Drug development is the process of bringing a novel drug from “bench to bedside”. It can take 10 to 15 years for a drug to be designed, developed and approved for use in patients (Fig 1). In some circumstances, the drug development and approval process can be expedited – for example, if the drug is the first available treatment for a condition, or it shows a significant benefit over existing drugs.
Before a drug can reach a patient, it must go through rigorous testing to determine whether it is safe, effective at treating the condition it was developed for, and to ascertain the correct dosage and appropriate administration route.
Pharmaceutical regulatory authorities are responsible for overseeing and regulating therapeutics; including prescription and over-the-counter drugs, vaccines, cell therapies and medical devices. They play a key role throughout the drug development process and are designed to ensure the safety, efficacy, accessibility and security of approved drugs. Throughout the development of the drug, the responsible pharmaceutical company will conduct pharmacovigilance activities.
Numerous different regulatory authorities exist worldwide. The USA’s regulatory agency is the US Food and Drug Administration (FDA) and the UK equivalent is known as the Medicines and Healthcare Regulatory Agency (MHRA) – every country has its own regulatory authority.
The Stages of Developing a Drug
1. Early Drug Discovery
Figure 1: An overview of the drug discovery, development and approval process.
There are several core “steps” that are carried out during drug discovery. Academic and industry scientists collaborate to identify potential druggable targets for a specific disease and work to discover and optimize drug compounds that can elicit an effect on a specific biological target implicated in a disease – in the hopes of treating it. Work at this stage is performed in the laboratory using in vitro and animal models.
- Target Identification and Validation
Having a clear understanding of the clinical spectrum of a disease and the exact role a target plays in that disease are key factors when designing a “good” drug. A biological target is deemed “druggable” if its activity can be altered by a therapeutic agent – whether it be a small molecule or biopharmaceutical. “Good” drug targets typically have “universal” advantageous properties and can be discovered in a variety of ways including; scouring published scientific literature, searching available databases, or via “practical” methods such as target deconvolution and target discovery Once a target is identified it is validated to verify its suitability for pharmaceutical development, prior to commencing a screening campaign designed to identify “hits”.
- Hit Identification and Validation
Numerous screening approaches can be used to identify a “hit” compound. A “hit” can be defined as a compound that interacts with the target of interest. There are several strategies that can be used to discover “hits” including; high-throughput screening, phenotypic screening, virtual screening, fragment-based screening and structure-based design.
In phenotypic screens, the specific drug target may not be immediately evident as the approach is based on determining if a compound exerts a desired effect by observing a change in phenotype. The target underlying the observed phenotypic change may be identified later – although there isn’t a regulatory requirement to know the target of a drug provided it demonstrates good safety and efficacy properties.
- Hit-to-Lead and Lead Optimization
The primary aim at this stage is to refine several of the most promising “hits” to create more potent and selective candidates with “optimized” pharmacokinetic properties. Typically the “original hits” have very low affinity to the biological target; medicinal chemists work to increase the affinity by several orders of magnitude. With advances in artificial intelligence (AI), an increasing number of pharma companies are realizing the value of adopting AI approaches – encouraging their medicinal chemists to working hand-in-hand with AI systems to quickly accumulate vast amounts of valuable biological, structural and chemical data. Off-target interactions is another key consideration at this stage as these can lead to adverse effects, so improving selectivity of the molecule against other biological targets should be investigated and addressed.
- Candidate Selection
At this stage you will need to determine, from several promising “high-quality” leads, which one you want to take forward as a clinical candidate. For a drug candidate to be deemed suitable for preclinical and clinical testing it should; bind selectively to the target, elicit the desired functional response when interacting with the target molecule, and must have adequate bioavailability and biodistribution to elicit the desired response. It must also have a toxicity profile. In addition to the above properties, you should also consider the following factors; future manufacturing suitability and scale-up, commercial viability and cost-effectiveness, as these will heavily impact the long-term success of the drug.
Preclinical testing is designed to deliver important information about a drug candidate’s efficacy and safety before it is tested in human subjects. Both in vitro and in vivo models are typically used to provide evidence of a candidate’s biological effect. Preclinical studies are required by regulatory authorities such as the FDA and MHRA before submitting an investigational new drug application (IND) which is required to progress to clinical development. Numerous questions are addressed at this stage:
- What does the drug do to the body?
- What does the body do to the drug?
- It is potent, but is it safe?
It is extremely important that the most appropriate animal model is used at this stage, as well as considering the gender of animals to be used to prevent sex-specific bias. A drug could elicit a different response in a male animal compared to a female. You will also need to consider species-specific physiology and similarities in terms of metabolic pathways and genetics (for example 99% of all mouse genes overlap with human ones).
3. Investigational New Drug Application
The FDA groups investigational new drugs (INDs) into three different types:
This is submitted by the physician responsible for initiating and investigating. The same physician will manage the administration and/or dispensing of the investigational drug. This type of application is typically requested for the study of an unapproved drug, or an approved drug for use of the drug in an unlicensed indication, or a different patient population.
- Emergency use
An emergency use IND enables the regulator (FDA) to authorize the use of an investigational drug in an urgent situation, without the obligation to submit and IND in accordance with 21 CFR, Sec. 312.23 or Sec. 312.20. This type of application is used for patients who do not meet existing clinical study criteria, or in situations where an approved clinical protocol doesn’t actually exist.
This type of IND application is submitted to gain access to an experimental drug that has shown promise in clinical trials for treating a serious or life-threatening condition, whilst the final clinical work is completed, and the new drug application is reviewed by the FDA.
An IND can be categorized as either “commercial” or “research”. For an IND application there are key areas that must be covered; animal model pharmacology and toxicology studies, manufacturing information, clinical study protocols and investigator information.
The IND sponsor is required to wait 30 days before starting clinical trials – this delayed period gives regulators the opportunity to review the information contained within the IND application.
4. Clinical Research
Clinical trials are designed to answer specific research questions related to an investigational new drug. The trials must follow a study protocol – a document that describes exactly how the clinical trial will be conducted. It details key study objectives, study design, and statistical considerations, to ensure the safety of participants and the integrity of the data collected during the study.
The clinical stage of drug development follows a series of “Phases”.
Number of participants: 20–100. These can either be “healthy” people or people diagnosed with the specific condition/disease you are developing the drug to treat.
Study length: Typically, several months.
Primary purpose: To determine safety in humans, and to gather information on dosage. Phase I studies also guide how best to administer the drug to limit toxicity and enhance therapeutic effect.
Number of participants: Several hundred. The participants will be diagnosed with the condition/ disease you are developing the drug to treat.
Study length: Spans from several months to two years.
Primary purpose: To acquire additional safety data – to determine efficacy and adverse effects. This information is used to optimize the design of the larger Phase III study.
Number of participants: 300–3000. The participants will be diagnosed with the condition/disease you are developing the drug to treat.
Study length: Spans from one to four years in length.
Primary purpose: To determine the drug’s efficacy and to monitor adverse reactions. Due to the increased number of participants during Phase III, long-term or rarer side effects that may have gone undetected in Phase I and Phase II are usually detected. The greatest proportion of safety information is collected during Phase III.
New Drug Application
The application process for marketing authorization in the USA is known as a New Drug Application (NDA). In the European Union and other countries worldwide, this same process is referred to as a Marketing Authorisation Application (MAA).
The regulatory authority is responsible for the scientific evaluation of the NDA or MAA. The goal of the application is to provide the regulator with enough information – gathered during preclinical and clinical studies – for them to be able to determine if:
- The drug is safe and effective as a treatment for the condition it has been developed for
- The drug’s therapeutic benefits outweigh the risks
- The drug’s labeling is fit-for-purpose and whether all required details are included
- The methods used to manufacture the drug and measures to ensure the drug's quality are satisfactory
Biologics License Application
The approval of biological products in the USA falls under the provisions of the Public Health Service (PHS) Act. The Act requires the manufacturer of the biologic to hold a license for that product. A Biologics License Application (BLA) must be submitted for therapeutic biological products including (but not limited to); monoclonal antibodies (for in vivo use), cytokines, growth factors, enzymes, immunomodulators, proteins, and non-vaccine therapeutic immunotherapies.
Once the drug receives approval from the relevant regulatory authority, numerous activities will need to be initiated to prepare for the launch of the product. These include:
- Manufacturing scale-up and serialization
- Printing of final product label information, packaging and artwork
- Product storage, shipping and distribution arrangements
- Production staff and quality team availability
Post-marketing Safety Surveillance
Post-marketing safety surveillance is the term used for the monitoring of a drug after it has received approval and has reached the market. It is designed to evaluate the long-term safety and efficacy of a drug, potential “real-world” problems with formulation, and use for unapproved conditions or “off-label” (e.g. use in an age group or at a dosage outside of that advised in the product label).
Phase IV studies are conducted after approval of the drug has been granted.
Number of participants: Several thousand. The volunteers will be diagnosed with the condition/disease that the drug is approved to treat.
The purpose of a Phase IV study is to obtain additional information about the long-term risks and benefits of taking a drug now that it is being more widely used. The “real-world” data can also help determine if there is scope to develop the drug further, for example:
- To explore the use of the drug for additional indications/ additional age groups
- To develop an alternative route of administration
Acronyms and Key Terms
|FDA||US Food and Drug Administration|
|EFPIA||European Federation of Pharmaceutical Industries and Associations|
|EMA||European Medicines Agency|
|IFPMA||International Federation of Pharmaceutical Manufacturers & Associations|
|MHRA||Medicines and Healthcare Regulatory Agency|
|PIPA||Pharmaceutical Information and Pharmacovigilance Association|
|ADR||Adverse Drug Reaction|
|BLA||Biologics License Application|
|BTD||Breakthrough Therapy Designation|
|ERB||Ethical Review Board|
|IEC||Independent Ethics Committee|
|IND||Investigational New Drug|
|IRB||Institutional Review Board|
|MAA||Marketing Authorisation Application|
|MAH||Marketing Authorisation Holder|
|NDA||New Drug Application|
|ODD||Orphan Drug Designation|
|SAE||Serious Adverse Event|
|SUSAR||Suspected Unexpected Serious Adverse Reaction|