercialisation

Figure 3: Technology Readiness Levels

1
You can read more on the NASA website: https://www.nasa.gov/directorates/heo/scan/engineering/technology/txt_accordion1.html

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PHARMACEUT i ca l PR O D U CTS 11

4 UCT’s Involvement in
the Drug Discovery Process
Whilst UCT does not take a drug right through • The Desmond Tutu HIV Centre (DTHC)
to market, different groupings within UCT • The South African Tuberculosis Vaccine
actively participate in all the stages of drug Initiative (SATVI)
discovery and development, which is shown
in Figure 4. A significant amount of funding Four extramural units of the South African
coming into the university is related to clinical Medical
trials that are undertaken. • Research Council (MRC)
• Immunology of Infectious Diseases Unit
These clinical trials attract top international • Drug Discovery and Development Unit
academics who work with global • Molecular Mycobacteriology Research
pharmaceutical companies and importantly Unit
provide access to drugs and treatments that
may not have been otherwise available to Within UCT itself:
patients in the Western Cape. • Human Genetics Unit
• The Centre for Computational Biology
These are a few of the groupings participating (CBIO)
in drug discovery and development at UCT: • The Biopharming Research Unit
• The Structural Biology Research Unit
• The UCT node of the DST/NRF Centre of
IDM Excellence for Biomedical TB Research
The Institute of Infectious Disease and
Molecular Medicine (IDM) is a trans-faculty,
multidisciplinary postgraduate research H3D Drug Development
enterprise that operates in the fields of infectious & Discovery Centre
disease and molecular medicine research. It is H3D is an accredited University of Cape Town
distinguished by the ability to drive world class research centre within the Faculty of Science.
research at the laboratory-clinic-community It has strong affiliations with the Faculty of
interface by engaging a wide Health Sciences and, more specifically, the
range of scientific and clinical Division of Pharmacology and the Institute for
disciplines. Infectious Diseases and Molecular Medicine
(IDM). H3D operates within UCT’s world-class
Together, the Members of the IDM represent translational medicine research environment.
more than 20 research groupings of varying H3D is Africa’s first integrated drug discovery
size, scope and type. and development centre. The Centre was
founded at UCT in April 2011 and pioneers
These include: world-class drug discovery in Africa. It focuses
on the identification of new drug candidates
Three multi-investigator groups that operate to combat diseases such as
in the TB/HIV space malaria and tuberculosis,
• The Clinical Infectious Diseases Research but also the development
Initiative (CIDRI) of African scientists.
12 R-2-M ROUTE-TO - M A R K E T G U I D E FO R I NVE N TO R S

Founder, Prof Kelly Chibale says that Pharmacology

historically, several factors have hampered UCT’s Pharmacology division provides a clinical
African-led innovation in drug discovery. and laboratory service to Groote Schuur
Among these was the absence of a critical hospital, as well as secondary and primary
mass of appropriately skilled scientists, along centres.
with poor access to infrastructure to enable
technology platforms and expertise. Some of the services it offers include:
• Therapeutic drug monitoring with input
from clinical pharmacologists for a wide
Scientific Computing variety of drugs, including antiretroviral and
The Scientific Computing Research anti-tuberculosis drugs
Unit (SCRU) directed by Prof Kevin • Clinical consultation to regional hospitals
Naidoo is built from the following laboratories: • Policy advice in the rational and cost-
• Computation & Modelling Laboratory1 effective use of drugs for local hospitals, the
• Cancer Translational Science Laboratory2 Western Cape Provincial Coding Committee,
• Informatics & Visualisation Laboratory3 the National Essential Medicines List
Committee, and international guidelines on
The SCRU’s research groups are mostly HIV, TB, and malaria.
interested in the development and application • Pre-clinical and clinical research focused on
of methods useful to Life Scientists and drugs for malaria, tuberculosis, and HIV.
Material Scientists.
The division also contributes to national
They develop computational and informatics medicines regulatory and pharmacovigilance
software, using methods in applied activities of the Medicines Control Council and
mathematics and physics to construct internationally through the Uppsala drug safety
algorithmic solutions useful to chemists and monitoring centre.
biologists.
The Medicines Information Centre provides a
The Cancer Translational Science Laboratory telephonic consultation service for healthcare
applies the computation and informatics professionals and runs the National HIV &
technologies to provide models for TB Healthcare Worker Helpline. The division
experimental scientists aiming to achieve produces the South African Medicines
Translational Research goals in medical and Formulary, currently in its 12th edition.
chemical science.
The research in these fields is broad and
Visit the Scientific Computing website for more encompasses drug discovery, pharmacokinetics
details4. and pharmacodynamics, pharmacometrics,
pharmacogenomics, clinical trials,
pharmacovigilance, and pharmacoeconomic
evaluation.

1
http://www.scientificomputing.uct.ac.za/scru/research/computation-modelling/
2
http://www.scientificomputing.uct.ac.za/scru/research/cancer-translation-laboratory/
3
http://www.scientificomputing.uct.ac.za/scru/research/informatics-visualisation/
4
http://www.scientificomputing.uct.ac.za/

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Figure 4: Key Phases in Taking a Pharmaceutical to Market.

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5 Combining Effective Intellectual

Property Protection and Publication:
the UCT Strategy
5.1 When to patent? The difference stems from the need to
Managing the patenting/ publish in a university environment.
publishing tightrope walk
In his 2014 review of the UCT pharmaceutical To meet the novelty requirement in
IP portfolio, Dr Richard Gordon concluded patenting one needs to file a provisional
that UCT files patents several years too patent application ahead of publication or
early, when compared to a pharmaceutical public presentation of the work on which
company’s practice (Figure 5). the invention is based.

Drug Discovery Value Chain

LEAD GENERATION LEAD OPTIMISATION PRE-CLINICAL CLINICAL TRIALS

Lead Candidate Formulation Toxicology

Screening Hit-to-lead optimisation profiling API synthesis PI PII PIII PIV

1 YEAR 2-3 YEARS 1-5 YEARS 7-9 YEARS

University patenting Typical point where

historically initiated a pharmaceutical
company patents.
Ideal point for
university patenting.
FIRST KEY MILESTONE SECOND KEY MILESTONE MAJOR MILESTONE
Activity in an in vivo disease model, No toxicity, API made No toxicity
good ADMET and PK profile Formulation complete Cures patients
Regulatory dossier filed Outperforms standard cure

Licensing deal size Break even $5 - $10M >$100M

Figure 5: Industry vs University Patenting Point and Value Propositions

Early patenting negatively impacts One strategy to address this has been
the value of the IP by shortening the the introduction of a confidential thesis
commercial life of the patent. A patent procedure at UCT, which enables a PhD
has a life of 20 years and it takes 12 to 15 thesis or and MSc dissertation to be
years to get a pharmaceutical product to maintained confidential for a period,
market. So, ideally one needs to patent whilst drug development is actively
as late as possible, else the commercial pursued, without impacting on the
partner would only have as little as five student’s graduation.
to eight years in which to recoup their
investments costs and generate a return. The second strategy attempts to rapidly

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PHARMACEUT i ca l PR O D U CTS 15

determine whether there is any merit and outsourcing to suitable service

in protecting the IP by conducting the platforms. Once the provisional patent is
necessary screening tests (generally applied for at the end of the fast-tracked
achieved in 3 to 6 months). If the development period, publication can
outcome of the tests looks promising, proceed (Figure 6).
then hopefully the researchers will
see the benefit of delaying publication Should the initial tests prove negative,
by a couple of years whilst development there will be no merit in protecting the
is fast-tracked; RC&I will assist with IP and the publication can proceed
fund raising for the development work immediately.

Pass 2 year confidentiality

NEW Rapid
DRUG ADMET
fail PUBLISH

Figure 6: Assessment and Publish / Patent Decision

UCT’s Preferred Drug Development Strategy

Develop Initial Outsource Decide on Fast-track Patent License to

lead efficacy ADMET – publication/ further commercial
testing encourage maintain development partner (biotech
in vitro use of confidentiality company or
platforms pharma company)

5.2 Why file a patent? for the commercial firm, during which
In the pharmaceutical space there has time they can recoup their investment.
been tension between patent protection When patents expire, generic drugs are
of pharmaceutical drugs and affordable generally waiting in the wings and enter
access especially in developing countries the market rapidly, significantly lowering
and for specific diseases (e.g. TB and HIV, prices.
etc.).
UCT elects to file patents for HIV and TB-
An issue is, however, that market related drugs, in particular, as a means
protection is required to encourage of ensuring the drug has the potential
a commercial partner to invest the to reach the market and it permits the
significant amounts required to bring university to control the terms of the
the drug to market, taking it through licensing deal. This is also in line with
the regulatory approvals, building up a the Intellectual Property from Publicly
production facility and distributing the Financed Research and Development
product. Act, which requires UCT to protect and
importantly commercialise IP emanating
A patent provides temporary protection from UCT’s research wherever possible
16 R-2-M ROUTE-TO - M A R K E T G U I D E FO R I NVE N TO R S

– particularly where there is a societal be specific to the mode of intended

benefit as opposed to a purely financial administration.
one.
Finally, if the method of synthesis is novel,
Currently in South Africa, one would need that too may be considered for protection.
to partner with a foreign commercial
partner who has access to the funding Need for Examples
required to bring a product to market. In For each of the “classes of variant” in a
licensing, UCT would seek to negotiate Markush structure one should have a
with the licensee to ensure that the drug representative example included in the
was made available in South Africa and patent specification to support the claims
developing countries at an affordable being made. Often inventors rely on the
price – especially to the public sector. 12-month provisional period to complete
the set of examples as they may not
all be available at the time of filing the
5.3 Patenting a drug provisional patent application.
Details of the patenting process, the
requirements for novelty, inventiveness Exclusions
and utility are available in both the UCT UCT filed a patent, which protected
Inventors Guide and on the RC&I website: analogues of the natural molecule
www.rci.uct.ac.za. They will not be dealt ajoene, which is found in garlic, for
with here. Some specific issues will, their anticancer properties. The natural
however, be discussed.

Compound claims can be made quite

broad by using a generic structure
onto which different chemical groups
can be substituted; these are known as
“Markush” patent claims.

An example in Figure 7 taken from a UCT

patent on dibemethins and their use as
anti-malarials.

In subsequent, often dependent claims,

one will seek to cover specific molecules
that are regarded as leads in the drug
discovery programme. One can then relate
the use of the drug for application in the
treatment or prevention of a particular
disease, e.g. for use as an anti-malarial.
One may also claim a pharmaceutical
composition, in which the active is
combined with pharmaceutical carriers,
binders, etc. The formulations may also Figure 7: UCT Patent example

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PHARMACEUT i ca l PR O D U CTS 17

molecule was characterised and known, A blog post by Joel Kirschbaum (UCSF
so was not included in the patent and a Technology Transfer Director) provides
molecule that had been published as part insight into whether or not drug
of a thesis was also specifically excluded. discovery targets identified through
university research should be patented2.
Should one protect drug targets?
Historically, patents tended to be filed Novelty Searches
for a drug target and, in UCT’s case, An excellent resource on search for so-
crystal structures were protected for the called “prior art”, i.e. published literature
Angiotensin Converting Enzyme (ACE) C and patents that could disclose your
and N domains. particular molecule(s), is Chemistry
and Pharmaceuticals Searching Best
This IP is profiled in our Innovation at Practices by Intellogist3:
UCT 2010 book1, available as a download
from the RC&I website. The real value They highlight the challenges that are
lies, however, in the actual drugs that are encountered by a searcher, especially
developed based on the target. where Markush patent claims (as
described above) are involved. With
In the case of ACE, it was developing novel different naming conventions it is
C-domain-selective inhibitors – these possible for a compound to also have
inhibitors can be patented in their own more than one formal name, although
right and two lead molecules have been this is often overcome by using the
patented. Chemical Abstracts Service (CAS)
10-digit unique compound identifier.
An infringer of a patent can only be
pursued once a patent has been granted, Chemspider4 is a free database,
which can take more than four years. provided by the Royal Society of
Typically, the university researcher would Chemistry, which collates chemical
want to publish the new drug target as structure information from a variety
soon as a provisional patent application of sources and also enables structure
had been filed. searches to be conducted by drawing
your structure using several different
Drug discovery companies could use the types of on-line editor.
target in their screening from the time
that it is published and would likely have The European Bioinformatics Institute
identified their lead molecules by the (EBI)5 also launched a free database that
time the patent for the target actually allows searches to be conducted on 15
came into force. It is only when the million chemical structures.
target has been kept confidential that it
has real commercial value. Derwent, a proprietary patent database,
which has had a long association with
More recently, in line with international the pharmaceutical industry, uses
trends, UCT focuses patent resources specific electronic indexing of chemical
on protecting the actual drugs that are formulae to facilitate searching.
developed, rather than the targets.

1
http://www.rci.uct.ac.za/sites/default/files/image_tool/images/100/innovation2010.pdf
2
http://mysdscience.com/group/scienceentrepreneurs/forum/topics/2110706:Topic:2035
3
http://www.intellogist.com/wiki/Chemistry_and_Pharmaceuticals_Searching_Best_Practices
4
http://www.chemspider.com/
5
https://www.surechembl.org/search/
18 R-2-M ROUTE-TO - M A R K E T G U I D E FO R I NVE N TO R S

6 Role of the Technology Transfer Office

The Research Contracts and Innovation Enterprise outsources most/all of these
Department (RC&I) acts as the liaison between activities as this is seen as the most effective
UCT’s research community and the private way to complete a pre-clinical dossier. Having
sector with regards to intellectual property, experts do the work, in a quicker time should
commercialisation and business development be seen as an investment in future returns and
activities. RC&I has helped to transfer not a liability.
numerous technologies from the university
laboratories to industry both locally and
internationally. 6.1 Intellectual Property (IP)
Protection
RC&I provides three key areas of support: RC&I assist researchers with the
1. IP Protection. Assistance with the identification, review and protection
screening of research outputs and the of IP arising from their research and
protection of intellectual property (IP) liaise with patent attorneys who are
generally through patenting; appointed by RC&I to prepare and file
patent applications and manage the
2. Technology Development (Innovation). patent examination process. UCT has
Fundraising to support the maturation of funding to support IP protection (which
the technology, and outsourcing where is supplemented by the National IP
necessary and moving the project through Management Office [NIPMO]) that is
the various Technology Readiness Levels administered by RC&I.
(TRLs); and
Following disclosure of an invention to
3. Technology Transfer / Commercialisation. RC&I the patent process involves the
Understanding the specific market that filing of a provisional patent (which
a drug will be entering (e.g. competitor runs for 12 months), filing of a Patent
drugs, etc.), marketing or advertising Co-operation Treaty (PCT) international
the IP both generally and to identified patent application (which lasts for 18
targets, e.g. to pharmaceutical companies months) and finally regional and national
whose product portfolios your drug will phase applications which, following
complement. successful examination where applicable,
result ultimately in granted national
Funding: a fund is needed to develop patents.
projects to a point where they are
commercially attractive. The fund needs to be A patent’s lifespan is 20 years, and this
sizeable, and flexible to drive projects forward runs from the time of filing the full
quickly. application (most commonly this is the
PCT filing).
Outsourcing: The quickest way to progress
a project and fill key information gaps is The patenting process is covered in more
to outsource key components. Cambridge detail in the UCT Inventors Guide1.

1
http://www.rci.uct.ac.za/usr/rcips/ip/inventors_handbook.pdf

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6.2 Technology Development • In vivo disease models: Does it cure the

Outsourcing key components to access disease in an animal model? Very few
skills (for small studies) is a wise strategy models are available in South Africa
and is simple to implement. For drug and would need to be outsourced
discovery, there are three key activities globally. This study phase presents the
that need to be considered: key hurdle in determining whether
a compound is worth patenting, as
• In vitro ADMET: This is a minimum activity in the disease model is the value
requirement and is cost effective. It point of inflection. It is vital that the
gives a guide to the physicochemical DOSE is known. Models can be carried
properties of the molecule and out at Contract Research Organisations
highlights any issues that may be who tend to specialise in these areas.
encountered. These properties Prices vary considerably depending
include: solubility and cardiotoxicity on the model, species of animal and
(hERG), etc number of animals used. For example:
Budget: R10-20,000. CNS and Alzheimer’s experiments cost
more than $10,000 per compound,
• In vivo pharmacology (PK): This is while Respiratory models cost $7,000-
a basic requirement, as it is simply 8,000 per compound.
not possible to make claims on the
potency of a substance. Companies Examples of organisations include:
offering these services and include1: • Argenta: https://www.
• Covance: www.covance.com argentaglobal.com/
• PPD: www.ppdi.com • Asthma: Newcastle
• Parexel: www.paraxel.com University, Australia
https://www.newcastle.edu.au/
• Quintiles: www.quintiles.com
https://www.newcastle.edu.
au/highlights/our-researchers/
The companies mentioned above are
health-medicine/biomedical-
enormous global CRO’s who focus mainly
sciences-pharmacy/lessons-from-
on clinical trials. They do however, do
experimental-models-of-disease
in vivo pharmacology.
• Oncology: Oncodesign
• BioFocus: www.biofocus.com
http://www.oncodesign.com
• Wuxi App Tech: www.wuxiapptec.
• CNS: Porsolt, Evotec
com
http://www.porsolt.com;
• ChemPartners: www.shangpharma. www.evotec.com
com/chempartner
• Various: Envigo - formed in 2015
• Pharmacopeia: www. by the amalgamation of several
pharmacopeia.com companies, including Huntingdon
• Albany Molecular: www.amri.com Life Sciences to become the
• Fideltia: www.fidelta.eu/ largest non-clinical CRO in
• Syngene: www.syngeneintl.com Europe. https://www.envigo.com/

1
UCT does not endorse any of the companies listed and the list merely indicates some current service providers. Other service providers will have been
omitted through no intention of the university.
20 R-2-M ROUTE-TO - M A R K E T G U I D E FO R I NVE N TO R S

A commercial partner or a major 6.3 Gate Review

translational research organisation For effective innovation, three parallel
could also provide an alternative processes need to be managed
approach to access such models and holistically to keep them synchronised.
assays could be accessed through a These are technology development,
collaboration. For example, Cancer intellectual property protection and
Research UK would be an ideal partner commercialisation (which includes
to access cancer Xenograph models. market research).
Although ideal, these relationships tend
to take longer and become clouded by They need to be matured simultaneously
IP constraints – hence outsourcing is as they impact on one another, e.g.
normally considered a more attractive knowledge of potential international
model. markets will inform the patenting
strategy and identifying the countries
If a program is showing promise, a in which patents should be applied for
clinical candidate package can be to maximise IP value. Knowledge of a
completed and a dossier compiled for market will also influence technology
commercial partners. These studies development, e.g. scale of manufacture,
typically cost about R1.5M and include quality or regulatory entry barriers (e.g.
key toxicology studies such as 7-14 rat clinical trials, certification), etc.
toxicology, Maximum Tolerated Dose
(MTD) calculations, etc. If these studies RC&I has established and is refining a
are successful, the program will have stage-gate process, largely driven by the
significant commercial potential, which stages of the patenting process (Figure 8),
a commercial partner may find of to review these areas and guide prudent
interest. spending of UCT’s patent budget.

DISCLOSURE PROVISIONAL PCT NATIONAL

Technology

IP Protection

Commercialisation

Figure 8: Stages of the Patenting Process

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PHARMACEUT i ca l PR O D U CTS 21

7 Seed and Innovation Funding

7.1 Seed Funding the SAMRC and the Department of
Various forms of seed funding are Science and Technology. They also
available within UCT and are administered create pools of funding that rely on co-
by RC&I, such as the PreSeed Fund and investment by overseas organisations
the Technology Innovation Agency (TIA) to leverage South African funding.
Seed Fund. SHIP funds innovation projects
focused on the development of new
These smaller amounts of funding drugs, treatments, vaccines, medical
can be used to support outsourcing of devices and prevention strategies.
ADMET testing, or for certain focussed • Bill & Melinda Gates Foundation: www.
experiments that aim to address gatesfoundation.org
significant concerns or provide key • Medicines for Malaria Venture (MMV):
proof of concept. This speeds up the www.mmv.org
drug discovery process and can inform • Wellcome Trust: www.wellcome.ac.uk
patenting decisions, but importantly the • Partnerships with large
outcomes reduce risk for a next-stage pharmaceutical companies, typically
investor. following their licensing of UCT IP.

Information regarding current seed

funding can be found on the RC&I
website1. You can also visit the TIA
website2 to find out more.

Regular calls also go out on the Research

Funding mailgroup.

7.2 Innovation Funding

Multimillion-Rand funding can be
sourced from a number of different
organisations, both in South Africa and
overseas, with funders typically having a
particular focus.

Sources that UCT researchers have

accessed include:
• TIA
• The South African Medical Research
Council (SAMRC) through its Strategic
Health Innovation Partnerships (SHIP)
unit3. This is a partnership between

1
http://www.rci.uct.ac.za/RC&I/fundinnov/overview
2
www.tia.org.za
3
http://www.samrc.ac.za/innovation/strategic-health-innovation-partnerships
22 R-2-M ROUTE-TO - M A R K E T G U I D E FO R I NVE N TO R S

8 Commercialisation
from a UCT Perspective
UCT approaches technology licensing and We also look for potential partners who are
commercialisation on a case-by-case basis and able to assist the innovation process through
can adopt a variety of strategies to achieve this, technology development, especially through
such as entering into both exclusive and non- scale-up, clinical trials and regulatory approval.
exclusive license agreements, or considering We often form consortia and partnerships to
the outright sale of its intellectual property, access funding to support these initiatives.
as well as taking equity (i.e. holding shares) in One of our core objectives is to stimulate
start-up and spin-out companies depending the growth of the South African economy
on the circumstances. by fostering small business development

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PHARMACEUT i ca l PR O D U CTS 23

and/or the creation of jobs through the their funded research (in the case of BMGF it is
commercialisation of UCT’s intellectual according to their “Global Access Policy”).
property. In the pharma sector, however, UCT
needs to partner with a biotechnology- or large Assignment Agreements usually include
pharmaceutical company to take the new a single payment for the IP at the time of
drug to market, due to the level of investment signing the contract, although instalments can
that is required. There can be scope for the be negotiated so that staggered payments
creation of a biotech start-up to focus on are made on completion of certain milestones
drug development outside of the academic (e.g. completion of different stages of clinical
environment. Large pharma companies often trials). Licenses tend to be based on royalties
look to acquire these small biotech firms to fill pegged as a certain percentage of invoiced
their pipelines. sales, but again may include a combination of
upfront (on signing) and milestone payments.
RC&I would negotiate an agreement with the These would effectively lead to a degree of
commercial partner, which could be in the risk-sharing, i.e. the licensor does not receive
form of: everything upfront but is rewarded as the drug
• An exclusive license to the intellectual is derisked and moved through the hurdles.
property for commercial exploitation –
this can be further limited to a particular Inventors may also be interested in forming
field (e.g. type of disease) or a region (a spin-off companies based on the IP that they
particular territory where there is patent have developed, and RC&I will assist them with
protection). This would mean that the developing Business Plans and conducting
licensee would have the sole right to use market research. RC&I Pre-Seed funding is
the IP for commercial purposes. Note that available to support these activities, which
UCT retains a right to continue to use the often require the advice of consultants.
IP for research and teaching purposes.
• A non-exclusive license, which means Licensing, as opposed to spin-off company
that one or more parties may have rights formation is, however, the most likely
to the IP. mode of commercialisation that UCT uses
• As assignment of the IP: Although less in the pharmaceutical space. This is due
frequent, it can sometimes be possible to the amount of funding that is involved,
to transfer the ownership of the IP to the the need for the scale-up of the actual
other party. chemical manufacture of drugs under Good
Manufacturing Conditions (GMP) for both
By virtue of the terms of some research clinical trials and commercial sales, the clinical
contracts, IP may also be automatically trials and regulatory approvals process and the
assigned to the funder, which is another mode marketing.
of innovation. In other cases, a funder - such as
the Bill and Melinda Gates Foundation (BMGF)
- may have specific requirements in terms of
commercialisation of the IP emanating from
24 R-2-M ROUTE-TO - M A R K E T G U I D E FO R I NVE N TO R S

9 Patenting and Data Exclusivity

as Protection Strategies
Intellectual Property (IP) protection plays generic manufacturers to rely on the data once
a crucial role in providing companies with the period has ended. This tends to delay the
incentives to invest in the long, costly journey competitor’s entry into the market, although it
of drug discovery. Strong IP protection does not preclude them from paying for and
makes it possible for companies to recoup gathering their own data. This can provide the
their investments, make a return for their initial applicant with a short additional period of
shareholders and fund future research. “protection” beyond the life of the patent.
Clinical trial data is submitted to a regulator
as part of the approval process. Generic Generic manufacturers typically target
manufacturers (competitors) may rely on the launching their own products immediately on
original company’s data to save the cost of the expiry of the patent. In certain instances, a
having to do trials themselves and also to fast- generics company may negotiate a deal with
track their applications. the data owner to gain early access to it.

Certain countries (e.g. USA’s FDA) will grant The FDA also offers two other key targeted
a period of “data exclusivity” and only permit incentives:
- Companies can receive an additional six
months of exclusivity when completing
and submitting paediatric studies that
meet the terms of a written request from
FDA.
- The first company obtaining FDA
approval of a designated drug
developed to treat a rare disease or
condition can receive seven years of
market exclusivity (i.e. another product
for the same disease or condition cannot
be approved during the seven years).
These “orphan” or “neglected” diseases
are often overlooked due to their
comparatively small market sizes. But
as “large markets” become congested
with little room to create a new drug
that has significantly greater benefit,
these neglected disease markets are
becoming increasingly attractive. You
can read more about this in section 12.2.

The PhRMA website is a great resource for

finding out more about protection strategies .

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10 Key Considerations
when Setting up Clinical Trials
‘A properly planned clinical trial is a powerful investigator (person taking responsibility
experimental technique for assessing the at the investigational site), and others,
effectiveness of an intervention’ 1. against claims arising from the trial. If
the funding body is unable to provide
Regulatory and ethical requirements for the indemnity OR fulfil the roles of sponsor
management and reporting of clinical trials were according to GCP-SA then UCT will need
originally developed for trials involving medicinal to take this responsibility. In order for this
products. However, these are now considered best to be agreed by the Faculty of Health
practice for all trials involving human participants, Sciences, there is a process to be followed.
including trials for complex interventions.
You can read more about it on the Clinical
What follows is a summary of key requirements Research Centre website4.
for setting up clinical trials from two sources:
the South African Good Clinical Practice (GCP)
Guidelines2 and the South African Medicines 10.3 Clinical investigation
Controls Council (MCC) regulatory requirements3. protocol (CIP)
The protocol is drawn up, agreed and
justified by the sponsor, the Principal
10.1 Definition and aim of clinical Investigator (PI), and/or sub-investigators.
investigation
Clinical evaluation is the assessment and The Clinical Research Centre (CRC) at UCT
analysis of clinical data pertaining to an has produced a template to assist PIs to
intervention in order to verify the clinical complete a CIP ensuring all aspects of the
safety, efficacy and/or effectiveness of the trial are considered in advance of applying
intervention. for ethical approval.

You can find it on the CRC website5.

10.2 Sponsorship of a clinical
investigation Templates are provided for trials of
The sponsor is an individual, company, medicinal products and trials of complex
institution or organisation taking interventions. Key considerations at this
responsibility for the initiation, stage include:
management, and/or financing of a 1. The Investigator’s Brochure (IB) - for
clinical trial. unregistered products, indications,
doses or uses, etc. This must be
The sponsor ensures that quality available to provide the PI with the
assurance and quality control principles preclinical, clinical and/or performance
apply to the investigation. An individual data of the intervention thus far.
is highly unlikely to take on the full role of 2. Case Report Forms (CRFs) – these
sponsor; typically, if a study is funded by forms must be carefully designed to
industry then industry takes this role. ensure that all relevant participant data
is captured for the analysis. The CRFs
However, a key component of being a are the subject of the monitor- and
sponsor is the provision of indemnity audit reviews. They may be in paper
(including no-fault insurance) for the or electronic format and must be

1
http://www.phrma.org/sites/default/files/pdf/rd_brochure_022307.pdf
2
http://www.crc.uct.ac.za/gcp
3
http://www.crc.uct.ac.za/mcc
4
http://www.crc.uct.ac.za/crc/sponsorship
5
http://www.crc.uct.ac.za/crc/services-facilities/study-design-and-protocol-development.
26 R-2-M ROUTE-TO - M A R K E T G U I D E FO R I NVE N TO R S

subjected to quality control or assurance A summary of considerations can be

checks throughout the study by the trial found at on the CRC website1.
staff, monitors and/or auditors.
3. Monitoring Plan – The sponsor will
designate a monitor and formulate 10.5 Clinical investigation documents
a risk-based monitoring plan for and documentation
each study. Monitoring of a study The general rule of thumb in clinical trials
is a constructive and collaborative is that if it is not written down, it did not
evaluation of adherence to the CIP happen. This is intended to reduce risks
and GCP-SA by the study team. Non- to the patient and ensure adherence
adherence is reported to the sponsor to the CIP. The safety of participants is
who addresses the issue with the continuously logged and monitored.
relevant team or client.
4. Site selection and training – every A key component of documentation is
member of a study team at every site the amendment of documents such as
must be GCP-SA trained and trained in the CIP, informed consent, IB and the CRF
the study specific documents. as required throughout the investigation.
5. Data Safety and Monitoring Documents must be version controlled
Committee (DSMB) – the sponsor may and logged.
decide to establish a DSMB depending
on the category of risk for the Further elaboration on the documents
intervention and for the participants. required for clinical investigation can be
6. Agreements and Contracts – These found on the CRC website2.
should be drawn up between the
sponsor, the PI, any outsourced
components, e.g. laboratories, and 10.6 Investigational product
should be taken through the FHS accountability
approval process before reaching the Access to the investigational product is
contracts office at UCT. controlled and it may only be used in the
investigation according to the CIP.

10.4 Clinical investigation conduct The sponsor either takes responsibility

The clinical investigation must for, or delegates, the role of ensuring and
be conducted according to the documenting the physical location of all
CIP. Planning the conduct of the products from shipment to investigation
investigation is arguably the most site until return or disposal.
important stage of the investigation.
Time spent here can save money and
achieve study closure on schedule. 10.7 Safety evaluation and reporting
All adverse events (AE) must be
As part of the plan, a full delegation log for adequately evaluated for relevance to the
roles and responsibilities must be drawn intervention or the study in general.
up and signed by each team member. It A report must be completed and
is the responsibility of the sponsor and submitted to the HREC, MCC and the
the PI to ensure each team member is sponsor according to their requirements.
adequately trained for their designated
role. The ability of a team to adhere to Forms for reporting AEs are available on
the CIP is evaluated by the monitor as the Faculty of Health Sciences website3.
described above.

1
http://www.crc.uct.ac.za/crc/toolkit
2
http://www.crc.uct.ac.za/crc/toolkit
3
www.health.uct.ac.za/fhs/research/humanethics/about

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10.8 Research governance financial implications for pharmaceutical

Oversight of the planning, conduct, safety companies. Buonansegna et al.1 (2014)
and quality control of an investigation is found that there are a number of factors
achieved by the establishment of a Trial that contribute to the failure of clinical
Steering Committee (TSC) and a Data trials. These include:
Safety and Management Board (DSMB). - chaotic and slow patient recruitment,
Members of these two committees are - lack of experience in choosing and
determined by the sponsor and the PI. monitoring partners,
- lack of feasibility of the study protocol,
A key member of the DSMB is a statistician. - low quality of the registered data,
If the trial is small, the role of the two - too high incidence of serious adverse
committees may be subsumed by the TSC. events and severe incidents,
- unmanageable level of portfolio
complexity,
10.9 Investigation close-out and report - incorrect assessment of the market
Routine close-out activities include potential or returns.
ensuring that:
• all documents are complete, and According to a recent study by The
quality checked Tufts Center for the Study of Drug
• all data queries are addressed, Development (Tufts CSDD), which
• remaining investigational products analysed the reasons for clinical failures of
are returned or disposed of 410 drugs, there are different reasons for
• all outstanding issues are resolved, failure in each of the different phases.
and all necessary parties informed
(HREC, MCC etc.) The leading cause of Phase 1 failures
proves to be commercial viability, as
A written Clinical Investigation Report opposed to safety.
(or equivalent) is then completed and
submitted to all parties. Safety issues account for one-third of all
drugs that failed in Phase I and Phase III
studies; and for 17% pf all Phase II failures.
10.10 Why clinical trials fail
A large percentage of new drug Efficacy issues account for more than half
candidates fail to reach the market during of the failures in Phase II and Phase III
clinical trials. Of course, this holds massive (54% and 52% respectively).

Reasons for Clinical Failures by Phase

60%

50%
Safety
40%
Efficacy
30%
Commercial Viability
20%
Other (e.g. formulation problems)
10%

0% Source: Tufts CSDD

PHASE I PHASE II PHASE III

Figure 9: Commercial viability - as opposed to safety - is the leading cause of Phase I failures

1
http://www.appliedclinicaltrialsonline.com/reasons-clinical-failures-phase
28 R-2-M ROUTE-TO - M A R K E T G U I D E FO R I NVE N TO R S

11 ETHICS
All clinical investigations should be conducted and redundancy, and anticipating
in accordance with the ethical principles needs for reliability, replicability, and
embedded in the Declaration of Helsinki1. The verification);
principles described here are the rights, safety • The design, methodology and execution
and well-being of human subjects which are of their research;
most important and should prevail over the • The development of a research plan that
interests of science and society. yields a high degree of validity;
• The identification, where appropriate, of
UCT has a strict code of ethics for research alternative hypotheses, methodologies,
involving human participants. The following and interpretations of data;
has been adapted from the full document • The dissemination of findings, and their
that is available on the UCT website. limitations, to ensure accessibility and
opportunities for peer-review.
UCT adheres to standards and principles
under which its investigators must aim to When planning their research, researchers
conduct research with scholarly integrity and should consider and articulate the
excellence. It requires close attention to social appropriateness and foreseeable
responsibility, and respect for the dignity, self- consequences of their research in the research
esteem, and human rights of the individuals proposal. In health science research, this often
who may be involved in or affected by research. requires consideration of the full range of
adverse events and problems that may occur
The University aspires to articulate standards and distinguishing which are likely, serious,
of conduct and procedures that ensure proper and relevant to the choice of participation.
accountability. In the pursuit of its ideals, the This merits explanation in study materials.
University subscribes to the interdependent Researchers should also keep in mind the
principles of scholarly responsibility, integrity requirement of prior research ethics review
and honesty of human dignity and of academic and clearance when planning the timeframes
freedom and openness. for their research. Ethics approvals may not be
obtained retrospectively.
Of specific relevance to investigators in health
sciences and those who may pursue novel Ethics considerations for research participants
medical agents, drugs, therapies, and devices are paramount. Research participants
with implications for intellectual property, should not be harmed in the course - or as a
UCT affirms the requirement that all research consequence of research, except in those cases
involving human participants be subject to where the research participants have no moral
prior ethics review. This must be in accordance claim not to be harmed in the ways that the
with faculty guidelines and the standard research may harm them.
operating procedures of the ethics committees
charged with the review and oversight of Researchers wishing to undertake research
research. that may harm participants must demonstrate
that, according to faculty guidelines, the
For purposes of ethics and responsible participants have no moral claim not to be
conduct, investigators assume broad and full harmed in the relevant ways. Risks of harm
responsibility for the following: must be minimised (though not necessarily
• The quality and originality of their eliminated as this may not be possible)
research questions (avoiding both waste and balanced against benefits. Specifically,

1
World Medical Association Declaration of Helsinki: ethical principles for medical research involving human subjects. JAMA. 2013 Nov 27;310(20):2191-4.

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PHARMACEUT i ca l PR O D U CTS 29

investigators must minimise or avoid exposure increasingly important considerations that bear
of participants to foreseeable legal, physical, on innovation. They relate to the responsible
psychological, or social harm or suffering conduct of research defined as responsibility
that might be experienced in the course of and care for the relationships on which the
research. discovery and dissemination of knowledge
depends, and the resonance between the
The risk of harm and the likelihood of direct conduct of research and the context(s) in which
benefit to participants must be discussed the research takes place and/or has effect.
as part of the consent process. Researchers
should be especially sensitive to the interests No research may be conducted on human
and rights of vulnerable populations such subjects without the signed permission of a
as minors, elderly persons, very poor and/or Human Research Ethics Committee (HREC).
illiterate persons.
The HREC will consider many aspects of the
As a guiding principle in human subjects study including the following principles:
research, participants should give informed, 1. Improper influence or inducement
voluntary consent, when appropriate, to 2. Participant informed consent,
participation in research. This includes respect confidentiality and privacy
of the right of individuals to refuse to participate 3. Compensation and additional health care
or, having agreed to participate, to withdraw 4. Responsibilities of the personnel and
their consent at any stage without prejudice. their designated roles during the
investigation.
Investigators should provide information that 5. Study design and participant inclusion.
explains the aims and implications of the It is considered unethical to carry out an
research project, the nature of participation and inappropriate study design in order to
any other considerations that might reasonably answer the question.
be expected to influence their willingness to 6. If National and Regional HREC
participate. This information must be provided requirements are less strict than the
in language that is understandable to the International requirements for the
potential participants. While the importance of project, then the stricter requirements
informed consent does not preclude research will be upheld
that uses observation or deception as part of its
methodology, such research must be justified In addition to ethical approval, if the study is
in its protocol and comply with best practices to be carried out on patients at a provincial
and ethics codes of its scientific or scholarly hospital, it needs to be approved. You can read
discipline. more about this on the CRC website1.

Finally, the privacy and confidentiality interests This may seem like a daunting process but
of participants must be taken into account in there are many people with the expertise to
the research process. Information that may assist you if you are new to clinical trials, and
identify individual persons should not be used there are flow charts and tools designed to
in research findings, unless the person has make your journey easier. You can find the full
expressly agreed to its release, having had the policy document on the UCT website2.
opportunity to consider the implications of
such release. To take a study from conception to start-up
at UCT, please contact the CRC for further
Future uses of data and/or biospecimen information or assistance or visit the toolkit
samples that may be obtained in the course on their website: http://www.crc.uct.ac.za/crc/
of health science research are especially and toolkit

1
http://www.crc.uct.ac.za/crc/services-facilities/regulatory
2
http://uct.ac.za/downloads/uct.ac.za/about/policies/humanresearch_ethics_policy.pdf
30 R-2-M ROUTE-TO - M A R K E T G U I D E FO R I NVE N TO R S

12 Regulatory Issues
12.1 Regulatory Bodies when a generic drug product that is the
There are various regulatory bodies therapeutic equivalent to an existing
whose job it is to ensure that only drugs drug approved by the FDA is ready to
that are safe and effective make it to enter the market. The existing drug is
market. known as the reference listed drug (RLD).
In order for an ANDA to be approved,
The following two are most relevant to there must be sufficient information to
drug development at UCT: show that the proposed generic product
is pharmaceutically equivalent and
FDA Center for Drug Evaluation and bioequivalent (therefore therapeutically
Research (CDER) equivalent) to the RLD. To be
The US Food and Drug Administration’s pharmaceutically equivalent, the generic
(FDA) Center for Drug Evaluation and drug needs to contain the same active
Research regulates both over-the- ingredient(s) as the RLD. It must also be
counter and prescription drugs. Apart identical in strength, dosage form, route
from medicines, it is also responsible for of administration, and meet compendial
regulating personal care products such or other applicable standards of strength,
as fluoride toothpaste, antiperspirant, quality, purity, and identity.
certain shampoos and sunscreen.
The sponsor must also be able to
SAHPRA (formerly MCC) demonstrate that the proposed generic
Formerly known as the Medicines Control drug is appropriately labelled and that
Council (MCC), the South African Health all patent protection issues have been
Products Regulatory Authority regulates resolved.
the manufacture, distribution, sale, and
marketing of medicines. They work Fig. 10 provides a comparison between
according to a set of standards laid down the requirements of an NDA and an
by the Medicines and Related Substances ANDA. The primary difference between
Act (Act 101 of 1965). the application requirements is that the
preclinical and clinical data in the NDA
that establishes the safety and efficacy
12.2 NDA versus ANDA review process1 of the drug product do not need to be
A New Drug Application (NDA) is repeated for the ANDA.
required for any drug entering the
market for the first time and can only be Apart from the differing requirements
completed once preclinical and clinical in the submission of clinical data, the
data proving its safety and efficacy has remaining requirements including
been gathered. those for chemistry, manufacturing,
controls, testing, and labelling are similar,
An Abbreviated New Drug Application regardless of whether the application is
(ANDA), on the other hand, is required an ANDA or NDA.

1
http://www.researchgate.net/profile/Mi_Furness/publication/8617391_Regulatory_considerations_of_pharmaceutical_solid_polymorphism_in_
Abbreviated_New_Drug_Applications_%28ANDAs%29/links/54f4d3ad0cf2ba61506421e0.pdf

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PHARMACEUT i ca l PR O D U CTS 31

NDA versus ANDA Review Process

Brand name drug Generic drug

NDA Requirements ANDA Requirements

1 Chemistry 1 Chemistry
2 Manufacturing 2 Manufacturing
3 Controls 3 Controls
4 Labeling 4 Labeling
5 Testing 5 Testing
6 Animal Studies
7 Clinical Studies 6 Bioequivalence
8 Bioavailability

Figure 10: Comparison between NDA and ANDA requirements1

12.3 Approval FDA drug development The center does not actually test drugs
and approval2, 3 itself, although it does conduct limited
In the US, CDER is the largest of the research in the areas of drug quality,
FDA’s six centres. It has responsibility for safety, and effectiveness standards.
both prescription and over-the-counter
(OTC) drugs. The other five FDA centres FDA’s priority review voucher (PRV)
have responsibility for medical and program4
radiological devices, food and cosmetics, The FDA reviews most drugs under
biologics, veterinary drugs, and tobacco “standard” review times, meaning it
products. has ten months per product to make a
decision.
A drug company wishing to sell a drug in
the United States must first have it tested However, the review clock stops each
to prove its efficacy and safety. Once this time the FDA requests additional
is done, the evidence of these tests is sent information from a sponsor, adding
to the CDER. several months to the review process.
The FDA has the ability to accelerate
A team of CDER physicians, statisticians, its review in the hopes of getting
chemists, pharmacologists, and other products to market more quickly. Drugs
scientists reviews the company’s data intended for “serious conditions,” or
and proposed labelling. If they come which “demonstrate the potential to be
to the conclusion that a drug’s health a significant improvement in safety or
benefits outweigh its known risks, the effectiveness,” are reviewed under the
drug is approved for sale. FDA’s Priority Review Designation (PRD)
pathway, which takes six months instead
of the standard ten.

1
S Raw, Andre & Furness, Mi & S Gill, Devinder & C Adams, Richard & O Holcombe, Frank & X Yu, Lawrence. (2004). Regulatory considerations
of pharmaceutical solid polymorphism in Abbreviated New Drug Applications (ANDAs). Advanced drug delivery reviews. 56. 397-414. 10.1016/j.
addr.2003.10.011.
2
http://www.fda.gov/Drugs/DevelopmentApprovalProcess/HowDrugsareDevelopedandApproved/default.htm
3
http://www.fda.gov/Drugs/DevelopmentApprovalProcess/
4
http://www.raps.org/Regulatory-Focus/News/2015/07/02/21722/Regulatory-Explainer-Everything-You-Need-to-Know-About-FDA%E2%80%99s-Priority-
Review-Vouchers/
32 R-2-M ROUTE-TO - M A R K E T G U I D E FO R I NVE N TO R S

The FDA offers priority review vouchers When considering whether a drug is
(PRVs) as incentives to spur the suitable for use of its intended purpose,
development of new treatments for SAHPRA asses its relative risk against its
diseases that would otherwise not be benefits.
deemed worthy of a company’s time and
effort to develop. Like the MCC, SAHPRA operates through
external experts who are members
The table below provides a list of tropical of Council Committee structures.
diseases that are eligible to PRV: The Council has 9 active technical

Eligible diseases under the Tropical Disease Priority Review Voucher System
Malaria Blinding trachoma Schistosomiasis
Buruli Ulcer Cholera Yaws
Dengue/Dengue haemorrhagic fever Leishmaniasis Tuberculosis
Dracunculiasis (Guinea-worm disease) Lymphatic filariasis Fascioliasis
Human African trypanosomiasis Leprosy
Soil transmitted heiminthiasis Onchoceriasis
Added by Congress
Cuevavirus Ebolavirus Marburgvirus
Added by FDA Order
Chagas Neurocysticerosis

12.4 Approval FDA drug development committees, with more than 14 members
and approval from various institutions in the country.
SAHPRA drug development and approval
The South African Health Products These include the Clinical Committee,
Regulatory Authority (SAHPRA), formerly Pharmaceutical and Analytical
known as the Medicines Control Council Committee, Clinical Trials Committee,
(MCC), fulfils a similar role as the FDA. Names & Scheduling Committee,
The Medicines and Related Substances Veterinary Clinical Committee,
Amendment Acts of 2008 has given Pharmacovigilance Committee,
SAHPRA final authority over the approval Biological Medicines Committee,
of new products and medical devices. Complementary Medicines Committee,
Previously, this required the approval and Legal Committee.
of the Minister of Health, often causing
significant time delays.

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H3D Drug Discovery and Development Centre was
founded in 2010 as a University of Cape Town accredited
research centre. H3D currently consists of >60 dedicated
personnel working across the integrated medicinal
chemistry, biology and Drug Metabolism and
Pharmacokinetic (DMPK) platforms.

In addition to supporting our existing portfolio of

projects and collaborations, H3D offers standard
screening assays as a service. H3D is a TIA (Technology
Innovation Agency) platform and can offer these services
at cost for local academic collaborators.

Biology:
• In vitro whole cell screening against Mycobacterium
tuberculosis (Tuberculosis, TB), Plasmodium
falciparum (Malaria) and Gram negative bacteria
• Biology triage and target identification studies for TB
• In vivo efficacy studies for malaria
DMPK:
• Suite of in vitro assays, including solubility,
microsomal metabolic stability, and permeability
• In vitro and in vivo metabolite identification studies
• In vivo PK/PD (pharmacokinetic and
pharmacodynamic) studies in rodents

We are also open to collaborating on drug discovery

projects, particularly in our focus area of infectious
diseases.

Contact us:
• www.H3D.uct.ac.za
• H3D@uct.ac.za
• T | 021 650 5495

To be the leading organisation for integrated drug

Vision
discovery and development on the African continent
34 R-2-M ROUTE-TO - M A R K E T G U I D E FO R I NVE N TO R S

UCT appreciates and acknowledges the support that the National Intellectual Property
Offoce (NIPMO) provides in terms of patenting rebates received from the IP Support Fund,
resourcing of Research Contracts & Innovation (RC&I) and for the publication of this book.

Research Contracts & Innovation

2 Rhodes Avenue
Mowbray
7700

Email innovation@uct.ac.za
Phone +27 (21) 650 4015
Twitter @UCT_RCI
Web www.rci.uct.ac.za

This work is licensed under the Creative Commons Attribution-NonCommercial-NoDerivatives 4.0

A INNOVATION G U I D E F R O M L A B TO CO M M E R C I A L I S AT I O N
International License.
To view a copy of this micense visit http://creticecommons.org/licenses/by-nc-nd/4.0/