Pre-Clinical Drug Development
All drug development starts in the laboratory in the phase that is
termed pre-clinical development. This process generally takes up to 6
years or longer. When considering drug development, researchers must
consider several fundamental questions during the pre-clinical phase.
These questions are especially crucial in an orphan disease like CF
where the margin for error is much smaller than for more common
diseases. First and foremost, investigators must determine whether there
is an unmet need. Are there any therapies available that addresses a
certain area of the disease? Are the available therapies insufficient
either from an efficacy or safety standpoint? Of the currently approved
drugs, are there limitations on availability to everyone, whether due to
cost, lack of effectiveness or adverse reactions? Other questions that
must be considered include: what aspect of the disease will be targeted?
Will the drug have to be active in several organs or just one organ?
Within an organ, what process will be targeted? For example, in the
lungs, will the drug impact the basic defect, abnormal airway
environment, mucus obstruction, chronic infection or exaggerated
inflammation (Figure 1)? Is the target a cell, a receptor, or a
molecule? Will the drug correct an abnormal protein structure like a
CFTR corrector, decrease something produced in excess like a
pro-inflammatory mediator, or increase something that is not produced or
produced in relatively low concentrations like anti-inflammatory
molecules or CFTR in people with two nonsense mutations?
In a complex target like airway inflammation where there are many
triggers impacting dozens of molecular pathways that result in the
increased production of pro-inflammatory molecules or decreased
production of counter-regulatory molecules, it is often difficult to
determine the most efficacious target that is also a safe target. These
complexities have made developing new anti-inflammatory therapies for CF
extremely difficult. Over the last 30 years, dozens of anti-inflammatory
drugs being considered for CF have failed along the way during the
various phases of drug development(8-10). One candidate drug was
actually associated with increased pulmonary exacerbations, the opposite
of the intended effect(11). The clinical trial of this investigational
product provided a lesson that highlights the importance of having
adequate pre-clinical safety data in a disease-relevant animal
model(12). The past provides a cautionary tale for all future drug
development, not just for anti-inflammatory drugs.
During the pre-clinical phase of drug development, the efficacy of an
investigational product is typically demonstrated in both in
vitro and in vivo models. During pre-clinical experiments,
having the correct assay is the cornerstone. The ideal assay is simple,
high-throughput, directly relevant to the intended therapeutic target,
and has the ability to discriminate between more or less efficacious
analogous molecules. The investigator must consider what outputs should
be used to measure efficacy and safety and how those outputs might be
adapted for use in a clinical trial. Toxicology studies in
disease-relevant animal models are important in order to determine
dose-limiting toxicities and establish initial dosages that are likely
to be safe in human studies. These are required as a part of the
regulatory process and are ultimately geared toward minimizing risk of
untoward effects happening in human trials. For example, when studying
anti-inflammatory drugs, an important determination is at what dose
might an anti-inflammatory (the target effect) become an
immunosuppressive (an untargeted and potentially deleterious
effect)(13)? This points to the importance of studying anti-inflammatory
drugs in a representative model system, e.g., a CF mouse model with an
active infection similar to what might occur in the human CF airway,
versus a dissimilar animal model, e.g., a sterile mouse model. Adequate
safety must be established in animals before proceeding to clinical
trials in humans. Pre-clinical safety studies should be conducted under
good laboratory practice (GLP) guidelines, which is defined as “a
quality system concerned with the organisational process and the
conditions under which non-clinical health and environmental safety
studies are planned, performed, monitored, recorded, archived and
reported ”(14).
The ultimate goal of the pre-clinical phase of drug development is to
file an Investigational New Drug (IND) application with the FDA. The
FDA’s primary objective in evaluating pre-IND research is to ensure the
rights and safety of human subjects are being protected. During the
pre-clinical phase, several molecules in the same drug class may be
under investigation, but eventually, a single lead compound, typically
with a similar, backup compound, must be selected. Prior to the
selection of the lead molecule, various modifications are considered to
optimize activity and chemical properties to help ensure that the
sponsor has the ability to make enough of the investigational product
under good manufacturing practice (GMP) guidelines to complete all of
the non-clinical safety tests. Under these guidelines, the production of
an investigational compound must be consistently of high quality between
batches. In the pre-clinical phase, animal studies provide information
regarding the pharmacology and toxicology of the molecule under
consideration. Animal studies also provide a basis for conducting a
clinical trial. Typically, animal studies consist of a rodent species
and a large non-rodent species. Once short-term toxicology data are
available, a clinical trial can start, but human studies cannot be
longer in duration than the duration of animal toxicology studies. For
therapies intended for chronic use, six-month animal toxicology data are
necessary for registration of the drug. The purpose of the animal
studies is to provide information on a dose range or therapeutic window,
initial dosages, an estimation of the risk:benefit ratio for humans,
identification of target organ toxicities and safety margin, and
identification of surrogate markers to monitor during clinical
trials(15). At this point, an IND application is submitted to the FDA
prior to proceeding to a clinical trial (Box 1). Once the FDA approves
an IND, the investigator is able to proceed to human trials.
No overview of the pre-clinical phase of drug development would be
complete without some discussion of funding. It is during the
pre-clinical phase that collaborations between academic and industry
colleagues are often forged. Prior to this point, academicians often
secure research funding for pre-clinical studies from government
agencies such as the NIH or private foundations such as the Cystic
Fibrosis Foundation, amongst other sources. However, for development to
proceed, academicians often must seek out industry collaborators.
Industry sponsors must determine whether the area of research aligns
with their priorities and whether the benefits of developing a new
therapy in a specific disease area outweighs the costs and risks.
Occasionally, a biotech firm may spinout from a university and the
investigator who owns the intellectual property. These companies often
support nascent projects through angel funding, which is start-up
funding provided by an individual or a group of individual investors in
return for equity in the company. The hope is to develop a candidate
drug to the point that the company becomes an attractive investment for
venture capitalists. Occasionally, these small biotech firms become cash
strapped as drug development proceeds and angel funding begins to
dwindle before the company becomes an attractive investment option for
venture capitalists. Intellectual property (i.e., the drug in
development) is often sold to a larger, more financially viable company;
otherwise, development may stop. The Cystic Fibrosis Foundation has
tried to bridge the gap between angel funding and venture capitalism
through a process known as venture philanthropy. In this process, the CF
Foundation supports drug development in return for equity in the
sponsor/drug. The CF Foundation has in turn reinvested equity in
development programs for other candidate drugs.
There are other mechanisms to encourage industry sponsors to work in CF,
including financial benefits conferred by the Orphan Drug Act of 1983.
The Orphan Drug Act recognizes that small populations of patients make
it difficult for companies to profit from developing drugs for those
diseases. The Orphan Drug Act provides benefits that include tax
incentives, enhanced patent protections and marketing rights for seven
years after approval, clinical research subsidies in the form of grants,
FDA support for protocol development and study design, and waiving of
Prescription Drug User Act filing fees. In addition, many drugs can be
granted fast track status from the FDA if they are developed for rare
pediatric diseases like CF. Fast track status will reduce the costs for
sponsors and shorten the time to approval, thus providing financial
incentives for sponsors to develop drugs for CF. These initiatives have
induced industry sponsors into CF drug development.